The Digestive Involvement in Systemic Autoimmune Diseases [2nd Edition] 9780444637178, 9780444637079

Table of contents :
Content:
Handbook of Systemic Autoimmune DiseasesPage ii
Front MatterPage iii
CopyrightPage iv
DedicationPages v-vi
List of ContributorsPages xix-xxi
PrefacePage xxiii
Chapter 1 - Digestive System and AutoimmunityPages 3-18H. Mix, M.P. Manns
Chapter 2 - Immunopathogenesis of Autoimmune Liver DamagePages 19-48A.J. Czaja
Chapter 3 - Autoantibodies in Gastrointestinal Autoimmune DiseasesPages 49-66D. Ben-Ami Shor, N.P. Papageorgiou, Y. Shoenfeld
Chapter 4 - Imaging Techniques in Digestive DiseasesPages 67-80C. Ayuso, M. Pagés, L. Donoso
Chapter 5 - Primary Biliary CholangitisaPages 83-101R. Abdalian, J. Heathcote, M. Ramos-Casals
Chapter 6 - Autoimmune HepatitisPages 103-117D. Vergani, G. Mieli-Vergani
Chapter 7 - Primary Sclerosing CholangitisPages 119-139R.W. Chapman, K.D. Williamson
Chapter 8 - Systemic and Autoimmune Manifestations of Hepatitis B Virus InfectionPages 143-171C. Pagnoux, L. Guillevin
Chapter 9 - Extrahepatic Manifestations in Patients With Chronic Hepatitis C Virus InfectionPages 173-202P. Brito-Zerón, S. Retamozo, X. Forns, J.-M. Sanchez-Tapias, J.R. Teixidor, M. Ramos-Casals
Chapter 10 - New Antivirals for Extrahepatic Manifestations of Hepatitis C Virus: The Model of Mixed Cryoglobulinemia VasculitisPages 203-211P. Cacoub, A.C. Desbois, M. Vauthier, C. Commarmond, F. Domont, L. Savey, D. Saadoun
Chapter 11 - Systemic Lupus ErythematosusPages 215-226M. Vilardell-Tarrés, A. Selva-O'Callaghan, J. Ordi-Ros
Chapter 12 - Digestive Involvement in the Antiphospholipid SyndromePages 227-241I. Rodríguez-Pintó, G. Espinosa, R. Cervera
Chapter 13 - Gastrointestinal Involvement in Systemic SclerosisPages 243-261A.B. Shreiner, D. Khanna
Chapter 14 - Gastrointestinal Involvement in Inflammatory MyositisPages 263-270M. Pérez-de-Lis Novo, R. Pérez-Álvarez, L. Pallarés-Ferreres, J.J. Fernández-Martín, M.-J. Soto Cárdenas, A. Selva-O'Callaghan
Chapter 15 - Digestive Involvement in Primary Sjögren's SyndromePages 271-292S. Retamozo, P. Brito-Zerón, C. Morcillo, B. Kostov, N. Acar-Denizli, M. Ramos-Casals
Chapter 16 - Gastrointestinal Involvement in Systemic VasculitisPages 293-320L. Quartuccio, S. De Vita
Chapter 17 - Mixed Connective Tissue DiseasePages 321-332J. Romero-Díaz, J. Sánchez-Guerrero
Chapter 18 - Gastrointestinal Manifestations of Rheumatoid ArthritisPages 333-348R.A. Ferrandiz, G.S. Alarcón
Chapter 19 - Spondyloarthritis and Gastrointestinal InvolvementPages 349-361F. Atzeni, R. Talotta, I.F. Masala, P. Sarzi-Puttini
Chapter 20 - Intestinal Behçet's DiseasePages 363-375R. Hamad, H. Direskeneli, J. Al Saleh, M. Khamashta
Chapter 21 - Gastrointestinal Involvement of SarcoidosisPages 377-397R.P. Baughman, K. Bari
Chapter 22 - IgG4-Related Disease: Gastrointestinal InvolvementPages 399-410P. Brito-Zerón, X. Bosch, M. Gandía, M.-J. Soto Cárdenas, M. Ramos-Casals, J.H. Stone
Chapter 23 - Gastrointestinal Complications of Antirheumatic DrugsPages 411-452K.D. Rainsford, I.R.L. Kean, W.F. Kean
IndexPages 453-470

Citation preview

Handbook of Systemic Autoimmune Diseases Series Editor: F. Atzeni and P. Sarzi-Puttini Volume 1 The Heart in Systemic Autoimmune Diseases Edited by: Andrea Doria and Paolo Pauletto Volume 2 Pulmonary Involvement in Systemic Autoimmune Diseases Edited by: Athol U. Wells and Christopher P. Denton Volume 3 Neurologic Involvement in Systemic Autoimmune Diseases Edited by: Doruk Erkan and Steven R. Levine Volume 4 Reproductive and Hormonal Aspects of Systemic Autoimmune Diseases Edited by: Michael Lockshin and Ware Branch Volume 5 The Skin in Systemic Autoimmune Diseases Edited by: Piercarlo Sarzi-Puttini, Andrea Doria, Giampiero Girolomoni and Annegret Kuhn Volume 6 Pediatrics in Systemic Autoimmune Diseases Edited by: Rolando Cimaz and Thomas Lehman Volume 7 The Kidney in Systemic Autoimmune Diseases Edited by: Justin C. Mason and Charles D. Pusey Volume 8 Digestive Involvement in Systemic Autoimmune Diseases Edited by: Josep Font, Manuel Ramos-Casals and Juan Rode´s Volume 9 Endocrine Manifestations of Systemic Autoimmune Diseases Edited by: Sara E. Walker and Luis J. Jara Volume 10 Antiphospholipid Syndrome in Systemic Autoimmune Diseases Edited by: Ricard Cervera, Joan Carles Reverter and Munther Khamashta Volume 11 Pediatrics in Systemic Autoimmune Diseases, Second Edition Edited by: Rolando Cimaz and Thomas Lehman Volume 12 Antiphospholipid Syndrome in Systemic Autoimmune Diseases, Second Edition Edited by: Ricard Cervera, Gerard Espinosa, and Munther Khamashta Volume 13 The Digestive Involvement in Systemic Autoimmune Diseases, Second Edition Edited by: Manuel Ramos-Casals, Munther Khamashta, Pilar BritoZero´n, Fabiola Atzeni, and Joan Rode´s Teixidor Volume 14 The Heart in Systemic Autoimmune Diseases, Second Edition Edited by: Fabiola Atzeni, Andrea Doria, Michael Nurmohamed, and Paolo Pauletto

Handbook of Systemic Autoimmune Diseases, Volume 13

The Digestive Involvement in Systemic Autoimmune Diseases SECOND EDITION

Edited by Manuel Ramos-Casals Sjo¨gren Syndrome Research Group (AGAUR), Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, University of Barcelona, Hospital Clı´nic, Barcelona, Spain

Munther Khamashta Graham Hughes Lupus Research Laboratory, Division of Women’s Health, King’s College London; The Rayne Institute, St Thomas’ Hospital, London, United Kingdom

Pilar Brito-Zero´n Autoimmune Diseases Unit, Department of Internal Medicine, Hospital CIMA-Sanitas, Barcelona, and Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, Hospital Clı´nic, Barcelona, Spain

Fabiola Atzeni Rheumatology Unit, L. Sacco University Hospital, Milan, Italy

Joan Rode´s Teixidor Liver Unit, ICMD, Ciberehd, Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain

AMSTERDAM l BOSTON l HEIDELBERG l LONDON l NEW YORK PARIS l SAN DIEGO l SAN FRANCISCO l SINGAPORE l SYDNEY

l l

OXFORD TOKYO

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2017 Elsevier B.V. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-444-63707-9 ISSN: 1571-5078 For information on all Elsevier publications visit our website at https://www.elsevier.com/

Publisher: Sara Tenney Acquisition Editor: Linda Versteeg-Buschmann Editorial Project Manager: Halima Williams Production Project Manager: Edward Taylor Designer: Victoria Pearson Typeset by TNQ Books and Journals

Dedication The first edition of this book was one of the last projects led by Dr. Josep Font (Barcelona, 1953e2006) before his unexpected death, and the remaining editors wish to dedicate these lines as a means of paying a deeply felt homage. Dr. Font devoted his professional career to the care of patients with systemic autoimmune diseases (SAD). He trained in Internal Medicine at the Hospital Clinic of Barcelona from 1978 to 1982 and obtained his PhD in 1984 for his thesis on systemic lupus erythematosus (SLE). His postdoctoral experience was closely linked with the Lupus Research Unit at St. Thomas’ Hospital, London. His research output was prodigious, with a total of over 500 scientific articles published over 25 years. In addition, he designed and coordinated many international projects including the Eurolupus, Europhospholipid, Catastrophic Antiphospholipid Syndrome (CAPS) Registry, Sjo¨gren syndrome-HCV Registry, and Hispanoamerican Registry of Extrahepatic Manifestations of HCV (HISPAMEC) and was an active member of some of the most prestigious international research groups, such as the Eurolupus Nephritis Trial and SLICC. In 1995, Dr. Font established the Department of Autoimmune Diseases at the Hospital Clinic, a pioneering unit in Europe specifically dedicated to the clinical management of patients with SAD. He played a leading role in creating a network of different specialists at the Hospital Clinic dedicated to the care of these patients. A key characteristic of his clinical research was its multidisciplinary design and the close collaboration between different medical specialties, of which this book is an excellent example. He was working actively until the last days of his life, and died like a soldier “with his boots on’.” His integrity, intelligence, and loyalty made him a formidable physician and a wonderful colleague and friend. He was undoubtedly one of the foremost figures in the field of autoimmune diseases in recent decades, and the immense human and professional legacy that he left must be maintained and continued by all who had the great fortune to know and work with him. For this second edition, we would also like to honor two of the main international experts in the field of autoimmunity and liver diseases who recently retired, professors Jenny Heathcote and Joan Rode´s. In June 2013 and after authoring 350 papers, conducting 800 lectures, mentoring 64 residents, and training 31 fellows in hepatology, Prof. Jenny Heathcote, a world-renowned liver specialist based at Toronto Western

vi Dedication

Hospital, fully retired from her position as Senior Scientist in the Toronto Western. In 2009 she received the Chair in Hepatology at the University and was awarded the EASL International Recognition Award (2010) for her sustained contribution to the knowledge and understanding of liver diseases. In the last decade, Prof. Heathcote has built up a world renowned liver unit and fostered many new initiatives. We have decided to maintain the original chapter written by Prof. Heathcote for the first edition of this book (including a brief update for the past 5 years) as a tribute from the editors to their outstanding work in liver diseases. Prof. Joan Rode´s, born in 1938 in Barcelona, is considered one of the most prestigious international hepatologists and his career is also closely linked to the Hospital Clinic of Barcelona; he was the Medical Director of the Hospital Clinic between 1984 and 1986 and General Director between 2003 and 2008. The recognition of his research work has led Prof. Rode´s to occupy positions in international organizations (President of the European Association for the Study of the Liver in 1991, President of the International Association for the Study of the Liver in 1992). He has authored or coauthored more than 500 papers in major medical journals internationally, and was also founder and Director of the Institute of Biomedical Research August Pi i Sunyer (IDIBAPS). The accumulation of merits and distinctions received by Prof. Rode´s is more than an expression of an exceptional personality; a tireless worker with extraordinary leadership qualities, able to create, enhance, and hold together a group of leading researchers and a proverbial modesty. Finally, we wish to thank Linda Versteeg-Buschman, Halima Williams and their staff at Elsevier for their hard work. It has been a great pleasure working together on this second edition. The Editors

List of Contributors R. Abdalian, University Health Network, Toronto, ON, Canada N. Acar-Denizli, Mimar Sinan Fine Arts University, Istanbul, Turkey G.S. Alarco´n, The University of Alabama at Birmingham, Birmingham, AL, United States J. Al Saleh, Dubai Hospital, Dubai, United Arab Emirates F. Atzeni, IRCCS Galeazzi Orthopedic Institute, Milan, Italy C. Ayuso, Hospital Clinic, University of Barcelona, Spain K. Bari, University of Cincinnati Medical Center, Cincinnati, OH, United States R.P. Baughman, University of Cincinnati Medical Center, Cincinnati, OH, United States D. Ben-Ami Shor, Tel-Aviv University, Israel X. Bosch, Hospital Clı´nic, Barcelona, Spain P. Brito-Zero´n, Hospital CIMA-Sanitas, Barcelona, Spain; Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, Hospital Clı´nic, Barcelona, Spain P. Cacoub, Sorbonne Universite´s, UPMC Univ Paris 06, UMR 7211, and InflammationImmunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France R. Cervera, Hospital Clı´nic, Barcelona, Spain R.W. Chapman, University of Oxford, Oxford, United Kingdom; John Radcliffe Hospital, Oxford, United Kingdom C. Commarmond, Sorbonne Universite´s, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France A.J. Czaja, Mayo Clinic College of Medicine, Rochester, MN, United States A.C. Desbois, Sorbonne Universite´s, UPMC Univ Paris 06, UMR 7211, and InflammationImmunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France S. De Vita, University of Udine, Udine, Italy

xix

xx List of Contributors H. Direskeneli, Marmara University, Istanbul, Turkey F. Domont, Sorbonne Universite´s, UPMC Univ Paris 06, UMR 7211, and InflammationImmunopathology-Biotherapy Department (DHU i2B), Paris, France; AP-HP, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France L. Donoso, Hospital Clinic, University of Barcelona, Spain G. Espinosa, Hospital Clı´nic, Barcelona, Spain ´ lvaro Cunqueiro, Vigo, Spain J.J. Ferna´ndez-Martı´n, Hospital A R.A. Ferrandiz, Hospital Nacional Cayetano Heredia and Universidad Peruana Cayetano Heredia, Lima, Peru´ X. Forns, Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain M. Gandı´a, Hospital Punta Europa, Algeciras (Ca´diz), Spain; Hospital Jerez Puerta del Sur-ASISA, Jerez de la Frontera (Ca´diz), Spain L. Guillevin, Universite´ Paris 5 e Rene´ Descartes, Paris, France R. Hamad, Dubai Hospital, Dubai, United Arab Emirates J. Heathcote, University Health Network, Toronto, ON, Canada I.R.L. Kean, University of WisconsineMadison, Madison, WI, United States W.F. Kean, McMaster University Faculty of Health Sciences, Hamilton, ON, Canada M. Khamashta, Dubai Hospital, Dubai, United Arab Emirates; King’s College London, London, United Kingdom D. Khanna, University of Michigan Medical School, Ann Arbor, MI, United States B. Kostov, Institut d’Investigacions Biome`diques August Pi i Sunyer, Barcelona and University of Barcelona M.P. Manns, Hannover Medical School, Hannover, Germany I.F. Masala, Santissima Trinita` Hospital, Cagliari, Italy G. Mieli-Vergani, King’s College London Faculty of Life Sciences & Medicine at King’s College Hospital, London, United Kingdom H. Mix, Hannover Medical School, Hannover, Germany C. Morcillo, Hospital CIMA-Sanitas, Barcelona J. Ordi-Ros, Vall D’Hebron General Hospital, Barcelona, Spain M. Page´s, Hospital Clinic, University of Barcelona, Spain C. Pagnoux, University of Toronto, Toronto, ON, Canada L. Pallare´s-Ferreres, Hospital de Son Espases, Palma de Mallorca, Spain N.P. Papageorgiou, American Medical Center, Nicosia, Cyprus ´ lvarez, Hospital A ´ lvaro Cunqueiro, Vigo, Spain R. Pe´rez-A ´ lvaro Cunqueiro, Vigo, Spain M. Pe´rez-de-Lis Novo, Hospital A L. Quartuccio, University of Udine, Udine, Italy

List of Contributors

xxi

K.D. Rainsford, Sheffield Hallam University, Sheffield, England, United Kingdom M. Ramos-Casals, Sjo¨gren Syndrome Research Group (AGAUR), Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, University of Barcelona, Hospital Clı´nic, Barcelona, Spain S. Retamozo, Hospital Privado Universitario de Co´rdoba, Institute University of Biomedical Sciences, University of Co´rdoba (IUCBC), Co´rdoba, Argentina I. Rodrı´guez-Pinto´, Hospital Clı´nic, Barcelona, Spain J. Romero-Dı´az, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Me´xico City, Me´xico D. Saadoun, Sorbonne Universite´s, UPMC Univ Paris 06, UMR 7211, and InflammationImmunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France J. Sa´nchez-Guerrero, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Me´xico City, Me´xico J.-M. Sanchez-Tapias, Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain P. Sarzi-Puttini, University Hospital L. Sacco, Milan, Italy L. Savey, Sorbonne Universite´s, UPMC Univ Paris 06, UMR 7211, and InflammationImmunopathology-Biotherapy Department (DHU i2B), Paris, France; AP-HP, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France A. Selva-O’Callaghan, Universitat Auto`noma de Barcelona, Barcelona, Spain; Vall D’Hebron General Hospital, Barcelona, Spain Y. Shoenfeld, Tel-Aviv University, Israel A.B. Shreiner, University of Michigan Medical School, Ann Arbor, MI, United States M.-J. Soto Ca´rdenas, University of Ca´diz, Hospital Puerta del Mar, Ca´diz, Spain J.H. Stone, Massachusetts General Hospital, Boston, MA 02114, United States R. Talotta, University Hospital L. Sacco, Milan, Italy J.R. Teixidor, Instituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain M. Vauthier, AP-HP, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France D. Vergani, King’s College London Faculty of Life Sciences & Medicine at King’s College Hospital, London, United Kingdom M. Vilardell-Tarre´s, Vall D’Hebron General Hospital, Barcelona, Spain K.D. Williamson, University of Oxford, Oxford, United Kingdom; John Radcliffe Hospital, Oxford, United Kingdom

Preface The second edition of The Digestive System in Systemic Autoimmune Diseases represents the state of the art in the field of digestive disorders for the most common systemic and organ-specific autoimmune diseases. This volume consists of an introductory section including chapters focusing on etiopathogenic aspects along with a specific chapter on imaging techniques in digestive diseases, followed by two chapters on organ-specific autoimmune diseases and autoimmune manifestations of viral hepatitis (including a new chapter on new anti-HCV agents). The final section deals with the digestive manifestations of patients with systemic and rheumatic autoimmune diseases, with the aim of being a practical guide to the identification, diagnosis, and treatment of digestive involvement in these patients that will be useful for all medical specialties. For this second edition, we have also included new chapters (spondyloarthropathies, Behc¸et disease, sarcoidosis and IgG4-related disease), expanding to other rheumatic diseases and rare systemic diseases. The final chapter is devoted to update the gastrointestinal and liver complications of the rheumatologic medications used in daily practice. We hope you will enjoy and learn from the second edition of this book. The Editors

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Chapter 1

Digestive System and Autoimmunity H. Mix and M.P. Manns Hannover Medical School, Hannover, Germany

1. THE DIGESTIVE SYSTEM AND GUT-ASSOCIATED IMMUNITY Mammals depend on feeding and digestion. While single-celled organisms can directly take in nutrients from their outside environment, multicellular organisms, with most of their cells removed from direct contact with the outside environment, have developed specialized structures for obtaining and breaking down their food. Large, complex molecules must be broken down into monomers that can then be distributed throughout the body to every cell. This vital function is accomplished by a series of specialized organs that comprise the digestive system. The human digestive system is a coiled, muscular tube about 6e9 m in length when fully extended, stretching from the mouth to the anus. Several specialized compartments occur along this length: the mouth, pharynx, esophagus, stomach, small intestine, large intestine, and anus. Accessory digestive organs are connected to the main system by a series of ducts, including salivary glands, the pancreas, and the liver with the biliary system. Like the skin, the digestive tract is situated at the interface between external and internal milieus. To maintain homeostasis, physical and chemical mechanisms as elements of the innate immune response are used to protect against exogenous, potentially noxious agents. The membranes of the digestive tract provide a physical barrier against invading pathogens. A huge number of chemical factors, including low pH in the stomach, pepsin, lysozyme, antimicrobial substances such as cryptidins and defensins, limit the growth and invasion of microorganisms [1] (Table 1.1). In addition to innate defense mechanisms, the digestive system is lined by mucosal lymphatic tissues [2]. It consists of diffuse lymphocytic infiltrates throughout the epithelium and lamina propria of the mucosa or nonencapsu-

The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00001-5 Copyright © 2017 Elsevier B.V. All rights reserved.

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4 SECTION j I Introduction

TABLE 1.1 Mechanisms to Minimize Self-Reactive Lymphocyte Differentiation and Activation Clonal deletion

Induction of apoptosis by inhibition of prosurvival pathways (BIM induction) or by activation of death receptors (FAS activation)

Receptor editing

Receptor editing through V(D)J recombination in primary lymphatic tissues (in T cells and B cells) or by somatic hypermutation in secondary lymphatic tissues (in B cells)

Clonal anergy and tuning

Intrinsic regulation by B or T cell receptor downregulation Induction of inhibitory receptors (CD5, CTLA4) Induction of phosphatases (SHP1, SHIP) Induction of ubiquitin ligases (cbl, GRAIL, Itch, Roquin)

Extrinsic regulation

Limitation of survival factors (BAFF, IL-7) Limitation of costimulation (CD40L, TLR ligands, B7 molecules) Active suppression (regulatory T cells)

lated lymphoid nodules in the submucosa of the intestinal tract. Peyer patches are the prototypical mucosal lymphatic tissue, specialized to sample environmental antigens. The Peyer patches contain lymphoid compartments that are analogous to the cortex and follicles of lymph nodes. Each follicle is covered by a single-layered follicle-associated epithelium, and a more diffuse area immediately below, called subepithelial dome. The follicle-associated epithelium is interrupted by specialized membranous cells (M cells) that have luminal microfolds instead of microvilli and lack the normal thick layer of mucus. The M cells differentiate from enterocytes under the influence of membrane-bound lymphotoxin-a1b2 present on local lymphoid cells [3e5]. These cells endocytose and transport various materials [6]. Antigen is delivered to lymphocytes, mononuclear phagocytes, and dendritic cells immediately beneath M cells. The germinal centers contain B cell blasts, follicular dendritic cells, macrophages, and unique T cells. B cells undergo immunoglobulin class switching from expression of IgM to IgA under the influence of several local factors, including transforming growth factor-b (TGF-b), interleukin-10 (IL-10), and other cellular signals that are delivered by dendritic cells and T cells [7]. Lymphocytes exit the Peyer patches through the draining lymphatics to the mesenteric lymph nodes, from where they migrate into the

Digestive System and Autoimmunity Chapter j 1

5

bloodstream and finally home to the mucosa. The exit of lymphocytes from the bloodstream into the mucosa is mediated by loss of L-selectin expression and selective upregulation of a4b7 integrin. The ligand for a4b7 integrin mucosal addressin cell-adhesion molecule 1 (MADCAM1) is highly expressed by the vasculature of mucosal surfaces and mediates the emigration from the bloodstream [8]. In addition, expression of the chemokine receptor CCR9 is induced in gut-derived T cells, allowing them to respond to the chemokine CCL25, which is exclusively expressed by small-bowel epithelial cells [9,10]. In contrast, T cells primed in peripheral lymphoid organs acquire the a4b1 integrin very late antigen 4 (VLA4) and the chemokine receptor CCR4 and do not migrate to mucosal surfaces [10,11]. Lymphocytes that home into the mucosa of the gut redistribute into distinct compartments. IgA-producing plasma cells remain in the lamina propria. CD4þ T cells are distributed more evenly throughout the villusecrypt unit within the lamina propria. CD8þ T cells preferentially reside in the epithelium. A memory phenotype of CD4þ and CD8þ T cells predominates in both the epithelium and the lamina propria, indicating that the cells have been exposed to antigen. CD4þ T cells in the lamina propria are of particular importance to local immune regulation. They produce large amounts of cytokines, particularly interferon-g (IFN-g), but also IL-4 and IL-10 [12e14]. Lamina propria CD8þ T cells can have potent cytotoxic T lymphocyte (CTL) activity [15]. Many of the properties of the lamina propria CD4þ T cells are similar to those of regulatory T cells in other systems [16e18]. The unresponsiveness of lamina propria T cells to commensal bacteria can be reversed by the depletion of IL-10 or TGF-b [19]. Mesenteric lymph nodes have a crucial role in the induction of mucosal immunity and tolerance. Antigen recognition in the mesenteric lymph nodes occurs within a few hours of feeding protein antigen [20e23]. More importantly, induction of oral tolerance is not possible in lymphotoxin-aedeficient or lymphotoxin-aedeficient tumor necrosis factor (TNF)-deficient mice, which lack mesenteric lymph nodes [24]. Furthermore, total and specific IgA-antibody responses are absent in mice lacking mesenteric lymph nodes, while responses to parenterally administered antigens are preserved in these mice [25,26]. Generally, immune responses to most tissue antigens are initiated in the draining lymph nodes. Recent evidence has suggested that na€ıve intestinal T cells first encounter antigen in the mesenteric lymph nodes and not in Peyer patches [27,28]. While priming of T cells selectively in Peyer patches would lead to efficient local immune responses or tolerance, priming of T cells in the mesenteric lymph nodes could explain that intestinal antigens are able to induce systemic immunity or tolerance. Peyer patches harbor distinctive subsets of dendritic cells, which have unusual phenotypic and functional characteristics [29]. Conventional subsets of CD8aCD11bþ (myeloid) and CD8aþCD11b (lymphoid) dendritic cells are

6 SECTION j I Introduction

present next to a large number of CD8aCD11b dendritic cells. Currently, little information is available about this subset of dendritic cells. They can be found outside the organized lymphoid areas, especially in the dome region, which is immediately beneath the follicle-associated epithelium, together with CD8aCD11bþ dendritic cells. Their presence depends on the production of macrophage inflammatory protein 3a (MIP3a), or CCL20, by local epithelial cells [30,31]. The predominant CD8aCD11bþ dendritic cell subset is distinctive in that it secretes IL-10. Interestingly, after ligation of the costimulator molecule receptor activator of NF-kB (RANK), the dendritic cells of Peyer patches respond by secretion of IL-10. Outside Peyer patches, i.e., in the spleen, the same conditions result in the production of IL-12 [32]. Dendritic cells in Peyer patches are also able to stimulate antigen-specific T cells to produce T-helper type 2 (TH2) cytokines and IL-10. Collectively, these observations underscore an important role of Peyer patch dendritic cells in maintaining a state of tolerance against food antigens and commensal bacteria in the digestive system [33]. In addition, intestinal epithelial cells have recently been identified as key elements in the development and regulation of mucosal immunity [34]. These cells have been implicated in the regulation of innate immunity and chronic inflammation before [35,36]; however, supporting data from in vivo experiments were lacking. The authors could show that mice, deficient in IkB kinaseb (IKK-b), produce reduced levels of the epithelial cellerestricted cytokine thymic stromal lymphopoietin. The mice were unable to mount an efficient CD4þ Th2 response against the parasite Trichuris. Severe intestinal inflammation was the result of exacerbated dendritic cellederived IL-12/23p40 and TNF-a production, as well as increased levels of CD4þ T cellederived IFN-g and IL-17. The results were proof that the balance of IKK-bedependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis in addition to the established pathways involved in pathogen recognition and initiation of immune responses in the gastrointestinal tract, which include M cells and specialized dendritic cell subsets that directly sample the luminal environment. The nervous innervation of the gastrointestinal tract is extensive, including Peyer patches, and the diversity of adrenergic, cholinergic, and peptidergic nerve endings in patches is greater than for any other peripheral lymphatic tissue. Noradrenergic fibers form interfollicular plexuses that ramify through the diffuse T-dependent areas near high endothelial venules. It is likely that the extensive innervation of Peyer patches is involved in regulating traffic and reactivity of mucosal immune cells. The nervous system, through the vagus nerve, was shown to significantly and rapidly inhibit the release of macrophage-derived TNF-a, thereby attenuating systemic inflammatory responses [37e39]. It could be demonstrated that this cholinergic antiinflammatory pathway of acetylcholine-mediated vagus nerve signals was mediated via the nicotinic acetylcholine receptor a7 subunit [40].

Digestive System and Autoimmunity Chapter j 1

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The liver as a member of the accessory digestive organs plays an important role in systemic immunity [41]. It contains large amounts of professional antigen-presenting cell, including liver sinusoidal endothelial cells, Kupffer cells, and dendritic cells. Potential antigen-rich blood is filtered, and pathogens are quickly eliminated by phagocytes or by the huge population of natural killer cells or natural killer T cells present in the liver. The liver has a high capacity to induce antigen-specific tolerance. It acts as a central regulator in systemic immune responses by synthesizing and secreting acute-phase proteins and other mediators.

2. SELF-TOLERANCE AND AUTOIMMUNITY Adaptive immune responses are essential for normal health. In some cases, adaptive immune responses are elicited by antigens not associated with infectious agents. The responses are essentially identical to adaptive immune responses to infectious agents; however, the antigens are different. Autoimmunity is the response to self-antigens in the absence of infection. The mammalian immune system is able to mount a response to any chemical structure imaginable. B cells and T cells express receptors with huge receptor diversity able to achieve specificity that differentiates molecules at the atomic level. This huge receptor diversity is encoded in the mammalian genome and is possible through two processes of somatic genome modification that occurs selectively in lymphocytes. In central lymphoid organs, i.e., bone marrow for B cells and the thymus for T cells, V(D)J recombination assembles unique receptor genes for B and T cells. In peripheral lymphoid tissues, B cell receptor genes can further be modified by single-nucleotide substitutions through somatic hypermutation. The random processes of V(D)J recombination and somatic hypermutation generate huge amounts, i.e., between 20% and 50%, of self-reactive B cells and T cells [42e45]. Remarkably, only 3e8% of the population develops an autoimmune disease [46]. Four mechanisms have been identified that limit the number of selfreactive lymphocytes. First, clonal deletion is used to trigger apoptosis of cells with self-reactive receptors. Second, cells with self-reactive receptors can edit their specificity by further V(D)J recombination or somatic hypermutation until the receptor does not bind to self-antigens [47]. Third, clonal anergy or tuning is the unresponsiveness of cells to signals from self-reactive receptors by changes in intrinsic biochemical processes and gene expression [48e50]. Collectively, these first three mechanisms are called immunologic ignorance. When cells have evaded all the three mechanisms, extrinsic controls can limit the potential of an autoimmune response by limiting the supply of growth factors, costimuli, proinflammatory mediators, and other factors, or through active suppression by regulatory T cells.

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3. TOLERANCE MECHANISMS FOR AUTOREACTIVE B CELLS IN THE BONE MARROW A series of events have been identified that occur if an immature B cell displays a self-reactive receptor in the bone marrow. The immature B cell internalizes the self-reactive receptor when the strength of receptor cross-linking and intracellular signaling exceeds a certain threshold [51,52]. As a result, homing receptors such as CD62 ligand, required to enter the lymph nodes, are not expressed [52]. In addition, B celleactivating factor (BAFF) receptors are only poorly induced [53]. BAFF is required to sustain peripheral B cell survival. Furthermore, recombination-activating gene 1 (RAG1) and RAG2, which encode the core enzymes for V(D)J recombination, continue to be expressed, allowing further editing of B cell receptors by rearranging a replacement B cell receptor light chain [54]. If the receptor cannot be edited to be less self-reactive, cell death is induced, either by withdrawal of growth factors and/or through increasing levels of BCL-2einteracting mediator of cell death (BIM), a proapoptotic factor that inhibits essential B cell survival proteins of the BCL-2 family [55]. Interestingly, BIM-deficient mice spontaneously produce anti-DNA autoantibodies [55].

4. TOLERANCE MECHANISMS FOR AUTOREACTIVE T CELLS IN THE THYMUS While B cells are designed to recognize native antigen, T cell receptors bind to peptide fragments of antigen displayed on MHC molecules. An array of selfpeptides are displayed on cortical thymic epithelial cells, and T cells that weakly bind to these ligands receive maturation signals that inhibit further RAG gene expression. They increase the level of surface receptor expression and upregulate homing receptors for chemokines found in the thymic medulla and the peripheral lymphoid tissues. This so-called positive selection is unique to the thymic cortical epithelium. Self-reactive T cells are further edited by downregulating the self-reactive receptor, and RAG expression continues until the self-reactive T cell receptor a-chain is replaced with another, less selfreactive chain. In the thymic medulla, the process of testing for self-reactivity continues with the help of medullary thymic epithelial cells and dendritic cells. The cells in the medulla express costimulatory molecules, including CD80 (B7.1) and CD86 (B7.2), the ligands for CD28. Here, T cell receptors that bind strongly to self-peptideeMHC complexes are triggered to induce cell death (negative selection). In animals, deficient in this process either through lack of medullary MHC expression or through B7 expression, huge amounts of self-reactive T cells reach the periphery, causing pathologies resembling graft-versus-host disease [56]. It can be speculated that the well-established association between particular MHC molecules and susceptibility to specific autoimmune

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diseases may stem from inefficient presentation of particular self-peptides during this phase of T cell receptor deletion [57,58]. Negative selection requires the tyrosine kinase zeta chain of T cell receptor associated protein kinase of 70 kDa (ZAP70). Mice deficient in ZAP70 develop a systemic inflammatory disorder resembling rheumatoid arthritis [59]. In addition, the following factors have been identified as being essential for negative selection: growth-factor-receptorebound (GRB) protein 2 [60], misshapen/Nck-interacting kinaseerelated kinase [61], extracellular signalregulated kinase (ERK), and p38 and Jun kinase activation [62]. Induction of cell death of autoreactive T cells requires BIM expression, which antagonizes BCL-2 and related proteins to release proapoptotic BAX and BAK. Furthermore, members of the Nur77 family of orphan nuclear receptors are induced during negative selection. T cell receptoreinduced thymocyte death is blocked in the absence of Nur77 [63].

5. CLONAL ANERGY AND TUNING The intrinsic cellular mechanisms of anergy are particularly well studied in B cells with self-reactive receptors [64]. Self-reactive B cell receptors can be internalized through accelerated endocytosis, resulting in reduction of up to 99% of the initial surface expression of a self-reactive receptor. Similarly, the transport of new receptors to the surface can be blocked [65]. It has been reported that self-reactive B cell receptors activate tyrosine kinase signaling poorly, which limits cell survival because of weak NF-kB1 activation. In parallel, weak signaling induces BIM expression to promote cell death [66] and ERK pathways that block Toll-like receptor 9 (TLR9)-induced differentiation into plasma cells [67]. So-called biochemical tuning can be achieved by increasing the threshold of B cell receptor activation, regardless of its specificity. Recruitment of the SH2-domainecontaining protein tyrosine phosphatase 1 through the surface proteins CD22 and PD1 to the activated B cell receptors increases its threshold for signaling [49]. Another example is the recruitment of the lipid phosphatase SH2-domainecontaining inositol-5-phosphatase to the activated B cell receptor through Fc receptor-g [68]. Spontaneous autoantibody production can occur if either one of these mechanisms is defective. Tuning of self-reactive T cells is achieved by increased expression of the inhibitory receptor CD5 [69,70]. Cytotoxic T lymphocyte antigen 4 (CTLA4) is another inhibitory receptor that acts through competition with CD28 for ligation with B7 molecules and transmitting inhibitory signals. CTLA4 was found to be upregulated in self-reactive T cells [71,72]. Massive accumulation of self-reactive T cells occurs in peripheral lymphoid and nonlymphoid tissues in the absence of CTLA4. Functional variants of the CTLA4 gene can lead to thyroid autoimmunity and type 1 diabetes in humans and mice [73].

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The ubiquitin ligases cbl-b, GRAIL, and Itch have been identified to be highly expressed in chronic T cell receptor signaling in vitro [74e76]. Ubiquitinylation of T cell receptors, CD28, and cytokine receptor signaling molecules can alter intracellular trafficking, promote proteolytic degradation, or can allosterically interfere with signaling [77,78]. Their importance for preventing autoimmunity in rodents has been clearly demonstrated: cbl-b deficiency coupled with a particular MHC haplotype causes type 1 diabetes in the Komeda diabetes prone rat strain [79]. Large numbers of activated T cells and high titers of autoantibodies can be found in mice lacking Itch, or cbl-b and its close relative c-cbl [77,78].

6. EXTRINSIC CONTROLS OF SELF-REACTIVE LYMPHOCYTES A well-documented extrinsic control mechanism of autoreactive B cells is their dependence on BAFF, which is produced in limiting quantities by lymphoid stromal cells [53]. Binding of BAFF to its receptor increases NF-kB2 activity maintaining peripheral B cell survival through induction of BCL-2 expression [80]. It also induces the expression of PIM2, a serine-threonine kinase, which has prosurvival effects by interfering with the proapoptotic protein BAD [81]. On the one hand, given the large numbers of circulating B cells with strong receptor signaling through high affinity to antigen, the self-reactive B cells do not receive enough BAFF and are competitively deleted [82]. On the other hand, in states of B cell lymphopenia or in phases when BAFF synthesis is high, i.e., during infection, self-reactive B cells are more likely to survive [53,66]. As with B cells, T cell survival in the periphery depends on continuous signaling through contact with MHC ligands and exposure to IL-7 [83e85]. Under normal circumstances, IL-7 levels are low and maintain T cells in interphase. However, in lymphopenia, IL-7 levels rise and amplify T cell receptor signaling and proliferation. This so-called homeostatic proliferation may also activate self-reactive T cells causing autoimmune diseases in extralymphatic sites, a common feature seen in people after T lymphopenia. Lymphopenia and defective T cell function in WiskotteAldrich syndrome is leading to an array of autoimmune and inflammatory conditions [86].

7. LIMITATION OF COSTIMULI To secrete antibodies, B cells must receive two signals: First, an antigen must bind to the B cell receptor; second, T-helper cells must signal through CD40 ligand (CD40L) and cytokines IL-2, IL-4, IL-5, and IL-21 to initiate B cell proliferation and differentiation into plasma cells [87,88]. Because negative selection in the thymus should have reduced the number of self-antigenespecific T cells, the latter signal to self-reactive B cells is limited.

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However, self-reactive B cells may receive signals from T-helper cells responding to foreign antigens during infections, so-called bystander activation. More importantly, infections only rarely trigger autoantibody diseases, like GuillaineBarre´ syndrome. Efficient B cell intrinsic tolerance mechanisms must be responsible for the fact that only 1 in 1000 people infected with Campylobacter pylori develops autoantibodies that cross-react with components of peripheral nerves [89]. Interestingly, antibody production can be partially independent of T cell help, when B cells receive stimulatory signals from bacterial flagellins, cellwall lipopolysaccharides, and unmethylated CpG dinucleotides, which are recognized by TLRs [90]. How this potentially dangerous pathway is dampened is not known in detail. Dysregulated activity of the TLR9 pathway leads to pathological accumulation of circulating IgGeself-DNA complexes and is a potent driver of the production of autoantibodies against IgG and DNA [91]. Inadequate clearance of apoptotic cells with exposed CpG DNA and other nuclear antigens may account for the striking association between systemic lupus erythematosus (SLE) and genetic deficiencies in classical complement pathway components [92]. Mature T cells are activated by T cell receptor ligation and costimulation. Without costimulation, tolerance is favored. The most important costimulus is the interaction of CD28 on T cells and the B7 proteins CD80 and CD86 on antigen-presenting cells. TLR signaling induces expression of B7 molecules and enhances the survival and clonal expansion of T cells. Therefore, blocking B7eCD28 interactions may be an attractive way to induce tolerance. However, this treatment may also decrease thymic deletion and interfere with regulatory T cell function and intrinsic T cell regulation by CTLA4.

8. REGULATION OF SELF-REACTIVE LYMPHOCYTES IN FOLLICLES Somatic hypermutation occurs in the periphery in germinal center follicles of secondary lymphoid organs [93,94]. Antibodies created by this process can have markedly increased affinities for self-antigens. Follicular B cell differentiation generates long-lived plasma and memory cells, which are able to secrete antibodies indefinitely [95]. Autologous DNA, an important selfantigen target in SLE, is abundantly presented by numerous apoptotic cells in germinal centers [96], where it represents a powerful potential stimulus for autoantibody production. It has been found that anti-double-stranded DNA antibodies are somatically mutated in animal models of SLE [93]. In addition to CD40L, follicular T cells display high levels of ICOS (inducible T-cell costimulator), which is required for germinal center antibody responses in mice and humans [71,97]. Follicular T cells are also dependent on costimulation through OX40L [98]. T cell entry into follicles is not induced in the absence of microbial TLR agonist [99]. Because self-antigens usually do

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not stimulate TLR signaling, this strict regulation of follicular T-helper cell differentiation may block self-reactive T cells from delivering help to germinal center B cells.

9. TOLERANCE AT THE EFFECTOR PHASE The mechanisms involved in preventing autoimmunity at target organs are only just beginning to be elucidated. Often pathology is limited to focal areas, such as circumscribed skin lesions in pemphigus or single-joint inflammation in rheumatoid arthritis. Pathology depends on multiple factors, including immunologic cascades involving Fc receptors, mast cells, neutrophils, and complement [100,101].

10. CONCLUSIONS The mucosa of the gastrointestinal tract is a major site of pathogen entry. The gut-associated immune system needs to remain hyporesponsive to food antigens and commensal bacteria while mounting an efficient response against pathogens. Immune responses must be exactly coordinated and regulated to effectively cure an infection and to avoid chronic inflammation. Autoimmune diseases can be considered as immune responses with defects in mechanisms that control self-tolerance. Every organ of the digestive system can be the target of an autoimmune response, either in systemic or in organ-specific autoimmune diseases. Although many self-tolerance mechanisms exist, defects in a single checkpoint can lead to autoimmune disease. Clinical manifestations of autoimmune diseases are often seen only after a latent period of many years and then only against a few proteins or organs. There seems to be hundreds of genes involved in the checkpoints of self-tolerance. Common analysis of DNA polymorphisms will not be effective in identifying predisposing defects, rather exon resequencing of individuals with autoimmune disease will be required.

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[79] Yokoi N, Komeda K, Wang HY, Yano H, Kitada K, Saitoh Y, Seino Y, Yasuda K, Serikawa T, Seino S. Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat Genet 2002;31:391e4. [80] Claudio E, Brown K, Park S, Wang H, Siebenlist U. BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat Immunol 2002;3:958e65. [81] Fox CJ, Hammerman PS, Cinalli RM, Master SR, Chodosh LA, Thompson CB. The serine/ threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev 2003;17:1841e54. [82] Thien M, Phan TG, Gardam S, Amesbury M, Basten A, Mackay F, Brink R. Excess BAFF rescues self- reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity 2004;20:785e98. [83] Barthlott T, Kassiotis G, Stockinger B. T cell regulation as a side effect of homeostasis and competition. J Exp Med 2003;197:451e60. [84] Marrack P, Kappler J. Control of T cell viability. Annu Rev Immunol 2004;22:765e87. [85] Sprent J, Surh CD. T cell memory. Annu Rev Immunol 2002;20:551e79. [86] Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F, de Saint Basile G, Delaunay J, Schwarz K, Casanova JL, Blanche S, Fischer A. Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics 2003;111:622e7. [87] Foy TM, Aruffo A, Bajorath J, Buhlmann JE, Noelle RJ. Immune regulation by CD40 and its ligand gp39. Annu Rev Immunol 1996;14:591e617. [88] Kovanen PE, Leonard WJ. Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol Rev 2004;202:67e83. [89] Ang CW, Jacobs BC, Laman JD. The Guillain-Barre´ syndrome: a true case of molecular mimicry. Trends Immunol 2004;25:61e6. [90] Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature 2004;430:257e63. [91] Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, MarshakRothstein A. Chromatin-IgG complexes activate B Cells by dual engagement of IgM and toll-like receptors. Nature 2002;416:603e7. [92] Taylor PR, Carugati A, Fadok VA, Cook HT, Andrews M, Carroll MC, Savill JS, Henson PM, Botto M, Walport MJ. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 2000;192:359e66. [93] Radic MZ, Weigert M. Genetic and structural evidence for antigen selection of anti-DNA antibodies. Annu Rev Immunol 1994;12:487e520. [94] Ray SK, Putterman C, Diamond B. Pathogenic autoantibodies are routinely generated during the response to foreign antigen: a paradigm for autoimmune disease. Proc Natl Acad Sci USA 1996;93:2019e24. [95] Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity 1998;8:363e72. [96] Rosen A, Casciola-Rosen L. Clearing the way to mechanisms of autoimmunity. Nat Med 2001;7:664e5. [97] Kroczek RA, Mages HW, Hutloff A. Emerging paradigms of T-cell co-stimulation. Curr Opin Immunol 2004;16:321e7. [98] Walker LS, Gulbranson-Judge A, Flynn S, Brocker T, Lane PJ. Co-stimulation and selection for T-cell help for germinal centres: the role of CD28 and OX40. Immunol Today 2000;21:333e7.

18 SECTION j I Introduction [99] Kearney ER, Pape KA, Loh DY, Jenkins MK. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1994;1:327e39. [100] Monach PA, Benoist C, Mathis D. The role of antibodies in mouse models of rheumatoid arthritis, and relevance to human disease. Adv Immunol 2004;82:217e48. [101] Wipke BT, Wang Z, Nagengast W, Reichert DE, Allen PM. Staging the initiation of autoantibody-induced arthritis: a critical role for immune complexes. J Immunol 2004;172:7694e702.

Chapter 2

Immunopathogenesis of Autoimmune Liver Damage A.J. Czaja Mayo Clinic College of Medicine, Rochester, MN, United States

1. INTRODUCTION Autoimmune liver damage implies that an immune attack has been misdirected against self [1]. This loss of self-tolerance may reflect deficiencies in the mechanisms by which immunocytes distinguish self-antigens from foreign antigens and perturbations in the regulatory networks that influence immunocyte activation, differentiation, proliferation, and disposal [2]. The predisposing factors for autoimmune liver damage can be extrinsic to the individual and represent indigenous environmental, toxic, or infectious agents that overwhelm self-tolerance by their absolute number or their repetitive stimulation [3]. They may also be intrinsic to the individual and represent genetic [4], cellular [5], or molecular [6] predispositions that favor protracted or exaggerated immune responses to the triggering antigen. Excess antigenic stimulation can relate to the magnitude of antigens with homologous epitopes that bombard the individual, the frequency of antigenic exposure, the responsiveness of the individual to a given antigen, or any combination of these factors [1,3]. Viruses and drugs have been implicated as triggers for autoimmune liver disease, and these reports imply that diverse antigenic stimuli can produce the same clinical result [1,7]. CD4 and CD8 T lymphocytes possess few antigen recognition sites [8], and molecular mimicry between homologous peptide sequences may explain how diverse antigens can trigger comparable immune responses [9]. The frequent concurrence of other autoimmune manifestations in patients with autoimmune liver disease also suggests that the antigen recognition sites on the activated immunocytes are imprecise [1,3]. Imprecise targeting by the activated lymphocytes can extend the range of targets to tissues anatomically different and distant from the liver (promiscuous activity) [3,10]. Epitopes The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00002-7 Copyright © 2017 Elsevier B.V. All rights reserved.

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triggering autoimmune liver disease are likely to have shared, easily mimicked, amino acid sequences that can activate immunocytes with promiscuous activity [1]. The long lag time between the onset of the disease and its clinical detection and the possibility that diverse antigens with shared epitopes can trigger the disease can complicate discovery of an initiating event. Host-dependent rather than disease-specific factors may also override selftolerance [11]. Genetic predisposition may naturally select individuals from the general population and favor the development of disease. Genetic risk factors for autoimmune hepatitis [12e15], primary biliary cholangitis (PBC) [16,17], and primary sclerosing cholangitis (PSC) [18] have been described, and certain genetic factors may also offer protection from these diseases [13,19e21]. Complex alterations in the counterregulatory networks of immune activation that are based on genetic factors may create a complex milieu that promotes or prevents these diseases [2]. In this context, the components of the milieu may vary greatly between individuals despite producing the same clinical consequence. The ability of subtle defects in a complex homeostatic system to be magnified into a disease state may explain the difficulty in identifying the core defect in autoimmune liver disease. In this review, the multifactorial nature of autoimmune liver disease is emphasized, and the various theoretical factors contributing to its occurrence are presented. These diverse factors are interactive, and the degree of their involvement can vary among individuals and modify the clinical expression and behavior of the disease.

2. ANTIGENS AND ANTIGEN RESPONSES 2.1 Target Antigen(s) Many antigens have been proposed as targets of the immune response in autoimmune liver disease, including components of the intestinal microbiota (Table 2.1) [22,23]. Cytochrome P450 2D6 (CYP2D6) has been recognized as the principal target antigen of type 2 autoimmune hepatitis [24], and antibodies to liver kidney microsome type 1 (anti-LKM1), which characterize type 2 autoimmune hepatitis, react mainly to the peptides spanning positions 193e212 of the recombinant molecule [25]. Formiminotransferase cyclodeaminase is the target antigen of antibodies to liver cytosol type 1 (anti-LC1), and anti-LC1 also characterize type 2 autoimmune hepatitis [26,27]. Both CYP2D6 and formiminotransferase cyclodeaminase have been able to induce autoimmune hepatitis in animals [23,28,29], and the body of clinical and laboratory evidence supports their candidacy as the principal targets of this form of autoimmune hepatitis. Other self-antigens have been less well-studied or strongly advanced in autoimmune liver disease. The cytochromes, CYP2A2 and CYP2A6, have been

TABLE 2.1 Antigens and Antigen Responses Possible Pathogenic Effects

Target antigens (main)

Cytochrome P450 2D6 (CYP2D6) [24] Formiminotransferase cyclodeaminase (FTCD) [26,27]

CYP2D6 targeted by anti-LKM1 [24] FTCD targeted by anti-LC1 [26,27] Associated with type 2 AIH [164]

Antigenic homologues (molecular mimicry)

Diverse antigens have similar peptide sequences or conformational epitopes [3] Foreign and self-antigens are similar [9] Humoral and cellular cross-reactivity [45]

Different antigens trigger the same immune response [9] Effectors have promiscuous targeting [10] Protracted or repeated exposures induce loss of self-tolerance [29,45] Molecular mimicry not identity required [45] Noncontiguous sites can be targeted [3]

Cryptic self-antigens or neoantigens

New antigens uncovered or created during primary immune responses [36,44] May be products of apoptosis [67]

Increase pool of homologous peptides [36,44] Increase the immune response and its outcome [44] Trigger or sustain adaptive immune response [67] May induce self-amplification loop [67]

Epitope spread

Immune response broadens with duration of disease to involve neighboring and remote regions of the triggering antigen [44]

Sensitization of new effector cells and activation of memory cells [44] Could intensify or sustain the immune response [44]

Promiscuous lymphocytic activity

TCRs have imprecise antigen recognition [10] Cells unable to distinguish between epitopes in different antigens [10]

Inability to distinguish self from foreign antigens [10] Extend immune response to diverse sites [3,9,10]

Loss of self-tolerance

Cross-reacting humoral and cellular immune responses triggered by homologous foreign antigens and sustained by deficient immune regulatory responses [1e3,29,79]

Self-perpetuating immune response against homologous selfepitopes (autoimmunity) [29]

AIH, autoimmune hepatitis; anti-LC1, antibodies to liver cytosol type 1; anti-LKM1, antibodies to liver kidney microsome type 1; TCRs, T cell antigen receptors. Numbers in square brackets are references.

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22 SECTION j I Introduction

implicated as target antigens in the autoimmune polyglandular syndrome type 1, which includes autoimmune hepatitis [30]. Uridine triphosphate glucuronosyltransferase [31], glutathione S-transferase [32], Sep (O-phosphoserine) transfer ribonucleic acid:Sec (selenocysteine) transfer ribonucleic acid synthase [33], alpha-actinin [34], and subunits of an inner mitochondrial membrane enzyme (F1 ATPase) [35] have also been proposed. The search for the principal target antigens in autoimmune liver disease is complicated by homologies between antigens that extend the range of candidates and the emergence of neoantigens during the inflammatory process [36].

2.2 Molecular Mimicry Molecular mimicry implies that multiple antigenic targets have the same or similar epitopes against which activated lymphocytes with imprecise antigen recognition sites (promiscuous activity) can be directed (Fig 2.1). Molecular mimicry can explain autoreactivity [9], but it has been difficult to prove in human disease [37,38]. Humoral cross-reactivity has been well described in autoimmune conditions [39e41], but cellular cross-reactivity has been difficult to demonstrate [42e45]. The hypothesis that protracted or repeated exposure to homologous peptide sequences can result in loss of self-tolerance has been supported mainly in animal models [43e45]. In the mouse model of experimental autoimmune hepatitis, infection with an adenovirus expressing human CYP2D6, the antigen implicated in one form of autoimmune hepatitis, breaks tolerance to mouse homologues of CYP2D6 [45]. In contrast, in transgenic mice expressing human CYP2D6, infection with the same human antigen delays the occurrence and reduces the severity of experimental autoimmune hepatitis [45]. Furthermore, mouse T cells specifically sensitized to human CYP2D6 react to human CYP2D6 peptides that have intermediate homology to mouse homologues, whereas they do not react to human CYP2D6 peptides that have close homology to mouse homologues [45]. These findings suggest that molecular mimicry can disrupt immune tolerance of homologous self-antigens, whereas molecular identity may enhance self-tolerance [45]. Molecular mimicry can occur when there are homologous amino acid sequences within peptides or similar conformational epitopes in structurally dissimilar peptides (Table 2.1) [3,9]. Cryptic self-antigens may be uncovered during the disease, and neoantigens may also be created that enlarge the pool of homologous sensitizing peptides [36,44]. The net effect of this proliferation of antigens is to favor additional molecular mimicries to sustain and extend the disease process. In patients with autoimmune hepatitis and animals infected with adenovirus expressing CYP2D6, the humoral response early in the course of the disease is against the immune-dominant epitope of the human antigen, whereas the immune response broadens later in the disease to involve epitopes in neighboring and remote regions of the human

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antigen (epitope spreading) [1,44]. The immune response may thereby be intensified by the sensitization of new effector cells and the activation of memory cells [46]. Homologies between various viral genomes [hepatitis C virus (HCV), cytomegalovirus, and herpes simplex type 1 virus] and recombinant CYP2D6 suggest that multiple exposures to viruses mimicking self may be a mechanism by which to break self-tolerance and induce autoimmune liver disease [25]. Cross-reactivity has also been demonstrated between HCV antigens and hostderived smooth muscle and nuclear antigens [40]. The human leukocyte antigen (HLA) B51 has been associated with cross-reactive immune responses between viral and microsomal antigens, and genetic factors may contribute to the propensity of viral antigens to promote an autoreactive immune response [41]. Geographic differences in the occurrence of certain indigenous viral agents or the frequencies of exposure to structurally similar viruses may explain regional variations in disease susceptibility and phenotype. Genetic differences reflected in the ethnic diversity of autoimmune hepatitis may also contribute [47].

2.3 Promiscuous Lymphocyte Targeting The ability of molecular mimicry to generate an autoreactive response depends in part on the promiscuous activity of the sensitized lymphocytes (Table 2.1). Promiscuous lymphocyte reactivity implies that the T cell antigen receptor (TCR) of the immunocyte cannot distinguish between closely homologous epitopes in different antigens (Fig. 2.1) [10]. This deficiency can promote and perpetuate an immune attack against self-antigens that resemble foreign antigens through molecular mimicry. Antigenic peptides are displayed in the antigen-binding groove of class II molecules of the major histocompatibility complex (MHC) (Fig. 2.1) [4,11,48]. These peptides are selected for presentation by the amino acid sequences within the peptide that interact with residues within the antigenbinding groove. Peptide binding to class II MHC molecules is highly degenerate in that each MHC molecule can bind a variety of peptides with varying affinities. Different MHC molecules show a strong bias for particular types of amino acids that are present at peptide positions P1, P4, P6, P7, and P9 from the N-terminal anchor position [10,48]. The critical contacts that take place between a TCR and its ligand involve residues of the antigenic peptide, the a-helical region of the class II MHC molecule, and the complementarity-determining regions (CDRs) of the a- and b-chains of the TCR [48]. The three variable CDR loops of the a-chain and CDR3 of the b-chain contact the a-helix of the MHC molecule. The CDR1 and CDR3 loops of both the a- and b-chains contact the bound peptide. CDR3 displays the greatest degree of diversity within the TCR, and it may respond to diverse homologous peptides in the antigen-binding groove.

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FIGURE 2.1 Cell-mediated mechanisms of liver injury. Foreign antigens resembling self-antigens (molecular mimicry) are presented by class II molecules of the major histocompatibility complex (MHC) on professional antigen presenting cells. Antigen-activated CD4 helper T lymphocytes differentiate and proliferate along type 1 and type 2 cytokine pathways. The type 1 cytokine pathway is mediated mainly by proinflammatory cytokines, including interleukin (IL)-1, interferon-gamma (IFN-g), and tumor necrosis factor-alpha (TNF-a). Clones of antigen-specific CD8 cytotoxic T lymphocytes differentiate, and they infiltrate the liver targeting self-antigens of varying homology (epitope spread). A cell-mediated cytotoxicity ensues, and the liver cells undergo receptor-mediated (extrinsic) apoptosis as Fas ligands (FasL) expressed on the surface of the CD8 lymphocytes activate Fas death receptors on the surface of hepatocytes. The type 2 cytokine pathway is mediated mainly by antiinflammatory cytokines, including IL-10 and transforming growth factor-beta (TGF-b). B lymphocytes develop and transform into plasma cells that produce mainly immunoglobulin G (IgG). Aggregates of immunoglobulin G and normal protein constituents of the hepatocyte membrane attract natural killer (NK) cells, and an antibody-dependent cell-mediated cytotoxicity ensues. Epitope spread increases the diversity of targeted antigens within the liver, and promiscuous lymphocyte targeting can involve other noncontiguous organs.

The TCRs of liver infiltrating lymphocytes are restricted [49], and there is limited clonal diversity among various liver diseases [50]. Liver infiltrating lymphocytes can overcome this lack of clonal diversity by targeting multiple similar antigens (promiscuous activity) [8,51]. Molecular mimicry and promiscuous lymphocyte activity are nurtured by the ability of multiple similar peptides to be presented by the same class II MHC molecules and by the ability of multiple class II MHC molecules to present the same or similar

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peptides [10,48]. Genetic factors can also influence the structure of the TCR and the nature and vigor of the immune response [4,13,48,52]. Patients with autoimmune hepatitis have homozygosity for the 10-kilobase Bgl II polymorphism of the TCR constant b gene more commonly than normal subjects, especially in patients without the HLAs DRB1*03 and DRB1*04 [52]. These observations suggest that susceptibility to autoimmune liver disease may relate to genetic factors affecting the antigen specificity of the TCRs on effector cells.

3. MOLECULAR MECHANISMS OF LIVER CELL INJURY 3.1 Chemokines and Cell Trafficking The migration of inflammatory and immune cells to sites of tissue injury is orchestrated by chemokines that are produced by distressed cells and by cells within the innate and adaptive immune systems (Table 2.2) [1,6,53]. The chemokines attract inflammatory and immune cells that express complementary ligand receptors, and they initiate a natural reparative process. Perturbations in the recruitment of these cells could theoretically alter the repair process or aberrantly attract excess numbers of effector cells that extend the tissue injury. The chemokines, CXCL9 (monokine induced by interferon-g, MIG) and CXCL10 (interferon-geinducible protein 10, IP-10), are increased in autoimmune hepatitis, and they have been associated with disease severity and progression [54,55]. T-helper 1 (Th1) lymphocytes and Th17 lymphocytes express the cognate receptor of CXCL9, which is CXCR3, and these cells are the principal effectors of the adaptive immune response [1,5]. The excess recruitment of these cells to sites of liver injury could enhance the cellmediated and antibody-dependent mechanisms of hepatocyte injury. CCL26 (eotaxin-3), CXCL11, CCL11 (eotaxin 1), CCL20, CXCL12 (stromal cellederived factor-1) and CX3CL1 (fractalkine) have also been implicated in the pathogenesis of autoimmune liver disease [6]. Perturbations of chemokine production in autoimmune liver disease have not been well studied, and increases in chemokine production may reflect the severity rather than the mechanism of tissue injury. Furthermore, the chemokines recruit pro- and antiinflammatory cells bearing the same cognate receptor, and hypotheses implicating chemokine perturbations in autoimmune liver disease must account for the apparent failure of these chemokines to recruit antiinflammatory cells in sufficient number or potency.

3.2 Pro- and Antiinflammatory Cytokines Cytokines are secreted by diverse cell populations, including activated cells of the innate and adaptive immune responses. They are critical for the activation, differentiation, and proliferation of lymphocytes into T and B cell effectors,

TABLE 2.2 Molecular Mechanisms of Liver Cell Injury Nature

Possible Pathogenic Effects

Chemokines

CXCL9 and CXCL10 increased in AIH [54,55] CCL26, CXCL11, CCL11, CCL20, CXCL12, and CX3CL1 (fractalkine) increased in autoimmune liver disease [6] Attracts effectors with specific cognate receptor, importantly CXCR3 [6]

Imbalance between pro- and antiinflammatory responses [6] Associated with severity, progression, and fibrosis [54,55]

Cytokines

Pro- (IL-1, IL-6, IL-8, IL-12, IFN-g, TNF-a) and antiinflammatory (IL-4, IL-10, IL-11, IL-13, TGF-b) cytokines [56,57]

Regulate activation, differentiation, and proliferation of lymphocytes [56,57] Genetic polymorphisms may affect homeostatic balance [58,59]

Apoptosis

Principal pathway of liver cell death in AIH [64] Mainly receptor-mediated triggered by liver-infiltrating lymphocytes (extrinsic pathway) [63] Mitochondrial damage by ROS may contribute (intrinsic pathway) [84]

Dysregulation can increase hepatocyte loss and disease severity or prolong survival of immune cells [65,66] Apoptotic bodies can enhance adaptive immune response [65,67] Genetic polymorphisms may affect homeostatic balance [74,75]

Hepatocyte necrosis

Cell-mediated cytotoxicity involves liver-infiltrating CD8 cytotoxic lymphocytes [76] Antibody-dependent cell-mediated cytotoxicity involves plasma cells and immunoglobulin production [77]

Can occur with apoptosis in AIH [78] Affected by cytokine profiles [3,79] Associated with disease activity [3,79]

Oxidative and nitrosative stress

ROS generated by Kupffer cells and myofibroblasts in inflammation [80] Nitric oxide metabolites increased in AIH [93] Decreased antioxidant, 25-hydroxyvitamin D, in chronic liver disease [94,95]

ROS increase hepatocyte apoptosis [84] Low serum 25-hydroxyvitamin D levels associated with severity and fibrosis [94,95] RNS alter protein structure and function and induce mitochondrial dysfunction [111]

AIH, autoimmune hepatitis; CXCL, cysteine (C) residues that are conserved at the amino terminus of the chemokine ligand (L) and the number of variable amino acids (X) that separate the conserved motifs; CXCR, cysteine (C) residues that are conserved at the amino terminus of the chemokine receptor and by the number of variable amino acids (X) that separate the conserved motifs; IFN-g, interferon-gamma; IL, interleukin; RNS, reactive nitrogen species; ROS, reactive oxygen species; TGF-b, transforming growth factor-beta; TNF-a, tumor necrosis factor-alpha. Numbers in square brackets are references.

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Molecular Mechanisms of Liver Cell Injury

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and they can modulate the immune response by cross-regulatory actions [56,57]. The principal proinflammatory cytokines are interleukin (IL)-1, IL-6, IL-8, IL-12, interferon-gamma (IFN-g), and tumor necrosis factor-alpha (TNF-a) [56,57]. The principal antiinflammatory cytokines are IL-4, IL-10, IL-11, IL-13, and transforming growth factor-beta (TGF-b) [56,57]. Imbalances between the pro- and antiinflammatory cytokines in autoimmune liver disease may reflect intrinsic cellular defects that are in part related to genetic factors. Polymorphisms of genes affecting the production of TNF-a, IL-2, IL4, IL-6, and IFN-g have been described in some populations with autoimmune hepatitis [58,59]. Other studies have had discrepant findings that suggest that the cytokine polymorphisms are different between ethnic groups or unimportant in the occurrence of autoimmune hepatitis [60,61]. Proinflammatory cytokines have been therapeutic targets in inflammatory bowel disease [57], and monoclonal antibodies to TNF-a (infliximab) have had preliminary success in autoimmune hepatitis [62].

3.3 Apoptotic Activity Apoptosis (programmed cell death) is the principal pathway of liver cell loss in autoimmune hepatitis, and it is mainly receptor mediated and triggered by liver-infiltrating cytotoxic lymphocytes (extrinsic apoptotic pathway) (Fig. 2.2) [63e65]. Apoptosis also influences the durability of the activated lymphocytes that provoke tissue injury. Overactive apoptosis can enhance the loss of hepatocytes and increase the severity of liver damage, whereas underactive apoptosis can prolong the survival of immune cells and sustain the autoreactive response [66]. The products of liver cell death (apoptotic bodies) may also contribute to the persistence and severity of the liver injury by serving as neoantigens (Table 2.2). Free apoptotic material can stimulate an adaptive immune response characterized by the development of autoantibodies and the generation of liver-infiltrating cytotoxic T cells (Fig. 2.2) [65,67]. Apoptotic bodies can also stimulate Kupffer cells to release chemokines and reactive oxygen species (ROS) that increase the apoptosis of hepatocytes and activate hepatic stellate cells [68]. The transformation of hepatic stellate cells into myofibroblasts can in turn increase the oxidative stress on the liver, enhance the apoptosis of hepatocytes, and promote liver fibrosis (Fig. 2.2) [69,70]. A selfamplification loop can be established in which the apoptosis of liver cells and the autoreactive response are sustained by the generation of apoptotic bodies, activation of Kupffer cells, stimulation of hepatic stellate cells, and the generation of ROS [65,67]. The surface expression of the Fas receptor (CD95/APO-1) is increased in lymphocyte subsets from patients with autoimmune hepatitis; levels of Fas ligand (FasL) are higher in liver tissue specimens from these patients than in patients with PBC; and progenitor cells in bone marrow cultures from

28 SECTION j I Introduction

FIGURE 2.2 Molecular mechanisms of hepatocyte death. Liver-infiltrating, antigen-specific CD8 cytotoxic T lymphocytes activate death receptors on the hepatocyte surface, mainly after the ligation of the Fas receptor (Fas) with the Fas ligand (FasL). An extrinsic (receptor-mediated) apoptotic pathway is activated, and a death-inducing signaling complex (DISC) develops. Caspases are activated, and the executioner caspases 3 and 7 emerge from the caspase cascade. Chromosomal deoxyribonucleic acid (DNA) is cleaved, and the dead hepatocyte becomes an apoptotic body. The apoptotic body can act as a neoantigen that stimulates an adaptive immune response and institutes a self-amplification loop (dashed red line). The apoptotic body can also be engulfed by Kupffer cells that in turn release reactive oxygen species (ROS). Hepatic stellate cells are activated, and collagen deposition proceeds. The activated hepatic stellate cells transform into myofibroblasts encouraged by transforming growth factor-beta (TGF-b), and the myofibroblasts in turn produce ROS that can activate more hepatic stellate cells and trigger the intrinsic (mitochondrial) apoptotic pathway. The ROS increase permeability of the mitochondrial outer membrane (MOM), and there is an efflux of cytochrome c into the cytoplasm. Cytochrome c complexes with apoptotic protease activating factor-1 (APAF-1) and deoxyadenosine triphosphate (dATP) to form an apoptosome in the cytoplasm. The apoptosome activates caspase 9, which activates other caspases until caspases 3 and 7 are available to execute the hepatocyte. The generation of apoptotic bodies recharges the selfamplification loop mediated by ROS (green solid line).

patients with autoimmune hepatitis have increased apoptotic markers compared to normal individuals [63,71,72]. Furthermore, activated lymphocytes expressing CD95/APO-1 fail to downregulate the antiapoptotic B cell lymphoma-2 (bcl-2) family of proteins, and bcl-2 proteins are present in high concentrations in liver-infiltrating lymphocytes [73]. The perturbations in apoptotic activity may reflect in part genetic polymorphisms [74,75]. The net effects of these aberrations in autoimmune hepatitis may be to protect activated effector cells from programmed cell death and promote the excessive apoptosis of hepatocytes [72].

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3.4 Hepatocyte Necrosis Hepatocyte necrosis is a consequence of two mechanisms that are triggered by the loss of immune intolerance (Table 2.2). Cell-mediated cytotoxicity involves liver-infiltrating, antigen-sensitized, cytotoxic CD8 lymphocytes that have differentiated from CD4 lymphocytes along a cytokine pathway mediated mainly by IL-1, IL-12, IFN-g, and TNF-a (type 1 cytokine pathway) (Fig. 2.1) [1,76]. Antibody-dependent cell-mediated cytotoxicity involves the differentiation of antigen-sensitized CD4 lymphocytes into B lymphocytes along a cytokine pathway mediated mainly by IL-4, IL-5, IL-10, and IL-13 (type 2 cytokine pathway) [1,77]. The B lymphocytes can differentiate further into clones of immunoglobulin-producing plasma cells, and the immunoglobulins can produce immune complexes on the surface of hepatocytes. Natural killer (NK) cells can then be attracted to the immune complexes and destroy the liver cells. Hepatocyte necrosis can occur in conjunction with apoptosis in autoimmune hepatitis, and they each may have variable activities during the course of the disease [78]. The components of the type 1 and type 2 cytokine pathways can be cross-regulatory, and the type 2 cytokines have antiinflammatory effects that can modulate the type 1 cytokine response. Type 1 cytokines tend to prevail during periods of active inflammation, and type 2 cytokines tend to prevail during intervals of quiescence [3,79]. Clarification of the molecular perturbations that affect hepatocyte necrosis and apoptosis promises to direct future therapeutic interventions.

3.5 Oxidative Stress ROS are generated mainly by activated Kupffer cells and myofibroblasts during liver inflammation and hepatocyte loss in autoimmune hepatitis [1,80,81]. Oxidative stress occurs when the production of ROS (peroxides, superoxide, hydroxyl radicals, and singlet oxygen) exceeds the capacity to remove them [82,83]. ROS can damage the mitochondrial outer membrane within the hepatocyte, increase its permeability, and activate the intrinsic apoptotic pathway (Fig. 2.2) [84]. The release of cytochrome c into the cytoplasm of the distressed liver cell forms a macromolecular complex (apoptosome) that facilitates the conversion of procaspase 9 to caspase 9 [85]. An activation cascade follows in which caspases 3 and 7 are activated, and the chromosomal deoxyribonucleic acid (DNA) of the distressed hepatocyte is cleaved [65]. DNA fragmentation and the release of apoptotic bodies can then activate Kupffer cells and institute a self-amplification loop that can extend the adaptive immune response, enhance the production of pro-inflammatory cytokines, activate hepatic stellate cells, generate ROS, and increase the extracellular matrix. The principal enzymes associated with ROS production in the liver are the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) [86,87]. The NADPH oxidases in the liver have been classified functionally as

30 SECTION j I Introduction

phagocytic (NOX2) and non-phagocytic (NOX1 and NOX4) isoforms [81,88]. The nonphagocytic isoforms (NOX1 and NOX4) are profibrotic, and they have nurtured speculation that NOX inhibitors might prevent progressive fibrosis in patients with chronic liver disease [81]. Glutathione, superoxide dismutase, glutathione peroxidase, and catalase are the principal antioxidants that defend against oxidative stress [82,83,87]. Nuclear factor erythroid 2erelated factor 2 (Nrf2) is a transcription factor that also defends against the production and accumulation of excess ROS [89,90]. It promotes expression of antioxidant response elements by cytoprotective genes, and it is activated when ROS release it from its bound form in the cytoplasm and allow it to translocate to the nucleus [91]. Transforming growth factor-beta (TGF-b) can counter the antioxidant responses by inhibiting the production of glutathione, inducing NOX4 activity, inactivating Nrf2, and stimulating hepatic stellate cells [82]. ROS can in turn release TGF-b from its latent form and sustain the oxidative stress [92]. Aging is associated with reduced production of glutathione, lower levels of Nrf2, increased production of ROS, and increased hepatic fibrosis. Aging is an important facilitator of oxidative stress [82,83]. Patients with advanced cirrhosis have laboratory markers of oxidative stress that are higher than in patients with less advanced liver disease, and the levels decrease with successful treatment (Table 2.2) [93]. Low serum levels of the anti-oxidant, 25-hydroxyvitamin D, have been found in diverse chronic liver diseases, including autoimmune hepatitis, and this deficiency has been associated with disease severity and fibrosis [94,95]. Oxidative stress is not disease-specific or the likely prime basis for autoimmune liver disease. Its frequent occurrence in severe liver inflammation and its noxious attributes have justified concern that oxidative stress may worsen or sustain inflammatory activity. This concern has driven investigational efforts that have included preliminary clinical trials of anti-oxidants in patients with alcoholic liver disease [96e100], non-alcoholic steatohepatitis [101], and chronic hepatitis C [102,103]. Importantly, meta-analyses have not demonstrated that supplemental antioxidant therapies have been beneficial in preventing cancer, cardiovascular diseases, and death, and such therapies may have had harmful effects, including an increase in all-cause mortality [104e106]. Similar meta-analyses in patients with liver disease have been unable to demonstrate that antioxidant therapies are effective or ineffective in autoimmune liver diseases, viral hepatitis, alcoholic liver disease, and cirrhosis [107].

3.6 Nitrosative Stress Reactive nitrogen species (RNS) that are overproduced or undereliminated cause nitrosative stress [108], and the consequences of nitrosative stress can include mitochondrial dysfunction, altered structure and function of critical

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protein mediators, and cell injury or death [109,110]. Nitric oxide, peroxynitrite, nitrotyrosine, and nitrosothiols are the principal RNS, and they can coexist and interact with ROS [111]. The interaction of nitric oxide with superoxide generates peroxynitrite [111,112], and the conjugation of thiols with glutathione produces nitrosothiols [113]. The nitration of tyrosine generates nitrotyrosine [114]. Peroxynitrite is the most reactive and potentially injurious RNS, and it has powerful oxidizing and nitrating actions [111,115]. The wide spectrum of substrates (lipids, thiols, amino acids, DNA) targeted by peroxynitrite can result in the lipid peroxidation of membranes, mitochondrial damage, posttranslational modifications of proteins, disturbances in cell signaling, apoptosis, and cell necrosis [111]. Peroxynitrite can also generate other RNS, including nitrogen dioxide and dinitrogen trioxide [116]. Thioredoxin cleaves nitrosothiols and suppresses the formation of peroxynitrite [117,118]. Thioredoxin is the principal defense against nitrosative stress, but other mechanisms can also help preserve cell function during oxidative and nitrosative stress. Autophagy degrades and recycles damaged or noncritical cell components as energy sources, and it can mitigate cell stress [119]. The unfolded protein response is another disease-nonspecific stress response that can preserve the function of the endoplasmic reticulum by limiting protein production, activating molecular chaperones that improve protein folding, and tagging misfolded proteins for degradation [120,121]. Nitric oxide derivatives are present in cirrhosis [122]; the intrahepatic expression of iNOS and the accumulation of nitrotyrosine are increased in autoimmune hepatitis and correlate with histological severity [80]; and serum concentrations of the metabolites of nitric oxide are higher in autoimmune hepatitis than in normal individuals [93]. Serum levels are also higher in patients with severe histological activity than in those with mild to moderate activity (Table 2.2) [93]. These findings implicate oxidative stress and nitrosative stress as processes that can develop during autoimmune hepatitis and extend the injury. ROS and RNS are attractive ancillary targets for interventions that can manipulate critical molecular pathways (NOX inhibition, Nrf2 activation, peroxynitrite elimination) in a precise, organ-specific fashion that minimizes collateral homeostatic disruptions [90,111,123].

4. CELLULAR MEDIATORS OF LIVER CELL INJURY 4.1 Innate and Adaptive Immune Responses Liver injury provokes an innate immune response that is characterized by its immediacy, nonspecificity, brevity, and lack of immunological memory [5]. An adaptive immune response follows, and it is characterized by highly specialized cells with immunological memory and the ability to target cells expressing “nonself” antigens [5]. The key cells of the innate immune response are the

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dendritic cells and NK cells, and the principal cells of the adaptive immune response are the Th lymphocytes (Th1, Th2, and Th17 cells), gamma delta lymphocytes, natural killer T (NKT) cells, and regulatory T cells (Table 2.3) [5]. Individual cell populations may contribute to both the innate and adaptive immune responses. NKT cells express surface markers typical of NK cells and T lymphocytes, and they have features of both the innate and adaptive immune responses [124,125]. Gamma delta T lymphocytes migrate to areas of tissue injury without antigen priming, but they can also recognize antigens and secrete proinflammatory cytokines [126]. Dendritic cells can be early responders to tissue injury but also process and present foreign and self-antigens [127]. The cellular effectors of the innate and adaptive immune responses have redundant and opposing actions, and they can modulate the severity of autoimmune liver disease. Deficiencies in the number or function of any cell population can upset homeostatic balance and promote or perpetuate the disease [5]. The principal cell populations studied in autoimmune liver disease have been the NKT cells, gamma delta cells, and the regulatory T cells.

4.2 Natural Killer T Cells NKT cells can have opposing immune modulatory functions (Table 2.3) [128]. Type I NKT cells express semivariant TCRs, and they recognize glycolipid antigens, mainly a-galactosylceramide, that are presented by the class I MHC molecule, CD1d [129]. Type I NKT cells can produce the proinflammatory cytokines, IFN-g and TNF-a [130], and they can also produce the antiinflammatory cytokines, IL-4 and IL-13 [131]. The nature of the activating lipid antigen can influence the nature of the cytokine response. Type II NKT cells have a large repertoire of TCRs, and they recognize mainly phospholipids and sulfatides [132]. Type II NKT cells activate dendritic cells and induce anergy in the type I NKT cells [133]. Preliminary studies have suggested that the number of intrahepatic NKT cells are reduced in autoimmune hepatitis compared to PBC and that levels of mRNA encoding soluble CD1d are lower [134]. Patients with reduced numbers of intrahepatic NKT have higher serum levels of aminotransferase and immunoglobulin G (IgG) than patients with increased numbers, and they may have a more active clinical disease. These findings suggest that factors affecting the number of intrahepatic NKT cells and their immunosuppressive activities can affect disease severity in autoimmune hepatitis. Treatments with a-galactosylceramide or synthetic analogues of this glycolipid have protected animal models of systemic lupus erythematosus [135], diabetes [136], and collagen-induced rheumatoid arthritis [137].

4.3 Gamma Delta Lymphocytes Gamma delta lymphocytes have TCRs that consist of one gamma chain and one delta chain [1,5]. These cells can contribute to both the innate and adaptive

TABLE 2.3 Cellular Mediators of Liver Cell Injury Nature

Possible Pathogenic Effects

Innate immune system

Dendritic cells [5] Natural killer cells [5] Macrophages, neutrophils, eosinophils [5] Mast cells, basophils [5]

First line of defense against pathogens [5] Responds to stress signals not antigens [5] Immediate but short duration response [5] Most lack immunological memory [5] Can induce antigen tolerance or intolerance [5] Can bridge to adaptive immune response [5]

Adaptive immune system

T-helper lymphocytes (Th1, Th2, Th17 cells) [5] NKT cells [5] Gamma delta cells [5] Regulatory T cells [5]

Highly specialized cells [5] Antigen sensitized with immune memory [5] Eliminates “nonself” targets [1e3,79] Perturbations induce autoimmunity [1,5]

NKT cells

Innate and adaptive immune responses [124,125] Dual stimulatory and inhibitory actions [128] Type I cells have semivariant TCRs, recognize mainly a-galactosylceramide, and produce pro- and antiinflammatory cytokines [129e131] Type II cells recognize phospholipids and sulfatides, activate dendritic cells, and induce anergy in type I cells [132,133]

Intrahepatic NKT cells reduced in AIH [134] Homeostatic imbalance increases severity [134] Synthetic analogues of glycolipid antigens may favorably modulate NKT cell activity [135e137]

Continued

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Cellular Mediators

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Possible Pathogenic Effects

Gamma delta lymphocytes

TCRs consist of gamma and delta chains [5] Innate and adaptive immune responses [5,138] Stimulatory and inhibitory immune actions [5]

Increased in blood and liver in AIH [138] Present in portal tracts of AIH, PBC, and PSC [139] Possible effector of liver cell injury [139] Produce antiinflammatory IL-10 [140] Induce apoptosis of hepatic stellate cells [141] Promote hepatic regeneration [142] Multiple protective actions [5]

Regulatory T cells

CD4þCD25þCD127þ(low)Foxp3þ phenotype [154] Inhibits IFN-g production and stimulates secretion of IL-4, IL-10, and TGF-b [143] Induces apoptosis of proinflammatory cells [147] Inhibits hepatic stellate cells [148] Limits proliferation of Th17 lymphocytes [149] Major immunosuppressive effects [5]

Decreased number and function in AIH [144,150] Reduced in hepatic portal tracts [151] Deficiencies could promote autoreactivity [151] Aberrations in AIH challenged [154]

AIH, autoimmune hepatitis; IFN-g, interferon-gamma; IL, interleukin; NKT, natural killer T cells; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; TCRs, T cell antigen receptors; TGF-b, transforming growth factor-beta; Th, T-helper. Numbers in square brackets are references.

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TABLE 2.3 Cellular Mediators of Liver Cell Injurydcont’d

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immune responses, and they are present in higher concentrations in the peripheral blood and liver tissue of patients with autoimmune hepatitis than in normal individuals (Table 2.3) [138]. Gamma delta cells accumulate in the portal tracts of patients with autoimmune hepatitis, PBC, or PSC, and they may be effectors of liver injury in autoimmune liver disease [139]. They also have protective actions that include production of the antiinflammatory cytokine, IL-10 [140], induction of apoptosis in hepatic stellate cells [141], and secretion of cytokines, IL-17 and IL-22, which can promote hepatic regeneration [142]. The stimulatory and inhibitory actions of the gamma delta cells offer additional opportunities for targeted therapeutic manipulation [5].

4.4 Regulatory T Cells Regulatory CD4þCD25þ T cells modulate CD8 T cell proliferation by exerting a direct suppressive effect on the production of IFN-g while increasing secretion of IL-4, IL-10, and TGF-b [143e146]. They can also induce the apoptosis of inflammatory and immune cells [147], inhibit hepatic stellate cells [148], impair the secretion of IL-17 [149], and limit the proliferation of Th17 lymphocytes [149]. These cells have been decreased in number and function in the peripheral blood of patients with autoimmune hepatitis [144,150,151], and they have been less evident in the portal tracts of liver specimens (Table 2.3) [151]. A signaling defect that influences the function of the regulatory T cells may also contribute to regulatory failure [5]. Galectin 9 is a beta galactosidaseebinding protein expressed on regulatory T cells, and its ligation with the mucin domain-3 receptor (TIM-3) on Th1 cells and dendritic cells induces the apoptosis of Th1 lymphocytes and dendritic cells [152,153]. In autoimmune hepatitis, the expression of galectin 9 on regulatory T cells and TIM-3 on Th1 cells is reduced, and these deficiencies may limit the ability of the regulatory T cells to restore immune tolerance [153]. Deficiencies in the function of regulatory T cells have also been described in the siblings and children of patients with PBC, and the suppressor activity of this subset may be modulated by genetic factors [146]. Regulatory T cells can be defined more rigidly by the phenotype CD4þCD25þCD127þ(low)Foxp3þ, and cells with this phenotype have had normal function in patients with autoimmune hepatitis. Furthermore, increased numbers of these cells have been described in the peripheral circulation and liver tissue of patients with autoimmune hepatitis [154]. These findings have challenged the hypothesis that perturbations in the regulatory T cell population are critical for the development of autoimmune hepatitis. The discrepant findings between studies may relate to differences in the phenotypic definition of the regulatory T cells, methods for the detection and evaluation of these cells, and the severity and treatment of the liver disease in the study population [155].

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The abnormalities associated with regulatory T cells may be transient and improved by medications (corticosteroids, mycophenolate mofetil, or rapamycin) and the resolution of inflammatory activity [5,144]. Relative imbalances between the number and functions of the regulatory T cells and effectors cells may be the critical factor affecting the autoreactive response rather than the absolute number and function of an individual cell population.

5. GENETIC PREDISPOSITIONS 5.1 Associations Within the Major Histocompatibility Complex Alleles within the MHC affect the selection and presentation of antigens to CD4 helper T lymphocytes by encoding the amino acid sequences that comprise their antigen-binding groove. The occurrence and severity of autoimmune liver disease have been associated with these alleles. Type 1 autoimmune hepatitis is characterized by the presence of antinuclear antibodies and/or smooth muscle antibodies, and it is the most common form of autoimmune hepatitis. The principal susceptibility alleles for type 1 autoimmune hepatitis in white North American and northern European patients reside on the DRB1 gene, and they are DRB1*0301 and DRB1*0401 (Table 2.4) [13,15]. DRB1*0404 and DRB1*0405 are the susceptibility alleles in Japan, mainland China, and Mexico; DRB1*0405 and DQB1*0401 are the susceptibility alleles in South Korea; and DRB1*1301 is the principal susceptibility allele in South America [1]. Other susceptibility alleles that have been implicated in South America by a large metaanalysis have been DQB1*02, DQB1*0603, and DRB1*0405 [156]. The key genetic risk factors for PSC are DRB3*0101-DRB1*0301 and DRB3*0101-DRB1*1301, and the haplotype containing DRB1*04-DQB1*0501 has been associated with protection from the disease [20]. The DRB1*08-DQB1*0402 haplotype in PBC extends weakly to the DPB1*0301 allele in British patients and to the DPB1*0501 allele in Japanese patients [157]. Chromosomes 6p21.3 and 2q have been implicated in the occurrence of PBC, and they include polymorphisms of genes that can alter the autoimmune response, such as cytotoxic T lymphocyte antigen-4 (CTLA-4), IL-12A and IL12RB2 [17,21,158e161]. Analyses of amino acid sequence variations encoded by the susceptibility alleles associated with autoimmune hepatitis in white North American and northern European patients indicate that the core susceptibility motif is a sixamino-acid sequence, encoded as L (leucine), L (leucine), E (glutamic acid), Q (glutamine), K (lysine), and R (arginine), at positions DRb67-72 of the antigen-binding groove of the class II MHC molecule (Table 2.4) [13,162]. The principal determinant of susceptibility may relate to a positively charged lysine (K) at position DRb71 [13]. In PSC, susceptibility and protection may relate to amino acid substitutions at position DRb38 [163]. Both DRB3*0101

TABLE 2.4 Genetic Predispositions in Autoimmune Liver Diseases Genetic Associations

Possible Pathogenic Effects

Associations with MHC

Type 1 AIH DRB1*0301, DRB1*0401 in white patients of North America and Europe [13,15] DRB1*0404, DRB1*0405 in Japan, mainland China, and Mexico [1] DRB1*0405, DQB1*0401 in South Korea [1] DRB1*1301, DQB1*02, DQB1*0603, DRB1*0405 in South America [156,166e169] Type 2 AIH DQB1*0201, DRB1*07, DRB1*03 in European children [165] PSC DRB3*0101-DRB1*0301 and DRB3*0101-DRB1*1301 [20] PBC DRB1*0801-DQB1*0402 in PBC with DPB1*0301 in Britain, DPB1*0501 in Japan [157]

Susceptibility alleles encode the antigen-binding groove of the class II MHC molecule to favor presentation of triggering antigens [13] Susceptibility motif in type 1 AIH is six-amino-acid sequence, leucine-leucine-glutamic acid-glutamine-lysine-arginine, at positions DRb67-72 of antigen-binding groove [13] Lysine at position DRb71 may be key determinant of susceptibility in type 1 AIH [13] Multiple alleles can encode the same or similar amino acid motif and affect disease occurrence similarly [162] DRB1*0301 associated with early age of onset and severity in type 1 AIH [173] DRB1*0401 associated with better outcome in type 1 AIH [172,173,176]

Associations outside MHC

AIH Polymorphisms of CTLA-4, Fas, TNFA, VDR, STAT4, TGF-b1, and genes of various cytokines [1] Polymorphisms of SH2B3 and CARD10 by GWAS in type 1 AIH [14] PBC Polymorphisms of CTLA-4 , IL-12A and IL-12RB2 [158,160,161]

May affect clinical phenotype and severity in AIH and PBC [58,75,178]

37

AIH, autoimmune hepatitis; CARD10, caspase recruitment domain family member 10 gene; CTLA-4, cytotoxic T lymphocyte antigen-4 gene; GWAS, genomewide association studies; IL, interleukin; MHC, major histocompatibility complex; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; SH2B3, Scr homology 2 adapter protein 3 gene; STAT4, signal transducer and activator of transcription 4 gene; TGF-b1, transforming growth factor-beta 1 gene; TNFA, tumor necrosis factor-a gene; VDR, vitamin D receptor gene. Numbers in square brackets are references.

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and DRB5*0101 encode a leucine at position DRb38, whereas the DRB4*0101 allele, which encodes DRw53, encodes an alanine at this position. Maximum relative risk for PSC may relate to a leucine at position DRb38, and minimum relative risk may relate to an alanine at this location. Different forms of autoimmune hepatitis may relate to different alleles of the MHC, and genetic predispositions can vary in different ethnic groups and age ranges. Type 2 autoimmune hepatitis, characterized by the presence of anti-LKM1, has been described mainly in European children [164], and DQB1*0201, which is in strong linkage disequilibrium with DRB1*07 and DRB1*03, has been proposed as the principal genetic determinant of this disease [165]. DRB1*1301 is associated with type 1 autoimmune hepatitis in young Argentine [166,167] and Brazilian patients [168e170], and this allele has been associated with protracted hepatitis A virus infection [171]. These findings suggest that individuals from different geographical regions, ethnic backgrounds, and age ranges may be selected to develop autoimmune hepatitis by susceptibility alleles that reflect the nature and frequency of indigenous antigenic triggers [47]. The alleles of the MHC can also influence the severity and outcome of autoimmune liver disease. In type 1 autoimmune hepatitis, DRB1*0301 has been associated with early age of disease onset, severe inflammatory activity, relative recalcitrance to corticosteroid treatment, relapse after drug withdrawal, frequent progression to cirrhosis, and increased mortality or requirement for liver transplantation [172e175]. In contrast, DRB1*0401 has been associated with corticosteroid responsiveness, low frequency of progression to cirrhosis, and reduced frequency of liver transplantation [172,173,176]. Further characterization of the genetic factors that affect disease behavior should improve the prediction of short- and long-term outcomes in autoimmune liver disease and improve the timeliness and vigor of therapeutic interventions.

5.2 Associations Outside the Major Histocompatibility Complex Polymorphisms outside the MHC are not disease-specific, and they may affect the clinical phenotype and severity of autoimmune liver disease [1,4]. Numerous polymorphisms have been described in autoimmune hepatitis, including polymorphisms of the CTLA-4 gene, Fas gene (tumor necrosis factor receptor superfamily gene), tumor necrosis factor-a (TNFA*2) gene, vitamin D receptor gene, signal transducer and activator of transcription 4 gene, TGF-b1 gene, and genes of various cytokines (Table 2.4) [1]. Polymorphisms of the CTLA-4 gene have also been recognized in PBC [158,160]. Genomewide association studies (GWAS) have found that a variant of the Scr homology 2 adapter protein 3 gene, which inhibits T cell activation, is associated with autoimmune hepatitis in northern European patients [14]. A variant of the caspase recruitment domain family member 10 gene has also

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been implicated by GWAS in type 1 autoimmune hepatitis, and it may affect the scaffolding proteins involved in proinflammatory signaling pathways [14]. Polymorphisms are not antigen directed, and their occurrence in autoimmune liver disease has varied among populations. Their importance has been supported mainly by animal studies of experimental autoimmune hepatitis [177] and by association studies in patient cohorts of variable size and nature [58,59,74,158,160,178].

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[145] Longhi MS, Hussain MJ, Mitry RR, Arora SK, Mieli-Vergani G, Vergani D, et al. Functional study of CD4þCD25þ regulatory T cells in health and autoimmune hepatitis. J Immunol 2006;176(7):4484e91. [146] Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y, et al. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 2006;43(4):729e37. [147] Harris SG, Phipps RP. The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis. Eur J Immunol 2001;31(4):1098e105. [148] Marra F, Efsen E, Romanelli RG, Caligiuri A, Pastacaldi S, Batignani G, et al. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 2000;119(2):466e78. [149] Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O’Farrelly C, et al. CD39þFoxp3þ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol 2009;183(11):7602e10. [150] Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D. Impairment of CD4(þ)CD25(þ) regulatory T-cells in autoimmune liver disease. J Hepatol 2004;41(1):31e7. [151] Ferri S, Longhi MS, De Molo C, Lalanne C, Muratori P, Granito A, et al. A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis. Hepatology 2010;52(3):999e1007. [152] Rodriguez-Manzanet R, DeKruyff R, Kuchroo VK, Umetsu DT. The costimulatory role of TIM molecules. Immunol Rev 2009;229(1):259e70. [153] Liberal R, Grant CR, Holder BS, Ma Y, Mieli-Vergani G, Vergani D, et al. The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway. Hepatology 2012;56(2):677e86. [154] Peiseler M, Sebode M, Franke B, Wortmann F, Schwinge D, Quaas A, et al. FOXP3þ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J Hepatol 2012;57(1):125e32. [155] Longhi MS, Ma Y, Mieli-Vergani G, Vergani D. Regulatory T cells in autoimmune hepatitis. J Hepatol 2012;57(4):932e3. [156] Duarte-Rey C, Pardo AL, Rodriguez-Velosa Y, Mantilla RD, Anaya JM, RojasVillarraga A. HLA class II association with autoimmune hepatitis in Latin America: a meta-analysis. Autoimmun Rev 2009;8(4):325e31. [157] Underhill JA, Donaldson PT, Doherty DG, Manabe K, Williams R. HLA DPB polymorphism in primary sclerosing cholangitis and primary biliary cirrhosis. Hepatology 1995;21(4):959e62. [158] Agarwal K, Jones DE, Daly AK, James OF, Vaidya B, Pearce S, et al. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J Hepatol 2000;32(4):538e41. [159] Jones DE, Donaldson PT. Genetic factors in the pathogenesis of primary biliary cirrhosis. Clin Liver Dis 2003;7(4):841e64. [160] Juran BD, Atkinson EJ, Schlicht EM, Fridley BL, Lazaridis KN. Primary biliary cirrhosis is associated with a genetic variant in the 3’ flanking region of the CTLA4 gene. Gastroenterology 2008;135(4):1200e6. [161] Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y, et al. Primary biliary cirrhosis associated with HLA, IL12A and IL12RB2 variants. N Engl J Med 2009;360:2544e55.

48 SECTION j I Introduction [162] Doherty DG, Donaldson PT, Underhill JA, Farrant JM, Duthie A, Mieli-Vergani G, et al. Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis. Hepatology 1994;19(3):609e15. [163] Farrant JM, Doherty DG, Donaldson PT, Vaughan RW, Hayllar KM, Welsh KI, et al. Amino acid substitutions at position 38 of the DR beta polypeptide confer susceptibility to and protection from primary sclerosing cholangitis. Hepatology 1992;16(2):390e5. [164] Homberg JC, Abuaf N, Bernard O, Islam S, Alvarez F, Khalil SH, et al. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of “autoimmune” hepatitis. Hepatology 1987;7(6):1333e9. [165] Djilali-Saiah I, Renous R, Caillat-Zucman S, Debray D, Alvarez F. Linkage disequilibrium between HLA class II region and autoimmune hepatitis in pediatric patients. J Hepatol 2004;40(6):904e9. [166] Fainboim L, Marcos Y, Pando M, Capucchio M, Reyes GB, Galoppo C, et al. Chronic active autoimmune hepatitis in children. Strong association with a particular HLA-DR6 (DRB1*1301) haplotype. Hum Immunol 1994;41(2):146e50. [167] Pando M, Larriba J, Fernandez GC, Fainboim H, Ciocca M, Ramonet M, et al. Pediatric and adult forms of type I autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. Hepatology 1999;30(6):1374e80. [168] Bittencourt PL, Goldberg AC, Cancado EL, Porta G, Carrilho FJ, Farias AQ, et al. Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2. Am J Gastroenterol 1999;94(7):1906e13. [169] Goldberg AC, Bittencourt PL, Mougin B, Cancado EL, Porta G, Carrilho F, et al. Analysis of HLA haplotypes in autoimmune hepatitis type 1: identifying the major susceptibility locus. Hum Immunol 2001;62(2):165e9. [170] Czaja AJ, Souto EO, Bittencourt PL, Cancado EL, Porta G, Goldberg AC, et al. Clinical distinctions and pathogenic implications of type 1 autoimmune hepatitis in Brazil and the United States. J Hepatol 2002;37(3):302e8. [171] Fainboim L, Canero Velasco MC, Marcos CY, Ciocca M, Roy A, Theiler G, et al. Protracted, but not acute, hepatitis A virus infection is strongly associated with HLA-DRB*1301, a marker for pediatric autoimmune hepatitis. Hepatology 2001;33(6):1512e7. [172] Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology 1993;105(5):1502e7. [173] Czaja AJ, Strettell MD, Thomson LJ, Santrach PJ, Moore SB, Donaldson PT, et al. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology 1997;25(2):317e23. [174] Czaja AJ, Carpenter HA. Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly. Hepatology 2006;43(3):532e8. [175] Czaja AJ. Rapidity of treatment response and outcome in type 1 autoimmune hepatitis. J Hepatol 2009;51(1):161e7. [176] Kirstein MM, Metzler F, Geiger E, Heinrich E, Hallensleben M, Manns MP, et al. Prediction of short- and long-term outcome in patients with autoimmune hepatitis. Hepatology 2015;62(5):1524e35. [177] Lapierre P, Beland K, Djilali-Saiah I, Alvarez F. Type 2 autoimmune hepatitis murine model: the influence of genetic background in disease development. J Autoimmun 2006;26(2):82e9. [178] Agarwal K, Czaja AJ, Jones DE, Donaldson PT. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology 2000;31(1):49e53.

Chapter 3

Autoantibodies in Gastrointestinal Autoimmune Diseases D. Ben-Ami Shor,* N.P. Papageorgiou{ and Y. Shoenfeld* *Tel-Aviv University, Israel; {American Medical Center, Nicosia, Cyprus

1. ANTIBODIES IN INFLAMMATORY BOWEL DISEASES Crohn disease (CD) and ulcerative colitis (UC), also known as inflammatory bowel diseases (IBD), are chronic diseases affecting the intestinal tract. Although the etiology is still unknown, it is believed that a combination of environmental factors, genetic predisposition, and a dysregulated immune response to endogenous bacteria in the gastrointestinal tract play a significant role in the development of these diseases [1,2]. Several antibodies have been described in the past that are associated with IBD and have been found to be useful for diagnosing and differentiating CD from UC [1,2]. The most important and frequently studied are (1) antieSaccharomyces cerevisiae antibodies (ASCAs), (2) atypical perinuclear antineutrophil cytoplasmic antibodies (pANCAs), (3) anti-OmpC (outer membrane porin from Escherichia coli), and (4) the antibody to CBir1 (antiCBir1 flagellin) [3e5].

1.1 The Antibodies ASCAs are antibodies of the IgG and IgA class directed against mannose sequences of S. cerevisiae cell wall [4,6,7]. ASCA is a highly specific serological marker of CD [6]. Atypical pANCAs are IgG class autoantibodies directed against antigens of the inner side of the nuclear membrane of the neutrophil [6,7]. Some studies showed that pANCAs are produced locally in the colonic mucosa, suggesting that antigens of microbial agents may be involved in the development of IBD [6]. Anti-OmpCs are antibodies The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00003-9 Copyright © 2017 Elsevier B.V. All rights reserved.

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50 SECTION j I Introduction

directed against the outer membrane porin C of E. coli. These antibodies are of IgA and IgG class found to be associated with both CD and UC [4,6,7]. Anti-CBir1 flagellin is an IgG class antibody against the flagellin CBir1, a bacterial antigen first identified in a murine model, which is associated with IBD, specifically with a subset of CD patients [5,8]. Additionally, antigoblet cell antibodies (GABs) and antibodies to glycoprotein 2 are associated with UC and CD, respectively [1,2]. Other antiglycan antibodies such as antilaminaribioside and antichitobioside have also been described in CD [9]. Detection of atypical pANCA IgG is performed usually by indirect immunofluorescence (IIF) technique on ethanol- and formalin-fixed neutrophils. Sera that show a perinuclear pattern on ethanol-fixed neutrophils but that are negative on formalin-fixed neutrophils are considered to be positive for atypical pANCAs [7]. In addition, positive samples marked as atypical pANCA can be further analyzed by enzyme-linked immunosorbent assay (ELISA) for the exclusion of antiproteinase 3, antimyeloperoxidase, and other known autoantibodies [3,4,7]. ASCA IgG and IgA are detected using an ELISA assay. A variety of ASCA tests are available today showing several sensitivities and specificities possibly due to different cutoff values [4]. An ELISA assay is also used for the detection of IgG and IgA anti-OmpC. Purified antigens isolated from E. coli are used to bind the antibodies [10]. In the same way, anti-CBir1 IgG detection is performed by ELISA analysis using the NH2-terminal fragment of CBir1 (147 AA) [5].

1.2 Genetics A landmark study in the field of IBD has identified 163 IBD loci; among them 110 were associated with both diseases, 30 were classified as CD-specific, and 23 as UC-specific [11]. It has been questioned if the antibodies associated with IBD are genetically determined. Data from several family studies showed an increased positivity of pANCAs in 16e30% of healthy first-degree relatives of UC patients [4,12]. Another study showed an increased HLA-DR2 expression in ANCA-positive UC patients [4]. Concerning ASCAs, they have also been demonstrated to be positive in 20e25% of unaffected first-degree relatives of patients with CD [3,4,12]. Likewise, an increased frequency of anti-OmpC was detected in unaffected family members of CD patients [13]. This indicates that ASCA as well as anti-OmpC may represent a genetic marker specific for susceptibility to CD. Whether these positive asymptomatic family members will eventually develop the disease and need to be monitored remains unknown. Definitely, larger studies need to be performed with long time period follow-up to obtain more conclusive data.

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1.3 Pathogenic Role The mechanisms triggering the development of IBD still remain enigmatic. However, several theories are proposed trying to illuminate the exact pathophysiologic concepts of these diseases and the pathogenetic role of the associated antibodies. Recently, Hepworth and colleagues suggested that a deficiency in the expression of ILC3-intrinsic major histocompatibility complex (MHC) class II causes autoinflammatory response and is related to bowel inflammation that resembles CD in the mice model [14]. CD and UC are characterized by a dysbiosis, meaning a change in the microbiome, the bacteria that colonize the gut. A loss of immune tolerance to endogenous bacteria of the gastrointestinal tract results in dysregulation of the immune response and the production of antibodies to certain bacterial antigens [6,12,15]. Possibly the development of the pANCA is due to cross-reactivity to bacterial antigens [4,12]. None of the ASCA, pANCA, or anti-OmpC have been shown to play a direct pathogenic role in IBD [16]. However, CBir1 flagellin has proven to induce the production of anti-CBir1 antibodies and T-helper-1 cell responses to flagellin leading to the development of colitis in mice. CBir1 flagellin possibly shows a similar immune response in patients with CD [5,8]. Some studies suggest that there is a correlation of serological markers with disease phenotype and that these serological markers can be used to predict not only the course of the disease but also the disease itself [3,10,17,18]. ASCA positivity and high titers are associated with the development of early complications, such as fistulae and abscesses [10,17,18]. The risk of progressing to a more aggressive phenotype is increased in those individuals with immune reactivity to more than one microbial antigen [5,18]. Preliminary data suggest that models combining NOD2 genotyping with serologic biomarkers, such as ASCA, anti-OmpC, anti-CBir1 pANCA, and anti-I2, might predict complicated disease behavior such as stricture or fistula [19].

1.4 Sensitivity and Specificity of AntieSaccharomyces cerevisiae Antibodies ASCA has a relatively high specificity for CD, above 95%, but its sensitivity is less than 50% [20]. IgG ASCA is more sensitive than IgA ASCA for diagnosing CD [21]. The prevalence of pANCA is reported to be 45e82% in patients with UC and from 2% to 28% in CD patients. The specificity of pANCA-positive test for UC can reach 94% [4]. Combining ASCA and pANCA increases the specificity and positive predictive value both for CD and

52 SECTION j I Introduction

UC [4,21,22]. Anti-CBir1 flagellin is present in 50e55% of patients with CD and in only 6% of patients with UC, making this marker specific for CD. In addition, this marker identifies a unique subgroup of CD patients who are negative to other serological markers [5]. The low sensitivity of these serologic biomarkers and the fact that they may be detected in other autoimmune gastrointestinal diseases make them unsuitable for routine screening [4,12,21]. Currently, serologic testing is an adjunct to diagnosis in selected cases. Limited data are available to establish the role of serologic markers in cases of indeterminate colitis [23]. In cases of patients with indeterminate colitis and positive serological response, positive ASCA/ negative pANCA predicts CD in 80% of patients and negative ASCA/positive pANCA predicts UC in 63.3% [1,12]. In addition, the fact that anti-CBir1 is present in 40e44% of positive pANCA CD patients and in only 4% of positive pANCA UC patients makes this marker a supplementary tool in the assessment of indeterminate colitis [5]. GAB and antibodies to glycoprotein 2 might also assist in identifying patients with UC and CD, respectively [1,2].

1.5 Clinical Practice IBD is a chronic idiopathic inflammatory disorder characterized by excessive inflammatory response of the gastrointestinal tract that results in tissue damaging and often in the production of several antibodies [1,2]. Strong evidence suggests the etiology to be multifactorial involving genetic factors and dysregulated immune reactivity to the microbiota of the gastrointestinal tract [14,15,24]. The presence of specific antibodies in the sera of IBD patients have always been the focus of intense studies. Such antibodies that have been shown to be related with the presence of IBD are the atypical pANCA, ASCA, anti-OmpC, and anti-CBir1 flagellin. These serological markers are highly specific for IBD and when combined together they increase the diagnostic ability. However, because of their low sensitivity, serologic testing is not used as a single test in the evaluation of suspected patients. Search for the ideal serological test that could lead to an accurate diagnosis of IBD or even to distinguish CD from UC is the challenge of the near future.

2. ANTIBODIES IN CELIAC DISEASE Celiac disease is a multisystem immune-based disorder that is triggered by the ingestion of gluten, a wheat protein, in genetically susceptible individuals. The prevalence of celiac disease has risen in recent decades and is currently about 1% in most Western populations [25]. The disease is thought to be underdiagnosed, in part owing to the fact that celiac disease is often characterized by associated conditions and extraintestinal manifestations that can

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misdirect and delay diagnosis [26]. Celiac disease is characterized by an infiltration of the mucosal epithelium by lymphocytes, villous atrophy, and hyperplastic crypts [27e29]. Glutendthe environmental triggerdcrosses the intestinal epithelium through different routes, as gut permeability is increased in celiac disease [30]. The ingestion of gluten in genetically predisposed patients leads to the occurrence of disease-specific reactive antibodies against the enzyme tissue transglutaminase type 2 (tTG2), endomysium, and gliadin [28,31,32]. Measurement of such antibodies in serum can help establish the diagnosis, but despite their high specificity and sensitivity, a small bowel biopsy should be performed to evaluate the histological findings and to confirm the diagnosis [27]. Antibody titers are strongly linked with the severity of intestinal damage and are considered as a valuable tool in celiac disease follow-up [33].

2.1 The Antibodies Antigliadin antibodies (AGAs) are antibodies of the IgA and IgG classes found in the sera of celiac disease patients. These antibodies mainly target gliadinderived peptides, which are the main proteins of gluten. AGAs are not specific for celiac disease as they are also found in patients with other gastrointestinal diseases such as gastritis, gastroenteritis, and IBD [28,34]. Antiendomysial antibodies (EMAs) are IgA class autoantibodies directed against endomysium, the collagen matrix of human and monkey tissues [29]. The antigen of the endomysium is considered to be the enzyme tTG2 [35]. tTG2 is a calcium-dependent cytosolic protein possessing both intracellular and extracellular functions, and it appears to play a critical role in controlling cell and tissue homeostasis [36]. Antitissue transglutaminase 2 (anti-tTG2) are autoantibodies of class IgA and IgG produced by tTG2-specific B cells [37]. Specifically, IgA autoantibodies recognize the enzyme tTG2, making specific markers for celiac disease [27,38]. The determination of AGA of the IgA and IgG classes can be established by immunofluorescence and ELISA. Because of their low diagnostic accuracy and the introduction of newer, more accurate serological tests, AGA testing is not commonly used today in the investigation of celiac disease [27]. IgA endomysial antibodies can be determined by an immunofluorescence test, using either the human umbilical cord as antigen or the monkey esophageal antigen. The test is based on the immunofluorescence findings of a reticular staining pattern when the antibody binds to the endomysium [29,31]. IgA tTG2 is most commonly based on an ELISA and less commonly on radioimmunoassay. There are recognized differences in test performance between the various commercially available test kits, but overall there is consistency in the sensitivity and specificity of the test [27].

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2.2 Pathogenic Role tTG, the target autoantigen in celiac disease, is suggested to exert at least two crucial roles in disease pathogenesis: as a delaminating enzyme, which can enhance the immunostimulatory effect of gluten, and as a target autoantigen in the immune response [39]. Studies showed that anti-tTG2 autoantibodies can inhibit the catalytic activity of human tTG2 both in vitro and in situ [37,40]. In addition to this, it was shown that differentiation of intestinal crypt epithelial cells dependent on transforming growth factor B can be inhibited by tTG2 autoantibodies [37,40,41]. It is also proposed that the presence of autoantibodies to tTG2 is involved in the extraintestinal manifestations of celiac disease [40]. A subset of anti-tTG2 autoantibodies have the ability to increase intestinal permeability and activate monocytes through binding with Toll-like receptor 4. These antibodies recognize rotavirus protein VP-7, suggesting that molecular mimicry may be a possible mechanism of viral involvement in the pathogenesis of the disease [42].

2.3 Genetics The concordance rate in the monozygotic twins is 86%, whereas in dizygotic twins it reaches only 20% [43]. The most important genetic risk factor for celiac disease is the presence of HLA-DQ heterodimers DQ2 (encoded by alleles A1*05 and B1*02) and DQ8 (encoded by alleles A1*03 and B1*0302) [27]. HLA-DQ2 (w95%) or HLA-DQ8 (w5%) are present in almost all patients with celiac disease [27,28]. Testing negative for both HLA-DQ types makes CD diagnosis very unlikely (NPV >99%) [27]. Modification of wheat gluten proteins by tissue transglutaminase into peptides with negatively charged amino acids leads to more efficient binding to the specific and positively charged HLA-DQ2 or DQ8 receptors [35,43,44]. T-cell activation by gliadinetTG2 complexes presented by HLA-DQ molecules provides the necessary help for production of anti-gliadin and anti-tTG2 antibodies [40,43,45]. Currently, it is well established that 6 MHC and 39 non-MHC loci, including a higher number of independent genetic variants, are associated to disease risk. Moreover, additional regions have been recently implicated in the disease, which would increase the number of involved loci [46]. Recently, light was shed on the interaction between host genetics and microbiota composition in relation to celiac disease susceptibility, connecting bugs and us and autoimmunity [47].

2.4 Sensitivity and Specificity A number of studies have been conducted to report the sensitivity and specificity of several serological tests used commercially for diagnosing celiac

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disease. The estimated sensitivity and specificity of commonly used serum antibody tests are outlined in Table 3.1 [27,48e51]. IgA and IgG AGAs, which are based on native gliadin as target antigen, are not specific and should be avoided [27]. Tests of anti-deamidated peptides of gliadin (DGP) have replaced classic AGA tests. Assays based on DGPs show excellent diagnostic accuracy, especially in the IgG class [52,53]. EMA IgA antibodies have shown good sensitivity and specificity in both adult and children population. The overall sensitivities ranged from 85% to 98% and specificities ranged from 97% to 100% [27]. A first look on results for tTG2 IgA can be misleading, suggesting lower overall sensitivity and specificity compared with EMA IgA; however, these studies used either guinea pig protein or human recombinant protein for anti-tTG2 determination. Antieguinea pig tTG2 has lower sensitivity and specificity than recombinant antihuman tTG2 [28,54]. Although EMA IgA and human recombinant tTG2 IgA have no significant differences in recognizing individuals suspected for celiac disease, EMA IgA testing is time-consuming and money consuming and operator dependent. This fact leads to the conclusion that the use of anti-tTG2 IgA using human recombinant antigen is the test of choice today for the detection of people with celiac disease [28,35,55]. The combination of IgG anti-DGP plus IgA anti-tTG assays show greater sensitivity than a single test, with very high specificity [55]. Physicians must keep in mind that IgA deficiency tends to coexist with autoimmune diseases, and IgA deficiency should be considered if the tTG2 IgA levels are undetectable [27,56]. Therefore in persons with IgA deficiency and suspicion of celiac disease, anti-tTG2 IgG and anti-DGP IgG are recommended as appropriate tests for evaluating these cases [27,28,55].

TABLE 3.1 Sensitivity and Specificity of Several Autoantibodies in Celiac Disease Autoantibodies

Sensitivity (%)

Specificity (%)

AGA IgG in celiac disease

69e85

73e90

AGA IgA in celiac disease

75e90

82e95

EMAa in celiac disease

85e98

97e100

tTGbin celiac disease

95e100

97e100

tTGc in celiac disease

95e98

94e95

AGA, antigliadin antibodies; CD, Crohn disease; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin; tTG, tissue transglutaminase. a Endomysial antibody by indirect immunofluorescence assay. b Human tTG ELISA. c Guinea pig tTG ELISA.

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2.5 Clinical Practice Celiac disease is a multifactorial disease involving both environmental and genetic factors. Gliadin plays a key role in the pathogenesis of celiac disease. Gliadin peptides, after ingestion and modification by the enzyme tTG2, are more easily recognized by the mucosal antigen-presenting cells that express HLA-DQ2 and HLA-DQ8 molecules leading to T-cell activation and finally to the production of highly disease-specific autoantibodies to tTG2. Tests using human recombinant or human purified tTG2 are considered to be highly specific and sensitive and are recommended as the initial test of choice in the diagnostic evaluation of celiac disease. However, endoscopy, accompanied by multiple duodenal biopsies, still remains the necessary diagnostic tool for confirming the diagnosis of celiac disease [27,28,36]. Antibody titer determination can be used for monitoring patients diagnosed with celiac disease [33]. It is too early to recommend a mass screening for celiac disease in asymptomatic individuals using serological tests [27].

3. ANTIBODIES IN AUTOIMMUNE LIVER DISEASES Autoimmune liver diseases are chronic diseases affecting the liver and are characterized by the presence of several autoantibodies, some of which are present in more than one autoimmune disease, whereas others are disease specific [57,58]. The three most important autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). AIH is a chronic, progressive hepatitis of unknown etiology occurring in individuals of all ages [59,60]. Based on the autoantibody profile, AIH may be divided into two subtypes: AIH type 1 that affects both adults and children and AIH type 2, which is mainly a pediatric disease, although it occasionally affects young adults [60]. PBC is a chronic cholestatic liver disease of unknown cause characterized by female predominance and by the destruction of small intrahepatic bile ducts that leads eventually to cirrhosis and liver failure [61]. PBC is considered a model autoimmune disease, and more than 90% of patients present very specific autoantibodies against mitochondrial antigens [62]. PSC is a fibrosing disease affecting the large bile ducts that are frequently associated with IBD [63]. The presence of autoantibodies in autoimmune liver diseases reflects immune reactivity and many times is helpful in establishing the diagnosis. Their presence may have a role in the pathogenesis of these diseases, but on the other hand, their existence may simply represent the result of liver injury. The basic autoantibodies used in diagnosing autoimmune liver diseases are antinuclear antibodies (ANA), smooth muscle antibodies (SMAs), antibodies to liverekidney microsome type 1 (anti-LKM1s), antimitochondrial antibodies (AMAs), and atypical pANCAs (Table 3.2). Today, more serological markers

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TABLE 3.2 Autoantibodies in Autoimmune Liver Diseases

Characteristic autoantibodies

AIH

PBC

PSC

ANA

AMA

Atypical pANCA

SMA

ANA

ANA

Anti-LKM1

Anti-gp210

Anti-LKM3

Anti-p62

Anti-LC1

Anti-lamin B receptor

Anti-SLA/LP Anti-ASGPR Atypical pANCA AIH, autoimmune hepatitis; AMA, antimitochondrial antibody; ANA, antinuclear antibody; antiASGPR, antibody to asialoglycoprotein receptor; anti-LC1, antibody to liver cytosol type 1; anti-LKM, antibody to liverekidney microsomes; anti-SLA/LP, antibody to soluble liver antigen/liver pancreas antigen; pANCA, perinuclear antineutrophil cytoplasmic antibody; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SMA, smooth muscle antibody.

are emerging, expanding the diagnostic capability in diagnosing autoimmune liver diseases [64].

3.1 The Antibodies 3.1.1 Antinuclear Antibodies ANA was the first autoantibody to be clearly associated with AIH. Usually, they are used as serological markers of AIH but are also present in PBC, PSC, and other autoimmune diseases such as systemic lupus erythematosus, Sjo¨gren syndrome and systemic sclerosis, and nonautoimmune conditions, such as viral hepatitis, drug-induced hepatitis, and alcoholic and nonalcoholic fatty liver diseases [65]. ANAs are commonly found in PBC in up to 70% of the cases, and in PSC the prevalence ranges from 7% to 77% [63,66]. In addition, the fact that a percentage of healthy individuals are ANA positive makes these markers least specific in AIH [64]. In AIH, ANA titers are considered 1/40 in adults and 1/20 in children as clinically important [67]. Several nuclear molecular targets have been recognized, but they are not specific of AIH: single-stranded DNA (57e85%) and double-stranded DNA (0e50%), histones (25e40%), chromatin (39%), ribonucleoprotein complexes (20e58%), heterogeneous nuclear ribonucleoprotein A2/B1 (52%), cyclin A (10e20%), and centromere (0e17%) [65]. Many ANAs in AIH are

58 SECTION j I Introduction

nonreactive to the major recombinant nuclear antigens, and the nuclear targets of ANA in AIH are uncertain. For this reason, clinicians prefer to assess ANA by IIF assay on human epithelial (HEp-2) cell lines or by an enzyme immunoassay using microtiter plates with adsorbed recombinant or highly purified antigens [68]. The patterns of nuclear fluorescence are the homogenous, the speckled, the peripheral or the rim pattern, and the centromeric pattern. Homogenous and speckled pattern appear more frequently in AIH. Immune reactivity to several nuclear antigens is associated with different patterns of immunofluorescence, but it may also be associated with different clinical features of the autoimmune liver diseases [66].

3.1.2 Smooth Muscle Antibodies SMAs are autoantibodies directed against actin and nonactin cytoskeleton components such as vimentin, tubulin, and desmin, and they are commonly used for the diagnosis of AIH [64,69]. SMAs with F-actin specificity are commonly regarded as specific markers of AIH-1 and are present in 85% of patients with AIH-1 [65]. But they are found in a variety of liver and nonliver diseases and their usefulness as diagnostic markers depends on their actin or nonactin specificity [70]. Detection of these antibodies is done by IIF using murine stomach, liver, and kidney as substrates, demonstrating a variety of staining patterns. In the kidney, three types of IFA were defined: SMA-V (vessels) when sera stained the vessel walls exclusively, SMA-G (glomeruli), and SMA-T (peritubular) when the sera recognized the vessels walls, the mesangial cells of the glomerulus, and peritubular fibrils (VGT pattern). The VG and VGT IFA patterns are considerably more specific for AIH than the solo V pattern, which has also been observed in liver disease of other etiologies, infectious diseases, and rheumatic disorders [67,70]. The presence of antiactin autoantibodies are associated with early age onset of the disease and worse prognosis [64,69]. Autoantibody titer of 1:40 is significant in adults, whereas in children titers of 1:20 for ANA and SMA are clinically significant [71]. 3.1.3 Antibodies to LivereKidney Microsome Anti-LKMs are detected by IIF on murine liver and kidney tissue, and subclassification is achieved by Western blotting and ELISA [72]. Anti-LKM1s are autoantibodies directed against the cytochrome monooxygenase P450 IID6 (CYP2D6), a significant enzyme system located in the cytosol of the liver. The presence of these antibodies is highly associated with type 2 AIH and should be routinely investigated to the diagnosis of type 2 AIH [71]. In 10% of patients with hepatitis C, anti-LKM1s are found to be positive possibly due to cross-reactivity between CYP2D6 and hepatitis C virus [64,69]. The sensitivity of anti-LKM1 is very low (4e20%) and varies among different geographic regions [64].

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Anti-LKM3s are autoantibodies, first described in chronic hepatitis D, that target a 55-kDa-molecular-weight molecule found to be the uridine diphosphate glucuronosyltransferase (UGT). Anti-LKM3s are present in 8e19% of patients with type 2 AIH and also in 6e13% of patients with chronic hepatitis D. They are highly specific for type 2 AIH as they were not detected in the sera of patients with other autoimmune liver diseases. Although LKM3 antibodies recognize many isoforms of UGT, they exhibit a higher reactivity with UGT1A1, the isoform that is involved in bilirubin glucuronidation [69,72,73]. It is diagnostically imperative to test for LKM3 when ANA, SMA, and LKM1 are negative [73].

3.1.4 Antimitochondrial Antibodies AMAs are autoantibodies directed against inner mitochondrial membrane proteins, which are the E2 subunits of pyruvate dehydrogenase complex (PDC), the branched chain 2-oxo acid dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, the E1a and E1b subunits of PDC, and the dehydrogenase-binding protein of the PDC [74,75]. The detection of AMAs is significant for the diagnosis of PBC [75]. The prevalence of AMAs in PBC reaches 95% with a specificity of 98% for the disease [61]. AMAs show the highest specificity for an autoimmune liver disease among the rest of the serological markers. AMAs can be seen in type 1 AIH, generally with ANA and/or SMA, but they rarely occur independently of other autoantibodies [76]. AMAs are detected by IIF on murine kidney and stomach tissues, but immunoblotting and ELISA may also be used, leading to an increase in sensitivity and specificity of the test [64,67]. 3.1.5 Atypical Perinuclear Antineutrophil Cytoplasmic Antibodies Atypical pANCA, currently better referred to as perinuclear antinuclear neutrophil antibody, is an additional marker of AIH-1. Staining is associated with peripheral nuclear membrane components [67]. Atypical pANCAs are autoantibodies against a variety of neutrophil antigens. Although the autoantigen is not clearly defined, it is proposed that atypical pANCAs are directed against several antigens such as catalase, enolase, cathepsin G, and bacterial/ permeability-increasing protein (BPI) [64,77]. Some other studies demonstrate that the autoantigen is considered to be a neutrophil-specific 50 kDa nuclear envelope protein [64,69]. Atypical pANCAs are found in 33e88% of patients with PSC and in 50e96% of patients with AIH [63,71]. These autoantibodies are not disease specific as they are also present in patients with UC [71]. 3.1.6 Antibodies to Liver Cytosol Type 1 Antibodies to liver cytosol type 1 (anti-LC1s) were originally described alone or in combination with anti-LKM1 to define AIH-2 [67]. These antibodies are

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specific for AIH and are also frequently expressed in patients positive for antiLKM1. They are found in 30e50% of patients with type 2 AIH and have been shown to be present in 10% of AIH patients negative to other serological markers [69]. Anti-LC1 antibodies are important for prognostic implications and severity of disease [71]. In addition, it was demonstrated that anti-LC1s are associated with disease activity and may represent markers of residual liver inflammation [67,71]. IIF and immunodiffusion are the preferable methods of detection of these autoantibodies [64].

3.1.7 Antibodies to Soluble Liver Antigen/Liver Pancreas Antigen Antibodies to soluble liver antigen (anti-SLAs) have emerged as possible prognostic markers that could help to identify patients with severe AIH, who are prone to relapse after corticosteroid withdrawal [68]. Anti-SLA autoantibodies react with a 50 kDa cytosolic transfer ribonucleoprotein complex, the same autoantigen recognized by antibodies to the liver/pancreas. Anti-SLA/ LPs (liver pancreas antigen) were shown to be highly specific markers for AIH occurring in 10e30% of the cases with the specificity reaching 99%. They are helpful markers in identifying a small group of patients with cryptogenic hepatitis [64,78]. In patients negative for conventional autoantibodies in whom AIH is suspected, other serological markers, including at least antiSLA and atypical pANCA, should be tested [71]. These autoantibodies are detected by an ELISA based on recombinant antigen from prokaryotic and eukaryotic systems [64]. 3.1.8 Antibodies to Asialoglycoprotein Receptor The asialoglycoprotein receptor antibody (ASGPR)da type II transmembrane glycoprotein also known as hepatic lectindis the only liver-specific autoantigen to be identified thus far [67]. Anti-ASGPR autoantibodies are directed against a liver-specific lipoprotein located on hepatocyte membranes that have a role in recognition and transportation of potential antigens [64]. AntiASGPRs are expressed in up to 88% of patients with AIH but are also present in other liver diseases such as PBC, alcoholic liver disease, and viral hepatitis [64,69]. In addition, these antibodies show a correlation with disease activity and treatment response as they are associated with more severe interface hepatitis and predict relapse after drug withdrawal [79]. Assays used to detect anti-ASGPRs are ELISA using human, rabbit, or rat ASGPR and radioimmunofiltration (RIFA) using rabbit ASGPR [64]. 3.1.9 Antibodies to Nuclear Pore Complex Antigens Antibodies to nuclear pore complex antigens were shown to be highly associated with the presence of PBC. Particularly, antibodies to glycoprotein gp210 are present in 10e41% of PBC patients with the specificity reaching over 99%. In addition, anti-gp210 antibodies are found in 20e41% of cases with negative

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AMAs, making these antibodies helpful serological markers for establishing a diagnosis in this group of patients. The prevalence of anti-p62 antibodies in PBC patients is lower (23e32%) but with high specificity, similar to antigp210. Anti-lamin B receptor antibodies are also highly specific for PBC, but they are characterized by very low sensitivity (1e3%). Antibodies to nuclear pore complex antigens are best identified by IIF using HEp-2 cells giving a membrane-like pattern of staining. The high specificity of these antibodies for PBC definitely points out their significance as serological markers for diagnosing patients with PBC [75,80].

3.2 Genetics Several studies in the literature suggest a genetic susceptibility to autoimmune liver diseases with specific genes identified to be associated with AIH, PBC, and PSC. HLA-DRBI*0301DRB3*0101DQA1*0501DQB1*0201 and HLADRB1*0401 are commonly associated with AIH. In addition, different populations have found to be related with specific alleles. Thus in South American populations, the most frequently related haplotype is HLA-DRB1*1301 and in Japan it is the HLA-DRB1*0405DQB1*0401. In addition, HLA- DRB1*03 and HLA-DRB1*13 alleles are more common in children populations [59]. Variations in the large and highly polymorphic HLA locus on chromosome 6 have been long associated with PBC. Initial studies linked the DRB*08:01 allele group with disease risk, but the populations explored in these studies were relatively small [81]. More recently, analysis of a much larger sample of PBC in the Italian population confirmed an association of risk for PBC with the HLA-DR alleles B1*08 and B1*02 and an apparently protective effect of B1*11 and B1*13 [82]. These observations have been clarified by subsequent genomewide association studies and Immunochip work, and a set of robust HLA associations now exists [83]. In PSC, a strong association was demonstrated with DRB1*03-DQA1*0501-DQB1*02 haplotype, whereas the HLA- DRB1*04-DQA1*03-DQB1*0302 haplotype is negatively associated with the disease [77].

3.3 Pathogenic Role As in many autoimmune diseases that are characterized by the presence of autoantibodies, a question is raised whether this presence reflects the outcome of the disease itself or has a direct pathogenic role in the development of the disease. The role of autoantibodies in autoimmune liver diseases still remains unclear. Nevertheless, several studies imply involvement of autoantibodies in the

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pathogenesis of the disease. It is proposed that destruction of biliary epithelial cells may be possible after binding of circulating AMAs with the specific autoantigens expressed on cell surface membranes in PBC patients [74,84]. In addition, AMA interference with cellular functions after penetration of biliary epithelial cells could be a possible mechanism [74,75]. However, these theories need to be confirmed. It is well known that catalase is an antioxidant enzyme found in the cytosol of hepatocytes and biliary epithelial cells, and its role is to protect cells from damage by oxygen-derived radicals. In PSC patients, impairment of catalase antioxidant functions by the presence of catalase-specific pANCA may lead to oxidative stress and biliary epithelial cell destruction [74,77]. In addition, neutrophil binding to bacterial lipopolysaccharide of gram-negative organism or endotoxins may be inhibited by pANCA autoantibodies targeting BPI [77]. Anti-LKM1 autoantibodies were found to inhibit CYP2D6 in vitro and induce liver-infiltrating T-lymphocytes activation, thus suggesting a role in the development of AIH [85].

4. CLINICAL PRACTICE The existence of autoantibodies and their importance in diagnosing autoimmune liver diseases are unquestionable. Their role in the pathogenesis of autoimmune liver diseases and their diagnostic specificity are well studied. The possibility that autoantibodies contribute to the development and progression of AIH, PBC, and PSC is supported by several studies, but more evidence needs to come forward. In addition, some autoantibodies such as anti-LC1 and anti-ASGPR may correlate with disease activity and treatment response. On the other hand, autoantibody production may be just the result and not the cause of liver injury, suggesting their nonpathogenic nature [64]. The ongoing effort of new autoantibody identification that will help to reveal new autoantigens and new immunopathogenic mechanisms and to improve the current diagnostic tools is of major significance.

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64 SECTION j I Introduction [23] Joossens S, Reinisch W, Vermeire S, Sendid B, Poulain D, Peeters M, et al. The value of serologic markers in indeterminate colitis: a prospective follow-up study. Gastroenterology 2002;122(5):1242e7. [24] de Souza HS, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol 2015;13(1):13e27. [25] Lebwohl B, Ludvigsson JF, Green PH. Celiac disease and non-celiac gluten sensitivity. BMJ 2015;351:h4347. [26] Leffler DA, Green PH, Fasano A. Extraintestinal manifestations of coeliac disease. Nat Rev Gastroenterol Hepatol 2015;12(10):561e71. [27] Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. American College of G. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013;108(5):656e76. quiz 77. [28] Basso D, Guariso G, Fogar P, Navaglia F, Zambon CF, Plebani M. Insights in the laboratory diagnosis of celiac disease. Lupus 2006;15(7):462e5. [29] Akbari MR, Mohammadkhani A, Fakheri H, Javad Zahedi M, Shahbazkhani B, Nouraie M, et al. Screening of the adult population in Iran for coeliac disease: comparison of the tissuetransglutaminase antibody and anti-endomysial antibody tests. Eur J Gastroenterol Hepatol 2006;18(11):1181e6. [30] Heyman M, Abed J, Lebreton C, Cerf-Bensussan N. Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis. Gut 2012;61(9):1355e64. [31] Collin P, Kaukinen K, Vogelsang H, Korponay-Szabo I, Sommer R, Schreier E, et al. Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study. Eur J Gastroenterol Hepatol 2005;17(1):85e91. [32] Hill ID. What are the sensitivity and specificity of serologic tests for celiac disease? Do sensitivity and specificity vary in different populations? Gastroenterology 2005;128(4 Suppl 1):S25e32. [33] de Chaisemartin L, Meatchi T, Malamut G, Fernani-Oukil F, Hosking F, Rault D, et al. Application of deamidated gliadin antibodies in the follow-up of treated celiac disease. PLoS One 2015;10(8):e0136745. [34] Bizzaro N, Tonutti E. In: Shoenfeld Y, MEG, Meroni PL, editors. Anti-gliadin antibodies. Amsterdam: Elsevier; 2007. [35] van Heel DA, West J. Recent advances in coeliac disease. Gut 2006;55(7):1037e46. [36] Caputo I, D’Amato A, Troncone R, Auricchio S, Esposito C. Transglutaminase 2 in celiac disease: minireview article. Amino Acids 2004;26(4):381e6. [37] Esposito C, Paparo F, Caputo I, Rossi M, Maglio M, Sblattero D, et al. Anti-tissue transglutaminase antibodies from coeliac patients inhibit transglutaminase activity both in vitro and in situ. Gut 2002;51(2):177e81. [38] Tonutti E, Bizzaro N. In: Shoenfeld Y, MEG, Meroni PL, editors. Anti-tissue transglutaminase and anti-endomysial antibodies. Amsterdam: Elsevier; 2007. p. 443e50. [39] Di Sabatino A, Vanoli A, Giuffrida P, Luinetti O, Solcia E, Corazza GR. The function of tissue transglutaminase in celiac disease. Autoimmun Rev 2012;11(10):746e53. [40] Sollid LM, Jabri B. Is celiac disease an autoimmune disorder? Curr Opin Immunol 2005;17(6):595e600. [41] Guandalini S, Gokhale R. Update on immunologic basis of celiac disease. Curr Opin Gastroenterol 2002;18(1):95e100. [42] Zanoni G, Navone R, Lunardi C, Tridente G, Bason C, Sivori S, et al. In celiac disease, a subset of autoantibodies against transglutaminase binds toll-like receptor 4 and induces activation of monocytes. PLoS Med 2006;3(9):e358.

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66 SECTION j I Introduction [67] Liberal R, Grant CR, Longhi MS, Mieli-Vergani G, Vergani D. Diagnostic criteria of autoimmune hepatitis. Autoimmun Rev 2014;13(4e5):435e40. [68] Zhang WC, Zhao FR, Chen J, Chen WX. Meta-analysis: diagnostic accuracy of antinuclear antibodies, smooth muscle antibodies and antibodies to a soluble liver antigen/liver pancreas in autoimmune hepatitis. PLoS One 2014;9(3):e92267. [69] Moritoki Y, Lian ZX, Ohsugi Y, Ueno Y, Gershwin ME. B cells and autoimmune liver diseases. Autoimmun Rev 2006;5(7):449e57. [70] Johanet C, Ballot E. Auto-antibodies in autoimmune hepatitis: anti-smooth muscle antibodies (ASMA). Clin Res Hepatol Gastroenterol 2012;36(2):189e91. [71] Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51(6):2193e213. [72] Fabien N, Desbos A, Bienvenu J, Magdalou J. Autoantibodies directed against the UDP-glucuronosyltransferases in human autoimmune hepatitis. Autoimmun Rev 2004;3(1):1e9. [73] Vierling JM. Diagnosis and treatment of autoimmune hepatitis. Curr Gastroenterol Rep 2012;14(1):25e36. [74] Medina J, Jones EA, Garcia-Monzon C, Moreno-Otero R. Immunopathogenesis of cholestatic autoimmune liver diseases. Eur J Clin Invest 2001;31(1):64e71. [75] Jones DE. Autoantigens in primary biliary cirrhosis. J Clin Pathol 2000;53(11):813e21. [76] Krawitt EL. Discrimination of autoimmune hepatitis: autoantibody typing and beyond. J Gastroenterol 2011;46(Suppl 1):39e41. [77] Aoki CA, Bowlus CL, Gershwin ME. The immunobiology of primary sclerosing cholangitis. Autoimmun Rev 2005;4(3):137e43. [78] Manns MP. Antibodies to soluble liver antigen: specific marker of autoimmune hepatitis. J Hepatol 2000;33(2):326e8. [79] Liberal R, Mieli-Vergani G, Vergani D. Clinical significance of autoantibodies in autoimmune hepatitis. J Autoimmun 2013;46:17e24. [80] Nesher G, Margalit R, Ashkenazi YJ. Anti-nuclear envelope antibodies: clinical associations. Semin Arthritis and Rheum 2001;30(5):313e20. [81] Manns MP, Bremm A, Schneider PM, Notghi A, Gerken G, Prager-Eberle M, et al. HLA DRw8 and complement C4 deficiency as risk factors in primary biliary cirrhosis. Gastroenterology 1991;101(5):1367e73. [82] Invernizzi P, Selmi C, Poli F, Frison S, Floreani A, Alvaro D, et al. Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls. Hepatology 2008;48(6):1906e12. [83] Webb GJ, Siminovitch KA, Hirschfield GM. The immunogenetics of primary biliary cirrhosis: a comprehensive review. J Autoimmun 2015;64:42e52. [84] Selmi C, Invernizzi P, Keeffe EB, Coppel RL, Podda M, Rossaro L, et al. Epidemiology and pathogenesis of primary biliary cirrhosis. J Clin Gastroenterol 2004;38(3):264e71. [85] Strassburg CP, Manns MP. Liver cytosol antigen type 1 autoantibodies, liver kidney microsomal autoantibodies, and liver microsomal autoantibodies. Amsterdam: Elsevier; 2007.

Chapter 4

Imaging Techniques in Digestive Diseases C. Ayuso, M. Page´s and L. Donoso Hospital Clinic, University of Barcelona, Spain

1. INTRODUCTION Gastrointestinal (GI) manifestations are common in patients with autoimmune diseases and can involve any part of the GI tract or the hepatobiliary system. Furthermore, abdominal symptoms may overlap those due to other factors related to the special circumstances of autoimmune diseases, such as side effects of medication. Imaging techniques have an important role in the diagnosis and management of pathologic abdominal conditions in these patients. Recent technological advances have brought about considerable improvement in abdominal imaging. This chapter provides an overview of the imaging modalities available in the diagnosis of GI involvement in the context of autoimmune diseases. A brief description of the basic principles underlying each technique is provided, and the advantages and limitations of the different imaging techniques, including the newest contrast agents for ultrasound (US) and magnetic resonance (MR), are discussed.

2. IMAGING MODALITIES 2.1 Plain Abdominal Film and Barium Studies Plain abdominal films are currently mostly indicated in the clinical context of acute abdominal disorders. Plain films can depict bowel distension or abnormalities in the distribution of abdominal gas, such as free intraperitoneal air, pneumatosis intestinalis, ileus or pseudoobstructive pattern, or pylephlebitis. Although the imaging examination based on plain films of the abdomen sometimes provides enough definitive information to indicate a particular surgical or conservative treatment, it more often represents the first step in a more complex diagnostic imaging process. The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00004-0 Copyright © 2017 Elsevier B.V. All rights reserved.

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Endoscopic procedures for the study of the GI pathology decreased the indications for barium studies. However, barium studies carried out using dynamic techniques such as videofluoroscopy are increasingly used to study the functional disorders of the pharynx and esophagus.

2.2 Ultrasound or Ultrasonography The commercial availability of high-resolution “gray scale” equipment since 1974 has made US one of the mainstays in the study of the abdomen and particularly the hepatobiliary system. The basic principle underlying US is the transmission of sound waves into the abdominal organs from a transducer, which converts electrical energy into sound waves and vice versa. As the US wave passes through the abdominal tissues, it is affected by changes in tissue type and is refracted and reflected at interfaces between tissues with differing acoustic impedance. The transducer is able to detect the reflected sound waves and uses the time delay from the transmission to calculate the depth within the body. The incoming vibrations are converted into electrical pulses and transformed into images by the US scanner. The general availability and relatively low cost of US, together with the fact that it does not employ ionizing radiation, have ensured that it is widely used to rule out abdominal pathology. US is often performed as the first step in the evaluation of abdominal emergencies. Moreover, it is the imaging technique of choice for screening patients with suspected focal liver lesions and also for evaluating gallbladder and biliary tree pathology. US enables real-time studies, and the radiologist can select the most appropriate cross-sectional plane to obtain the desired information. This property enables US to guide a wide range of interventional procedures, such as aspiration biopsies, drainage of abdominal collections, or percutaneous ablative treatments of primary tumors and metastases. There are no contraindications for US although its effectiveness decreases in obese patients and in those with air-distended bowel loops, which make it difficult to evaluate the underlying tissues. In fact, air interposed between the transducer and the pancreas often limits the assessment of this organ. Color, spectral, and power Doppler imaging provide a noninvasive method of measuring flow in the abdominal vessels and assessing vascularity within a lesion. Spectral Doppler provides a tracing of the Doppler wave from which it is possible to calculate various indices, including peak systolic velocity and resistive indices. Color Doppler enables the direction of blood flow to be determined. Power Doppler displays the integrated power of the color signal to depict the presence of blood flow. The pulsed Doppler technique can provide Doppler shift data selectively from a small segment along the US beam, enabling us to select a small vessel and quantify the velocity of flow through it (Fig. 4.1).

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FIGURE 4.1 Doppler ultrasound demonstrates patency of the portal vein. Doppler is displayed in images (color Doppler) and graphically (spectral Doppler).

Tissue harmonic imaging uses secondary frequencies that are multiples of the fundamental transmitted frequency. The resulting harmonic images have fewer artifacts and better space resolution. Harmonic imaging is especially useful when contrast agents are used. US contrast agents consist of very small gas-filled microbubbles, which are supported by a shell of biologically inert material. Microbubbles produce unique acoustic signatures that allow their signal to be separated from tissue echoes. The US system takes advantage of the strong echogenicity of the contrast agent to create an enhanced image of the area of interest. US contrast agents are especially useful for characterizing liver lesions [1,2] and assessing the efficacy of percutaneous treatments. Recent technical advances allow fusion of two different imaging modalities, and real-time US is usually fused with CT or MR to biopsy or to treat challenging small lesions that would otherwise not be possible [3].

2.3 Computed Tomography Computed tomography (CT) shows cross-sectional views of patient anatomy. CT involves multiple X-ray transmission measurements through the patient. The information acquired is processed by a computer, which uses mathematical techniques to generate a picture of the internal structures in cross section. Body CT was introduced in 1974. Rapid development led to the early abandonment of the initial dual-slice scanner in favor of single-detector row scanners and incremental technology. At the end of 1980s, improvements in

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tube technology and computing led to the advent of helical CT. This faster volumetric acquisition allowed better quality image reconstructions to be obtained in different planes. The development of multidetector CT (MDCT) began in earnest in 1998 when four-slice scanners were introduced. Systems with 6-, 8-, 10-, 16-, 40-, and 64-detector arrays have since become available. The simultaneous acquisition of multiple (16, 64, or even more) continuous slices during one subsecond gantry rotation has improved acquisition speed, resulting in faster imaging protocols. Furthermore, improvements in the z-axis coverage speed have enabled nearly isotropic image acquisition, providing high resolution multiplanar reformations (MPRs) and making excellent threedimensional (3-D) displays possible [4]. The advantages of MDCT are a consequence of (1) shorter scan duration, which reduces motion artifacts and enables a well-defined solid parenchymal phase of contrast enhancement and thus better adjustment of contrast medium injection rate, volume, and concentration; (2) longer scan ranges that permit very good quality CT angiographic studies of the whole body; and (3) thinner sections that permit arbitrary imaging planes, MPR (Fig. 4.2), and 3-D rendering (Fig. 4.3). A challenge presented by multidetector-row CT is posed by the substantial increase in the number of reconstructed cross sections (easily more than 1000 axial images) that are rapidly created and in need of analysis. This situation requires more sophisticated visualization techniques for the assessment of volumetric data, not only in terms of 3-D workstations but also in fast automated processing and user interfaces to replace the analysis of transverse reconstructions by other alternatives. The large data load means that new ways

FIGURE 4.2 Computed tomography angiogram. (A) Arterial phase: multiplanar reformation (MPR) in a sagittal view shows the normal anatomy of the abdominal aorta and the superior mesenteric artery. (B) Portal phase: MPR in an oblique-coronal plane shows the regular patency of the portal, splenic, and superior mesenteric veins.

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FIGURE 4.3 Computed tomography angiogram provides exquisite detail of the anatomical distribution of the celiac artery and superior mesenteric artery. The hepatic artery and its segmental branches are also displayed. (A) Maximum intensity projection image. (B) Volume-rendered image.

of viewing, processing, archiving, and displaying images are necessary, and more time is needed to analyze the data than with single-slice helical CT. Images obtained with MDCT show increased image noise as the section collimation is reduced. To keep the noise low, thicker sections have to be reconstructed. Special attention has to be paid to avoid a dramatic increase in the radiation dose to the patients using MDCT protocols, and acquisition protocols must be carefully adjusted to reduce the radiation dose. The indications for abdominal CT in patients with autoimmune diseases cover a wide spectrum ranging from inflammatory conditions, such as abdominal sepsis or acute pancreatitis [5], to neoplastic diseases, such as lymphoma or other solid tumors, where CT is a useful tool to define the tumor extension. One of the most important indications for CT is to rule out vascular complications that are fairly common in this context, such as BuddeChiari syndrome; however, the most common and most challenging diagnostic and therapeutic problem is acute abdominal pain. Ischemic bowel disease is a very common and severe complication in patients with autoimmune diseases, and it has a very poor prognosis when the diagnosis is delayed. CT can also be used to direct percutaneous interventional diagnostic procedures such as fine-needle biopsy of solid focal lesions (Fig. 4.4), tru-cut biopsies of solid organs (liver, kidney) to rule out diffuse parenchymal

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FIGURE 4.4 Computed tomography (CT) fluoroscopyeguided fine-needle biopsy. Irregular thickening of the bladder wall can be seen secondary to a primary bladder neoplasm. A 20-gauge needle is placed in an enlarged left iliac lymph node. Metastatic tumor nests were found in the pathologic study of the sample.

disease, or percutaneous therapeutic procedures such as the drainage of abdominal fluid collections. Low-dose CT fluoroscopy allows continuous control of the tip of the needle in real-time mode to avoid damage to vital structures during interventional procedures. MDCT angiography has become a valuable minimally invasive tool for the visualization of normal vascular anatomy and its variants, as well as pathological conditions of abdominal vessels. As abdominal pain is a frequent clinical problem in patients with autoimmune diseases and bowel ischemia has to be ruled out, the discussion of MDCT angiography in this chapter will focus on the mesenteric vessels. Although mesenteric MDCT angiography can be specifically performed as a single study, it is often carried out in combination with studies of solid organs or more generalized abdominal imaging. In patients with suspected mesenteric ischemia, CT may help detect ischemic changes in the affected small bowel loops and mesentery, such as bowel wall thickening, submucosal hemorrhage, increased or decreased enhancement of the bowel wall, or even pathologic changes in the mesenteric vasculature such as atherosclerotic stenosis, thrombosis, or occlusion (Fig. 4.5). To depict these findings, both unenhanced and biphase CT abdominal studies (arterial and venous phases) are usually performed. Bowel opacification should be avoided to improve vascular visualization in 3-D imaging postprocessing. A total of 100e150 mL of nonionic iodinated contrast material (300e370 mg of iodine per milliliter) is usually

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FIGURE 4.5 Acute intestinal ischemia due to nearly total occlusion of the superior mesenteric artery (SMA). (A) Axial computed tomography (CT) section at the level of the SMA origin shows a very significant reduction in the patent lumen of the artery. (B) A small amount of gas can be seen in the superior mesenteric vein. (C) There is some gas collection in the wall of the right colon and also in the wall of the terminal ileum due to intestinal pneumatosis.

administered with a power injector at a rate of 2e4 mL/s. Three-dimensional imaging postprocessing of data sets from the arterial and venous phases in the workstation allows real-time viewing of axial and multiplanar images and provides additional sophisticated rendering options, such as thick and curved MPR, thin-slab maximum intensity projection, and volume rendering reconstructions. The sensitivity of CT in detecting bowel ischemia has reached 82% [6] and is comparable to that of angiography. For this reason, the indications for angiography are moving from diagnostic to therapeutic aspects. Angiography enables endovascular treatment, such as percutaneous transluminal angioplasty or stent placement, in selected patients with acute mesenteric ischemia caused by vascular occlusion [7]. CT angiography can provide useful insights into the thickness and composition of vessel wall by differentiating lumen and arterial wall, allowing the evaluation of vasculitis [8]. CT is useful to detect wall thickenings, pseudoaneurysms, thrombus, or inflammatory changes in the surrounding tissues (Fig. 4.6).

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FIGURE 4.6 Polyarteritis nodosa (PAN). (A) Axial computed tomography (CT) section at the level of the celiac trunk shows a soft tissue mass surrounding the vessel. (B) A pseudoaneurysm is detected in the volume rendering reconstruction.

2.4 Magnetic Resonance MR is based on the relaxation properties of hydrogen atoms when they are subjected to a strong magnetic field, and the power of MR equipment is quantified by Tesla (T), a measurement of magnetic flux density. The first commercial MR scanners became available in the early 1980s. MR applications in relatively motionless body parts, such as the brain, spine, or musculoskeletal system, quickly took hold in the field of medical diagnosis because high-quality images not conditioned by artifacts due to bone structures were obtained, with far better contrast resolution than CT. However, abdominal MR imaging was limited by long acquisition times that produced severe motion artifacts due to respiratory and peristaltic movements. These limitations were overcome through technical advances such as the development of ultrafast single-shot sequences, and images providing excellent anatomic detail can now be obtained routinely. Abdominal MR is currently a widely accepted imaging technique for the study of multiple pathologies of the GI, including pancreatic and hepatobiliary diseases. Technical improvements have led to the development of new MR techniques, such as MR cholangiopancreatography (MRC) or MR angiography.

2.4.1 Magnetic Resonance Technique MR abdominal studies are routinely obtained with a torso phased-array surface coil. MR examinations consist of the acquisition of different sequences according to particular study protocols, depending on the abdominal organ studied or the suspected pathology. However, most of the abdominal protocols include T1-weighted sequences (in-phase/opposed phase to detect fatty

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infiltration and/or fat-suppressed sequences), T2-weighted sequences (useful in tumor characterization), and a dynamic contrast-enhanced sequence (to demonstrate the enhancing vascular pattern of the lesions). MR’s multiplanar capacity is one of the most interesting characteristics of this imaging modality: MR images can be acquired in any sectional plane. This property was initially one of the main advantages of MR over CT although currently MDCT also allows high-quality reconstructions in any orientation. MR has higher contrast resolution than CT although it has less spatial resolution. In other words, there are more signal intensity changes between tissues, although less definition in limiting structures.

2.4.2 Contrast Agents The most common MR contrast agents are the chelates of gadolinium, which are nonspecific extracellular contrast agents. After intravenous administration, they are initially distributed in the intravascular space, but they are rapidly cleared into the interstitial space, filtered through the capillaries into the extracellular space, and are eventually excreted by the kidneys. The main indications of contrast-enhanced MR include the study of neoplastic lesions to assess tumor vascularity, vascular pathologies, and MR angiography. One advantage of these contrast agents versus the iodinated contrast media used in CT examinations is their lower or nonexistent nephrotoxicity, and gadolinium contrast-enhanced MR studies have long been a viable alternative in patients with renal failure or iodine allergy. However, a new severe entity, which seems to be related to some gadolinium chelates, has recently been reported in patients with renal failure: nephrogenic systemic fibrosis [9]. Thus the chelates of gadolinium should only be administered in these patients when it is essential. Hepatobiliary contrast agents partially pass from blood through the hepatobiliary system with partial excretion through the kidneys and the bile ducts. These liver-specific contrast agents are selectively uptaken by the hepatocytes, leading to an increase in signal intensity on T1-weighted sequences of the normal liver parenchyma and also of the focal hepatocellular liver lesions. Some of the hepatobiliary contrast agents can be rapidly injected and dynamic hepatic studies can be performed to assess the anatomy of the biliary tree, to detect bile leaks, and also to detect and characterize hepatic tumors (Fig. 4.7). 2.4.3 Indications and Limitations Absolute contraindications for MR studies are pacemakers and other ferromagnetic implants, such as cochlear implants, vagus nerve stimulators, or insulin pumps. Although other modern medical devices are mainly manufactured without ferromagnetic materials, the magnetic properties of valvular prostheses and stents must be evaluated before a patient can undergo MR.

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FIGURE 4.7 Focal nodular hyperplasia studied by magnetic resonance (MR) imaging. (A) T1-weighted gradient-echo MR image with fat suppression. The lesion exhibits homogeneous intense enhancement in the arterial phase (20 s following the injection of hepatobiliary contrast agent). (B) 20 min after injection (same sequence as A), the lesion is slightly hyperintense in comparison to normal liver parenchyma due to its hepatocellular nature.

Patients must be queried about possible ferromagnetic foreign bodies, and a plain film X-ray is sometimes necessary to rule out their presence. Liver MR is an excellent imaging technique to characterize nonspecific focal lesions previously detected on US or CT studies. Among other indications, hepatic MR is widely used to stage primary hepatic tumors, to evaluate potential living liver donors, and to evaluate complications after liver transplantation. It is also usually performed in patients with liver metastasis prior to surgical resection. MRC is a noninvasive technique to depict the biliary tree and the pancreatic ducts. The images obtained are comparable to endoscopic retrograde cholangiography (ERC). MRC is performed using heavily T2-weighted sequences that demonstrate the fluid-containing bile ducts as high-signal-intensity structures. This technique has demonstrated high sensitivity and specificity in the diagnosis of the location and etiology of biliary obstruction (Fig. 4.8) to the extent that ERC is usually indicated only when a therapeutic approach is needed. MRC is helpful in determining the status of the bile ducts in primary sclerosing cholangitis, characterizing the morphologic features of the hepatic parenchyma, and evaluating for the development of cholangiocarcinoma. MRC can diagnose IgG4-related sclerosing cholangitis, which is frequently associated with autoimmune pancreatitis [10]. MR enterography is an emerging technique for the evaluation small bowel diseases. It combines the study of luminal, mural, and extramural abnormalities. It can evaluate not only bowel wall ulcers but also transmural complications in inflammatory bowel disease [11] (Fig. 4.9). MR angiography provides high-quality arterial and venous images without ionizing irradiation. MR angiography is an alternative to CT angiography in patients with allergies to iodinated contrast media.

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FIGURE 4.8 Magnetic resonance (MR) cholangiography depicts the biliary tree and pancreatic ducts. Multiple filling defects typical of stones are shown in the lumen of the common bile duct.

FIGURE 4.9 Magnetic resonance (MR) enterography shows anatomic demonstration of the small bowel. Coronal MR image clearly depicts fluid-filled bowel loops and provides excellent contrast between the bowel wall and surrounding structures.

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FIGURE 4.10 Images for staging an anaplastic lymphoma. Positron emission tomography/ computed tomography (PET/CT) images. (A) Axial CT image at the pelvis shows an enlarged external iliac lymph node. (B) Corresponding axial maximum intensity projection image showing intense fluorodeoxyglucose (FDG) uptake in the external iliac lymph node. (C) PET/CT fused image at the same pelvic level confirms the coincidence of both pathologic images.

2.5 Positron Emission Tomography Positron emission tomography (PET) is an operator-independent, noninvasive metabolic imaging modality based on the regional distribution of 18 F-fluorodeoxyglucose ([18F]FDG); PET plays a major role in the management of oncology patients [12,13]. Furthermore, activated inflammatory cells have also been shown to overexpress glucose transporters and to accumulate increased amounts of glucose and structurally related substances such as [18F] FDG. Some authors have reported the usefulness of this imaging technique in assessing the activity and the extent of large-vessel vasculitis [14,15].

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Recently, functional PET images have been used in combination with CT to enable the anatomical or morphologic features of tumors to be assessed as well. PET and CT images obtained at the same position provide the precise localization of lesions with increased glucose metabolism over the whole body in a single session (Fig. 4.10). PET and/or PET/CT using FDG is now widely employed as an advanced clinical imaging tool for the diagnosis, staging, and restaging of cancer, as well as for the assessment of tumor therapy.

3. FUTURE PROSPECTS The last fifteen years have witnessed enormous technological advances in abdominal imaging techniques as well as the development or improvement of different contrast media for use with US, CT, and MRI. Consequently, a wide variety of high-quality diagnostic images can quickly be obtained and more functional protocols can be applied with noninvasive or minimally invasive procedures, while classic invasive imaging techniques have moved toward therapeutic indications. On the other hand, many percutaneous diagnostic and therapeutic procedures can be guided by imaging techniques, especially US and CT fluoroscopy, leading to faster diagnosis and treatment of abdominal pathological conditions. In the near future, the development of hybrid technology might allow highresolution images, functional images, and metabolic information to be combined. This “one store shop” would contribute to a quicker and earlier specific diagnosis leading to improved management of abdominal diseases and thus improved prognoses.

REFERENCES [1]

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[6]

Burns PM, Wilson SR. Focal liver masses: enhancement patterns on contrast-enhanced imagesdconcordance of US scans with CT scans and MR images. Radiology 2007;242(1):162e74. von Herbay A, Vogt C, Willers R, Haussinger D. Real-time imaging with the sonographic contrast agent SonoVue: differentiation between benign and malignant hepatic lesions. J Ultrasound Med 2004;23:1557e68. Lee MW. Fusion imaging of real-time ultrasonography with CT or MRI for hepatic intervention. Ultrasonography October 2014;33(4):227e39. Prokop M. MDCT: technical principles and future trends. In: Marchal G, Vogl TJ, Heiken JP, Rubin GD, editors. Multidetector-row computed tomography. Scanning and contrast protocols. Springer Milan; 2005. p. 5e12. Shimosegawa T, Chari ST, Frulloni L, Kamisawa T, Kawa S, Mino-Kenudson M, Kim MH, Klo¨ppel G, Lerch MM, Lo¨hr M, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas 2011;40:352e8. Klein HM, Lensing R, KiosterhaLfen B, Tons C, Rolf WG. Diagnostic imaging of mesenteric infarction. Radiology 1995;197:79e82.

80 SECTION j I Introduction [7] Resch T, Lindh, Dias N, Sonesson B, Uher P, Malina M, Ivancev K. Endovascular recanalisation in occlusive mesenteric ischemia, feasibility and early results. Eur J Vasc Endovasc Surg 2005;29:199e203. [8] Kumamaru KK, Hoppel BE, Mather RT, Rybicki FJ. CT angiography: current technology and clinical use. Radiol Clin North Am March 2010;48(2):213e35. [9] Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, Thomsen HS. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrastenhanced magnetic resonance imaging. J Am Soc Nephrol 2006;17(9):2359e62. [10] Katabathina VS, Dasyam AK, Dasyam N, Hosseinzadeh K. Adult bile duct strictures: role of MR imaging and MR cholangiopancreatography in characterization. Radiographics MayeJune 2014;34(3):565e86. http://dx.doi.org/10.1148/rg.343125211. [11] Wiarda BM, Kuipers EJ, Heitbrink MA, van Oijen A, Stoker J. MR enteroclysis of inflammatory small-bowel diseases. AJR 2006;187(2):522e31. [12] Endo K, Oriuchi N, Higuchi T, Iida Y, Hanaoka H, Miyakubo M, Ishikita T, Koyama K. PET and PET/CT using 18F-FDG in the diagnosis and management of cancer patients. Int J Clin Oncol 2006;11:286e96. [13] Rao KV, Carrasquillo JA, Dale JK, Bacharach SL, Whatley M, Dugan F, Tretler J, Fleisher T, Puck JM, Wilson W, Jaffe ES, Avila N, Chen CC, Straus SE. Fluorodeoxyglucose positron emission tomography (FDG-PET) for monitoring lymphadenopathy in the autoimmune lymphoproliferative syndrome (ALPS). Am J Hematol 2006;81:81e5. [14] Meller J, Strutz F, Siefker U, Scheel A, Sahlmann CO, Lehmann K, Conrad M, Vosshenrich R. Early diagnosis and follow-up of aortitis with [18F]FDG-PET and MRI. Eur J Nucl Med Mol Imaging 2003;30:730e6. [15] Walter MA, Melzer RA, Schindler C, Mu¨ller-Brand J, Tyndall A, Nitzsche EU. The value of [18F]FDG-PET in the diagnosis of large-vessel vasculitis and the assessment of activity and extent of disease. Eur J Nucl Med Mol Imaging 2005;32:674e81.

Chapter 5

Primary Biliary Cholangitisa R. Abdalian,* J. Heathcote* and M. Ramos-Casalsx

*University Health Network, Toronto, ON, Canada; xUniversity of Barcelona, Hospital Clı´nic, Barcelona, Spain

1. INTRODUCTION Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the chronic progressive loss of interlobular bile ducts. An immune-mediated destruction of the bile duct epithelium is thought to mediate its pathogenesis. It is a disease that primarily affects middle-aged women of all races. Histologically, it is characterized by portal inflammation comprising aggregates of lymphoid cells and/or granulomas, which invade and destroy biliary epithelial cells (Fig. 5.1). This causes secondary duct loss, decreased bile secretion, and cholestasis that promotes hepatic fibrosis, cirrhosis, and, eventually, liver failure. Serologically, the diagnostic hallmark finding is antimitochondrial antibody (AMA). PBC was first described in 1851 by Addison and Gull [1]; and subsequently in 1952 the confirmation of an association with hyperlipidemia and cutaneous xanothomas led to the initial description of “xanothomatous biliary cirrhosis” [2]. The label of “primary biliary cirrhosis” was adopted a year later at the Rockefeller Institute, despite opposition from those who argued that not all patients present with cirrhosis at diagnosis. The later description of “chronic nonsuppurative destructive cholangitis” was deemed more plausible clinically, yet it never grew to replace the more popular designation of PBC.

a. This chapter is published in their original form included in the first edition of this book as a means of paying a deeply felt homage to Prof. Abdalian and Heathcote for your contribution to the understanding of the disease. MRC added a brief paragraph at the end of the chapter summarizing the main advances published in the last 5 years. The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00005-2 Copyright © 2017 Elsevier B.V. All rights reserved.

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FIGURE 5.1 Typical bile duct lesion of primary biliary cirrhosis (center).

2. EPIDEMIOLOGICAL HIGHLIGHTS Initial studies published between 1974 and 1985 described annual incidence rates for PBC ranging between 0.6 and 13.7 cases per million population [3,4]. Subsequent studies from Europe reported incidence rates ranging from 0.7 to 48 cases per million. In North America, the incidence rate of 27 cases per million population with prevalence rates between 160 and 402 cases per million have been reported within specific regions [5,6]. The age- and gender-adjusted prevalence per 100,000 persons was 65.4 for women and 12.1 for men in a well-defined population from Minnesota [6]. The concept of a “northesouth” gradient as in other autoimmune conditions can also be postulated in PBC. The highest incidence and prevalence rates have been reported in the United Kingdom, Scandinavia, Canada, and the United States, whereas the lowest in Australia. Notably high rates have been reported in clusters of populations such as one large First Nations family near Vancouver, Canada [7], as well as a group of individuals living in close proximity to the Nagasaki atomic bomb explosion site in Japan [8]. A selection bias as well as variable diagnostic criteria may account for this geographic variability. The absence of population-based standardized methodology limits the reliability of these findings. As more sophisticated testing for AMA are developed and diagnostic criteria further refined and universally applied, more cases may be identified. Little information is available regarding the contribution of race and ethnicity to the pathogenesis of PBC. In a recent report from Australia, the prevalence rates in migrants from Great Britain (41 cases per million), Italy

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(200 cases per million), and Greece (208 cases per million) were significantly higher when compared to the local indigenous population surveyed [9]. In women older than 40 years, the PBC prevalence in British-born immigrants to Victoria was significantly higher than that of Australian-born women. With our current knowledge of genetic susceptibility in PBC, it is difficult to delineate the true interaction between the environment and the host. An interesting case report described development of PBC in a daughter, her mother, and a close unrelated friend who had nursed the daughter through her terminal illness [10]. This suggests that host susceptibility plays a significant role in the development of PBC. The peak incidence of PBC occurs in the fifth decade of life, and it is uncommon under the age of 25 years. The onset is usually between the ages of 30 and 65, but it has been reported in women as young as 15 and as old as 93. A 90% female preponderance is observed. A familial predisposition is now well recognized as well. Relatives of patients with PBC are more likely to exhibit immune system derangements. Various reports have estimated prevalence rates of PBC among first-degree relatives ranging between 5% and 6% [11]. This correlation is the strongest among sisters and daughters who are younger at diagnosis compared to index cases [12]. It is noteworthy to mention, however, that family clustering may reflect ascertainment bias and shared environmental factors. To this day, specific HLA associations with PBC have been only weak at best, and reports of specific inherited alleles altering immune responsiveness have failed to convincingly highlight any diseasespecific associations [13].

3. PATHOPHYSIOLOGICAL INSIGHTS An immune-mediated destruction of bile duct epithelial cells is thought to drive the pathogenesis of PBC. Chronic inflammation and repeated injury to the small ducts promote a repair mechanism that involves expansion of portal tracts with proliferating bile ductules. The ensuing myofibroblastic response results in the net accumulation of collagen matrix, which, with time, expands to adjacent portal areas, leading to the typical biliary pattern of fibrosis and eventually of cirrhosis. Inflammatory responses likely stem from recognition of aberrant expression of mitochondrial self-antigens and/or breakdown of immunologic tolerance, resulting in the generation of specific T and B lymphocytes that mediate production of proinflammatory cytokines and autoantibodies [14]. The mechanisms that mediate the fibrogenic response to bile duct injury have been recently subjected to considerable investigation. Immature cholangiocytes have been shown to generate autocrine growth factors (e.g., hepatocyte growth factor, epidermal growth factor) as well as cytokines (e.g., platelet-derived growth factor b) that are believed to mediate the proliferation of myofibroblastic cells [15]. Therefore, signaling between biliary

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epithelial cells and stromal cells may modulate the mechanism whereby bile ducts are damaged. The Hedgehog family of ligands has recently been shown to promote the growth of both of these cell types [16]. They function as viability factors for many types of progenitors, and have been shown to play a pivotal role in tissue morphogenesis during embryological development [17]. They mediate the signaling between mesenchymal and epithelial cells and thus modulate remodeling responses after injury during adult life [16]. Using immunohistochemistry, Jung et al. [18] demonstrated that proliferating bile ductular cells are a rich source of Hedgehog ligands, further supporting the hypothesis that an epithelialemesenchymal “cross-talk” promotes the fibroproliferative response to bile duct injury via autocrine and/or paracrine regulation of hepatic progenitor cell populations. An inappropriate upregulation of connective tissue elements in bile-duct-ligated mice with a genetic defect limiting downregulation of the Hedgehog pathway activity has been reported as well, further supporting this hypothesis [15]. A more concerted research effort in unraveling the Hedgehog pathway intricacies and that of other systems that modulate progenitor cell proliferation, apoptosis, and differentiation may shed further light into the complex pathogenesis of PBC. PBC is considered an organ-specific autoimmune disease associated with the presence of well-characterized AMAs. These target at least three components of the M2 family of mitochondrial antigens: the E2 subunit of pyruvate dehydrogenase complex (PDC-E2), the 2-oxoglutarate dehydrogenase complex, and branched-chain 2 oxoacid dehydrogenase complex. Additional targets such as the ketoglutaric acid dehydrogenase complex and the dihydrolipoamide dehydrogenase-binding protein have been described [19]. Marked homology exists between these different antigenic targets; all share a lipoic acid moiety and are involved in oxidative phosphorylation. They are located on the inner mitochondrial matrix and play a critical role in the metabolism of ketoacid substrates. These AMAs are detected in the sera of at least 95% of affected individuals and have been validated as highly sensitive and specific tools in the diagnosis of PBC [20]. PBC seems to be the only disease in which autoreactive T cells and B cells responding to the PDC-E2 are detected. Autoantibodies directed at nuclear antigens have been described in w50% of patients with PBC and often in patients who possess AMAs [20]. Their pathogenic role is further supported by reports demonstrating secretory IgA autoantibodies against PDC in the saliva, bile, and urine specimens of patients with PBC [21,22]. Examples of antinuclear antibodies include those against the nuclear pore proteins gp210 and p62, both of which are believed to be associated with more active and severe disease [23]. The nuclear body protein sp100 is another identified target. The nuclear-rim and nuclear-dot antinuclear patterns of these are highly specific for the disease [24]. The main paradox in the aforementioned hypothesis, however, is the fact that mitochondrial proteins are present in all nucleated cells, yet the targets of

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autoimmune injury are the biliary epithelium and salivary duct cells. It is believed that cellular apoptosis can increase the exposure of PDC-E2 domain to the immune system via modification of its lysine-lipoyl moiety by glutathione [25]. The immunoreactivity is decreased by glutathionylation, whereas it is sustained by inhibition of glutathionylation. It is speculated that this intricate control of immune expressivity is impaired in cells involved in the pathogenesis of PBC. Cellular apoptosis itself can cause aberrant expression of PDC-E2 on cell surface, which leads to the failure of attachment of this key regulatory glutathione group [25]. In vitro caspase cleavage of PDC-E2 has been shown to generate immunologically active protein fragments [26]. In addition, specific xenobiotic modifications of the inner lysine-lipoyl domain of the PDC-E2 are immunoreactive when tested with the serum of patients with PBC, further supporting this mechanism [27]. Markers of ongoing apoptosis have been reported within affected portal tracts, including downregulation of the antiapoptotic protein bcl-2 [28]. The T-cell mitochondrial responses also contribute to bile duct injury in PBC. PDC-E2especific CD4þ and CD8þ T cells have been identified in the peripheral blood and liver of PBC patients, mostly during early disease states [29,30]. Epitope mapping studies have identified the HLADR40101-restricted T-cell epitope that spans amino acid residues 163 through 176 of the PDC-E2 domain. Also, CD8þ T cells from livers of patients with PBC demonstrate cytotoxicity against PDC-E2 159e167 pulsed autologous cells [30]. Recently, a mouse model for PBC has been described. Irie et al. [31] demonstrated that the NOD.c3c4 mice congenically derived from a nonobese diabetic strain develop an autoimmune biliary disease that models human PBC. These mice develop antibodies to PDC-E2 that are specific for the inner lipoyl domain. The affected biliary epithelium is infiltrated with CD3þ, CD4þ, and CD8þ T cells, and treatment with monoclonal antibody to CD3 protects further bile duct injury. Histological analysis reveals destructive cholangitis, granuloma, and eosinophilic infiltration as seen in PBC, although, unlike PBC, the extrahepatic biliary ducts are also affected. There have been reports of two other mouse models that are associated with AMA and chronic biliary diseasedboth have deficient T regulatory cells [32,33]. Potential associations between specific environmental exposures and the development of PBC have shed some light into its pathogenesis. Molecular mimicry is the most widely proposed mechanism for the initiation of autoimmunity [34]. Its underlying concept is that of cross-reactivity with selfantigens from circulating antibodies developed in response to infection. Several causative culprits have been identified, including bacteria, viruses, and environmental pollutants. Examples of bacterial pathogens linked to PBC are Escherichia coli, Pseudomonas aeruginosa, Helicobacter pylori, Chlamydia pneumoniae, and Haemophilus influenza. The most intriguing association is Novosphingobium aromaticivorans, a ubiquitous pathogen, whose own PDC-E2 domain contains 12 of 13 contiguous amino acid sequence identical

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to human PDC-E2 [34]. Two caseecontrol studies describe a greater than expected frequency of previous urinary tract infection in patients with PBC [35,36]. There is a report of a human b retrovirus resembling mouse mammary tumor virus in patients with PBC [37], although this work has not been reproduced. The potential role of microorganisms in triggering PBC via their interaction with the innate immune system has been proposed [38]. A recent investigation described the association between PBC and residency near superfund toxic waste sites in New York city [39]. Whether these findings are mere coincidental associations or etiologically relevant is a matter of ongoing debate. It has been suggested that pregnancy is a risk factor for PBC. Persistence of fetal cells in the maternal circulation may play a role in the pathogenesis of PBC. However, existing data from clinical investigations are quite disparate on this issue [40,41]. The association between oral contraceptive use and PBC is weak, but recent data suggest that current or prior use of hormone replacement therapy is observed at higher than expected rates in patients with PBC compared to unaffected controls [42]. Less well investigated are the impact of diet and lifestyle. Smoking history was observed in 76% of patients with PBC surveyed in one series from the United Kingdom, compared to 57% of unaffected controls [36]. A greater than 20-pack-year history of smoking was associated with even a higher prevalence rate of PBC. Such an association is biologically plausible, as toxic compounds found in cigarette smoke activate T lymphocyte cytokine responses that could play a role in the pathogenesis of PBC. The older literature reporting a higher frequency of extrahepatic autoimmune diseases among patients with PBC supports the autoimmune basis of the condition [43]. However, studies documenting prevalence rates for specific associations have reported divergent data. Both rheumatoid arthritis and thyroid disease were reported as often in PBC as in unaffected controls in one series, whereas the risk of Sjo¨gren syndrome and Raynaud phenomenon was approximately fourfold higher [44]. Classic rheumatoid arthritis develops in 5e10% of patients and approximately 40e65% have symptoms of Sjo¨gren syndrome, including keratoconjunctivitis and/or xerostomia. Clonal expansion of T cells bearing a specific beta chain variable region has been demonstrated in some of these patients, suggesting that patients with PBC and CREST may have a distinct disorder [45]. The significance of systemic lupus erythematosus (SLE) as risk factor for PBC was also recently confirmed by multivariate analysis [44]. These associations further support the hypothesis of genetic susceptibility as a predisposing factor for PBC.

4. CLINICAL PRESENTATIONS PBC is diagnosed much earlier now than previously. Nearly 60% are asymptomatic at diagnosis and underlying liver disease is often identified just

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by an elevation in serum ALP in an asymptomatic individual. This may be accompanied by two- to fourfold rise in serum aminotranferase levels [46]. Fatigue and pruritus are the most common presenting complaints [47]. Fatigue itself has been a reported complaint in up to 78% of patients and can be a cause for significant disability [48]. The cause of this fatigue, which is not refreshed by sleep, remains elusive. Recent data suggest a possible association between the fatigue of PBC with altered autonomic control and daytime somnolence [49]. It is not necessarily improved by liver transplantation [50] and is not associated with liver disease severity [51]. The pruritus of PBC, whether local or diffuse, can also be severely distressing at times. It may interfere with sleep, as it is usually worst at night. Its onset often precedes the onset of jaundice and lessens with progression of the disease! The precise mechanism that promotes pruritus in chronic cholestasis remains uncertain, but as partial biliary diversion and plasmapheresis alleviate this symptom the pruritigen is obviously present in both bile and blood [52,53]. Unexplained intermittent right upper quadrant pain is noted in w10% of patients. The severity of liver disease may be discordant from the severity of symptoms. Overt symptomatic disease develops within 2e4 years in the majority of initially asymptomatic patients, although nearly one-third of patients will remain symptom-free for many years [46]. Additional findings in PBC include hyperlipidemia, hypothyroidism, metabolic bone disease (with advanced liver disease), and coexisting autoimmune disease such as Sjo¨gren syndrome and scleroderma [44]. Portal hypertension and related complications may occur early in the course of illness because of obliteration of the portal venous radicals probably secondary to the inflammatory response within the portal triads causing nodular regeneration hyperplasia [54]. Once cirrhotic, patients present with ascites, hepatic encephalopathy, and/or esophageal variceal hemorrhage. Fat-soluble vitamin deficiency, malabsorption, and steatorrhea occur only when jaundice is present. With longstanding, histologically advanced PBC, the risk of hepatocellular carcinoma is significantly elevated [55]. The physical examination is usually normal in patients with asymptomatic PBC. As in all chronic cholestatic diseases, increased melanin pigmentation of the skin develops with time and made worse by chronic excoriation caused by pruritus. Xanthelasma are seen in a minority of patients, and xanthomas are rare. Hepatosplenomegaly is another feature predominant in a few. Jaundice is now rarely noted (likely due to current therapy), but ascites and edema suggest onset of liver failure [56]. Histologically, PBC is divided into four distinct stages. However, the liver is not always uniformly involved, and a single biopsy may demonstrate the presence of all four stages simultaneously. The characteristic lesion of PBC is the asymmetric destruction of the bile ducts within portal triads. Stage 1 is defined by portal inflammation. Stage 2 is defined by extension of this inflammation beyond portal tracts into the surrounding parenchyma with or

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TABLE 5.1 Antimitochondrial Antibody (AMA)eNegative Primary Biliary Cirrhosis (PBC) Versus AMA-Positive PBC Clinical Picture

AMA Negative (17)

AMA Positive (17)

Female:male

14:3

14:3

Age at diagnosis (mean)

51.1

55.0

Jaundice

3

3

Fatigue

8

7

Pruritus

9

11

Hypothyroidism

3

3

Polyarthralgias

5

3

Sicca syndrome

3

7

Raynaud

2

4

without associated duct loss. In stage 3, fibrous septa link adjacent portal triads. Stage 4 represents end-stage liver disease, characterized by frank cirrhosis within regenerative nodules. The diagnosis of PBC is, therefore, based on a constellation of findings. Current criteria require the presence of detectable AMA, abnormal liver enzymes (mostly alkaline phosphatase, ALP) for more than 6 months, and histological findings in the liver that are compatible with the PBC to make a “definite” diagnosis. A “possible” diagnosis is made if any two of these findings are present. Liver biopsy allows the severity of disease to be clarified and may indicate the need for specific therapeutic regimens. As many as 10% of patients are AMA negative, but their disease course seems identical to that in patients with classic PBC [57] (Table 5.1).

5. NATURAL HISTORY AND PROGNOSTIC CONSIDERATIONS Historically, the first case descriptions of PBC were almost uniformly described in patients who had presented with jaundice with or without endstage liver disease. Access to routine screening of liver chemistries has since generated a large cohort of asymptomatic patients. Asymptomatic PBC accounts for over 60% of newly diagnosed cases [56]. In a population-based cohort of 469 patients with asymptomatic PBC, the cumulative 1-year incidence rates for developing fatigue, pruritus, and complications from portal hypertension were 15, 13, and 5%, respectively [46]. However, 10 years later, only 20% continued to remain asymptomatic.

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Despite refined diagnostic and clinical tools, unfortunately not all patients with PBC receive their diagnosis when the disease is still in an early histological stage. In a study of 262 patients with PBC, the probability of succumbing to liver failure or requiring a liver transplant in those with advanced disease, as compared with a healthy age- and sex-matched population, was significantly increased despite ursodeoxycholic acid (UDCA) therapy (relative risk 2.2) [58]. In a large cohort of 770 patients from northern England, the median time until death or liver transplant referral was only 9.3 years [56]. Patients who were asymptomatic at diagnosis did not live longer than their symptomatic counterparts in stark contrast to other studies ascribing a clear survival advantage to those with early and asymptomatic disease [59]. This difference is likely related to agedthe cohort from the studies in the north of England being at least one decade older at the time of initial diagnosis. Of note, there is no distinguishing feature that helps predict which patients will remain asymptomatic indefinitely [60]. Neither the presence nor the AMA titer affects risk of disease progression, survival, or treatment responsiveness [61]. But recent data suggest that presence of anti-gp210 antibodies, and particularly when in high titer, may predict those patients with poor outcome [23]. Prospective cohort studies with long follow-up periods and serial clinical, biochemical, and histological data will prove invaluable in unraveling markers of disease progression in PBC. For symptomatic PBC, advanced age, elevated INR, jaundice, low serum albumin, edema, ascites, and advanced histological stage are strongly correlated with median survival rates less than 5 years from the time of diagnosis. Serum total bilirubin remains the most reliable clinical variable for survival estimates and is a key component in current mathematical predictive models of PBC [62]. Liver failure remains the predominant cause of death in patients with PBC. A 60% mortality from liver-related causes is reported in symptomatic patients [56]. Thirty percent of initially asymptomatic patients will succumb to liver failure as well [46]. Such numbers, however, are derived from studies in large tertiary referral centers before the widespread use of UDCA, and thus findings may not reflect the more current and contemporary experience of PBC therapy. Liver failure has been described in patients without cirrhosis but with severe cholestasis and marked ductopenia [63]. Noneliverrelated mortality risk is nearly doubled in patients with asymptomatic disease [56], an observation that may stem from a surveillance bias during the evaluation of more significant medical comorbidities, although cigarette smoking is more common in patients with PBC than the general population [42].

6. TREATMENT CONSIDERATIONS The Food and Drug administration has approved UDCA at 13e15 mg/kg body weight as the preferred pharmacological agent of choice for the treatment of PBC. UDCA is an epimer of chenodeoxycholic acid and comprises 2% of

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human bile acids. It functions as a choleretic agent. It decreases serum levels of bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, cholesterol, and IgM. In a study that combined data from three controlled trials, UDCA 13e15 mg/kg/day was found to decrease likelihood of liver transplantation and death after 4 years [64]. However, the clinical use and therapeutic benefits of UDCA in PBC remain controversial. Two separate metaanalyses highlighted no clear survival difference between UDCA-treated and placebo-treated patients [65,66]. However, the surveyed randomized trials had questionable validity, as marked differences in followup periods and UDCA doses (at times suboptimal) may have flawed the results. However, no difference was observed even if short-duration trials were analyzed separately than longer-duration ones. A third metaanalysis featuring data from more methodologically sound trials demonstrated that the risk of death and liver transplantation was 32% lower in the UDCA-treated group [58], but the most recent metaanalysis of randomized clinical trials (RCTs) using Bayesian approach indicated no benefit of UDCA on morbidity, mortality, and need for liver transplantation [65]. The life expectancy of patients treated with and responding to UDCA was similar to that of age- and sexmatched healthy controls for up to 20 years in another survey; nevertheless, detailed histological studies indicate that UDCA slows disease progression particularly in those with early-stage histological involvement [67,68], but no disease regression is observed. The last three decades have seen a variety of adjuvant medications that have been used alone or in combination with UDCA in patients with an incomplete response to UDCA monotherapy. These include systemic corticosteroids, budesonide, azathioprine, mycophenolate mofetil, methotrexate, colchicine, silymarin, and bezafibrate. Neither the larger trials nor the pilot studies have indicated any survival benefit from their agents. Now that serum bilirubin levels remain normal for so many years there is no surrogate marker available as an indirect measure of outcome. Hence, therapeutic trials in early PBC are very difficult to conduct as patients are intolerant of prolonged trials and the costs of running the same are prohibitive. At the present time, UDCA in combination with various other adjuvant products is not recommended outside of research protocols.

7. CONCLUSION There is still ongoing debate about the pathophysiology of PBC since its original description in 1851. With the advent of sensitive diagnostic and research tools, it has become a liver disease, which is well recognized worldwide; thus, the majority of patients are now diagnosed at an early asymptomatic stage. Epidemiological data indicate that geographic clustering occurs, implicating both genetic and environmental influences in its pathogenesis. Given a genetically primed host, both xenobiotics and viral infections

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could promote the development of PBC. The recent description of mice models for PBC is exciting and will surely guide further genetic research. The pathophysiological basis of PBC seems to lie in the demonstrated defects in immune tolerance that results in the activation and expansion of self-antigenespecific T and B lymphocyte clones and the production of circulating autoantibodies, cytokines, and other inflammatory mediators. Larger prospective cohort studies with longitudinal clinical, serological, genetical, and histological data will prove invaluable in unraveling new associations, and perhaps highlighting markers of disease progression. The true impact of UDCA on disease course and natural history needs more definitive scrutiny. Its inadequate efficacy in causing disease regression gives impetus to further studies of the pathogenetic mechanisms of the disease and drives the endless search for new therapies.

8. FIVE-YEAR UPDATE 8.1 Changing Nomenclature The early diagnosis of PBC and the introduction of UDCA and other therapies have dramatically improved the disease outcomes allowing that only a minority of patients currently develop cirrhosis. During the 2014 European Association for the Study of the Liver (EASL) Conference, patient representatives requested to remove the term “cirrhosis.” A panel of experts has recently proposed [69] to change the term “cirrhosis” by “cholangitis.” The term “cholangitis” is a general description of an autoimmune-mediated damage of the intra- and/or extrahepatic bile ducts, and some experts have stated that this may lead to confusion in daily clinical practice with other forms of immune-mediated cholangitis such as primary sclerosing cholangitis (PSC). However, it seems a nomenclature more pleasant for patients for whom the word “cirrhosis” represent a “stigma” of an incurable disease.

8.2 Autoantibodies Nearly 5% of patients with PBC do not have detectable AMA [70], and liver biopsy is mandatory to establish the diagnosis. In these patients, testing for other autoantibodies (anti-GP210 and anti-Sp100 antibodies) may be helpful. A recent metaanalysis assessment of anti-GP210 and anti-Sp100 in patients with PBC [71] has reported a sensitivity and specificity of 27/99% for antiGP210 and of 23/98% for anti-Sp100 for the diagnosis of PBC. In addition, these autoantibodies have been associated with a more severe disease. AntiGP210 antibodies are a strong risk factor for progression to jaundice and hepatic failure [72] and have been related to a worse alkaline phosphatase/ alanine aminotransferase response to UDCA [72].

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8.3 Bile AcideBased New Therapies UDCA is the only drug approved by the US Food and Drug Administration to treat PBC [73]. Unfortunately, one-third of patients show incomplete responses to UDCA with a poor prognosis [74], and several therapeutic alternatives to UDCA are currently under evaluation. Recent studies are investigating new therapeutic agents beyond UDCA such as fibrates, budesonide, and obeticholic acid (OCA). Bezafibrate, a ligand of the peroxisome proliferatoreactivated receptor, has shown safety and tolerability in two small studies. Lens et al. [75] evaluated 30 women with PBC who did not respond to UDCA and found that almost half had normalization of alkaline phosphatase after the addition of bezafibrate to UDCA therapy and no severe adverse effects were observed. Hosonuma et al. [76] have carried out a randomized controlled study to compare the long-term clinical results of the combination therapy in 27 patients refractory to UDCA monotherapy and found that serum alkaline phosphatase levels and the Mayo risk score were significantly lower in the combination therapy group after a mean of 8 years of follow-up, although the survival rate was similar in the two groups. A statistically significant increase in serum creatinine levels was found in the combination therapy group in comparison with the UDCA monotherapy group. Budesonide, in combination with UDCA, has shown biochemical and histological improvement in small trials with a better safety profile in comparison with the side effects often associated with glucocorticosteroids [77], although budesonide is not recommended for patients with cirrhosis. OCA is a semisynthetic analog of chenodeoxycholic acid (6-a-ethylchenodeoxycholic acid) that has a higher affinity for the farnesoid X receptor (FXR) [70]. A recent RCT has evaluated the safety and efficacy of OCA in 165 patients nonresponding to UDCA [78] randomly assigned to receive 10 mg, 25 mg, or 50 mg once-daily doses of OCA or placebo added to UDCA for 3 months (NCT00550862 trial). All patients treated with OCA showed statistically significant reductions in baseline mean ALP levels. Biochemical responses to OCA were maintained in a 12-month open-label extension trial [79]. Pruritus was the principal adverse event, especially in patients who received the highest doses of OCA (80e87%). Another recently discovered bile acid receptor is the transmembrane G-protein-coupled receptor (TGR-5) that is expressed on the biliary epithelial cells [79]. A TGR-5-selective agonist (INT-777) has been shown to increase bile flow in animal models, while a steroidal semisynthetic bile acid analog (INT-767), which is a dual FXR and tgr-5 agonist, has been shown to reduce liver injury by promoting biliary bicarbonate excretion cells [79]. Finally, an analog of the human FGF19 hormone (NGM282), which is a primary regulator of bile acid synthesis in the liver, is under investigation in phase 2 trials for PBC (NCT02135536) [70].

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Given the absence of comparative trials, the choice between second-line treatments should be evaluated in a patient-by-patient basis on the basis of the biochemical and histological characteristics and the expected efficacy and safety drug profiles.

8.4 Biological Therapies Glucocorticoids and immunosuppressive agents (methotrexate, azathioprine, cyclosporine A, mycophenolate mofetil, colchicine, D-penicillamine) have shown few therapeutic benefits in PBC patients. Recent studies are investigating the usefulness of biological therapies as rescue therapies, mainly focused on B celletargeted therapies. In 2012, Tsuda et al. [80] reported the use of two fortnightly doses of 1000 mg of rituximab in six patients with an incomplete response to UDCA. After 1 year of follow-up, serum alkaline phosphatase levels were significantly reduced, and the study also showed that B cell depletion with rituximab significantly reduced the number of AMA-producing B cells, AMA titers, plasma IgA and IgG levels, with no serious adverse events. In 2013, Myers et al. [81] treated 14 PBC patients refractory to UDCA with two rituximab infusions (1000 mg) 2 weeks apart; normalization or improvement of ALP levels was observed in only 3 (23%) patients. Although rituximab was well tolerated, one patient showed an asthma exacerbation during the first infusion, and exacerbation of pruritus was reported in 60% of patients at 12 months. Additional studies in murine models have found an exacerbation of liver disease after B-cell depletion [79], and Tajiri et al. [82] have recently reported a patient with PBC treated with rituximab for an associated lymphoma who progressed rapidly after treatment. Jopson et al. [83] is conducting an RCT testing rituximab as a treatment for fatigue related to PBC; the trial started recruiting in October 2012, and 78 patients with PBC and moderate to severe fatigue will be randomized to receive two infusions of rituximab or placebo. The results of this trial could be essential to define the safety and efficacy of rituximab in PBC patients. Other etiopathogenic pathways are currently under investigation. Some studies have suggested a key role for IL-12 and IL-23 in the etiopathogenesis of PBC [84], and recent studies are testing the use of biological agents specifically targeting either IL-12 or IL-23. The monoclonal antibody ustekinumab targets the IL-12 and has been used in patients with psoriasis and Crohn disease. A recent multicenter, open-label, proof-of-concept study has evaluated the use of ustekinumab (90 mg subcutaneous at weeks 0 and 4, then every 8 weeks through week 20) in 20 patients with PBC and an inadequate response to UDCA [85]. No patient achieved ALP response or remission, with a median percent ALP reduction from baseline to week 28 of 12%. The authors concluded that although the use of ustekinumab was associated with a modest

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decrease in ALP after 28 weeks of therapy, an overt proof-of-concept efficacy was not established. The CXC motif chemokine 10 (CXCL10), or IFN-g-inducible protein-10, plays a role in the recruitment of T cells during biliary injury and has been involved in the pathogenesis of PBC. A trial using anti-CXCL10 (NI-0801) in PBC patients found no clinical efficacy (NCT01430429) [79].

8.5 Antifibrotic Agents Antifibrotic agents could play a potential therapeutic role in PBC. The integrin aVb6 is expressed during epithelial repair and has a key role in the local activation of TGF-b1 [86]. Preclinical studies have reported a protective effect of aVb6 inhibition in the bile duct ligation [87]. STX-100 is a humanized monoclonal antibody that targets aVb6 and that is tested in other organspecific autoimmune-mediated diseases such as idiopathic pulmonary fibrosis and chronic allograft nephropathy [86]. The lysyloxidase homolog 2 (LOXL2) is an enzyme involved in the progression of fibrosis because it promotes collagen and elastin cross-linking; LOXL2 expression is enhanced in PBC as well as in other liver diseases, and there is ongoing trials testing antiLOXL2 (GS-6624) in patients with liver diseases such as NASH or PSC [86].

8.6 Targeting Multiple Etiopathogenic Pathways Monotherapy with UDCA is currently considered the standard of care as the first-line therapeutic approach of PBC. Recent studies are suggesting that future therapeutic approaches may evolve from monotherapies to combined therapies, as it is reasonable to consider that the blockade of different etiopathogenic pathways may produce better and longer-lasting results. A better prognostic classification and the development of markers that may help to quantify the specific weight of each of the main etiopathogenic pathways in a given patient at a given time should be the goal to reach hopefully in a near future. Combined approaches using agents with anticholestatic, autoimmune, or antifibrotic mechanisms might be needed, including agents with dual efficacy against cholestatic and fibrotic injury processes [86].

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Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, Lindor KD, Kaplan MM, Vierling JM. USA PBC epidemiology group. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005;42(5):1194e202. Howel D, Fischbacher CM, Bhopal RS, Gray J, Metcalf JV, James OF. An exploratory population-based case-control study of primary biliary cirrhosis. Hepatology 2000;31(5):1055e60. Mason A, Xu L, Neuberger J. Proof of principal studies to assess the role of the human betaretrovirus in patients with primary biliary cirrhosis. Am J Gastroenterol 2004;99(12):2499e500. Hartmann G, Krieg AM. Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J Immunol 2000;164(2):944e53. Ala A, Stanca CM, Bu-Ghanim M, Ahmado I, Branch AD, Schiano TD, Odin JA, Bach N. Increased prevalence of primary biliary cirrhosis near superfund toxic waste sites. Hepatology 2006;43(3):525e31. Corpechot C, Barbu V, Chazouilleres O, Poupon R. Fetal microchimerism in primary biliary cirrhosis. J Hepatol 2000;33(5):696e700. Schoniger-Hekele M, Muller C, Ackermann J, Drach J, Wrba F, Penner E, Ferenci P. Lack of evidence for involvement of fetal microchimerism in pathogenesis of primary biliary cirrhosis. Dig Dis Sci 2002;47(9):1909e14. Parikh-Patel A, Gold EB, Worman H, Krivy KE, Gershwin ME. Risk factors for primary biliary cirrhosis in a cohort of patients from the United States. Hepatology 2001;33(1):16e21. Culp KS, Fleming CR, Duffy J, Baldus WP, Dickson ER. Autoimmune associations in primary biliary cirrhosis. Mayo Clin Proc 1982;57(6):365e70. Watt FE, James OF, Jones DE. Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study. QJM 2004;97(7):397e406. Mayo MJ, Jenkins RN, Combes B, Lipsky PE. Association of clonally expanded T cells with the syndrome of primary biliary cirrhosis and limited scleroderma. Hepatology 1999;29(6):1635e42. Prince MI, Chetwynd A, Craig WL, Metcalf JV, James OF. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut 2004;53(6):865e70. Erratum in: Gut. 2004; 53(8), 1216. Witt-Sullivan H, Heathcote J, Cauch K, Blendis L, Ghent C, Katz A, Milner R, Pappas SC, Rankin J, Wanless IR. The demography of primary biliary cirrhosis in Ontario, Canada. Hepatology 1990;12(1):98e105. Forton DM, Patel N, Oatridge A, Hamilton G, Hajnal JV, Thomas HC, Taylor-Robinson SD, Prince M, Goldblatt DE, Bassendine M, Jones DE. Fatigue in primary biliary cirrhosis. Gut 2005;54(3):438. Newton JL, Gibson GJ, Tomlinson M, Wilton K, Jones D. Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence. Hepatology 2006;44(1):91e8. Goldblatt J, Taylor PJ, Lipman T, Prince MI, Baragiotta A, Bassendine MF, James OF, Jones DE. The true impact of fatigue in primary biliary cirrhosis: a population study. Gastroenterology 2002;122(5):1235e41. Cauch-Dudek K, Abbey S, Stewart DE, Heathcote EJ. Fatigue in primary biliary cirrhosis. Gut 1998;43(5):705e10. Cohen LB, Ambinder EP, Wolke AM, Field SP, Schaffiner F. Role of plasmapheresis in primary biliary cirrhosis. Gut 1985;26:291e4.

100 SECTION j II Autoimmune Liver Diseases [53] Ng VL, Ryckman FC, Porta G, Miura IK, de Carvalho E, Servidoni MF, Bezerra JA, Balistreri WF. Long-term outcome after partial external biliary diversion for intractable pruritus in patients with intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 2000;30(2):152e6. [54] Colina F, Pinedo F, Solis JA, Moreno D, Nevado M. Nodular regenerative hyperplasia of the liver in early histological stages of primary biliary cirrhosis. Gastroenterology 1992;102:1319e24. [55] Nijhawan PK, Therneau TM, Dickson ER, Boynton J, Lindor KD. Incidence of cancer in primary biliary cirrhosis: the Mayo experience. Hepatology 1999;29(5):1396e8. [56] Prince MI, Chetwynd A, Newman W, Metcalf JV, James OF. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: followup for up to 28 years. Gastroenterology 2002;123(4):1044e51. [57] Michieletti P, Wanless IR, Katz A, Scheuer PJ, Yeaman SJ, Bassendine MF, Palmer JM, Heathcote EJ. Antimitochondrial antibody negative primary biliary cirrhosis: a distinct syndrome of autoimmune cholangitis. Gut 1994;35:260e5. [58] Corpechot C, Carrat F, Bahr A, Chretien Y, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 2005;128(2):297e303. [59] Pares A, Caballeria L, Rodes J, Bruguera M, Rodrigo L, Garcia-Plaza A, Berenguer J, Rodriguez-Martinez D, Mercader J, Velicia R. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCACooperative Group from the Spanish Association for the Study of the Liver. J Hepatol 2000;32(4):561e6. [60] Springer J, Cauch-Dudek K, O’Rourke K, Wanless IR, Heathcote EJ. Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis. Am J Gastroenterol 1999;94(1):47e53. [61] Van Norstrand MD, Malinchoc M, Lindor KD, Therneau TM, Gershwin ME, Leung PS, Dickson ER, Homburger HA. Quantitative measurement of autoantibodies to recombinant mitochondrial antigens in patients with primary biliary cirrhosis: relationship of levels of autoantibodies to disease progression. Hepatology 1997;25(1):6e11. [62] Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology 1989;10(1):1e7. [63] Vleggaar FP, van Buuren HR, Zondervan PE, ten Kate FJ, Hop WC. Dutch Multicentre PBC study group. Jaundice in non-cirrhotic primary biliary cirrhosis: the premature ductopenic variant. Gut 2001;49(2):276e81. [64] Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997;113(3):884e90. [65] Gong Y, Huang Z, Christensen E, Gluud C. Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systematic review and meta-analysis of randomized clinical trials using Bayesian approach as sensitivity analyses. Am J Gastroenterol 2007;102(8):1799e807. [66] Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet 1999;354(9184):1053e60. [67] Angulo P, Batts KP, Therneau TM, Jorgensen RA, Dickson ER, Lindor KD. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis. Hepatology 1999;29(3):644e7.

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Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology 2000;32(6):1196e9. Beuers U, et al. Changing nomenclature for PBC: from “cirrhosis” to “cholangitis”. Gastroenterology 2015;149(6):1627e9. Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet (London, England) 2015;386(10003):1565e75. Hu S-L, et al. Meta-analysis assessment of GP210 and SP100 for the diagnosis of primary biliary cirrhosis. PloS One 2014;9(7):e101916. Nakamura M, et al. Autoantibody status and histological variables influence biochemical response to treatment and long-term outcomes in Japanese patients with primary biliary cirrhosis. Hepatol Res 2015;45(8):846e55. Corpechot C. Primary biliary cirrhosis beyond ursodeoxycholic acid. Semin Liver Dis 2016;36(1):15e26. Wang L, Zhang F-C, Zhang X. Therapeutic advances for primary biliary cholangitis: the old and the new. Eur J Gastroenterol Hepatol 2016;28(6):615e21. Lens S, et al. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int 2014;34(2):197e203. Hosonuma K, et al. A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia. Am J Gastroenterol 2015;110(3):423e31. Zhu G-Q, et al. Network meta-analysis of randomized controlled trials: efficacy and safety of UDCA-based therapies in primary biliary cirrhosis. Medicine 2015;94(11):e609. Dong R, Zheng S, Chen G. The appropriate timing and dose of obeticholic acid in patients with primary biliary cirrhosis. Gastroenterology 2015;149(2):508. Mousa HS, et al. Advances in pharmacotherapy for primary biliary cirrhosis. Expert Opin Pharmacother 2015;16(5):633e43. Tsuda M, et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology (Baltimore, Md) 2012;55(2):512e21. Myers RP, et al. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol 2013;108(6):933e41. Tajiri K, et al. A case of primary biliary cirrhosis that progressed rapidly after treatment involving rituximab. Case Rep Gastroenterol 2013;7(1):195e201. Jopson L, et al. RITPBC: B-cell depleting therapy (rituximab) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial. BMJ Open 2015;5(8):e007985. Yang C-Y, et al. IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: implications for therapy. Hepatology (Baltimore, Md) 2014;59(5):1944e53. Hirschfield GM, et al. Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: a proof-of-concept study. Hepatology (Baltimore, Md) 2015;64(1):189e99. Dyson JK, et al. Novel therapeutic targets in primary biliary cirrhosis. Nat Rev Gastroenterol Hepatol 2015;12(3):147e58. Patsenker E, et al. Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology 2008;135(2):660e70.

Chapter 6

Autoimmune Hepatitis D. Vergani and G. Mieli-Vergani King’s College London Faculty of Life Sciences & Medicine at King’s College Hospital, London, United Kingdom

1. INTRODUCTION Autoimmune hepatitis (AIH) is a progressive inflammatory liver disorder, preferentially affecting females, characterized histologically by interface hepatitis (Fig. 6.1) and serologically by high levels of transaminases, immunoglobulin G (IgG) and presence of autoantibodies, in the absence of a known etiology. AIH is divided into two main types according to the autoantibody profile: type 1 (AIH-1) is positive for antinuclear (ANA) and/or antiesmooth muscle (SMA) antibody and type 2 (AIH-2) is positive for antibodies to

FIGURE 6.1 Portal and periportal lymphocyte and plasma cell infiltrate, extending to and disrupting the parenchymal limiting plate (interface hepatitis). Swollen hepatocytes, pyknotic necroses, and acinar inflammation are present. Hematoxylin and eosin staining. (Picture kindly provided by Dr. Alberto Quaglia) The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00006-4 103 Copyright © 2017 Elsevier B.V. All rights reserved.

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liverekidney microsome type 1 (anti-LKM1), and/or antibodies to liver cytosol type 1 (anti-LC1). AIH responds satisfactorily to immunosuppressive treatment.

2. HISTORY AND EPIDEMIOLOGY AIH is a recently recognized disease having been first described by Waldenstro¨m in 1950 [1]. Seropositivity for ANA, the hallmark of systemic lupus erythematosus, led Mackay to call it “lupoid hepatitis” [2], a term no longer used. The disease frequently presents acutely, therefore the term “chronic active hepatitis” is obsolete, which implied that the disease should be chronic, i.e., of at least 6 months duration, before institution of immunosuppression. Before the efficacy of immunosuppression was established, untreated severe AIH had a mortality of 50% at 5 years and 90% at 10 years [3]. The exact incidence and prevalence of AIH are unknown because most studies were conducted before the introduction of standardized criteria developed by the International Autoimmune Hepatitis Group (IAIHG) [4]. Reported prevalence rates vary from 11.6 cases per 100,000 inhabitants over the age of 14 in Spain to 24.5 per 100,000 in New Zealand and 35.9 cases per 100,000 in Alaskan natives [3]. Reported mean annual incidences are 1.9 cases per 100,000 inhabitants in the Norwegian population and 3 cases per 100,000 inhabitants in the United Kingdom [3]. A recent nationwide registry-based cohort Danish study reported an incidence rate of 1.68 cases per 100,000 people and demonstrated that the incidence of the disease increased during 1994e2012 [5]. AIH is thought to be less frequent in Asia; in Japan the incidence and prevalence rates are estimated to be 1.5 and 15.0 cases per 100,000 people, respectively [6].

3. CLINICAL FEATURES [7] The diagnosis of AIH is based on the presence of positive autoantibodies, elevated transaminase and IgG levels, and interface hepatitis on liver biopsy. The latter is required to confirm the diagnosis and to evaluate the severity of liver damage. The levels of transaminases and IgG do not reflect the extent of the histological inflammatory activity, nor indicate the presence or absence of cirrhosis. Other hepatic disorders that may share some of the aforementioned features need to be considered in the differential diagnosis. These include viral hepatitides (in particular B, C, and E), Wilson disease, nonalcoholic steatohepatitis, and drug-induced liver disease (minocycline, nitrofurantoin, isoniazid, propylthiouracil, diclofenac, pemoline, atorvastatin, and alpha-methyldopa). Female patients outnumber male patients by 3:1. Although the peak incidences of the disease are in adolescence and at 30e45 years of age, AIH can affect children and adults of all ages. A family history of autoimmune diseases is present in some 40% of the patients.

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Associated autoimmune disorders are present at diagnosis or develop during follow-up in at least one-fifth of the patients and include thyroiditis, ulcerative colitis, insulin-dependent diabetes, vitiligo, nephrotic syndrome, hypoparathyroidism, and Addison disease, the latter two being observed in particular in anti-LKM1epositive patients or in patients with autoimmune polyendocrinopathy-candidiasiseectodermal dystrophy (APECED), a monogenic disorder with a variable phenotype that includes AIH in about 20% of the cases. Typically, AIH responds to immunosuppressive treatment, which should be instituted as soon as the diagnosis is made. The onset of AIH is often illdefined, and it frequently mimics acute hepatitis, particularly in young patients. Two main types of AIH are recognized, according to the presence of SMA and/or ANA or anti-LKM1 and/or anti-LC1. The distinction in type 1 and type 2 AIH is particularly relevant in pediatrics because antiLKM1epositive disease is quite rare, but not absent, in adults. In pediatrics, anti-LKM1epositive AIH represents one-third of all cases and has a clinical course similar to ANA/SMA-positive AIH, although anti-LKM1epositive children present at a younger age, more often with an acute onset, including fulminant hepatitis, and have associated partial IgA deficiency [7]. There are three main patterns of disease presentation: an acute onset, characterized by malaise, nausea/vomiting, anorexia, and abdominal pain, followed by jaundice, dark urine, and pale stools; an insidious onset, with an illness characterized by progressive fatigue, relapsing jaundice, headache, anorexia, amenorrhea, and weight loss; and finally a presentation with complications of portal hypertension, such as hematemesis from esophageal varices, bleeding diathesis, chronic diarrhea, weight loss, and vomiting. The mode of presentation of AIH is therefore variable, and the disease should be suspected and excluded in all patients presenting with symptoms and signs of prolonged or severe liver disease. Some patients, however, are completely asymptomatic and are diagnosed after incidental discovery of abnormal liver function tests. The course of disease can be fluctuating, with flares and spontaneous remissions, a pattern which may result in delayed referral and diagnosis. The majority of the patients, however, on physical examination have clinical signs of an underlying chronic liver disease, i.e., cutaneous stigmata (spider nevi, palmar erythema, leukonikia, striae), firm liver, and splenomegaly; at ultrasound the liver parenchyma is often nodular and heterogeneous.

4. DIAGNOSIS AND LABORATORY FINDINGS Diagnosis of AIH is based on a series of positive and negative criteria elaborated by the IAIHG [4,8]. Liver biopsy is necessary to establish the diagnosis, the typical histological picture including a dense mononuclear and plasma cell infiltration of the portal areas, which expands into the liver lobule; destruction of the hepatocytes at the periphery of the lobule with erosion of the limiting plate (“interface hepatitis”); connective tissue collapse resulting from the

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death of hepatocytes and expanding from the portal area into the lobule (“bridging collapse”); and hepatic regeneration with “rosette” formation (Fig. 6.1). In addition, there are other nonspecific features that may point to the diagnosis of AIH, such as emperipolesis, i.e., the presence of inflammatory cells within hepatocytes. In addition to the typical histology, other positive criteria include elevated serum transaminase and IgG/gamma globulin levels and the presence of ANA, SMA, anti-LKM1, or anti-LC1. A key component of the criteria developed by the IAIHG [4,8,9] is the detection by indirect immunofluorescence (IIF) of ANA, SMA, anti-LKM1, and anti-LC1. Autoantibody detection assists in the diagnosis and allows differentiation of AIH types. Recognition and interpretation of the IIF patterns is not always straightforward. Problems exist between the laboratory reporting and clinical interpretation of the results that are partly dependent on insufficient standardization of the tests. In regard to standardization, guidelines have been issued by the IAIHG serology committee [9]. The basic technique for the routine testing of autoantibodies relevant to AIH is IIF on a freshly prepared rodent substrate that should include the kidney, liver, and stomach to allow the detection of ANA, SMA, anti-LKM1, and anti-LC1, but also of antimitochondrial antibody, diagnostic of primary biliary cholangitis (PBC). Because healthy adults may show reactivity at the conventional starting serum dilution of 1/10, the arbitrary dilution of 1/40 is considered clinically significant by the IAIHG. In contrast, in healthy children autoantibody reactivity is infrequent, so that titers of 1/20 for ANA and SMA and 1/10 for anti-LKM1 are clinically relevant. In most AIH cases, but not in all, the ANA pattern is homogeneous. To obtain a clearer definition of the nuclear pattern, HEp2 cells that have prominent nuclei are used. HEp2 cells, however, should not be used for screening purposes because nuclear reactivity to these cells is frequent at low serum dilution (1/40) in the normal population [10]. Although the use of recombinant or purified nuclear antigens in solid-phase assays enables the definition of some ANA specificities, detection of ANA by IIF remains the gold standard because ANA can be positive by IIF but not by solid-phase assays [11]. SMA is detected on the kidney, stomach, and liver, where it stains the walls of the arteries. In the stomach it also stains the muscularis mucosa and the lamina propria. On the renal substrate, it is possible to visualize the V, G, and T patterns; V refers to vessels, G to glomeruli, and T to tubules [9]. The V pattern is present also in nonautoimmune inflammatory liver disease and in autoimmune diseases not affecting the liver and in viral infections, but the VG and VGT patterns are more specific for AIH. The VGT pattern corresponds to the so-called “F actin” or microfilament (MF) pattern observed using cultured fibroblasts as substrate. Neither the VGT nor the anti-MF patterns are, however, entirely specific for the diagnosis of AIH-1. Although “antiactin” reactivity is strongly associated with AIH-1, some 20% of SMA positive AIH-1

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patients do not have the F-actin/VGT pattern [12]. The absence, therefore, of antiactin SMA does not exclude the diagnosis of AIH. Anti-LKM1 stains brightly the liver cell cytoplasm and the P3 portion of the renal tubules, but does not stain gastric parietal cells. The identification of the molecular targets of anti-LKM1, cytochrome P4502D6 (CYP2D6), has led to the establishment of immunoassays based on the use of the recombinant or purified antigen. Anti-LC1, which can be present on its own, but frequently occurs in association with anti-LKM1, is an additional marker for AIH-2 and targets formiminotransferase cyclodeaminase [9]. Other autoantibodies less commonly tested but of diagnostic importance include antineutrophil cytoplasm (ANCA) and antisoluble liver antigen (SLA). There are three types of ANCA, cytoplasmic, perinuclear, and atypical perinuclear, the target of which is a peripheral nuclear and not cytoplasmic perinuclear antigen (hence the suggested name of pANNA, i.e., peripheral antinuclear neutrophil antibody). The type found in AIH-1 is pANNA, which is also found in inflammatory bowel disease and sclerosing cholangitis, while it is virtually absent in AIH-2. Anti-SLA, which targets UGA tRNA suppressoreassociated antigenic protein (SEPSECS) [13], was originally described as the hallmark of a third type of AIH [14], but is also found in some 50% of AIH-1 and AIH-2 cases, where it defines a more severe course [3]. Anti-SLA is detectable by molecularly based assays and not by IIF. After assessment of all the specificities described earlier, there remains a small proportion of AIH cases without detectable autoantibodies. This condition, which responds to immunosuppression like the seropositive form, represents seronegative AIH and its prevalence and clinical characteristics remain to be defined.

5. PATHOPHYSIOLOGY 5.1 Genetics AIH is a “complex trait” disease, i.e., a condition not inherited in a Mendelian autosomal dominant, autosomal recessive, or sex-linked fashion. The mode of inheritance of a complex trait disorder is unknown and involves one or more genes, operating alone or in concert, to increase or reduce the risk of the trait, and interacting with environmental factors. Susceptibility to AIH-1 has been linked to the human leukocyte antigen (HLA) DRB1 alleles encoding the similar amino acid sequences LLEQKR and LLEQRR at positions 67e72 of the DRb polypeptide. These motifs are encoded by the DRB1*0301 and DRB1*0401 alleles, which predispose adult Caucasians from Northern Europe and Northern America to AIH-1 [15], by DRB1*0405, susceptibility allele in Japan and Argentina, and by DRB1*0404, the AIH predisposing allele in Mexico [16]. DRB1*1501, which is associated with protection against AIH-1, encodes alanine (A) at position 71, suggesting

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that the amino acid at this position is a primary determinant of disease susceptibility or resistance [15]. Recently, the first AIH genomewide association study (GWAS), conducted in Dutch adult AIH-1 patients and replicated in a German cohort, confirmed DRB1*0301 and DRB1*0401 as the primary and secondary susceptibility genotypes [17]. Susceptibility to AIH-2 has been linked to DRB1*0701 and DRB1*0301 alleles in the United Kingdom and Brazil [16]. Polymorphisms outside the HLA locus have also been reported to influence susceptibility to AIH-1, including those within the CTLA-4, the TNF-a gene promoter, and the Fas genes [16]. The GWAS mentioned previously reported that AIH-1 is associated not only with polymorphisms within the HLA region but also with variants of CARD10 and SH2B3 genes [17], the latter being also linked to PBC and primary sclerosing cholangitis susceptibility. Moreover, patients with both AIH-1 and AIH-2 have isolated partial deficiency of the HLA class III complement component C4, which is genetically determined [18]. The occurrence of an AIH-like picture in patients with rare monogenic disorders, such as APECED or immunodysregulation polyendocrinopathy enteropathy X-linked syndromesdcaused by mutations in AIRE-1 and FOXP3 genes, respectivelydas well as in patients with CTLA-4 or GATA-2 mutations, further supports the role of non-HLA genes in the pathogenesis of AIH [19]. Interestingly, in all these conditions patients have an impairment of regulatory T cells (Tregs), a feature that characterizes AIH and is likely to be involved in its pathogenesis.

5.2 Immune Mechanisms [20] The typical histologic picture of AIH, interface hepatitis, is characterized by a dense mononuclear cell infiltrate eroding the limiting plate and invading the parenchyma. Immunocytochemical studies have identified the phenotype of the infiltrating cells. T lymphocytes mounting the alpha/beta T-cell receptor predominate. Among the T cells, a majority of the cells are positive for the CD4 helper/inducer phenotype and a sizable minority of cells are positive for the CD8 cytotoxic phenotype. Lymphocytes of noneT cell lineage are fewer and include (in decreasing order of frequency) natural killer cells (CD16/CD56 positive), macrophages, and B lymphocytes. Natural killer T cells, which express simultaneously markers of both natural killer (CD56) and T cells (CD3), are involved in liver damage in an animal model of AIH. A powerful stimulus must be promoting the formation of the massive inflammatory cell infiltrate present at diagnosis. Whatever be the initial trigger, it is most probable that such a high number of activated inflammatory cells cause liver damage.

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There are different possible pathways that an autoimmune attack can follow to inflict damage on hepatocytes, which are summarized in Fig. 6.2. Over the past three decades different aspects of the pathogenic scenario depicted in Fig. 6.2 have been investigated [20].

5.2.1 Regulatory T Cells [21] Autoimmunity arises on the background of defective immunoregulation, and this has been repeatedly reported in AIH. Early studies showed that patients with AIH had low levels of circulating T cells expressing the CD8þ marker, and impaired suppressor cell function, which segregates with the possession of the disease-predisposing HLA haplotype B*08/DRB1*03 (formerly B8/DR3) and is correctable by therapeutic doses of corticosteroids. It is possible, although not formally tested, that these early characterized CD8þ T cells with a suppressor

IL-17

NK APC Liver cell

Class II Peptide

Class II

Co-stimuli

Th0 Treg IL-4 TGF-β

IFN-γ

IL-12

Th1

IL-1

Class I

CTL

IL-2

M

IFN-γ

Th2 IL-4

IL-10

IL-17

TNF-α

IL-13

P B Th17

IL-6

FIGURE 6.2 Autoimmune attack to the liver cell. A specific autoantigenic peptide is presented to an uncommitted T-helper (Th0) lymphocyte within the HLA class II molecule of an antigenpresenting cell (APC). Th0 cells become activated and, according to the presence in the microenvironment of interleukin (IL)-12 or IL-4 and the nature of the antigen, differentiate into Th1 or Th2 and initiate a series of immune reactions determined by the cytokines they produce: Th2 secretes mainly IL-4, IL-10, and IL-13 and directs autoantibody production by B lymphocytes; Th1 secretes IL-2 and interferon-gamma (IFN-g), which stimulates cytotoxic T lymphocytes (CTL), enhances expression of class I, and induces expression of class II HLA molecules on hepatocytes and activates macrophages; the activated macrophages release IL-1 and tumor necrosis factor alpha (TNF-a). If regulatory T cells (Treg) do not oppose, a variety of effector mechanisms are triggered: liver cell destruction could result from the action of CTL; cytokines released by Th1 and recruited macrophages; complement activation or engagement of Fc receptor-bearing cells such as natural killer (NK) lymphocytes by the autoantibody bound to the hepatocyte surface. The role of Th17 cells, which arise in the presence of tissue growth factor beta (TGF-b) and IL-6, is under investigation.

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function represent the more recently defined CD8þCD28 suppressor T cells. Furthermore, patients with AIH were shown to have a defect in a subpopulation of T cells controlling the immune response to liver-specific membrane antigens. Evidence that emerged in the last decade confirms an impairment of the immunoregulatory function in AIH [22]. Among T cell subsets with potential immunosuppressive function, CD4þ T cells constitutively expressing the IL-2 receptor alpha chain (CD25) (Tregs) represent the dominant immunoregulatory subset of lymphocytes. These cells, which constitute some 5% of the total population of peripheral CD4þ T cells in health, control innate and adaptive immune responses by preventing proliferation and effector function of autoreactive T cells. In patients with AIH, Tregs are defective in number and function compared to normal controls, and this impairment relates to the stage of disease, being more evident at diagnosis than during drug-induced remission. The percentage of Tregs inversely correlates with markers of disease severity, such as anti-SLA and anti-LKM1 autoantibody titers, suggesting that a reduction in Tregs favors the serological expressions of autoimmune liver disease. A recent study, focused on a more stringent definition of Tregs, i.e., CD4þCD25þCD127, has shown that in AIH circulating CD4þCD25þCD127 Tregs are decreased compared to health, their frequency being inversely correlated with parameters of disease activity and not affected by the immunosuppressive treatment [23]. These “bona fide” Tregs produce less IL-10 and are impaired in their ability to suppress CD4 target cells, a feature that in healthy subjects, but not in patients, is dependent on IL-10 secretion. Notably, decreased IL-10 production by Tregs in AIH is linked to defective responsiveness to IL-2 and pSTAT-5 upregulation [23]. The reasons for Treg impairment in AIH remain unclear. There is evidence showing that Tregs in AIH are defective in the expression of CD39, an ectonucleotidase that initiates an ATP/ADP hydrolysis cascade culminating with the generation of immunosuppressive adenosine [24]. CD39þ Tregs from AIH patients are therefore defective in their ectoenzymatic activity and inhibition of Th17 cell function. Of note, in AIH but not in healthy individuals, CD39þ Tregs undergo a marked increase in the production of IFN-g and IL-17 on challenge with proinflammatory stimuli. This suggests that in AIH Tregs are more prone to be skewed into effector cells, therefore contributing to the maintenance of the effector lymphocyte pool and to the perpetuation of autoimmune liver damage. If loss of immunoregulation is central to the pathogenesis of AIH, research should concentrate on restoring the ability to expand terminally differentiated Tregs, with the ultimate aim of exploiting them therapeutically.

5.2.2 Autoreactive T Cells To trigger an autoimmune response, a peptide embraced by an HLA class II molecule must be presented to uncommitted T helper (Th0) cells by

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professional APCs (Fig. 6.2). Given the impaired regulatory function described earlier, it is likely that in AIH an autoantigenic peptide is indeed presented to the helper/inducer T cells, leading to their sustained activation. Advances in the study of T cells have occurred mainly in AIH-2, as the target antigen of anti-LKM1 is known to be CYP2D6. CD4 T cells from patients with AIH-2 positive for the predisposing HLA allele DRB1*0701 recognize seven regions of CYP2D6, five of which have been shown to be also recognized by CD8 T cells [25,26]. High numbers of IFN-g producing CD4 T cells and CD8 T cells are associated with biochemical evidence of liver damage, suggesting a combined cellular immune attack. What triggers the immune system to react to an autoantigen is unknown. A lesson may be learned by the study of humoral autoimmune responses during viral infections. Thus studies aimed at determining the specificity of antiLKM1, present in both the juvenile form of AIH and in some patients with chronic HCV infection, have shown a high amino acid sequence homology between the HCV polyprotein and CYP2D6, the molecular target of antiLKM1, implicating a mechanism of molecular mimicry as a trigger for the production of anti-LKM1 in HCV infection [27]. It is therefore conceivable that an as-yet-unknown viral infection may be at the origin of the autoimmune attack in AIH. The establishment of cell lines and clones has shown that the majority of T-cell clones obtained from the peripheral blood and a proportion of those from the liver of patients with AIH are CD4þ and use the conventional alpha/ beta T-cell receptor [20]. Some of these CD4þ clones were found to react with partially purified antigens, such as crude preparations of liver cell membrane or liver-specific lipoprotein, and with purified asialoglycoprotein receptor or recombinant CYP2D6 and to be restricted by HLA class II molecules in their response [20]. These clones were able to help autologous B lymphocytes in the production of immunoglobulin in vitro, and their coculture with B lymphocytes resulted in a dramatic increase in autoantibody production. All of the aforementioned experimental evidence indicates that cellular immune responses are involved in the liver damage of AIH.

6. MANAGEMENT AND PROGNOSIS The goal of AIH treatment is to induce and maintain complete suppression of the inflammatory activity, thus preventing progression to cirrhosis and liver decompensation. In contrast to previous guidelines [28]dwhere remission was defined by achievement of transaminase levels below twice the upper limit of normaldcurrent guidelines require normal levels of transaminases, bilirubin, and IgG [29,30]. The induction regimen usually consists of high-dose predniso(lo)ne with or without azathioprine. When used as monotherapy, the starting dosage of steroids is 60 mg/day in adults and 1e2 mg/Kg/day (up to 60 mg/day) in children [29]. Regarding combination therapy, there are

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differences between the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) guidelines: while AASLD recommends starting either a fixed dosage of 50 mg/day or 1e2 mg/Kg/day of azathioprine at the same time as steroids [29], EASL recommends 1e2 mg/Kg/day of azathioprine to be started only 2 weeks after the introduction of steroids [30]. EASL guidelines suggest that remission can also be induced by replacing prednisolone with budesonide in noncirrhotic patients in whom the occurrence of steroid-specific side effects are expected [30]. The use of budesonide as first-line treatment has been investigated in a multicenter-controlled European trial in noncirrhotic AIH patients [31]. Treatment with azathioprine plus budesonide 9 mg/day was compared with azathioprine plus prednisolone 40 mg/day (tapered to 10 mg/ day); steroid-specific side effects were less frequent in patients on budesonide compared to those on prednisone (28% versus 53%), and remission was achieved in 60% of the budesonide arm versus 39% of the prednisolone arm. This rate of remission is lower than that observed when a higher starting dose of prednisolone is used. Moreover, when the results in children and adolescents within the European trial were analyzed separately, they showed that budesonide at the dose employed offers no benefit over prednisone in children and adolescents, a group of patients in whom much higher remission rates are obtained with standard prednisolone and azathioprine treatment [32]. In addition, budesonide cannot be used in the presence of cirrhosis, excluding at least one-third of AIH patients who have cirrhosis at diagnosis. Once remission is achieved, it can be maintained with azathioprine monotherapy or a combination of steroids with azathioprine. The optimal duration of treatment is unknown. It is prudent not to attempt withdrawal of immunosuppression within 2 years of diagnosis. During withdrawal attempts, it is essential to closely monitor the liver function tests because relapse may be severe and even fatal. Patients who have successfully stopped immunosuppression should be followed up long term because relapse may occur even 10 years later. Nonadherence to treatment is common, particularly in adolescents and young adults, and is one of the most important causes of relapse [33]. In patients who are intolerant to standard treatment, alternative therapies have been proposed. If prednisolone is not tolerated, budesonide is an adequate alternative in the absence of cirrhosis. In case of azathioprine intolerance or known thiopurine methyltransferase deficiency, steroids in monotherapy or in combination with mycophenolate mofetil (MMF) or 6-mercaptopurine have been tried with success [34]. For patients who fail to achieve remission on standard immunosuppression, alternative therapies are based on anecdotal experience [35]. MMF has been reported to be ineffective in azathioprine nonresponders, although some studies show that it can induce remission in these patients, particularly within

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the pediatric population. Calcineurin inhibitors, cyclosporine and tacrolimus, have been used as a rescue treatment for difficult-to-treat cases. Infliximab has been reported to be effective in AIH patients not responding to other therapies, but the treatment was complicated by a high rate of infections [36]. Anecdotal evidence also suggests some benefits in the use of inhibitors of the mammalian target of rapamycin [37]das well as of rituximabdan anti-B-cell monoclonal antibodydin the management of patients who fail to respond to other therapies [38]. A question frequently asked is whether treatment can be safely continued during pregnancy. Although the experience is limited, there are no adverse events for mother and baby [39]. In particular, no teratogenic effects have been described with azathioprine in humans; although for women concerned about its use, treatment with steroids alone can be considered. It is now clear that there are patients with a milder form of the disease who may be asymptomatic or paucisymptomatic and are detected incidentally, during routine checkups. For these patients the approach to treatment is less prescriptive [29,30]. The benefit of therapy is undefined, and it may be so low that the risk of corticosteroid side effects is unjustified. This is particularly relevant to postmenopausal women and the elderly patients. The latter, however, may have severe disease that needs active management to achieve normal life expectancy. A theoretical long-term complication of continuous immunosuppressive therapy is the development of malignancies. The risk of extrahepatic cancer in AIH has been reported to be 1.4-fold higher than that of an age- and sexmatched normal population [40]. Akin to other chronic liver diseases, the risk of primary hepatocellular cancer is related mainly to the presence of cirrhosis and is generally reported to be uncommon [41]. Liver transplantation is the ultimate treatment for most patients who present with fulminant hepatic failure and those who reach end-stage chronic liver disease. Transplantation in AIH has an excellent prognosis, with a 5-year patient and graft survival between 80% and 90%. Before transplantation is considered, however, it is important to remember that even patients presenting with decompensated cirrhosis can respond to immunosuppressive treatment and avoid surgery for a long time. AIH may recur after transplant.

7. AUTOIMMUNE HEPATITIS AND LIVER TRANSPLANT 7.1 Recurrence of Autoimmune Hepatitis After Transplant Recurrence of AIH after liver transplant has been shown in several studies [42,43]. The diagnosis is based on reappearance of clinical symptoms and signs, histological features of periportal hepatitis, elevation of transaminases, circulating autoantibodies, and elevated IgG, associated to response to steroids and azathioprine. Possession of the HLA DR3 allele appears to confer

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predisposition to disease recurrence, as it does to the original AIH, although this has not been universally confirmed. Recurrence has been noted both in adult and pediatric series, and although the rate of this complication increases with the posttransplant interval, it may appear as early as 1 month postsurgery. Most transplant recipients with recurrent AIH respond to an increase in the dose of corticosteroids and azathioprine, but, in a few, recurrence can lead to graft failure and to the need for retransplantation. Caution should be taken in weaning immunosuppression in patients who undergo transplantation for AIH because discontinuation of corticosteroid therapy may increase the risk for recurrent disease.

7.2 De Novo Autoimmune Hepatitis After Transplant Tissue autoantibodies after liver transplantation, in particular ANA and SMA, are common also in patients transplanted for nonautoimmune liver disease [42,43]. The described prevalence of posteliver transplant autoantibodies is variable, probably reflecting different techniques used for their detection, the cutoff point above which the autoantibodies are considered positive, the time posttransplant at which they are tested, the nature of the clinical condition leading to transplantation, and the presence or absence of posttransplant complications. In the late 1990s, it was observed that AIH can arise de novo after liver transplantation in patients who had not been transplanted for autoimmune liver disease [44]. After the original report in children, de novo AIH after liver transplant has been confirmed by several studies both in adult and pediatric patients [42,43]. Importantly, treatment with prednisolone and azathioprine, using the same schedule for classical AIH, is also effective in de novo AIH leading to excellent graft and patient survival. It is of interest that these patients do not respond satisfactorily to standard antirejection treatment, making it essential to reach an early diagnosis to avoid graft loss. Recurrence of AIH posttransplant can be readily explained. The recipient’s immune system is sensitized to species-specific antigens and has a pool of memory cells, which are restimulated and reexpanded when the target antigens, “autoantigens,” are presented to the recipient’s immune system by either recipient’s APC repopulating the grafted liver or by donor’s APC sharing histocompatibility antigens with the recipient. In contrast, akin to autoimmune liver disease outside transplantation, the pathogenesis of posttransplant de novo AIH remains to be defined. There are several nonmutually exclusive explanations: in addition to release of autoantigens from the damaged tissue, a possible mechanism is molecular mimicry, whereby exposure to viruses sharing amino acid sequences with autoantigens leads to cross-reactive immunity. Viral infections, which are frequent posttransplant, may lead to autoimmunity also through other mechanisms, including polyclonal stimulation, enhancement and induction of membrane expression of MHC class I and II antigens and/or interference with immunoregulatory cells. Another possible

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mechanism is suggested by animal experiments showing that the use of calcineurin inhibitors predisposes to autoimmunity and autoimmune disease, possibly by interfering with the maturation of T lymphocytes or with the function of Tregs, with consequent emergence and activation of autoaggressive T-cell clones. Another proposed mechanism stems from observations by Aguilera’s group [45], who reported that an antibody directed to glutathioneS-transferase T1 (GSTT1) characterized their patients with de novo AIH. Because the gene encoding this protein is defective in one-fifth of Caucasian subjects and the encoded enzyme was absent in patients experiencing de novo AIH, the authors speculated that graft dysfunction resulted from recognition as foreign of GSTT1 acquired with the graft. We have been, however, unable to confirm this observation, having investigated sequentially on 60 occasions the reactivity against GSTT1 in 20 patients with post-LT de novo AIH (Komorowski L et al., unpublished data).

8. CONCLUSION With immunosuppressive treatment, prognosis of AIH is excellent with symptom-free long-term survival in the majority of patients. Since the late 1970s, several pathogenic aspects of AIH have been elucidated, including predisposing genetic factors and disease-specific humoral and cellular immune responses. Tasks for the future include further elucidation of its pathogenesis and the establishment of novel treatments aimed at arresting specifically liver autoaggression or, ideally, at reinstating tolerance to liver antigens.

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116 SECTION j II Autoimmune Liver Diseases [9] Vergani D, Alvarez F, Bianchi FB, Cancado EL, Mackay IR, Manns MP, et al. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol 2004;41(4):677e83. [10] Tan EM, Feltkamp TE, Smolen JS, Butcher B, Dawkins R, Fritzler MJ, et al. Range of antinuclear antibodies in “healthy” individuals. Arthritis Rheum 1997;40(9):1601e11. [11] Meroni PL, Schur PH. ANA screening: an old test with new recommendations. Ann Rheum Dis 2010;69(8):1420e2. [12] Muratori P, Muratori L, Agostinelli D, Pappas G, Veronesi L, Granito A, et al. Smooth muscle antibodies and type 1 autoimmune hepatitis. Autoimmunity 2002;35(8):497e500. [13] Wies I, Brunner S, Henninger J, Herkel J, Kanzler S, Meyer zum Buschenfelde KH, et al. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis [see comments]. Lancet 2000;355(9214):1510e5. [14] Manns M, Gerken G, Kyriatsoulis A, Staritz M. Meyer zum Buschenfelde KH. Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen. Lancet 1987;1(8528):292e4. [15] Doherty DG, Donaldson PT, Underhill JA, Farrant JM, Duthie A, Mieli-Vergani G, et al. Allelic sequence variation in the HLA class II genes and proteins on patients with autoimmune hepatitis. Hepatology 1994;19:609e15. [16] Liberal R, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: a comprehensive review. J Autoimmun 2013;41:126e39. [17] de Boer YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology 2014;147(2):443e452 e5. [18] Vergani D, Wells L, Larcher VF, Nasaruddin BA, Davies ET, Mieli-Vergani G, et al. Genetically determined low C4: a predisposing factor to autoimmune chronic active hepatitis. Lancet 1985;2(8450):294e8. [19] Webb GJ, Hirschfield GM. Using GWAS to identify genetic predisposition in hepatic autoimmunity. J Autoimmun 2016;66:25e39. [20] Vergani D, Mieli-Vergani G. Cutting edge issues in autoimmune hepatitis. Clin Rev Allergy Immunol 2012;42(3):309e21. [21] Liberal R, Grant CR, Longhi MS, Mieli-Vergani G, Vergani D. Regulatory T cells: mechanisms of suppression and impairment in autoimmune liver disease. IUBMB Life 2015;67(2):88e97. [22] Longhi MS, Ma Y, Mieli-Vergani G, Vergani D. Aetiopathogenesis of autoimmune hepatitis. J Autoimmun 2010;34(1):7e14. [23] Liberal R, Grant CR, Holder BS, Cardone J, Martinez-Llordella M, Ma Y, et al. In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression. Hepatology 2015;62(3):863e75. [24] Grant CR, Liberal R, Holder BS, Cardone J, Ma Y, Robson SC, et al. Dysfunctional CD39(POS) regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis. Hepatology 2014;59(3):1007e15. [25] Ma Y, Bogdanos DP, Hussain MJ, Underhill J, Bansal S, Longhi MS, et al. Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2. Gastroenterology 2006;130(3):868e82. [26] Longhi MS, Hussain MJ, Bogdanos DP, Quaglia A, Mieli-Vergani G, Ma Y, et al. Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2. Hepatology 2007;46(2):472e84.

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Chapter 7

Primary Sclerosing Cholangitis R.W. Chapman*, x and K.D. Williamson*, x

*University of Oxford, Oxford, United Kingdom; xJohn Radcliffe Hospital, Oxford, United Kingdom

ABBREVIATIONS AIH ALP CCA CCR9 CRC CT DIA ERCP FISH GGT GWAS HLA IBD IgG IgG4-SC MAdCAM-1 Mdr2 MPO MRCP p-ANCA PBC PR3 PSC SNP SSC UC UDCA ULN US VAP-1

Autoimmune hepatitis Alkaline phosphatase Cholangiocarcinoma Chemokine (CeC motif) receptor 9 Colorectal cancer Computed tomography Digital image analysis Endoscopic retrograde cholangiopancreatography Fluorescent in situ hybridization Gamma-glutamyltranspeptidase Genomewide association studies Human leukocyte antigen Inflammatory bowel disease Immunoglobulin G IgG4-sclerosing cholangitis Mucosal addressin cell adhesion molecule Multidrug resistance protein 2 Myeloperoxidase Magnetic resonance cholangiography Perinuclear antineutrophil cytoplasmic antibodies Primary biliary cholangitis Proteinase 3 Primary sclerosing cholangitis Single nuclear polymorphisms Secondary sclerosing cholangitis Ulcerative colitis Ursodeoxycholic acid Upper limit of normal Ultrasound Vascular adhesion protein-1

The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00007-6 119 Copyright © 2017 Elsevier B.V. All rights reserved.

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1. INTRODUCTION Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease characterized by inflammation and concentric obliterative fibrosis of both small and large bile ducts of the liver. Sclerosing cholangitis was first described in the 1860s by Hoffman [1], and cases of sclerosing cholangitis as a primary entity associated with inflammatory bowel disease (IBD) were published in the 1960s. The advent of endoscopic retrograde cholangiopancreatography (ERCP) helped then facilitate the diagnosis of this condition, which was further improved by magnetic resonance cholangiography (MRCP) in the 1990s, which to date remains the primary modality for diagnosis. The clinical picture can range from an incidental finding of a raised alkaline phosphatase (ALP) in an asymptomatic patient to fatigue, lethargy, and pruritus, and over many years it can often lead to cirrhosis of the liver, and liver failure or death, necessitating liver transplantation. The etiology remains elusive, and there are no proven medical therapies, which, together with its significant morbidity and mortality, make its management challenging indeed. There is a strong association with IBD, usually ulcerative colitis (UC), which often runs an independent course from the liver disease. It is overrepresented in men compared with women, and although considered a rare disease, its incidence is increasing around the world. There is also an increased prevalence of hepatobiliary malignancy and colorectal malignancy, which accounts for a significant proportion of morbidity and mortality.

2. EPIDEMIOLOGY PSC is a rare disease, which is predominantly manifested in men compared with women, at a ratio of around two to one. Although the disease can present at any age, the mean age of presentation is 40 years. Prevalence rates are of the order of 0.22 per 100,000 population to as high as 16.2 per 100,000 population [2e4]. A recent systematic review found the incidence to be as high as 1.3 per 100,000 per year in some populations [5]. For unknown reasons, the incidence and prevalence varies according to geographic distribution, with an increasing prevalence in Europe the further north one goes. The incidence appears to be increasing worldwide, although it is not clear whether this is a true increase, or whether this reflects improved detection and diagnosis [6]. There is an inherited genetic predisposition to the disease, which is discussed further in the following text, with first-degree relatives of affected patients having a 10- to 20-fold increased risk of developing the disease above that of the general population. Environmental factors are also involved with the absence of cigarette smoking, in common with UC, appearing to be a predisposing risk factor [7,8]. In one study, 4.9% of patients with PSC smoked compared with 26.1% of controls [9]. The mechanism by which smoking protects against both disorders (PSC and UC) is unknown, although

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trials of nicotine therapy have shown no benefit in altering disease progression. There is a strong association with IBD, the strength of which varies, again dependent on geographic location. About two-thirds of Northern European patients with PSC will have IBD, compared with about half of Southern Europeans. Only 20% of Japanese patients with PSC are associated IBD. There have also associations with other organ-specific autoimmune diseases including thyroid disease, celiac disease, rheumatoid arthritis, and type 1 diabetes.

3. ETIOPATHOGENESIS For over 30 years, PSC has been considered to be an immunologically mediated disease, probably triggered by acquired toxic or infectious agents that may gain access through the colon. Although current understanding continues to support this, the etiology and pathogenesis of PSC are not yet fully elucidated. Indeed, it is likely that a combination of mechanisms result in the development of PSC. Autoimmunity is very likely to play a major role as supported by the strong human-specific leukocyte antigen (HLA) haplotype association in PSC, high frequency of other autoimmune diseases such as rheumatoid arthritis, high prevalence of autoantibodies in patient sera, and the strong link with IBD.

3.1 Genetic Factors There are many studies published on various genes associated with PSC, initially from a host of candidate gene studies starting some 20 years ago, followed by genomewide associated studies (GWAS) from Northern Europe [10]. Most recently, an international multicenter Immunochip-based study was published, comparing 130,422 single nuclear polymorphisms in 3789 patients with PSC with 25,079 controls [11]. The strongest evidence that PSC is an immune-mediated disease is the genes found in the early studies and then backed up strongly by the more recent GWAS and Immunochip studies are immune-related, particularly those encoding the human leukocyte antigens (HLA). Many of the HLA associations and other immune response genes were also shared and present in a number of other autoimmune diseases such as coeliac disease, IBD, type 1 diabetes mellitus, multiple sclerosis, and other autoimmune liver diseases. HLA-A1 B8 DR3, HLA-D2, and HLA-DR6 are the three genes most strongly associated with PSC, and these are evenly distributed among patients with PSC, regardless of whether they have IBD (Table 7.1). It has been suggested that DR3, DR6, and DR2 encode for amino acids in the HLA b-chain that may enhance antigen presentation by the HLA molecule to the T-cell receptor.

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TABLE 7.1 Key Human Leukocyte Antigen (HLA) Haplotypes Associated With Primary Sclerosing Cholangitis (PSC) [107] Haplotype

Significance in PSC

B8-TNF*2-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201

Strong association with disease susceptibility

DRB3*0101-DRB1*1301-DQA1*0103-DQB1*0603

Strong association with disease susceptibility

DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602

Weak association with disease susceptibility

DRB4*0103-DRB1*0401-DQA1*03-DQB1*0302

Strong association with protection against disease

MICA*008

Strong association with disease susceptibility

3.2 Other Proposed Mechanisms Other factors are felt to play a role in pathogenesis, such as a toxic effect of bile on damaged biliary epithelium, and the so-called leaky gut theory, where preexisting IBD predisposes to increased bowel wall permeability, and therefore increased exposure of the bile ducts to bacteria and other pathogens. One hypothesis to explain the association between IBD and liver disease is that PSC is mediated by long-lived memory T cells derived from the inflamed gut that enter the enterohepatic circulation [12]. Aberrant expression of chemokines and adhesion molecules on liver endothelial cells may cause recruitment of these T cells, in turn, leading to biliary inflammation, fibrosis, and bile duct stricturing. In support of this, patients with PSC have been demonstrated to aberrantly express adhesion molecules including vascular adhesion protein-1 and mucosal addressin cell adhesion molecule-1 on biliary epithelium [13]. Additionally, the chemokine CCL25, ordinarily confined to the gut, is upregulated in the liver in PSC, helping recruit CCR9þ T cells [14]. The mechanisms that lead to aberrant expression of adhesion molecules remain unknown, but it may be that in genetically susceptible individuals, bacterial antigens, arising from a “leaky gut” from the inflamed colon, act as molecular mimics and cause an immune reaction responsible for initiating PSC. It is possible that

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specific colonic bacterial species are associated with development of PSC/ IBD. Fickert et al. proposed that a process similar to arteriosclerosis may also play a role in the pathogenesis of PSC [15]. Work with multidrug resistance knockout mice (Mdr2/) that are unable to produce phospholipids suggests a subsequent inability to form mixed micelles (bile acids/phospholipids/ cholesterol) resulting in accumulation of hepatotoxic bile acids and cholesterol-supersaturated bile. Support for this theory in humans is, however, lacking. Genetic studies of the human ortholog of Mdr2 (MDR3) have not demonstrated any association between MDR3 genetic variants and susceptibility to PSC.

4. CLINICAL FEATURES 4.1 Symptoms and Signs The clinical presentation is variable. The patient is often completely asymptomatic, with investigation being prompted by an incidental finding of a raised ALP on a routine blood test, typically in a young to middle-aged male with coexisting IBD. Conversely, patients may suffer from lethargy, intermittent jaundice, weight loss, right upper quadrant discomfort, and pruritus. Rarely, patients present with decompensated liver disease. During the course of the disease, patients may occasionally develop symptoms of acute cholangitis, such as fever, rigors, and abdominal pain, because of infection proximal to a dominant stricture. Physical examination findings are few. Hepatomegaly and splenomegaly are the most common findings.

4.2 Serology Up to 60% of patients have a mildly raised serum immunoglobulin G (IgG) level, up to 1.5 the upper limit of normal, and it is almost always raised in children. Around half of patients with advanced disease have raised immunoglobulin M (IgM) levels. Serum IgG4 levels are raised in 9e26% of patients with PSC, compared with only 1% of patients with another biliary disease, primary biliary cholangitis (PBC) [16e19]. It is important to test serum IgG4 levels in all patients with PSC, as elevated levels (>1.4 g/L) may confer a poorer prognosis [16,18]. Although autoantigens such as smooth muscle antibodies, antinuclear antibodies, and perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) are often detected in patient serum in PSC, none of these are specific to PSC. The prevalence of p-ANCA approaches 88% in some studies, but it is also found in patients with UC alone (60e87%) and in patients with type I autoimmune hepatitis (AIH) (50e96%) and PBC [20e22]. The type of ANCA is distinct from those in vasculitides, which are against proteinase 3 and myeloperoxidase

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and are probably directed against nuclear envelope antigens. However, in view of the lack of specificity it is unlikely p-ANCA is involved directly in the pathogenesis of PSC and it is not a useful screening test.

5. DIAGNOSIS 5.1 Laboratory Investigations Serum biochemistry typically reveals a cholestatic picture, with ALP often to levels at least three times the upper limit of normal and raised gammaglutamyltranspeptidase, usually in the setting of a patient with IBD. A normal ALP does not preclude the diagnosis if suspected. Serum aminotransferases are also often mildly raised to two to three times the upper limit of normal, although can be normal. Bilirubin is uncommonly raised at presentation and often rises in the latter course of the illness, representing more advanced disease.

5.2 Radiological Features The diagnosis of PSC may be established in the setting of chronic cholestasis by supportive cholangiographic findings (see Fig. 7.1). Usually, MRCP is used as the diagnostic imaging modality of choice, with ERCP, given its associated risks, reserved only for therapeutic options and/or poor-quality MRCP. The

FIGURE 7.1 Endoscopic cholangiographic cholangipancreotography (ERCP) image showing typical features in primary sclerosing cholangitis with structuring, beading, and dilatation of both intrahepatic and extrahepatic ducts.

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MRCP usually demonstrates characteristic bile duct changes of multifocal stricturing and segmental dilatations, causing a “beaded appearance,” in the absence of a secondary cause (see later discussion).

5.3 Liver Histology When the radiological findings support the diagnosis of PSC, histological examination of the liver is not required to confirm this and only exposes patients to unnecessary morbidity. However, if the cholangiogram is normal, but PSC is suspected, a liver biopsy is performed (Fig. 7.2). Additionally, if there is some concern regarding a possible overlap syndrome with AIH, which would necessitate a different management plan, then liver biopsy is indicated again (see later discussion). While the pathologic findings in PSC can be highly variable, characteristic features include portal tract inflammation with lymphocytes, progressing to obliterative concentric fibrosis (so-called onion-skinning) and bile duct destruction (“ductopenia”). The basement membrane of the bile duct is often thickened, and there is usually copper deposition present. Histology is diagnostic in only one-third of PSC patients, although in another one-third there may be findings suggestive of biliary disease. The focal nature of both early and late changes in PSC can make staging liver biopsies unreliable.

FIGURE 7.2 Part of a portal tract in primary sclerosing cholangitis, showing a bile duct (arrow) with mild reactive changes in the epithelium and with concentric (“onion skin”) fibrosis. An adjacent hepatic artery branch (chevron) is also seen. Only a very light chronic inflammatory cell infiltrate comprising lymphocytes and plasma cells is present. Hematoxylin and eosin stain. Magnification  200. Photo courtesy of Adrian Bateman, Southampton, UK.

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6. SPECIAL PATIENT POPULATIONS 6.1 Secondary Sclerosing Cholangitis When a diagnosis of PSC is suggested by imaging and histology, there are a number of causes of secondary sclerosing cholangitis (SSC) that must be considered (Table 7.2). Causes of SSC include previous biliary surgery; bile duct stones; toxic damage to bile ducts, e.g., intrahepatic injection of formalin, 5-fluorodeoxyuridine, and alcohol; AIDS; and most importantly IgG4-related sclerosing cholangitis (see later discussion). At times, it can be very difficult to distinguish these from PSC, particularly in PSC patients who have coexisting pathology such as choledocolithiasis. In these patients, the clinical history, presence of IBD, and distribution of cholangiographic abnormalities are most helpful in identifying the predominant disease process [23].

6.2 Small Duct Primary Sclerosing Cholangitis Small duct PSC is normally diagnosed in the patients with IBD who have cholestatic serum biochemistry with a normal cholangiogram, but it may occur in patients without IBD. It is characterized by histological changes on liver biopsy characteristic of PSC. It occurs in w10% of the PSC population [24e26]. A recent study from the Calgary health region in Canada has shown an incidence of small duct PSC of 0.15/100,000. In children the incidence rate was 0.23/100,000 compared with 1.11/100,000 in adults [27]. TABLE 7.2 Secondary Causes of Sclerosing Cholangitis Cholangiocarcinoma Choledocholithiasis (with sepsis) Diffuse intrahepatic metastasis Chemotherapy (e.g., FUDR) Biliary infectionsdCMV and immunodeficiency l Cryptosporidium and immunodeficiency l Ascariasis l Ascending cholangitis Eosinophilic cholangitis Hepatic inflammatory pseudotumor Histiocytosis X IgG4-associated cholangitis Ischemic cholangitis Mast cell cholangiopathy Portal hypertensive biliopathy Recurrent pancreatitis Surgical biliary trauma AIDS cholangiopathy AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus; FUDR, fluorodeoxyuridine; IgG4, immunoglobulin-G4.

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Small duct PSC typically runs a milder course than large duct disease with a reduced likelihood of progression to cirrhosis and with a significantly improved survival compared with large duct disease. To date, there have been no reports of cholangiocarcinoma (CCA) or colonic malignancy in the small duct PSC patient population [28,29]. Approximately one-quarter of small duct PSC patients will subsequently develop large duct disease over a period of 10 years [28e31]. Any worsening in either symptoms such as pruritis or serum biochemistry such as an increase in serum bilirubin or ALP, etc., should prompt the clinician to reimage to patient with small duct PSC to look for cholangiographic transition to classical PSC, in which case the prognosis conferred is then that of classical PSC.

6.3 Autoimmune Hepatitis Overlap Various studies suggest that between 1.4% and 8% of PSC patients have coexisting AIHdrecently defined as PSC-AIH syndrome [32e35]. PSC-AIH is more commonly found in children and young adults and characterized by clinical, biochemical, and histological features of AIH in the presence of cholangiographic findings identical to PSC [36e39]. PSC-AIH should be considered if the aminotransferase level is elevated more than twice the upper limit of normal and the serum IgG is elevated. Rarely, AIH features can develop in patients with established PSC. A liver biopsy should always be performed in these patients to confirm the diagnosis before treating with immunosuppressants, such as corticosteroids. Immunosuppression is helpful in improving disease progression in this group.

6.4 IgG4-Related Sclerosing Cholangitis IgG4-sclerosing cholangitis (IgG4-SC) is the biliary manifestation of the systemic fibroinflammatory condition, IgG4-related disease. Most commonly it affects men in their seventh decade, but accurate estimates of incidence and prevalence are unknown, particularly in the Western world. Usually, the disease manifests with obstructive jaundice and its appearance on imaging is often indistinguishable from PSC or CCA. However, IgG4-SC is a distinct separate disease from PSC, and making this distinction is paramount to avoid patients undergoing unnecessary surgical resections for suspected cancer or treatment for PSC. Although serum IgG4 is raised in 80% of cases, this is not specific to the disease and diagnosis is based on the combination of this finding together with imaging, histology, involvement of other organs, and responsiveness to steroid therapy (HISORt criteria) [40]. Histologically, disease lesions have a lymphoplasmacytic infiltration of T cells and IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Steroids are highly effective at treating IgG4-SC (unlike in PSC), but a high proportion of patients relapse. In the long term, patients are at risk of pancreatobiliary cancer and irreversible fibrosis. The immunological

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mechanisms of pathogenesis are not yet clear, although there is evidence that both B cells and T cells are involved.

6.5 High Serum IgG4 Levels in Primary Sclerosing Cholangitis Recent retrospective studies have found elevated serum IgG4 levels in 9e20% of classical PSC patients with levels up to twice the upper limit of the normal range [16e19,41]. IgG4-positive PSC patients have a reduced incidence of IBD and a more severe disease course when compared with IgG4-negative patients. No controlled trials of immunosuppressants have yet been performed in this selected group.

7. INFLAMMATORY BOWEL DISEASE IN PRIMARY SCLEROSING CHOLANGITIS As mentioned earlier, there is a strong association of PSC with IBD. All patients diagnosed with PSC should be evaluated for IBD with a full colonoscopy if a preexisting diagnosis of IBD does not yet exist. Around 75e80% of the concomitant IBD is UC, with 10e15% being Crohn disease (predominantly colitis) and 5e10% being IBD-unspecified (colitis). Conversely, around 2e10% of patients with IBD will develop PSC, and persisting elevation in ALP in patients with IBD (particularly with pancolitis) should always prompt investigation [42e44]. The genotype and phenotype of IBD in the setting of PSC is distinct from IBD without PSC [45,46]. Current evidence suggests that PSC/IBD is a separate disease entity from IBD alone. The IBD predominantly is a pancolitis and is usually worse in severity on the right compared with the left. Backwash ileitis is more common in UC associated with PSC compared with UC alone, and it is usually relatively less symptomatic than its endoscopic appearance would suggest, often running a fairly indolent course clinically. The IBD is diagnosed at an earlier age in PSC, compared with IBD without PSC, and IBD usually but not invariably predates the diagnosis of PSC. In one large study of a well-defined Dutch cohort of 380 patients with PSC and IBD, 75% had UC, 21% had Crohn disease, and 4% had IBD-unspecified [47]. Of those with UC, 83% had a pancolitis, 13% a left-sided colitis, and 4% had proctitis only. Of those with Crohn disease, 95% had ileocolitis, and only 5% had ileitis alone. In a subgroup analysis of 80 PSC-IBD patients compared with 80 IBD-controls, 85% of PSC-IBD patients had inflammation of the right hemicolon, compared with 54% of those with IBD alone. The clinical activity of the IBD is not related to the severity of the PSC and appears to run an independent course. However, there is some evidence suggesting that the more severe the course of PSC, the milder the form of UC, with fewer flares and a reduced need for surgery [48]. Interestingly, when a patient undergoes liver transplantation for PSC, their IBD may

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worsen in severity, raising the issue of whether the presence of PSC has a protective effect on the course of the IBD [49,50]. However, a recent study contradicts this, displaying a lower index of clinical activity in those with PSC-IBD who have undergone liver transplantation compared with those who have not [51].

8. PRIMARY SCLEROSING CHOLANGITIS AND MALIGNANCY Patients with PSC have a high rate of malignancy and currently more patients die of malignancy than end-stage liver failure [52]. The reason for the high rate of malignancy is probably explained by chronic inflammation in the biliary system and the colon, although whether PSC patients have a particular genetic susceptibility to develop cancer is unclear.

8.1 Colorectal Cancer The increased risk of colorectal cancer (CRC) in UC compared with the general population is well established [53e57]. Earlier studies suggested the cumulative probability of CRC from diagnosis of PSC to be as high as 2% by 10 years, 8% by 20 years, and 18% by 30 years [58]. Based on a metaanalysis of 11 studies, in UC patients with coexisting PSC this risk is elevated five times higher again (OR of 4.79; 95% CI 3.58e6.41). This risk increases with time and continues even after liver transplantation [59,60]. Although CRC can present at any time in the disease course, the median time from diagnosis of colitis to development of CRC is 17 years [61]. Interestingly, the majority of these cancers (76%) are right sided [57]. It has been proposed that this right-sided predominance may result from a carcinogenic effect of increased cecal concentrations of secondary bile acids such as lithocholic acid. Considering the absolute risk for colonic dysplasia or cancer in PSC/UC approaches 31% after 20 years of colitis [62], it is understandable that guidelines recommend 1- to 2-year interval colonoscopies with biopsies from the time of diagnosis of PSC/IBD [63,64]. Ursodeoxycholic acid (UDCA) treatment in patients with PSC and UC may decrease the risk of colorectal dysplasia and CRC [65,66].

8.2 Cholangiocarcinoma CCA complicates the clinical course of PSC in 10e20% of patients, with an annual incidence (starting 1 year after diagnosis of PSC) of 0.5e1.5% [2,67e69]. Male gender, smoking, and a long history of IBD were identified as risk factors for CCA in a case-controlled review of 39 PSC patients presenting with CCA [70].

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One-third of patients who develop CCA are diagnosed within 1 year of the diagnosis of their PSC. The likely explanation for this is that the development of symptomatic CCA brings a number of patients with previously unrecognized PSC to medical attention. The diagnosis of CCA can be challenging in PSC patients and early detection is difficult. Often patients with CCA are asymptomatic and when symptoms develop they are nonspecific, typically indicate metastatic disease, and mimic PSC disease progression. Worsening jaundice/bilirubin levels, pruritus, weight loss, and abdominal pain in any PSC patient should always prompt evaluation for CCA. Unfortunately, computed tomography, ultrasonography (US), and MRCP have poor sensitivity for early detection of CCA. Annual MRCP has been suggested as a surveillance method for CCA in patients with large duct PSC, but there is no evidence to support this approach. Tumor markers play a limited role in the early detection of CCA [64,69,71e74]. Using a cutoff level for carbohydrate antigen 19-9 (CA 19-9) of 130U/ml (normal 4 kg

Loss of 4 kg or more of body weight since illness began, not due to dieting or other factors

2

Livedo reticularis

Mottled reticular pattern over the skin of portions of the extremities or torso

3

Testicular pain or tenderness

Pain or tenderness of the testicles, not due to infection, trauma, or other causes

4

Myalgias, weakness, or polyneuropathy

Diffuse myalgias (excluding shoulder and hip girdle) or weakness of muscles or tenderness of leg muscles

5

Mononeuropathy or polyneuropathy

Development of mononeuropathy, multiple mononeuropathies, or polyneuropathy

6

Diastolic blood pressure >90 mmHg

Development of hypertension with the diastolic blood pressure higher than 90 mmHg

7

Elevated blood urea nitrogen or creatinine

Elevation of blood urea nitrogen >40 mg/dL (14.3 mmol/L) or creatinine >1.5 mg/dL (132 mmol/L), not due to deshydratation or obstruction

8

Hepatitis B virus

Presence of HBs Ag or anti-HBs Ab in serum

9

Arteriographic abnormality

Arteriogram showing aneurysms or occlusions of the visceral arteries, not due to arteriosclerosis, fibromuscular dysplasia, or noninflammatory causes

10

Biopsy of small- or mediumsized artery containing polymorphonuclear neutrophils

Histologic changes showing the presence of granulocytes or mixed leukocytes infiltrate in the artery wall

A patient with vasculitis can be classified as having polyarteritis nodosa if at least 3 of these 10 criteria are present. The presence of any three or more criteria yields a sensitivity of 82.2% and a specificity of 86.6%. Adapted from Lightfoot Jr., R.W., Michel, B.A., Bloch, D.A., Hunder, G.G., Zvaifler, N.J., McShane, D.J., et al., 1990. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 33 (8), 1088e93.

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small-sized vessel vasculitides such as microscopic polyangiitis or granulomatosis with polyangiitis. Notably, HBV-associated vasculitis patients tend to have malignant hypertension (5%), renal infarction, and/or orchi-epididymitis (25%) less frequently than those with PAN not linked to HBV infection [44]. Only very rare cases of glomerulonephritis occurring in PAN or HBV-associated vasculitis patients have been reported. Hence, kidney biopsy is not part of the usual diagnostic and/or initial investigations in patients with suspected or established PAN, and, whenever it is performed, if there are no renal microaneurysms on angiography that would contraindicate the biopsy, the presence of glomerulonephritis should primarily lead to reconsider the diagnosis. Hepatitis habitually remains silent before the onset of vasculitis symptoms, which can be the first manifestations of HBV infection. Transaminase (SGPT/ ALT and SGOT/AST) levels are usually only moderately elevated and even remain at normal levels in one-third of patients [16], whereas cholestasis is usually absent or minor. Liver biopsy, when performed, frequently reveals signs of chronic hepatitis, even when taken just a few months after HBV infection, which further suggests that pathogenic mechanisms differ between liver disease in HBV-associated vasculitis and that in acute hepatitis. Notably, hepatic biopsy must not be performed for the diagnosis of HBV-associated vasculitis because vasculitis is rarely seen on histology, and the biopsy itself can be hazardous because of the possible traumatic injury of microaneurysms with subsequent and potentially life-threatening bleeding. The diagnosis of HBV-associated vasculitis ideally relies on the combination of clinical symptoms, radiological investigations, especially angiography, when patients have abdominal pain resembling mesenteric ischemia, biopsy of an affected tissue, especially nerve and muscle in case of neuropathy, but also sometimes of skin lesions, and, of course, the detection of replicative HBV infection. Patients must, of course, be tested for other possible coinfections, such as HCV or HIV. As already emphasized, kidney and/or liver biopsies should theoretically not be performed in patients with PAN, regardless of relation to HBV or not because they may be dangerous and because PAN is a medium-sized vessel vasculitides, usually without evidence of vasculitis in the liver parenchyma or glomerular involvement.

3.2.5 Treatment For HBV-associated vasculitis, PAN-type, conventional treatment with glucocorticoids and cyclophosphamide is not recommended because it favors virus replication and, hence, facilitates evolution to chronic infection. Therefore a combination strategy has been devised [16,46]: l

to rapidly control the most severe and potentially life-threatening manifestations, initial and short treatment with glucocorticoids (1e2 weeks at a 1 mg/kg/day equivalent dosage of prednisone), then their abrupt

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l

l

discontinuation to enhance immunological clearance of the HBV-infected hepatocytes and favor seroconversion of HBe Ag to anti-HBe Ab; to clear circulating immune complexes and control the course of the disease, plasma exchange (60 mL/kg three to four times a week for 3 weeks and then two to three times a week for 2 weeks, progressively tapered and discontinued when HBe Ab is detected to avoid the clearance of the newly synthesized immunoglobulins); antiviral agents for several months, at least until virologic response with seroconversion and complete remission are achieved.

Immunosuppressants should only be given to patients with worsening manifestations of vasculitis despite well-conducted therapy as recommended previously. The efficacy of this antiviral strategy was confirmed in a series of 115 HBV-associated vasculitis patients [16]: among the 80 who were treated with the antiviral strategy, 73 (91%) exhibited remission, 4 (5%) relapsed, and 24 (30%) died as compared with 20 (57%) remissions, 5 (14%) relapses, and 17 (49%) deaths (not significant) among the remaining 35 who received glucocorticoids alone or in combination with cyclophosphamide and/or plasma exchange but no antiviral agents. Moreover, seroconversion rates for HBe Ag to anti-HBe Ab for the two groups were 49% and 15%, respectively (p < .001). The antiviral agents and their dosages for these patients should be similar to those prescribed for chronic HBV hepatitis and included vidarabine for the first patients treated, historically, then interferon (IFN)-alpha or lamivudine. Indeed, vidarabine is no longer used because of its high and frequent occurrence of neurological and hematological toxicity. Lamivudine (100 mg/day) has been shown to increase seroconversion rate in up to 60% of patients [16] but was not able to improve survival rate at 18 months as compared with conventional treatment without antiviral drugs (mortality rate at 18 months was 28% vs. 18% with combined antiviral therapy, p ¼ .46). Lamivudine can still be used due to its low cost and long-term safety profile, but is now considered as a second-line treatment because of the possible risk of genetically induced resistances. Newer agents, possibly in combination, such as pegylated IFN-alpha (weekly injections), entecavir (0.5 mg/day), and/or tenofovir disoproxil fumarate (300 mg/day) should preferentially be prescribed, nowadays, the two latter being highly potent inhibitors of the HBV polymerase with a high genetic barrier to drug resistance. Adefovir dipivoxil (10 mg/day) and telbivudine (600 mg/day) are other agents to be considered [47,48]. Because of the rarity of HBV-associated vasculitis, a trial investigating these different agents and combinations issue is very unlikely. Although these antiviral drugs, especially the newest ones, can help control HBV infection, they can also induce adverse events (not detailed in this chapter; mainly nephrotoxicity and lactic acidosis), which have to be distinguished from HBV-related extrahepatic manifestations [49,50].

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3.2.6 Outcome HBV-associated vasculitis is an acute disease that can be severe initially, in its systemic form, but the outcome is excellent in most cases with the timely application of adequate treatment. With the application of the effective, precise, combined antiviral strategy defined earlier, the prognosis of HBV-associated vasculitis has improved and the overall survival rate has increased to between 64% and 70% [16]. Seroconversion usually parallels recovery. Once remission has been obtained, PAN tends not to recur. Indeed, only 8e12% of HBV-related PAN and 19e32% of non-HBVerelated PAN tend to relapse, with a mean time to the first relapse of 37 and 29 months, respectively [51,52]. Notably, HBV-associated vasculitis relapses occur almost exclusively in patients with continued active virus replication despite treatment. In these rare cases, the clinical pattern of relapse does not necessarily repeat the original presentation. However, even after disease cure, damage such as vascular nephropathy or peripheral neuropathy may persist for years or sometimes indefinitely.

3.3 Hepatitis B ViruseRelated Glomerulonephritis Besides ischemic renal vasculopathy seen in HBV-associated vasculitis, different forms of renal diseases have been described with HBV infection: membranous nephropathy, membranoproliferative glomerulonephritis, mesangial proliferative glomerulonephritis, and, more rarely, minimal change disease, IgA nephropathy, or focal segmental glomerulosclerosis [53]. Cases of cryoglobulinemic glomerulonephritis (membranous or membranoproliferative, with hyaline thrombi) associated with HBV infection are extremely rare [54]. Although rare in Asia and North America, HBV-related or, more cautiously, HBV-associated glomerulonephritis remains among the most common causes of glomerulonephritis in children in endemic countries such as China [53,55,56]. In a Chinese study, up to 12% of membranous nephropathy cases were due to HBV [55]. Inversely, glomerulopathy was diagnosed in 5% of adult patients with chronic HBV infection in a French cross-sectional study [23], but it has also been reported during acute HBV infection. The potential causative role of HBV in these renal diseases is supported by their decreased incidence following vaccination campaigns [57] and by the results of a Chinese study revealing that people with HBV-infected diabetes were significantly more prone to develop end-stage renal disease than their HBV-negative counterparts (8.7% vs. 6.4%), after controlling for potential confounding factors such as age or glycemic control [58]. A direct cytopathogenic role of HBV in the kidney cannot be excluded. HBV Ag was found to be expressed in kidney tissue in some studies, as was HBV-DNA in the nucleus and cytoplasm of epithelial cells of renal tubules, which correlates with the duration of proteinuria [59]. In some patients with

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chronic HBV infection, especially those positive for HBV-DNA, serum showed the in vitro ability to promote apoptosis in renal tubular cells through a Fas/Fas-ligand pathway [60]. However, the more frequently invoked mechanism for glomerular injury in HBV infection is, once again, the formation of immune complexes of viral Ag and anti-HBV Ab, with their subsequent subendothelial and/or mesangial deposition in the kidneys. Indeed, the expression of HBV-DNA could persist in renal tissues, leading to the continuous expression of viral Ag. Earlier studies suggested that HBe Ag was the most likely HBV Ag responsible, but controversies further emerged concerning this point because all types of glomerular depositions, with HBs Ag, HBc Ag, and/or HBe Ag, have been reported [61]. Finally, why nephropathy develops only in some individuals with chronic HBV infection remains unknown, and the underlying genetic and/or socioenvironmental factors and/or a predisposing host immunological abnormality, especially concerning HBV-specific cellular immune response, may therefore also play a role [53]. The main symptoms of these HBV-related glomerulopathies are proteinuria and nephrotic syndrome, occurring predominantly in males, especially children. As for HBV-associated vasculitis, liver functions are generally spared, and most patients with renal involvement are chronic “asymptomatic” carriers and do not have chronic hepatitis. HBV-related membranous nephropathy is the most frequent form and resolves spontaneously in most children, usually in parallel with HBe Ag clearance, whereas progression to renal failure may occur in up to one-third of adults [62]. Glucocorticoids do not have any beneficial effect and can induce virus replication. Antiviral treatment, with IFN-alpha and/or other, newer antiviral drugs and/or combinations, can be more efficiently used. In the study by Lin et al. [63], complete resolution of proteinuria was obtained in all 40 patients treated with IFN-alpha, and seroconversion of HBe Ag to anti-HBe Ab was achieved in 16 as compared with none of the 20 patients receiving only supportive treatment, for both parameters. Oral antiviral agents (lamivudine, tenofovir, entecavir) should likely be favored today, keeping in mind that they all are excreted through kidneys and their dose must be adjusted to the glomerular function rate [56,64,65].

3.4 GianottieCrosti Syndrome GianottieCrosti syndrome, also named infantile papular acrodermatitis, is characterized by an acral, self-limiting, symmetrical, papular rash in children. It is preferentially located on the dorsal faces of hands and feet [66,67], but it can also affect, although rarely, the face and/or buttocks (Fig. 8.3). Diagnostic criteria include three positive clinical features (at least a 10-day duration of symmetrical papules or papulovesicles, 1e10 mm in diameter, on at least three of the following four sitesdcheeks, buttocks, extensor surfaces of the forearms, extensor surfaces of legs) and two negative features (extensive truncal lesions, scaly lesions) [68]. The cutaneous lesions spontaneously resolve

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FIGURE 8.3 GianottieCrosti syndrome (infantile papular acrodermatitis). Pseudourticarial rash on the dorsum of the hands and on the calves.

within a few weeks, usually in parallel to the clearance of HBs Ag and hence do not warrant any specific therapy. The syndrome can occur during acute HBV infection and was reported in a nonnegligible number of cases in conjunction with superinfection with measles or after a concomitant vaccination against both these latter viruses [69]. The underlying mechanisms remain elusive, even though the syndrome might also be related to the formation of immune complexes during the acute phase of the infection, in a particular genetic and environmental setting. In earlier papers, HBV serotypes ayw, adr, and adw were preferentially associated with this syndrome. No HBV genotype study has been performed since, largely because of the rarity of the syndrome. Some single case-report descriptions have suggested that HBV genotype D might be more frequently associated with the syndrome [70]. However, the syndrome is a very rare HBV-associated manifestation, whose frequency has decreased during the past decades, for some not completely explainable reasons. Of note, the syndrome is not specific to HBV because it was also reported with EpsteineBarr virus, respiratory syncytial virus, enterovirus or human herpes virus 6 [71,72], some bacterial infections [73], or after vaccination against hepatitis A virus, diphtheria, pertussis, and tetanus or the varicella virus live vaccine [74e77].

3.5 Porphyria Cutanea Tarda Porphyria cutanea tarda is a relatively rare disease, with an estimated overall prevalence of approximately 1/25,000 inhabitants in the United Kingdom. Two

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forms exist: the familial form, and the sporadic form, which accounts for 80e90% of cases. The disorder is characterized by skin lesions and liver damage in most cases, especially in the familial form, in relation to a metabolic disorder caused by reduced hepatic uroporphyrinogen decarboxylase activity [78]. Skin lesions include fragile skin, subepidermal bullae, pigmentation in sun-exposed areas such as the dorsal faces of the hands, and hypertrichosis, particularly on the forehead and upper cheeks. Patients do not have increased risk of acute neurological manifestations as compared with those affected by variegate porphyria or hereditary coproporphyria, who might have similar skin lesions. In the sporadic form, etiological and/or associated factors include alcohol and estrogen use, iron overload, and toxins such as hexachlorobenzene but also HCV and/or HBV infection(s) [79]. Indeed, serologic markers of chronic infection with HCV or HBV were detected in 91% and 41%, respectively, of 34 patients in one study, with viral genomes of HCV or HBV detected in 65% and 40%, respectively [80]. However, available data are not all in concordance, and in another study of 66 patients, the frequency of HBV or HCV infection was somewhat lower, 21% for each, and one-third of the infected patients had both infections [81]. The truth probably lies somewhere between these values, with chronic HCV infection probably more frequent than chronic HBV infection [82]. No specific treatment is recommended, except for usual skin care and avoidance of sunlight, alcohol, and, possibly, estrogen therapy [83]. Antiviral treatment is indicated only for chronic HBV hepatitis, when necessary, with insufficient data to predict its effect, if any, on this particular cutaneous manifestation.

3.6 Diabetes Mellitus An association of diabetes mellitus and both HBV and/or HCV infection(s) has been suggested by some study results, especially those conducted in regions with high HBV and HCV prevalence [84]. Indeed, diabetes mellitus was significantly more frequent (65% vs. 27.5% for HBV-negative controls) in a study of Asian-Americans with HBV infection, as well as in patients infected with HCV or both HBV and HCV [85]. In a study in Niger, 9% of patients with diabetes showed HBs Ag in sera as compared with 2.9% of nondiabetic controls [86]. Gestational diabetes mellitus was also diagnosed slightly more frequently in women with chronic HBV infection than in HBV-negative pregnant women [87,88]. However, HBV was indeed not identified as being associated with diabetes mellitus in several other studies, including from Asia [89,90], except perhaps in those patients with chronic liver disease, with comparable frequencies with HCV or HBV infection (diabetes mellitus prevalence of 24.5% and 19.4%, respectively) [91]. Globally, a recent metaanalysis of most of these studies, involving 12,974,690 HBV-infected patients and 231,776,232 controls,

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demonstrated an odds ratio (OR) for the prevalence of diabetes mellitus of 1.33 (95% confidence interval: 1.09e1.62; p ¼ .005) between the patients with HBV infection and the controls [84]. Patients with diabetes may have greater exposure to the virus through poor hygiene practice in insulin injections and/or the use of finger sticks [92]. Indeed, in a European study, HBV markers were more frequently detected in diabetic patients treated with insulin than in those treated orally [93]. In addition, a subsequent series in the same regions showed a decline or even disappearance in frequency of HBV Ab among diabetic patients [94], perhaps due to improved hygienic measures. Conversely, a Turkish study revealed a significant difference in prevalence of HBV markers between diabetic patients and controls (51% vs. 25%) not related to diabetes duration, patient age, and, more importantly, insulin injections [95], which suggests that other mechanisms may explain the possible link between HBV and diabetes mellitus. Diabetic patients may have impaired ability for HBV removal and/or be highly susceptible to subclinical HBV infection, whereas HBV itself, or some serum constituents of infected patients, may play a causative or participating role in the development of diabetes mellitus. Potential pancreatic damage secondary to extrahepatic viral replication has been evoked to support this latter theory.

3.7 Metabolic Syndrome Whereas HCV infection was shown to increase the risk of metabolic syndrome and diabetes mellitus, chronic HBV infection appeared in a few studies inversely associated with the prevalence of metabolic syndrome, irrespective of age and gender [96,97]. In a study from Taiwan, 15.5% of HBV-infected subjects had metabolic syndrome versus 16.9% in the noninfected controls. In addition, HBs Ageseropositive subjects had lower odds of metabolic syndrome, irrespective of their sex and age (OR: 0.76, 95% confidence interval: 0.68e0.85), and after adjustment for body mass index and serum alanine aminotransferase levels, as well as lower odds for hypertriglyceridemia and low HDL-cholesterol levels [97]. Another study from Iran showed a similar negative association between chronic HBV infection and metabolic syndrome in men (OR: 0.85; 95% confidence interval: 0.79e0.99), but not in women (OR: 1.23; 95% confidence interval: 1.07e1.42; p < .004) [98]. In this latter study, however, there was no association between chronic HBV infection and mortality from vascular events. In a Chinese study, 23% of the patients with chronic HBV infection were found to have nonalcoholic fatty liver disease, most of them (89%) with mild steatosis [99]. The possible direct favorable effect of chronic HBV infection on lipid metabolism could be related to an increase in serum adiponectin levels, through activation of the peroxisome proliferator-activated receptor g gene expression, but this remains to be confirmed by other studies [97].

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3.8 Thyroid Manifestations Thyroxine- and triiodothyronine-binding sites are present on the spherical particles associated with HBs Ag, but the pathophysiological meaning of this finding remains unclear [100]. Serum thyroxine level had increased proportional to transaminase levels in 60% of patients with acute HBV infection, presumably because of the release of thyroxin-binding globulin into the circulation from injured hepatocytes [101]. The thyroxine level usually returns to normal after HBV recovery [102]. Data on serum triiodothyronine levels are conflicting; levels were reported to increase in 10% of acute HBV cases in one study [101] but decrease in another [102], with a return to normal levels after HBV recovery in both. The prevalence of hyperthyroidism and hypothyroidism was low, at no more than 1.6% each, in another Chinese study in patients with chronic HBV infection [99]. In HBV-infected children, thyroid hormones were within the normal range in those positive for antithyroid Ab, but thyrotropin-releasing hormone stimulation test revealed subclinical hypothyroidism [103]. However, antithyroid peroxidase Ab and antithyroglobulin Ab can be detected in up to 5% and 3% of HBV-infected patients, respectively, before any antiviral treatment [104] and do not appear to be majorly influenced by subsequent IFN-alpha therapy [105], except in one study in which 45% of the patients developed antithyroid auto-Abs 4e8 months after beginning IFN-alpha therapy [106]. Thyroid gland dysfunction is indeed a known complication of INF-alpha therapy in patients with chronic viral hepatitis, apparently more with HCV than HBV infection [107,108]. In patients treated with IFN-alpha for chronic HBV infection, thyroid disease was diagnosed in 6e7% of them, mainly in women [108e110].

3.9 Autoimmune Manifestations HBV infection can potentially be associated with other autoimmune manifestations, although some remain debated or with weak level of evidence. Diverse other auto-Abs have been reported with chronic viral hepatitis, including HBV infection, and usually occur as an epiphenomenon and at relatively low titers [111]. These other auto-Abs do not seem to be overly related to or influenced by IFN-alpha therapy [105].

3.9.1 Antiphospholipid Syndrome Anticardiolipin Abs of IgG, IgM, and/or IgA isotype(s) have been found in 14e21.5% of patients with HBV infection, especially with chronic infection [112e114]. In a metaanalysis conducted in 2014, an association with anticardiolipin Ab was confirmed, with a similar magnitude with HBV (OR: 11.2; 95% confidence interval: 6.7e18.8) and HCV (OR: 11.3; 95% confidence interval: 6.82e18.59) [115]. In earliest studies, anticardiolipin Ab titers were relatively low and the levels and distribution of isotypes did not differ much

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between patients with acute or chronic HBV infection [116]. High anticardiolipin Ab level was also found more frequently among patients coinfected with HDV (42.8%) [113]. Importantly, the detection of anticardiolipin Ab was not significantly associated with most classical thrombotic features of antiphospholipid syndrome (only a trend, with OR: 7; 95% confidence interval: 0.5e97.3), but with some extrahepatic manifestations such as leukocytoclastic angiitis or membranoproliferative glomerulonephritis, and perhaps, among patients with HBV-related hepatocellular carcinoma, a higher risk of venous portal thrombosis [112,115]. Anti-beta2-glycoprotein I (GPI) Abs were found in only 2% [113] of patients with HBV infection, possibly arguing for cofactor beta2-GPI independency in most cases [116]. In the 2014 metaanalysis, anti-beta2-GPI Abs were still more frequently found in HBV-infected (OR: 14.1; 95% confidence interval: 3.06e64.66) and HCV-infected patients (OR: 5.6; 95% confidence interval: 1.69e18.77) than in healthy controls. No study has yet evaluated the association of anti-beta2-GPI Ab with thrombosis in HBV infection [115], and only few reported on the frequency of lupus anticoagulant (1.3% in a study on 143 patients) [117].

3.9.2 Other Autoantibodies About 15% of the HBV-infected patients have at least one other detectable auto-Abs, particularly an auto-Ab to proliferating cell nuclear Ag (between 3% and 12%), antiesmooth muscle cell Ab (7%), antinuclear Ab (3%), antinucleosome Ab, rheumatoid factor, anti-liver/kidney microsome, Ab and/or cryoglobulin (2% for each) [23,111,114,118,119]. In children, the prevalence of an auto-Ab, especially antiesmooth muscle cell and antinuclear Ab, can be as high as 34% [105]. Mutant precore virus frequently associated with such auto-Abs has been detected but only by univariate analysis; no correlation with any HBV genotype has been identified [23].

3.10 Miscellaneous During acute HBV infection, other manifestations have been reported, such as isolated arthralgias, myalgias, or, more rarely, neuropathy, GuillaineBarre´elike syndrome [15,21], or epididymitis [120]; such manifestations might correspond to a minor prodromal preicteric phase or to limited forms of systemic HBV-associated vasculitis. Similar concerns relate to other extrahepatic manifestations infrequently reported for patients with chronic HBV infection; examples include skin vasculitis (1%), pruritus (1%), Raynaud phenomenon (2%), uveitis (2%), myalgias (3%), arthralgias (3%), sicca syndrome (3%), sensory-motor neuropathy (5%), and/or psoriasis skin lesions (1% of patients) [23]. Most of these manifestations occur in the early years following infection or during an acute

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increase of HBV replication and, if not purely coincidental, might also correspond to mild and/or localized forms of HBV-associated vasculitis. Insomnia and sleep disorders have also been reported in up to 64.2% of the patients with chronic HBV infection (vs. 35% in controls) [121]. Isolated acute pancreatitis, a possible feature of severe HBV-associated vasculitis, has been documented in acute HBV infection but also in acute exacerbation of chronic HBV infection [122], sometimes following liver transplantation. Patients with possible HBV-associated vasculitiserelated isolated pancreatitis seem to have a higher mortality rate (80%) than patients with pancreatitis from other causes (12%) or with acute exacerbation of chronic HBV infection without pancreatitis (2%) [123]. In some patients with fatal acute necrotizing pancreatitis, damage of both exocrine and endocrine epithelial cells with inflammatory responses were observed on autopsy, whereas immunohistochemistry and in situ hybridization of the pancreas revealed the presence of HBs Ag and HBV-DNA in the cytoplasm of acinar cells and electron-microscopically showed core-like particles in the nucleus and cytoplasm [124,125]. HBV-related ophthalmological manifestations, mainly vasculitic retinal ischemia [126,127], are rare but can occur during HBV-associated vasculitis, as in PAN not due to HBV, but also during chronic HBV infection, with conjunctival and perilimbic microcirculation abnormalities, possibly resulting in scleritis, peripheral ulcerative keratitis, nongranulomatous uveitis, and/or central retinal artery occlusion and/or optic nerve dysfunctions [128,129]. Myalgias are frequent during acute prodromal preicteric syndrome and in HBV-associated vasculitis, as mentioned previously. HBV serology is therefore often included in the initial diagnostic investigations for patients with suspected myositis. However, less than 10 cases of polymyositis or dermatomyositis supposedly related to HBV infection have been reported. Importantly only the simultaneous occurrence of hepatitis and myositis or the worsening of myositis following exacerbation of hepatitis in chronically infected patients supported that this association might be more than purely coincidental [130]. Immunofluorescence of both muscle and liver revealed HBs Ag/anti-HBs Ab immune complexes and complement deposits in only few patients [131,132], and in almost all patients, corticosteroid therapy alone was effective. The effect HBV infection on bone mineral density in patients without advanced liver disease remains unclear [24]. Few studies showed reduced bone mineral density in patients with chronic HBV infection, expectedly more often in those with decompensated liver functions. A cohort study from Taiwan on 36,146 subjects with HBV infection and 144,584 noninfected controls showed that HBV-infected patients had a higher hazard ratio for osteoporosis (1.14; 95% confidence interval: 1.03e1.25), after adjusting for age, sex, and usual comorbidities and osteoporosis risk factors, including liver function tests [133]. However, this HBV-related risk of osteoporosis was not as strong as for most other risk factors, and the risk of osteoporotic fracture was comparable

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between patients with HBV infection and the comparison cohort. Another US-based cohort study showed on the opposite an increased risk of hip fracture in untreated black and, to a lesser degree, white (but not Asian) patients with chronic HBV infection and without hepatic decompensation (adjusted hazard ratio: 2.52; 95% confidence interval: 1.3e4.8) [24]. For patients under treatment for their HBV infection, this association was not statistically significant. Besides the risk of cirrhosis and hepatocellular carcinoma, few studies suggested possible increased risks of some cancers. A statistically significant relationship between HBV infection and increased risk of multiple myeloma was reported in a metaanalysis, but only in a subanalysis of high-quality studies only [134]. The results of all these exploratory studies would require confirmation and, presently, remain clearly debatable. On the other hand, there is no statistically significant association between HBV and the risk of pancreatic cancer [135].

KEY POINTS l

l

l

l

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Vaccination campaigns have greatly reduced the incidence of HBV infection, but the disease remains a public health problem, particularly in developing countries. Acute HBV infection can be responsible for transient icterus in 10e30% of patients and fulminant hepatitis in 1%. In another 5e10%, the virus cannot be cleared, and patients become chronic asymptomatic carriers or chronic hepatitis develops, then hepatic cirrhosis for some, potentially leading to hepatocellular carcinoma. Extrahepatic systemic and/or autoimmune manifestations are rare and less frequently observed with HBV than with HCV infection. They may occur in both acute and chronic viral infections, usually independently of hepatitis and regardless of the virus genotype. Prodromal preicteric syndrome, mainly characterized by arthralgias and urticarial rash, is the most common extrahepatic manifestation of acute infection, corresponding to a serum sicknesselike disease in the context of high viral replication and immune response with the formation of circulating immune complexes. HBV-associated vasculitis is a systemic necrotizing medium-sized vessel vasculitis (a form of PAN), which has become extremely rare and typically occurs within the early months following acute infection but is rare. The main symptoms are weight loss, fever, myalgias, arthralgias, asthenia, cutaneous lesions (livedo, cutaneous nodules, and/or necrosis), mononeuritis multiplex, gastrointestinal tract involvement, and/or hypertension. The disease is acute and potentially severe, but the outcome is good with timely, adequate treatment, combining antiviral agents, plasma exchange, and short-duration treatment with glucocorticoids to control the initial severe and/or life-threatening manifestations.

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HBV-related glomerulonephritis has remained one of the leading causes of renal diseases in children in developing countries, in whom the natural history of HBV infection differs, mainly because of the predominant maternofetal transmission of the virus. HBV infection may also result in infantile papular acrodermatitis (GianottieCrosti syndrome) or porphyria cutanea tarda. The association between HBV and some other clinical and/or biological features (more diabetes mellitus, thyroid gland dysfunction and/or osteoporosis, less metabolic syndrome, detection of diverse autoantibodies, including anticardiolipin antibodies) remains less well documented and/or controversial. Although several effective antiviral drugs can now help control HBV infection, they can also induce various adverse events, which have to be distinguished from HBV-related extrahepatic manifestations.

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[85] Li-Ng M, Tropp S, Danoff A, Bini EJ. Association between chronic hepatitis B virus infection and diabetes among Asian Americans and Pacific Islanders. Dig Liver Dis 2007;39(6):549e56. [86] Oli JM, Okafor GO. The prevalence of hepatitis B surface antigen in Nigerian diabetics. Trop Geogr Med 1980;32(1):40e4. [87] Lao TT, Chan BC, Leung WC, Ho LF, Tse KY. Maternal hepatitis B infection and gestational diabetes mellitus. J Hepatol 2007;47(1):46e50. [88] Lao TT, Tse KY, Chan LY, Tam KF, Ho LF. HBsAg carrier status and the association between gestational diabetes with increased serum ferritin concentration in Chinese women. Diabetes Care 2003;26(11):3011e6. [89] Chen HF, Li CY, Chen P, See TT, Lee HY. Seroprevalence of hepatitis B and C in type 2 diabetic patients. J Chin Med Assoc 2006;69(4):146e52. [90] Okan V, Araz M, Aktaran S, Karsligil T, Meram I, Bayraktaroglu Z, et al. Increased frequency of HCV but not HBV infection in type 2 diabetic patients in Turkey. Int J Clin Pract 2002;56(3):175e7. [91] Qureshi H, Ahsan T, Mujeeb SA, Jawad F, Mehdi I, Ahmed W, et al. Diabetes mellitus is equally frequent in chronic HCV and HBV infection. J Pak Med Assoc 2002;52(7):280e3. [92] Khan AJ, Cotter SM, Schulz B, Hu X, Rosenberg J, Robertson BH, et al. Nosocomial transmission of hepatitis B virus infection among residents with diabetes in a skilled nursing facility. Infect Control Hosp Epidemiol 2002;23(6):313e8. [93] Hasslacher C, Thamer G, Wahl P, Kommerell B. Antibodies against the hepatitis B surface antigen in diabetics. Diabete Metab 1977;3(1):19e21. [94] Onyekwere CA, Anomneze EE, Wali SS. Prevalence of serological markers of chronic hepatitis B virus infection in diabetics in the Lagos University Teaching Hospital, Lagos. Niger Postgrad Med J 2002;9(3):129e33. [95] Khuri KG, Shamma’a MH, Abourizk N. Hepatitis B virus markers in diabetes mellitus. Diabetes Care 1985;8(3):250e3. [96] Jinjuvadia R, Liangpunsakul S. Association between metabolic syndrome and its individual components with viral hepatitis B. Am J Med Sci 2014;347(1):23e7. [97] Huang CY, Lu CW, Liu YL, Chiang CH, Lee LT, Huang KC. Relationship between chronic hepatitis B and metabolic syndrome: a structural equation modeling approach. Obesity (Silver Spring) 2016;24(2):483e9. [98] Katoonizadeh A, Ghoroghi S, Sharafkhah M, Khoshnia M, Mirzaei S, Shayanrad A, et al. Chronic hepatitis B infection is not associated with increased risk of vascular mortality while having an association with metabolic syndrome. J Med Virol 2016;88(7):1230e7. [99] Ding WJ, Wang MM, Wang GS, Shen F, Qin JJ, Fan JG. Thyroid function is associated with non-alcoholic fatty liver disease in chronic hepatitis B-infected subjects. J Gastroenterol Hepatol 2015;30(12):1753e8. [100] Neurath AR, Korcek L, Prince AM, Lippin A, Chen M. Thyroxine binding by hepatitis B surface antigen. J Infect Dis 1975;131(2):172e6. [101] Zafar MN, Rizvi SJ, Syed S. Thyroid hormone levels in hepatitis B. J Pak Med Assoc 1992;42(3):56e7. [102] Gardner DF, Carithers Jr RL, Utiger RD. Thyroid function tests in patients with acute and resolved hepatitis B virus infection. Ann Intern Med 1982;96(4):450e2. [103] Kansu A, Kuloglu Z, Demirceken F, Girgin N. Autoantibodies in children with chronic hepatitis B infection and the influence of interferon alpha. Turk J Gastroenterol 2004;15(4):213e8.

170 SECTION j III Autoimmune Manifestations of Viral Hepatitis [104] Fernandez-Soto L, Gonzalez A, Escobar-Jimenez F, Vazquez R, Ocete E, Olea N, et al. Increased risk of autoimmune thyroid disease in hepatitis C vs hepatitis B before, during, and after discontinuing interferon therapy. Arch Intern Med 1998;158(13):1445e8. [105] Gregorio GV, Jones H, Choudhuri K, Vegnente A, Bortolotti F, Mieli-Vergani G, et al. Autoantibody prevalence in chronic hepatitis B virus infection: effect in interferon alfa. Hepatology 1996;24(3):520e3. [106] Mayet WJ, Hess G, Gerken G, Rossol S, Voth R, Manns M, et al. Treatment of chronic type B hepatitis with recombinant alpha-interferon induces autoantibodies not specific for autoimmune chronic hepatitis. Hepatology 1989;10(1):24e8. [107] Wong V, Fu AX, George J, Cheung NW. Thyrotoxicosis induced by alpha-interferon therapy in chronic viral hepatitis. Clin Endocrinol (Oxf) 2002;56(6):793e8. [108] Kozielewicz D, Zalesna A, Dybowska D. Can pegylated interferon alpha 2a cause development of thyroid disorders in patients with chronic hepatitis B? Expert Opin Drug Saf 2014;13(8):1009e14. [109] Chen XF, Chen XP, Ma XJ, Chen WL, Huang J, Luo XD. Prevalence and clinical characteristics of thyroid disease induced by chronic hepatitis B treated with polyethylene glycol (peg) interferon-alpha. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2012;26(2):117e9. [110] Yang R, Shan Z, Li Y, Fan C, Li C, Teng W. Prevalence of thyroid autoantibodies in hepatitis C and hepatitis B infection in China. Intern Med 2011;50(8):811e5. [111] Maya R, Gershwin ME, Shoenfeld Y. Hepatitis B virus (HBV) and autoimmune disease. Clin Rev Allergy Immunol 2008;34(1):85e102. [112] Elefsiniotis IS, Diamantis ID, Dourakis SP, Kafiri G, Pantazis K, Mavrogiannis C. Anticardiolipin antibodies in chronic hepatitis B and chronic hepatitis D infection, and hepatitis B-related hepatocellular carcinoma. Relationship with portal vein thrombosis. Eur J Gastroenterol Hepatol 2003;15(7):721e6. [113] Zachou K, Liaskos C, Christodoulou DK, Kardasi M, Papadamou G, Gatselis N, et al. Anti-cardiolipin antibodies in patients with chronic viral hepatitis are independent of beta2-glycoprotein I cofactor or features of antiphospholipid syndrome. Eur J Clin Invest 2003;33(2):161e8. [114] Mangia A, Margaglione M, Cascavilla I, Gentile R, Cappucci G, Facciorusso D, et al. Anticardiolipin antibodies in patients with liver disease. Am J Gastroenterol 1999;94(10):2983e7. [115] Ambrosino P, Lupoli R, Tarantino P, Di Minno A, Tarantino L, Di Minno MN. Viral hepatitis and anti-phospholipid antibodies positivity: a systematic review and meta-analysis. Dig Liver Dis 2015;47(6):478e87. [116] Guglielmone H, Vitozzi S, Elbarcha O, Fernandez E. Cofactor dependence and isotype distribution of anticardiolipin antibodies in viral infections. Ann Rheum Dis 2001;60(5):500e4. [117] Huh JY, Yi DY, Hwang SG, Choi JJ, Kang MS. Characterization of antiphospholipid antibodies in chronic hepatitis B infection. Korean J Hematol 2011;46(1):36e40. [118] Lohse AW, Gerken G, Mohr H, Lohr HF, Treichel U, Dienes HP, et al. Relation between autoimmune liver diseases and viral hepatitis: clinical and serological characteristics in 859 patients. Z Gastroenterol 1995;33(9):527e33. [119] Tzang BS, Chen TY, Hsu TC, Liu YC, Tsay GJ. Presentation of autoantibody to proliferating cell nuclear antigen in patients with chronic hepatitis B and C virus infection. Ann Rheum Dis 1999;58(10):630e4. [120] Tasar MA, Bostanci I, Karabulut B, Dallar Y. A rare extrahepatic syndrome related to acute hepatitis type B: epididymitis in an adolescent. Acta Gastroenterol Belg 2005;68(2):270e1.

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[121] Guo HM, Liu M, Xiang YT, Zhao J, Ungvari GS, Correll CU, et al. Insomnia in adults with chronic hepatitis B, liver failure, and cirrhosis: a case-control study. Perspect Psychiatr Care December 2015 [Epub ahead of print]. [122] Fournier V, Duquesne A, Pasquier JM, Parchoux B, Larbre F. Nephrotic syndrome, pancreatitis, hepatitis B. Report of a case. Pediatrie 1991;46(11):735e8. [123] Yuen MF, Chan TM, Hui CK, Chan AO, Ng IO, Lai CL. Acute pancreatitis complicating acute exacerbation of chronic hepatitis B infection carries a poor prognosis. J Viral Hepat 2001;8(6):459e64. [124] Cavallari A, Vivarelli M, D’Errico A, Bellusci R, Scarani P, DeRaffele E, et al. Fatal necrotizing pancreatitis caused by hepatitis B virus infection in a liver transplant recipient. J Hepatol 1995;22(6):685e90. [125] Yoshimura M, Sakurai I, Shimoda T, Abe K, Okano T, Shikata T. Detection of HBsAg in the pancreas. Acta Pathol Jpn 1981;31(4):711e7. [126] Akova YA, Jabbur NS, Foster CS. Ocular presentation of polyarteritis nodosa. Clinical course and management with steroid and cytotoxic therapy. Ophthalmology 1993;100(12):1775e81. [127] Lortholary O, Boudes P, Cohen D, Chaine G, Guillevin L. Early isolated ophthalmological relapse in a case of periarteritis nodosa related to hepatitis B virus. Presse Med 1989;18(14):727e8. [128] Cusnir V, Slepova O, Dumbrava V, Zaiteva N, Cusnir R, Midrigan I. Ocular manifestations of hepatitis B. Oftalmologia 1997;41(2):25e7. [129] Morgan CM, Foster CS, D’Amico DJ, Gragoudas ES. Retinal vasculitis in polyarteritis nodosa. Retina 1986;6(4):205e9. [130] Nojima T, Hirakata M, Sato S, Fujii T, Suwa A, Mimori T, et al. A case of polymyositis associated with hepatitis B infection. Clin Exp Rheumatol 2000;18(1):86e8. [131] Mihas AA, Kirby JD, Kent SP. Hepatitis B antigen and polymyositis. JAMA 1978;239(3):221e2. [132] Pittsley RA, Shearn MA, Kaufman L. Acute hepatitis B simulating dermatomyositis. JAMA 1978;239(10):959. [133] Chen CH, Lin CL, Kao CH. Association between chronic hepatitis B virus infection and risk of osteoporosis: a nationwide population-based study. Medicine (Baltimore) 2015;94(50):e2276. [134] Li Y, Bai O, Liu C, Du Z, Wang X, Wang G, et al. Association between hepatitis B virus infection and risk of multiple myeloma: a systematic review and meta-analysis. Intern Med J 2016;46(3):307e14. [135] Krull-Abe SK, Inoue M, Sawada N, Iwasaki M, Shimazu T, Yamaji T, et al. Hepatitis B and C virus infection and risk of pancreatic cancer: a population-based cohort study (JPHC Study Cohort II). Cancer Epidemiol Biomarkers Prev 2016;25(3):555e7.

Chapter 9

Extrahepatic Manifestations in Patients With Chronic Hepatitis C Virus Infection P. Brito-Zero´n,*, x S. Retamozo,{ X. Forns,jj J.-M. Sanchez-Tapias,jj J.R. Teixidorjj and M. Ramos-Casals#

*Hospital CIMA-Sanitas, Barcelona, Spain; xLaboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, Hospital Clı´nic, Barcelona, Spain; {Hospital Privado Universitario de Co´rdoba, Institute University of Biomedical Sciences, University of Co´rdoba (IUCBC), Co´rdoba, Argentina; jjInstituto de Investigaciones Biome´dicas August Pi I Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain; #Sjo¨gren Syndrome Research Group (AGAUR), Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, University of Barcelona, Hospital Clı´nic, Barcelona, Spain

1. INTRODUCTION Autoimmunity and viral infections are closely related fields, and viruses have been proposed as possible etiologic or triggering agents of systemic autoimmune diseases (SAD). The hepatitis C virus (HCV), a linear, single-stranded RNA virus identified in 1989 [1], is recognized as one of the viruses most often associated with autoimmune features. A decade ago, various authors described the association of HCV infection with a heterogeneous group of extrahepatic conditions, such as pulmonary fibrosis, cutaneous vasculitis, glomerulonephritis, Mooren ulcers, porphyria cutanea tarda, or lichen planus [2], although it is currently accepted that a weak degree of association exists in some of them [3]. More recently, there has been a growing interest in the relationship between HCV and SAD [4]. The clinical association of the different SAD with chronic HCV infection may be analyzed from two different, but complementary, points of view. Firstly, a review of the literature found nearly 500 patients with coexisting SAD and chronic HCV infection [5], with Sjo¨gren syndrome (SS; 182 cases), rheumatoid arthritis (RA; 94 cases), systemic lupus erythematosus (SLE; 67 cases), and polyarteritis nodosa

The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00009-X 173 Copyright © 2017 Elsevier B.V. All rights reserved.

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(PAN; 41 cases) being the most frequent SAD described. Secondly, analysis of all references to a series of patients with SAD tested for HCV shows the highest prevalence rates of HCV infection in patients with SS (17.6%), PAN (14.4%), SLE (9.6%), and RA (5.9%) [5]. Other recent studies have focused on the association between chronic HCV infection and circulating autoantibodies, organ-specific autoimmune diseases, and lymphoproliferative processes.

2. AUTOANTIBODIES AND HEPATITIS C VIRUS Circulating autoantibodies are often detected in patients with chronic HCV infection. Antinuclear antibodies (ANA), rheumatoid factor (RF), and antiesmooth muscle antibodies are the most frequently found, while other autoantibodies (such as anti-dsDNA, antiextractable nuclear antigens, antimitochondrial antibodies, or antieliver/kidney microsomes antibodies) are infrequent [6e21] (Table 9.1). ANA have been detected in 589 (18.6%) out of 3169 unselected HCV patients included in 16 studies (Table 9.1), although the geographic prevalence varied significantly [21]. Yee et al. [21] reported a threefold higher prevalence of ANA in HCV females compared with males, with no correlation between ANA and the response to antiviral therapy, while Stroffolini et al. [20] found no correlation between noneorgan-specific autoantibodies (NOSA) and the main HCV-related epidemiological, biochemical, and histological features, or the response to antiviral treatment. TABLE 9.1 Metaanalysis of the Main Studies Analyzing Prevalence of Autoantibodies in Unselected Series of Patients With Chronic Hepatitis C Virus (HCV) Infection Autoantibodies

HCV Patients Tested

Positive Markers

Percentage (%)

Cryoglobulins

514

204

39.7

Rheumatoid factor

738

281

38.1

Anti-SMA

2203

481

21.8

Antinuclear antibodies

3169

589

18.6

Anti-LKM

2193

75

3.4

Anti-dsDNA

606

16

2.6

Anti-ENA

444

11

2.5

1210

4

0.3

AMA

AMA, antimitochondrial antibodies; ENA, antiextractable nuclear antigens (anti-Ro/SS-A, anti-La/ SS-B, anti-RNP, anti-Sm); LKM, antieliver/kidney microsomes antibodies; SMA, antiesmooth muscle antibodies.

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This suggests that the presence of ANA or NOSA in HCV patients should not be considered a contraindication for antiviral treatment. Combined antiviral treatment [interferon (IFN)eribavirin (RBV)] is safe and effective in NOSA-positive HCV patients, with a similar prevalence of long-term response between NOSA-positive and NOSA-negative patients (49% vs. 57%) [22]. With respect to other immunological markers, Watt et al. [23] found a correlation between serum immunoglobulin levels in HCV patients (IgA, IgG, and total Ig) and histological progression to liver fibrosis. These results are consistent with our findings in 321 patients with HCV-related cryoglobulinemia, in whom hypergammaglobulinemia was observed more frequently in cirrhotic than in noncirrhotic patients [24].

3. ORGAN-SPECIFIC AUTOIMMUNE DISEASES AND HEPATITIS C VIRUS 3.1 Thyroiditis The role of HCV in inducing thyroid autoimmunity is still unclear. Bini and Mehandru [25] described the development of thyroid disease (overt or subclinical) in the 11% of 225 male HCV-infected patients treated with combined antiviral therapy, although the thyroid disease responded well to specific treatment and was reversible in most cases. Antonelli et al. [26] reported a higher frequency of hypothyroidism (13%) and antithyroid antibodies (21%) in 630 treatmentna€ıve HCV patients compared with normal controls and also found similar results in a subset of these HCV patients with associated mixed cryoglobulinemia (MC) [27]. However, other studies, performed in the same geographical area, did not find this close association [28]. Floreani et al. [29] tested 697 Italian subjects for thyroid autoantibodies and anti-HCV antibodies. Of the 71 HCV-positive patients, 4 (6%) were positive for at least one thyroid autoantibody, compared with 7 (5%) of the HCV-negative sex- and age-matched controls.

3.2 Diabetes Mellitus and Steatosis Several clinical studies have suggested a possible link between chronic hepatitis caused by HCV and the development of diabetes mellitus (DM). Antonelli et al. [30] have also reported that the prevalence of type 2 diabetes is higher in patients with MC-HCV than in controls, with diabetic MC-HCV patients having a more pronounced autoimmune reactivity than non-HCV patients with type 2 diabetes. The development of liver fibrosis has been associated with insulin resistance in HCV-infected patients [31] and that of DM may contribute to the presence and severity of hepatic encephalopathy independent of the severity of liver disease. Metabolic in HCV patients may be related to the development of steatosis, whose clinical significance in HCV patients has been recently emphasized

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[32]. Various factors are associated with hepatic steatosis, including obesity, high alcohol consumption, type 2 DM, and hyperlipidemia. These factors may contribute to steatosis in HCV patients. Indeed, after antiviral treatment, HCV-related steatosis disappears [33]. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Leandro et al. [34] conducted a metaanalysis from 3068 patients with histologically confirmed chronic hepatitis C. Steatosis was present in 1561 patients (51%) and fibrosis in 2688 (88%). Steatosis was independently associated with genotype 3, fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. The association between steatosis and fibrosis was invariably dependent on a simultaneous association between steatosis and hepatic inflammation. Control of metabolic factors such as overweight by lifestyle adjustments appears important in the management of chronic hepatitis C. A recent metaanalysis has reported that concomitant DM is associated with an increased risk of hepatocellular carcinoma, in association with BMI and steatosis [35], while Hwang et al. [36] have reported that chronic HCV infection increases the risk of development of endstage renal failure in patients diagnosed with DM.

4. SYSTEMIC AUTOIMMUNE DISEASES AND HEPATITIS C VIRUS The association between HCV and SAD has generated a growing interest in the last 10 years. The extrahepatic manifestations often observed in patients with chronic HCV infection (both clinical and immunological) may lead to the fulfillment of the current classification criteria for some SAD (Table 9.2). The largest reported study was published in 2009 by the HISPAMEC International Study Group [37]. The HISPAMEC Registry is a multicenter international study group dedicated to collecting data on patients diagnosed with SAD with serological evidence of chronic HCV infection. The study included 1020 HCVþ patients diagnosed with a concomitant SAD reported from Southern Europe (60%), North America (15%), Asia (14%), Northern Europe (9%), South America (1%), and Australia (1%). The most frequently reported SAD included SS (483 cases), RA (150 cases), SLE (129 cases), PAN (78 cases), antiphospholipid syndrome (APS) (59 cases), inflammatory myopathies (39 cases), and sarcoidosis (28 cases). Therefore the SAD most commonly reported in association with chronic HCV infection were SS (nearly half the cases), RA, and SLE, with nearly two-thirds of cases being reported from the Mediterranean area. In HCV-SAD patients, ANA, RF, and cryoglobulin are the predominant immunological features.

4.1 Sjo¨gren Syndrome Several lines of experimental [38,39], virological [40,41], and clinical evidence [42e44] have revealed a close association between HCV and SS. In 2002, we formed the SS-HCV Study Group, a multicenter international

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TABLE 9.2 Different Degrees of Association Between Hepatitis C Virus (HCV) and Systemic Autoimmune Diseases Degree of Association

Extrahepatic HCV Features Overlapping With the Classification Criteria

High Sjo¨gren syndrome

Xerostomia, xerophthalmia, ocular tests (þ), salivary biopsy (þ), ANA, RF

Rheumatoid arthritis

Arthritis of three or more joint areas, arthritis of hand joints, symmetric arthritis, RF

Systemic lupus erythematosus

Articular involvement, renal involvement, ANA, aPL, cytopenias

Intermediate Polyarteritis nodosa

Weakness, peripheral neuropathy, elevated creatinine, positive HBV markers

Antiphospholipid syndrome

Positive aPL, atypical thrombotic events

Sarcoidosis

Pulmonary fibrosis

Inflammatory myopathies

Weakness, elevated GOT, GPT

Low Systemic sclerosis

Pulmonary fibrosis

Wegener granulomatosis

Renal involvement

Giant cell arteritis

Age >50 years

Polymyalgia rheumatica

e

Ankylosing spondylitis

e

ANA, antinuclear antibodies; HBV, hepatitis B virus; RF, rheumatoid factor.

collaboration that has, so far, recruited 137 SS-HCV patients [45]. We found that HCV-associated SS is indistinguishable in most cases from the primary form using the most recent set of classification criteria, and we have proposed the term “SS secondary to HCV” in those HCV patients who fulfill the 2002 Classification Criteria [46]. Chronic HCV infection should be considered an exclusion criterion for the classification of primary SS, not because it mimics primary SS, but because the virus may be implicated in the development of SS in a specific subset of patients [47]. There is a considerable overlap between European diagnostic criteria for SS and some extrahepatic features of HCV infection (Table 9.3). Extrapolating from the main studies with large series of HCV patients, xerostomia was

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TABLE 9.3 Prevalence of the 1993 European Criteria for Sjo¨gren syndrome (SS) Diagnosis in Large Series of Patients With Chronic Hepatitis C Virus (HCV) Infection 1993 European Criteria

Present Feature/HCV Patients

Prevalence (%)

Xerostomia

158/859

18

Xerophthalmia

129/769

17

Positive ocular tests

83/216

38

Parotid scintigraphy

No data

No data

Salivary gland biopsy

64/251

25

Antinuclear antibodies

481/2641

18

Rheumatoid factor

357/1117

40

Ro/SS-A

30/765

4

La/SS-B

27/765

3

Immunological Tests

observed in 158 (18%) of 859 patients, xerophthalmia in 129 (17%) of 769, positive ocular tests in 83 (38%) of 216, positive salivary gland biopsy (grades 3e4 of ChisholmeMason classification) in 64 (25%) of 251, positive ANA in 481 (18%) of 2641, and positive RF in 357 (40%) of 1117 HCV patients. In contrast, positive anti-Ro/SS-A antibodies were described in only 30 (4%) of 765 HCV patients and anti-La/SS-B in 27 (3%) of 765. These percentages suggest that a diagnosis of SS could be easily made in HCV patients presenting sicca syndrome, positive ANA, and/or RF. The SS diagnosed in these HCV patients may be considered as one of the extrahepatic manifestations of chronic HCV infection. The main differential aspect between primary and HCV-related SS is the immunological pattern, with a predominance of cryoglobulinemic-related markers (mixed cryoglobulins, RF, hypocomplementemia) over SS-related markers (anti-Ro/SS-A and anti-La/SS-B autoantibodies) in HCV-related SS [45]. We found a threefold higher prevalence of hypocomplementemia in SS-HCV patients compared with patients with primary SS [48]. Cryoglobulinemia seems to be the key immunological marker of SS associated with HCV, having a close association with RF activity and complement activation. Recently, we have reported a prevalence of 13% of chronic HCV infection in 783 patients with SS. Patients with SS-HCV had a higher mean age (59.6 years vs. 51 years, P ¼ .03) and a higher frequency of low C3 levels

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(53% vs. 10%, P < .001), low C4 levels (65% vs. 7%, P < .001), cryoglobulins (53% vs. 10%, P < .001), a predominance of lambda monoclonal gammopathies (71% vs. 30%, P ¼ .041), and a higher frequency of death (41% vs. 8%, P ¼ .001) compared with patients without HCV. The frequency of anti-La antibodies compared with anti-Ro antibodies was higher in patients with SS-HCV (17% vs. 15%) and lower in patients without HCV infection (30% vs. 43%). The frequency of concomitant detection of the three main cryoglobulinrelated markers (cryoglobulins, RF activity, and C4 consumption) was threefold higher in patients with SS-HCV compared with patients without HCV. SS-HCV patients with genotype 1b showed the highest frequencies of immunological abnormalities related to cryoglobulins and the lowest frequencies of anti-Ro/La antibodies. This immunological pattern may contribute to the poor outcomes found in patients with SS-HCV [49]. In a recent metaanalysis, Wang et al. [50] have demonstrated a significant positive association between HCV infection and the development of SS/sicca syndrome, with a pooled OR of 3.31 (95% CI, 1.46e7.48; P < .001). In 2007 [51] we firstly described the disease characteristics of B-cell lymphoma in SS-HCV patients, its treatment, outcome, and survival prognosis. These patients are clinically characterized by a high frequency of parotid enlargement and vasculitis, an immunologic pattern overwhelmingly dominated by the presence of RF and mixed type II cryoglobulins, the predominance of MALT lymphomas, and an elevated frequency of primary extranodal involvement in organs in which HCV replicates (exocrine glands, liver, and stomach). The triple association between SS, HCV, and B-cell lymphoma suggests an important role for associated autoimmune and chronic viral diseases in the pathogenesis of B-cell lymphoproliferative disorders and reinforces the idea that autoimmunity, infection, and cancer may be closely related. A careful evaluation and follow-up of HCV patients with associated SS to aid early diagnosis and treatment of possible B-cell lymphoma should be recommended.

4.2 Rheumatoid Arthritis It is understandable that HCV patients with polyarthritis and positive RF may be clinically classified as having RA. Of the 1988 revised American College of Rheumatology (ACR) criteria, there are four (arthritis of three or more joint areas, arthritis of hand joints, symmetric arthritis, and RF) that some HCV patients may present. Rosner et al. [52] reviewed the prevalence and clinical characteristics of the HCV-related arthritis exhaustively and also analyzed the significant overlap with RA. The most frequent clinical presentation of HCV-related arthritis is chronic inflammatory polyarthritis, which may lead to the fulfillment of the ACR classification criteria for RA in more than 50% of cases. The existence of morning stiffness, rheumatoid nodules, and erosive

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arthritis (rarely described in the setting of HCV infection) [53,54] may be useful to diagnose a true coexistence of RA and HCV. Some studies have focused on the prevalence and clinical significance of antibodies to cyclic citrullinated peptide (CCP) in patients with chronic HCV infection. Wener et al. [55] found no anti-CCP antibodies in HCV patients, although some false-positive results were observed in patients with MC, while Bombardieri et al. [56] found anti-CCP antibodies in 76% of patients with RA and in 60% of those with coexisting RA and HCV, but not in HCV patients, irrespective of their articular involvement. Lienesch et al. [57] found anti-CCP antibodies in 1/50 HCV patients without arthritis. Sene et al. [58] investigated the diagnostic reliability of anti-CCP antibodies in distinguishing HCV-associated rheumatological manifestations from RA. Anti-CCP antibodies were detected in only two HCV-infected patients with articular involvement (6%), in none without arthralgia and in 78% of patients with RA. With a specificity of 93% and a positive predictive value of 96%, anti-CCP antibodies were the most specific biological marker for RA. Recent studies have confirmed that anti-CCP antibodies may be useful in discriminating HCV patients with a true RA from those with HCV-associated arthropathy [59]. Ezzat et al. [60] tested the sera of 30 patients with RA and 22 patients with HCV-related polyarthropathy and found anti-CCP antibodies in 83% of patients with RA in comparison with only 4.5% of HCVþ patients with polyarthropathy; determination of anti-CCP antibodies showed a higher specificity for diagnosing RA with respect to RF (95.4% vs. 18.2%), while the sensitivity was similar (83.3% vs. 90%). Patel et al. [61] identified 92 HCVþ patients (5.1%) out of 1706 patients with RA. In comparison with HCV-negative RA patients, HCV-positive patients were younger, more often African-American, and more frequently smokers; with respect to the therapeutic approach, HCV-positive patients were less likely to receive methotrexate and more likely to receive prednisone and antitumor necrosis factor a (anti-TNFa) therapies. The authors concluded that RA patients with associated chronic HCV infection had a higher disease activity score (mainly associated with higher patient-reported measures) and were more likely to be treated with prednisone and anti-TNFa therapies and less likely to receive methotrexate compared to HCV-negative patients.

4.3 Systemic Lupus Erythematosus Viruses have been postulated as potential etiologic or triggering agents in the pathogenesis of SLE. Chronic HCV infection can induce clinical and serologic features (arthritis, nephropathy, hemocytopenias, and low titers of ANA or anti-dsDNA), which, in combination, may meet the ACR 1982 criteria for SLE. In this context of autoimmunity related to HCV, some reports have suggested that HCV infection may mimic SLE. Some authors have analyzed the

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prevalence of HCV infection in SLE patients [62e64], and case reports of their association have also been published [65,66]. Cacoub et al. [62] found antiHCV antibodies (ELISA-2) in 7 (11%) of 62 patients, although RIBA-2 was positive in only 1 (2%). Kowdley et al. [63] found anti-HCV antibodies (ELISA-2) in 5 (12%) of 42 SLE patients, but only 3 (7%) patients were positive in the immunoblot analysis and 2 (5%) were PCR positive. None of these patients had chronic liver disease symptoms, and only one had abnormal liver test results. We analyzed a large series of SLE patients and found that HCV infection was present in 11% of an unselected SLE population [67]. This prevalence is significantly higher than the prevalence of HCV infection found in the control group (1%) and in the general population in Catalonia (1.2%) and suggests a possible link between HCV infection and SLE. Similar results have been obtained by Ahmed et al. [68] in the United States (10% in SLE patients compared with 1.3% in the general population). In comparison with patients with idiopathic SLE, SLE-HCV patients have a different pattern of clinical and immunologic manifestations, mainly characterized by a lower frequency of cutaneous SLE features, a higher prevalence of liver involvement, a lower frequency of anti-dsDNA antibodies, and a higher prevalence of hypocomplementemia and cryoglobulinemia. Thus it appears that several SLE criteria are very specific to SLE and are rarely present in HCV infection (malar rash, discoid lesions, subacute cutaneous lesions, photosensitivity, neurological manifestations, high titers of ANA or antidsDNA, and presence of anti-Sm antibodies). Two differentiated subsets of SLE-HCV patients may be defined: patients with HCV infection and a “true” SLE, in which HCV might be a concomitant process or, perhaps, might act as a triggering factor and patients with a “lupuslike syndrome” possibly caused by HCV infection. The first group of patients has at least two of the following specific SLE features: malar rash, discoid lesions, subacute cutaneous lesions, photosensitivity, neurological criteria, ANA Z1/160, anti-dsDNA W15 U/mL, or anti-Sm antibodies. We believe that this subset of SLE-HCV patients should be considered as having a “true” SLE with an associated HCV infection. Although the pathogenic role of HCV infection in these patients is unclear, it is possible that HCV acts, in our geographical area, as a triggering factor in some patients with a definite genetic background. The second subset presents a “mild” SLE, mainly characterized by articular involvement, hematologic features, lower titers of ANA and anti-dsDNA, and positive cryoglobulins in the majority of cases. It is known that patients with cryoglobulinemia can show several features commonly observed in SLE, such as arthritis, nephropathy, or hypocomplementemia [69]. In this subset of patients, it is possible that chronic HCV infection (associated with cryoglobulinemia in some cases) may produce a “lupuslike syndrome,” mimicking a “true” SLE according to the 1982 revised criteria for SLE classification. These studies suggest that HCV testing should be considered in the diagnosis of SLE, especially in patients without

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typical SLE cutaneous features and with low titers of autoantibodies (ANA and anti-dsDNA), liver involvement, or cryoglobulinemia. Conversely, patients with chronic HCV infection and extrahepatic features mimicking SLE should be tested for the presence of ANA and anti-dsDNA. In 2009, Mohan et al. [70] tested HCV infection in 50 SLE patients (48 females, 2 males). Anti-HCV antibodies were detected in three patients with SLE, but none of them was positive by PCR, and the authors reported a statistically significant difference between the prevalence of anti-HCV antibodies in patients with SLE (n ¼ 3%; 6%) and the prevalence found in controls (n ¼ 44%; 0.43%).

4.4 Antiphospholipid Syndrome The possible association of APS with viruses has generated a growing interest. Historically, antiphospholipid antibodies have always being closely associated with infectious agents, ever since they were first detected in sera from syphilis patients [71]. In a recent review, Uthman and Gharavi [72] have analyzed the etiopathogenic role of viruses in APS and described isolated cases associated with viruses such as cytomegalovirus, varicella zoster, EpsteineBarr virus, and HCV. We have recently analyzed a total of 45 HCV patients with clinical features related to APS [73]. In comparison with general APS series, APS-HCV patients had a higher mean age and a differentiated clinical spectrum of thrombotic involvement, with a lower frequency of the more typical APS features such as peripheral thrombosis or neurological features and, in contrast, a higher prevalence of atypical or infrequent APS features, such as myocardial infarction or intraabdominal thrombotic events. In addition, a higher frequency of positive immunological markers that are often detected in chronic HCV infection, such as ANA, cryoglobulins, hypocomplementemia, and RF, was observed in patients with APS-HCV. In addition, the higher presence of LA (80%) in APS-HCV patients may well explain the occurrence of thrombotic events in this subset of HCV patients because its prevalence in unselected series of HCV patients is extremely low (less than 1%). Infectious agents may play a diverse etiopathogenic role in the clinical expression of APS, with bacterial infections probably acting as acute triggering agents of a devastating, multiorganic form of APS (catastrophic APS), while chronic viral infections (such as HCV and HIV) may trigger a heterogeneous, atypical presentation of APS.

4.5 Cryoglobulinemic Vasculitis Patients with cryoglobulinemia present a very broad spectrum of clinical features. Although more than 50% of patients present a relatively benign clinical course with a good prognosis and survival [74], some patients may present severe, life-threatening internal organ involvement. Why some

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cryoglobulinemic patients present this severe cryoglobulinemic vasculitis remains unclear. Ferri et al. [74] recently found that 35% of their patients with cryoglobulinemic vasculitis had a moderate to severe clinical course, with the prognosis being severely affected not only by cryoglobulinemic involvement but also by associated conditions such as HCV-related liver failure. Two studies have analyzed the clinical characteristics of HCV-related cryoglobulinemia in a large series of patients. Sene et al. [75] studied 125 patients with MC retrospectively and found that cryoglobulinemic vasculitis was associated with advanced age, longer duration of HCV infection, type II MC, and a higher MC serum level. Ferri et al. [74] analyzed demographic, clinical, and serologic features and survival in 231 patients with MC. One hundred sixty eight patients were tested for HCV infection, with one hundred fifty five (92%) being positive. Malignancies were observed in 15% of patients, mainly non-Hodgkin lymphoma (NHL) and hepatocellular carcinoma, and the main causes of death were related to MC (64%), NHL (13%), and liver involvement (13%). Life-threatening cryoglobulinemia is found in 10e15% of patients with cryoglobulinemic syndrome. The most frequent type of life-threatening involvement is renal failure due to cryoglobulinemic glomerulonephritis. Recent data suggest that cryoglobulinemic glomerulonephritis significantly affects the prognosis and survival [76]. Ferri et al. [74] described renal failure secondary to cryoglobulinemic glomerulonephritis as the main cause of death in their patients with cryoglobulinemia, with a survival rate of 33% after a mean follow-up of 10 years, while Tarantino et al. [77] described a survival rate of 49% at 10 years after renal biopsy in 105 patients with cryoglobulinemic glomerulonephritis. We found a survival rate of 39%, with cryoglobulinemic involvement contributing directly to death in only one-third of cases, with infection and liver disease being the most frequent causes of death [78]. Likewise, Tarantino et al. [77] found that the main causes of death were cardiovascular disease, hepatopathy, and infection. Cryoglobulinemic glomerulonephritis seems to have a poor prognosis in patients with HCV-related cryoglobulinemia. Most of our patients with severe renal involvement had chronic HCV infection, while Beddhu et al. [79] reported that all their patients whose serum creatinine doubled or who progressed to end-stage renal disease were HCV positive. Impaired renal function at diagnosis has also been related to poor prognosis. Tarantino et al. [77] found that patients with an initial serum creatinine level higher than 1.5 mg/dL had a higher risk of end-stage renal disease or death. However, more recently, Matignon et al. [80] found that 10% of non-HCV patients with cryoglobulinemic glomerulonephritis entered end-stage renal failure, a percentage double that found in our study in HCV patients presenting with renal failure, suggesting that the prognosis may have improved in HCV patients, possibly related to the progressive standardization of the use of antiviral therapies. Roccatello et al. [81] evaluated 146 patients with cryoglobulinemic

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nephritis, of whom 87% (n ¼ 127) were HCV positive, and noted type II cryoglobulins (IgG/IgM-k) in 74.4% of cases; the rest had type III cryoglobulins. Diffuse MPGN was the most common histologic pattern (83%), and older age, higher serum creatinine level, and greater proteinuria at diagnosis were associated with the development of kidney failure and death. Survival at 10 years was only 30%, with cardiovascular disease the cause of death in >60% of patients. Additional causes of death included infections (10%), liver failure (19%), and neoplasia (3%). In a more recent study, 151 consecutive HCV-RNAepositive patients with MC vasculitis were prospectively followed up between 1993 and 2009. Factors predictive of poor prognosis were severe liver fibrosis [hazard ratio (HR), 5.3], as well as heart (HR, 4.2), central nervous system (HR, 2.7), and kidney (HR, 1.9) involvement at baseline. Patients treated with antiviral drugs were observed to have a better prognosis, but use of immunosuppressant agents was associated with a worse prognosis. The 1-, 3-, 5-, and 10-year survival rates (since the time of the mixed cryoglobulinemia diagnosis) were 96%, 86%, 75%, and 63%, respectively [82]. In addition, chronic renal failure may enhance immunosuppression and the risk of infectious processes. In fact, four out of the five patients who died in our series due to infectious processes had chronic renal failure due to cryoglobulinemic glomerulonephritis [78]. Gastrointestinal vasculitis and pulmonary hemorrhage are very rare and had a very poor prognosis in patients with cryoglobulinemia. Of the 33 well-reported cases, 26 (80%) died [78]. This illustrates the extremely poor prognosis of cryoglobulinemic pulmonary and intestinal involvement, with a high mortality at presentation and a poor prognosis in survivors presenting a further episode. The lack of a therapeutic protocol (due to the rarity of this type of involvement) together with the high mortality in patients with other types of vasculitis means that both clinical presentations are one of the main challenges in dealing with patients with cryoglobulinemia.

4.6 Sarcoidosis The first association between sarcoidosis and HCV was reported in 1993 by Blum et al. [83]; and was directly related to the onset of a-IFN therapy. We analyzed the clinical characteristics and outcome of 68 cases of coexisting sarcoidosis and chronic HCV infection, in nearly 75% of whom sarcoidosis was triggered by antiviral therapy [84]. Two other patterns of association between sarcoidosis and HCV have been described: the coexistence of both diseases in treatment-na€ıve HCV patients and the reactivation of a preexisting sarcoidosis in HCV patients subsequently treated with anti-HCV therapies.

4.6.1 Sarcoidosis Triggered by Antiviral Therapy Sarcoidosis may be precipitated or exacerbated in some HCV patients receiving antiviral therapy. Nevertheless, this phenomenon remains uncommon. We recorded five cases of sarcoidosis triggered by antiviral therapy from

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nearly 2000 HCV patients treated in our Liver Unit [45], a prevalence of 0.2%, which is very similar to that observed by Leclerc et al. [85], who described 1 case out of 1159 HCV patients treated with a-IFN (0.1%). Thus a prevalence of 1e2 cases of sarcoidosis per 1000 HCV patients treated with antiviral agents should be postulated. As the estimated prevalence of sarcoidosis ranges from 1 to 40 cases per 100,000 population, the frequency of sarcoidosis seems to be higher in HCV patients receiving antiviral therapy than in the general population. Analysis of 50 cases of sarcoidosis triggered by antiviral therapy for HCV infection [84] has permitted a better definition of the main clinical manifestations and outcome of this induced form of sarcoidosis. It appears predominantly in middle-aged women, of whom a round a quarter had received previous antiviral courses, with no response in most cases. In two-thirds of the 50 cases, sarcoidosis was triggered in the first 6 months of antiviral therapy. Although less frequent, sarcoidosis may also appear after completion of antiviral therapy, but in all these cases the disease emerged in the first 3 months after completion. The causeeeffect relationship between IFN administration and the development of sarcoidosis seems to be clear in nearly all cases. However, a possible additional role for RBV should be considered. In 10 out of 12 patients who had received a-IFN monotherapy before the development of sarcoidosis, the granulomatous lesion appeared during the second course of treatment with IFN and RBV and not earlier with IFN alone. RBV may enhance the Th1 response by increasing production and expression of IL-12 mRNA, by increasing production of IFN-g and TNFa, and by lowering the Th2 response. Consequently, the enhancement of a Th1-type immune reaction induced by the combined therapy might trigger granulomatous reactions more frequently than a-IFN monotherapy. This might explain the progressively higher number of cases published in recent years: only 10 cases published between 1993 and 1999, while in the last 4 years, coinciding with the generalized use of combined therapy, the number of cases reported has increased fourfold. A specific clinical pattern was observed in HCV patients with sarcoidosis triggered by the antiviral therapy, with a higher prevalence of cutaneous and articular involvement and a lower frequency of hilar and extrapulmonary adenopathies in comparison with unselected HCV-negative patients with sarcoidosis. The lungs are affected in more than 90% of all patients with sarcoidosis, while in the HCV patients with sarcoidosis the observed percentage is 76%. In contrast, while cutaneous involvement usually occurs in about 25% of all sarcoidosis patients, the percentage in sarcoidosis triggered by antiviral therapy is 60%. In addition, cutaneous sarcoidosis was the only clinical feature in six patients [84], a clinical presentation rarely observed in non-HCV patients. The reasons for this specific predilection for cutaneous involvement are not known. Although cutaneous sarcoidosis may occur in isolation, it is more commonly seen as a manifestation of systemic disease.

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Severe sarcoid involvement (e.g., progressive pulmonary fibrosis, cardiac, and central nervous system) was observed in less than 5% of HCV patients with sarcoidosis triggered by antiviral therapy [84], a similar figure to those reported in general series of sarcoidosis patients [86]. Although the natural history of sarcoidosis is highly variable, spontaneous remission occurs in nearly two-thirds of patients, while the course is chronic and progressive in 10e30% [86]. Nearly 85% of cases of sarcoidosis triggered by anti-HCV therapy improved or remitted spontaneously [84], with less than 10% of cases having a chronic and stable course. Improvement or remission was clearly related to discontinuation of antiviral therapy, with only 35% of patients requiring systemic corticosteroids. In most large published series, 30e50% of unselected patients with sarcoidosis were treated with corticosteroids [86], although the symptoms requiring corticosteroid therapy remain controversial. In patients with mild disease (mainly skin), topical steroids may be all that is necessary, while in those with systemic, symptomatic disease, oral corticosteroids are often employed. Few data are available about the response to antiviral therapy in HCV-sarcoidosis patients. Near to 50% of our patients treated with IFN/RBV presented a viral response at the end of the therapy, a similar prevalence to that observed in unselected HCV patients. We have also reviewed the response to anti-HCV patients in the cases published in the literature [84]. The response was detailed in only 23 cases, with a rate of viral response of 48%. According to these figures, a similar viral response to anti-HCV therapy seems to be observed in HCV patients with sarcoidosis compared with the most recent series of unselected HCV patients. Some recommendations for the management of HCV patients with triggered sarcoidosis should be suggested for the daily clinical practice (Table 9.4). Firstly, an accurate evaluation of the IFN-related adverse effects (such as arthralgias, fever, myalgias, or fatigue) should be made, to clearly separate these effects from the symptomatology originated by the triggered sarcoidosis, discarding the existence of an underlying triggered sarcoidosis in patients with more severe side effects. Secondly, we suggest a baseline chest X-ray upon starting antiviral therapy, with a specific follow-up centered on the possible development of cutaneous or respiratory symptoms. Thirdly, a different therapeutic approach should be considered according to the severity of the triggered sarcoidosis. In patients with mild disease (cutaneous involvement, lymphadenopathy) cessation of antiviral therapy will probably be sufficient, although continuation might be considered under close follow-up (especially in patients with isolated cutaneous lesions). In patients with severe disease (diffuse pulmonary involvement, systemic disease) cessation of antiviral therapy is mandatory, probably together with initiation of oral corticosteroids (adding immunosuppressive agents according to the clinical evolution). In these cases, a close monitoring of liver function, HCV-RNA levels, and cell counts is mandatory. Finally, with respect to the use of antiviral therapy in HCV patients

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TABLE 9.4 Recommendations for the Management of Sarcoidosis in Patients With Chronic Hepatitis C Virus Infection Perform baseline chest X-ray upon starting antiviral therapy Evaluate interferon (IFN)-related adverse effects accurately, discarding the existence of an undiagnosed sarcoidosis in patients with unexpectedly severe or prolonged IFN-related side effects Specific follow-up centered on the possible development of cutaneous or respiratory symptoms suggestive of sarcoidosis Discontinue antiviral therapy in patients with mild sarcoidosis (cutaneous involvement, lymphadenopathy), although continuation might be considered under close follow-up In patients with severe sarcoidosis (diffuse pulmonary involvement, systemic involvement), cessation of antiviral therapy is mandatory When the severity of sarcoid involvement requires treatment with corticosteroids and/or immunosuppressive agents, a close monitoring of liver function, HCV-RNA levels, and cell counts is mandatory In HCV patients with previous sarcoidosis, antiviral therapy should only be indicated with extreme caution and strict individualized assessment

with previous sarcoidosis, antiviral therapy in these patients should only be indicated with extreme caution and strict individualized assessment, especially in patients who received previous antiviral courses.

4.6.2 Sarcoidosis in Treatment-Na€ıve Patients The first case of sarcoidosis in treatment-na€ıve HCV patient was reported by Belgodere et al. [87] in 1999, and the association of the two diseases was considered casual. Eighteen additional cases have been published over the last 4 years, suggesting that this situation may be more frequent than previously supposed. However, this association should be considered as less frequent than that associated with anti-HCV treatment. No differences in clinical features or prognosis were found between treatment-na€ıve HCV patients and sarcoidosis triggered by anti-HCV therapy. In fact, no study has analyzed the prevalence of HCV infection in large series of unselected patients with sarcoidosis, although Bonnet et al. [88] have reported a higher prevalence in a small series of patients with sarcoidosis, detecting HCV infection in 5 out of 32 patients with sarcoidosis. Although a casual coexistence of two independent diseases can occur in some of these patients, the role of HCV as an etiopathogenic agent for sarcoidosis should be investigated in future large matched caseecontrol studies. In the HISPAMEC Registry [37], we reported 28 HCV patients with sarcoidosis unrelated to antiviral therapy (70% women, mean age

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50  4.76 years at diagnosis of sarcoidosis and 54  3.75 years at diagnosis of HCV). 20 out of 24 (83%) patients presented respiratory symptoms, 10/24 (42%) cutaneous involvement, extrapulmonary adenopathies in 12/24 (50%; cervical in 8, supraclavicular in 3, inguinal in 2, abdominal in 1), articular involvement in 3/24 (13%) patients, renal involvement in 1/24 (4%), and parotid gland involvement in 2/24 (7%).

4.7 Noncryoglobulinemic Systemic Vasculitis PAN is considered the most frequent systemic vasculitis associated with chronic HCV infection. More than 60 HCV patients have been reported, in some cases in association with hepatitis B virus (HBV) coinfection [5]. In addition, the prevalence of HCV markers in patients with PAN is high, with positive HCV antibodies being detected in 25 (14%) of the 173 patients analyzed. Several of the 1990 criteria for the classification of PAN, such as weight loss, myalgias or weakness, peripheral neuropathy, elevated BUN/ creatinine, and positive HBV markers, are often observed in HCV patients. Although cryoglobulinemic vasculitis could histologically mimic cutaneous or renal involvement observed in microscopic polyarteritis, classic PAN shows necrotizing inflammation of small- or medium-sized arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Thus the main difference between the two types of systemic vasculitis most frequently associated with HCV (PAN and cryoglobulinemia) is the different size of the vasa involved. The high specificity of this histologic criterium may be useful in the differential diagnosis of PAN or HCV-cryoglobulinemic vasculitis. Other systemic vasculitides are rarely associated with chronic HCV infection, such as giant cell arteritis, Takayasu arteritis, Wegener granulomatosis, ChurgeStrauss vasculitis, and HenocheScho¨nlein purpura [89]. The 1990 criteria for these vasculitides showed a small overlap with the most common extrahepatic features observed in HCV infection, and the coexistence of these vasculitides with HCV infection may be considered a chance phenomenon. In the HISPAMEC Registry [37], we reported 78 HCVþ patients diagnosed with PAN (41% women, mean age 44  3.6 years at PAN diagnosis and 42  3.7 years at HCV diagnosis). Patients fulfilled the classification criteria of PAN: necrotizing inflammation of medium or small arteries in biopsy specimens in 54/57 (95%) patients, livedo reticularis in 35/57 (61%), weight loss in 34/57 (60%), polyneuropathy in 34/57 (60%), myalgias or weakness in 33/57 (58%), altered arteriography in 28/57 (49%), hypertension in 21/57 (37%), raised creatinine in 15/57 (26%), and positive HBsAg in 15/57 (26%). No patient presented with testicular involvement. In a French cohort of 161 patients with HCV-related vasculitis, Saadoun et al. [90] identified 31 (19%) diagnosed with PAN (mean age of 64.5 years at diagnosis, 55% women). In comparison with a control group of patients with

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HCV-related cryoglobulinemic vasculitis (HCV-MC), HCV-PAN showed a higher frequency of fever and weight loss, severe hypertension, gastrointestinal involvement, severe acute sensory-motor multifocal mononeuropathy, kidney and liver microaneurysms, and increased C-reactive protein levels.

4.8 Inflammatory Myopathies The association of HCV with inflammatory myopathies is mainly found in isolated case reports, with a total of 36 cases published, of which 21 were polymyositis [89]. In contrast, only three studies have analyzed the prevalence of HCV in a series of patients with inflammatory myopathies and found HCV infection in 12 of 126 (9.5%) patients [89]. The criteria of Bohan and Peter show a small degree of overlap with HCV infection because HCV patients infrequently present muscle weakness with elevation of muscle enzyme levels or electromyographic evidence of a generalized myopathy. Thus, at present, inflammatory myopathies are tenuously associated with HCV infection. In the HISPAMEC Registry [37], we reported 39 HCV patients with inflammatory myopathies (59% women, mean age at diagnosis of 52 years). Patients fulfilled the following classification criteria for inflammatory myopathies: myopathic changes on electromyography in 34/34 (100%), proximal muscle weakness in 33/34 (97%), increased serum concentrations of muscle enzymes in 33/34 (97%), histopathological findings consistent with inflammatory myositis in 33/34 (97%), and skin lesions suggestive of dermatomyositis in 13/34 (38%). A caseecontrol study by Uruha et al. [91] has evaluated the prevalence of HCV infection in 114 patients with biopsy-proven inclusion-body myositis (IBM) and in 44 age-matched patients with polymyositis diagnosed in the same period. A higher frequency of HCV infection was found in patients with IBM in comparison with those with polymyositis and with the prevalence of HCV infection in the Japanese general population (28% vs. 4.5% vs. 3.4%), suggesting a possible etiopathogenic link between HCV and IBM.

4.9 Other Systemic Autoimmune Diseases Although we have described seven patients with systemic sclerosis (SSc) and HCV infection (76), this association should be considered as very infrequent. The criteria for the diagnosis of SSc are highly specific because the existence of cutaneous sclerosis and positive anti-Scl70/anticentromere antibodies is infrequently described in HCV patients. In 2013, Giuggioli et al. [92] reported four SSc patients with limited scleroderma and positive anticentromere antibodies with symptomatic MC, all of whom presented with complicated skin ulcers of the lower limbs and pulmonary hypertension. In all cases, the diagnosis of SSc preceded the clinical onset of cryoglobulinemic manifestations.

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Other SAD associated with HCV have been reported, including Behcet disease (seven cases), Still disease (one case), ankylosing spondylitis (one case), and mixed connective tissue disease (one case) [5]. Herrera et al. [93] reported a patient with relapsing polychondritis (RP), HCV, and MC, in whom treatment with anti-HCV therapy improved the symptoms of RP.

5. HEMATOLOGICAL DISEASES AND HEPATITIS C VIRUS The specific tropism of HCV for many extrahepatic cell types (Table 9.5), especially for circulating blood cells, has been suggested by several studies [40,41,94e103], providing a clear link between HCV and the development of autoimmune and neoplastic hematological processes. The susceptibility of blood cells to HCV infection might be enhanced by coexisting additional chronic viral infections. Laskus et al. [104] reported that HIV facilitates the infection and replication of HCV in circulating blood cells, a fact that might be related to the development of severe cytopenias in some HCV-HIV patients [105].

5.1 Autoimmune Cytopenias Although HCV-related cytopenias are not uncommon, they are usually considered as mild laboratory abnormalities with no clinical significance, especially in patients with hypersplenism. The most frequent is thrombocytopenia, which has a chronic clinical course with severe bleeding being uncommon. de Almeida et al. [98] found no association between HCV genotypes and thrombocytopenia, although HCV-RNA was detected more frequently in the platelets of thrombocytopenic patients than in those with a normal platelet count. Wang et al. [106] described a 10-fold higher frequency of thrombocytopenia in HCV patients compared with HCV-negative controls, and thrombocytopenia correlated with the severity of HCV-related liver disease. Severe cytopenias are observed in some HCV patients, related or not to antiviral therapy. Thrombocytopenia may be severe (2 log drop viremia at month þ3) was independently associated with a complete clinical response of HCV-Cryovas [odds ratio (OR), 3.53; 95% CI 1.18e10.59], whereas a glomerular filtration rate lower than 70 mL/min was negatively associated with a complete clinical response (OR 0.18; 95% CI 0.05e0.67). Of note, side effects were frequent in 39/70 (56%) patients, including fatigue (47.2%), fever (37.5%), anemia (33.3%), myalgia (25%), neutropenia (20%), depression (15.2%), thrombocytopenia (5%), pruritus (4.1%), and alopecia (2.7%). Similar rates were noted in patients who received IFNa-2b/ribavirin or Peg-IFNa-2b/ribavirin (53.1% vs. 55%, respectively). More recent advances in HCV treatment are based on new class of HCV drugs, i.e., direct acting antiviral agents (DAA), which showed higher SVR rates. The first antiviral combination including a DAA in HCV-Cryovas patients was based on a combination of Peg-IFNa, ribavirin, and a DAA (i.e., Boceprevir or Telaprevir) in patients infected with HCV genotype 1. In a prospective cohort study [28], the efficacy of an NS3 protease inhibitor [boceprevir or telaprevir (thrice daily)]), in combination with Peg-INFa2a (180 mg) or 2b (1.5 mg/kg) and ribavirin (800e1400 mg/day), has been evaluated in 23 HCV-Cryovas patients with genotype 1. Thirteen patients (56.5%) were complete clinical responders, and 10 (43.5%) were partial responders at week 24. The virological response (i.e., HCV RNA negativation) was of 69.6% at week 24 (p ¼ .005). The cryoglobulin level decreased from 0.44 to 0.06 g/L (p ¼ .0006) and the C4 level increased from 0.09 to 0.15 g/L (p ¼ .045). However, grade 3 and 4 adverse events (mainly anemia, neutropenia, and thrombocytopenia) were observed in 43.5%: 20 patients (87%) received erythropoietin, 9 (39.1%) had red cell transfusion, and 2 (8.7%) had granulocyte stimulating agents. Antiviral therapy discontinuation was required in eight (34.7%) patients for virological nonresponse (n ¼ 5), virological relapse (n ¼ 2), and depression (n ¼ 1). In another prospective, single-center controlled Italian cohort study [29], 35 HCV genotype 1 patients received Peg-IFN/ribavirin for 48 weeks in combination to boceprevir, after a 4-week period of Peg-IFN/ribavirin. Patients showed a drastic reduction of the cryocrit values and an improvement of HCV-Cryovas symptoms. When compared with matched HCV controls without HCV-Cryovas, Cryovas patients showed an SVR (23.9% vs. 70%; p ¼ .01) less frequently. During the last 2 years, all oral interferon-free, DAA regimens have been used in HCV-Cryovas. Such combination led to remove interferon alpha, which had the potential to exacerbate autoimmune disease states. The VASCUVALDIC enrolled 24 consecutive patients (median age 56.5 years, 46% women) with HCV-Cryovas who received sofosbuvir (400 mg/day) associated to ribavirin (200e1,400 mg/day), for 24 weeks [30]. The primary efficacy end point was a complete clinical response of the Cryovas at the end of treatment (week 24). Rituximab (four weekly infusions at 375 mg/m2) was used in four cases, in addition with prednisone (50 mg/day progressively tapered) and

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plasmapheresis in two patients. Main features of HCV-Cryovas included purpura and peripheral neuropathy (67%), arthralgia (58%), glomerulonephritis (21%), and skin ulcers (12%). Twenty one (87.5%) patients were complete clinical responders at week 24. Complete clinical response was very rapid as noted in six (25%) patients at week 4, four (16.6%) at week 8, seven (29.2%) at week 12, three (12.5%) at week 16, and one (4.2%) at week 20. The cryoglobulin level decreased from 0.35 (0.16e0.83) at baseline to 0.15 (0.05e0.45) g/L at week 24. The C4 serum level increased from 0.10 (0.07e0.19) to 0.17 (0.09e0.23) g/L at week 24. Seventy four percent of patients had an SVR at week 12 posttreatment. The most common side effects were fatigue, insomnia, and anemia. Only two serious adverse events were observed. Sise et al. have reported 12 HCV-Cryovas patients treated with sofosbuvir-based regimens between December 2013 and September 2014 [31]. Median age was 61 years, 58% were male, and 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7e2.47 mg/dL). Four patients received rituximab concurrent with DAA therapy. The SVR at 12 weeks posttreatment was 83%. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with a median percent decreasing from 1.5% to 0.5%, and completely disappeared in 4/9 cases. Serious adverse events were infrequent (17%). The historical cohort of this study treated with pegylated-IFN and ribavirin experienced only 10% SVR12 rate with 100% experiencing at least one adverse event and 50% experiencing premature discontinuation due to adverse events [29].

2.2 Other Nonvirological Treatments Rituximab rapidly appeared as an interesting therapy in HCV-Cryovas because it targets activated B cells, which are responsible for cryoglobulin production and finally Cryovas lesions. Two randomized controlled trial showed that rituximab has a better efficacy in HCV-Cryovas than conventional treatments (i.e., glucocorticoids, azathioprine, cyclophosphamide, or plasmapheresis) or placebo [32,33]. A combination therapy with rituximab and optimal HCV treatment appeared logical as it targeted both the B-cell arm of autoimmunity and the viral trigger. Two controlled clinical trials showed that addition of rituximab to pegylated-IFN/ribavirin led to a shorter time to clinical remission, better renal response rate, and higher rates of cryoglobulin clearance [34,35]. However, some patients may experience a severe flare of vasculitis after rituximab infusion, notably those with high cryoglobulin levels [36]. In vitro immunochemical assays showed that rituximab formed a complex with the cryoprecipitating IgM kappa that had RF activity. In vitro addition of rituximab to serum containing a RF-positive IgM kappa type II mixed cryoglobulin was associated with accelerated cryoprecipitation. Therefore rituximab should be administered with caution in HCV-Cryovas patients, with use of the

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375 mg/m2 protocol, associated with plasma exchanges prior to rituximab infusion in patients with high baseline cryoglobulin levels. Corticosteroids, used alone or in addition to IFNa, did not favorably affect the response of HCV-Cryovas manifestations in two controlled studies [37,38]. Low-dose corticosteroids may help to control minor intermittent inflammatory signs such arthralgia, but do not succeed in cases of major organ involvement (i.e., neurologic, renal, cardiac), or in the long-term control of vasculitis. Plasmapheresis offers the advantage of removing the pathogenic cryoglobulins from the circulation of patients with HCV-Cryovas and is particularly effective for rapidly progressive glomerulonephritis and/or severe skin necrosis or ulcers. Immunosuppressive therapy is usually needed associated with plasma exchange to avoid the rebound increase in cryoglobulin serum level seen after discontinuation of apheresis. When used in combination with HCV treatment, plasmapheresis did not modify the virologic response if IFNa was given after each plasma exchange session. Interleukin 2 (IL-2), a cytokine that promotes Treg survival and function, could be beneficial for HCV-Cryovas patients resistant to HCV therapy. Safety and immunological effects of low-dose IL-2 has been reported in a prospective open-label phase I/IIa study [13]. Ten patients with HCV-Cryovas refractory to conventional antiviral and/or rituximab therapy received one IL-2 course of 1.5 million IU/day for 5 days, followed by three 5-day courses of 3 million IU/ day at week 3, 6, and 9. Improvement of the vasculitis symptoms was found in 8 of 10 patients. Administration of low-dose IL-2 was followed by an increase in the percentage of CD4þCD25hiCD127Foxp3þ Tregs with potent suppressive activity in all subjects and a concomitantly decreased proportion of marginal zone B cells. Transcriptome studies of peripheral blood mononuclear cells revealed that IL-2 induced a global attenuation of inflammatory/oxidative stress mediators.

2.3 Therapeutic Guidelines Aggressive optimal antiviral therapy with IFN-free DAA combination should be considered as induction therapy for HCV-Cryovas patients with mild to moderate disease severity and activity (i.e., without rapidly progressive nephritis, motor neuropathy, or other life-threatening complications). The duration of antiviral therapy in HCV-Cryovas patients is 12e24 weeks according to the regimen of DAA used and to predictive factors of virological response (i.e., liver cirrhosis, genotype 3, or nonresponse to previous antiviral drugs). Low-dose corticosteroids may also help to control minor intermittent inflammatory signs such arthralgia or purpura. In patients presenting with more severe HCV-Cryovas disease (i.e., worsening of renal function, mononeuritis multiplex, extensive skin disease including ulcers and distal necrosis), combination therapy with rituximab plus

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IFN-free DAA combination is recommended as it may target both the downstream B-cell arm of autoimmunity and the viral trigger: (1) weekly administration of four intravenous infusions of rituximab at 375 mg/m2 (on days 1, 8, 15, and 22) and (2) antiviral combination of IFN-free DAA starting at the same time of rituximab for 12e24 weeks duration. For patients presenting with the fulminant forms of HCV-Cryovas including skin necrosis, rapidly progressive glomerulonephritis; digestive, cardiac, pulmonary, and/or central nervous system involvement; or signs of hyperviscosity, apheresis can have immediate beneficial effects. It must be combined with immunosuppression to avoid postapheresis rebound of cryoglobulinemia. High-dose steroids, rituximab, and sometimes cyclophosphamide combination appeared as an effective salvage treatment for refractory HCV-Cryovas. In such cases, antiviral therapy should be differed after the critical phase.

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Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet January 28, 2012;379(9813):348e60. [2] Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D. Cryoglobulinemia vasculitis. Am J Med September 2015;128(9):950e5. [3] Saadoun D, Delluc A, Piette JC, Cacoub P. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol January 2008;20(1):23e8. [4] Sansonno D, Dammacco F. Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. Lancet Infect Dis April 2005;5(4):227e36. [5] Cacoub P, Poynard T, Ghillani P, Charlotte F, Olivi M, Piette JC, et al. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment Virus C. Arthritis Rheum October 1999;42(10):2204e12. [6] Sansonno D, De Vita S, Iacobelli AR, Cornacchiulo V, Boiocchi M, Dammacco F. Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia. J Immunol April 1, 1998;160(7):3594e601. [7] Ivanovski M, Silvestri F, Pozzato G, Anand S, Mazzaro C, Burrone OR, et al. Somatic hypermutation, clonal diversity, and preferential expression of the VH 51p1/VL kv325 immunoglobulin gene combination in hepatitis C virus-associated immunocytomas. Blood April 1, 1998;91(7):2433e42. [8] Saadoun D, Sellam J, Ghillani-Dalbin P, Crecel R, Piette JC, Cacoub P. Increased risks of lymphoma and death among patients with non-hepatitis C virus-related mixed cryoglobulinemia. Arch Intern Med October 23, 2006;166(19):2101e8. [9] Monti G, Pioltelli P, Saccardo F, Campanini M, Candela M, Cavallero G, et al. Incidence and characteristics of non-Hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias. Arch Intern Med 2005;165:101e5. [10] Gorevic PD, Kassab HJ, Levo Y, Kohn R, Meltzer M, Prose P, et al. Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med August 1980;69(2):287e308.

210 SECTION j III Autoimmune Manifestations of Viral Hepatitis [11] Quartuccio L, Isola M, Corazza L, Ramos-Casals M, Retamozo S, Ragab GM, et al. Validation of the classification criteria for cryoglobulinaemic vasculitis. Rheumatology (Oxford) December 2014;53(12):2209e13. [12] Saadoun D, Bieche I, Maisonobe T, Asselah T, Laurendeau I, Piette JC, et al. Involvement of chemokines and type 1 cytokines in the pathogenesis of hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy. Arthritis Rheum 2005;52(9):2917e25. [13] Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med December 1, 2011;365(22):2067e77. [14] Zignego AL, Wojcik GL, Cacoub P, Visentini M, Casato M, Mangia A, et al. Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis. Genes Immun October 2014;15(7):500e5. [15] Sene D, Ghillani-Dalbin P, Thibault V, Guis L, Musset L, Duhaut P, et al. Longterm course of mixed cryoglobulinemia in patients infected with hepatitis C virus. J Rheumatol November 2004;31(11):2199e206. [16] Vallat L, Benhamou Y, Gutierrez M, Ghillani P, Hercher C, Thibault V, et al. Clonal B cell populations in the blood and liver of patients with chronic hepatitis C virus infection. Arthritis Rheum November 2004;50(11):3668e78. [17] Ferri C, Sebastiani M, Giuggioli D, Cazzato M, Longombardo G, Antonelli A, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum June 2004;33(6):355e74. [18] Terrier B, Semoun O, Saadoun D, Se`ne D, Resche-Rigon M, Cacoub P. Prognostic factors in patients with hepatitis C virus infection and systemic vasculitis. Arthritis Rheum 2011;63(6):1748e57. [19] Ramos-Casals M, Robles A, Brito-Zero´n P, Nardi N, Nicola´s JM, Forns X, et al. Lifethreatening cryoglobulinemia: clinical and immunological characterization of 29 cases. Semin Arthritis Rheum 2006;36(3):189e96. [20] Misiani R, Bellavita P, Fenili D, Vicari O, Marchesi D, Sironi PL, et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med March 17, 1994;330(11):751e6. [21] Zuckerman E, Keren D, Slobodin G, Rosner I, Rozenbaum M, Toubi E, et al. Treatment of refractory, symptomatic, hepatitis C virus related mixed cryoglobulinemia with ribavirin and interferon-alpha. J Rheumatol September 2000;27(9):2172e8. [22] Naarendorp M, Kallemuchikkal U, Nuovo GJ, Gorevic PD. Longterm efficacy of interferonalpha for extrahepatic disease associated with hepatitis C virus infection. J Rheumatol November 2001;28(11):2466e73. [23] Cacoub P, Lidove O, Maisonobe T, Duhaut P, Thibault V, Ghillani P, et al. Interferon-alpha and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum December 2002;46(12):3317e26. [24] Bruchfeld A, Lindahl K, Stahle L, Soderberg M, Schvarcz R. Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant August 2003;18(8):1573e80. [25] Alric L, Plaisier E, Thebault S, Peron JM, Rostaing L, Pourrat J, et al. Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN. Am J Kidney Dis April 2004;43(4):617e23. [26] Mazzaro C, Zorat F, Caizzi M, Donada C, Di Gennaro G, Maso LD, et al. Treatment with peg-interferon alfa-2b and ribavirin of hepatitis C virus-associated mixed cryoglobulinemia: a pilot study. J Hepatol May 2005;42(5):632e8.

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Saadoun D, Resche-Rigon M, Thibault V, Piette JC, Cacoub P. Antiviral therapy for hepatitis C viruseassociated mixed cryoglobulinemia vasculitis: a long-term followup study. Arthritis Rheum November 2006;54(11):3696e706. Saadoun D, Resche Rigon M, Thibault V, Longuet M, Pol S, Blanc F, et al. Peg-IFNalpha/ ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: results at week 24. Ann Rheum Dis April 20, 2013;73. Gragnani L, Fabbrizzi A, Triboli E, Urraro T, Boldrini B, Fognani E, et al. Triple antiviral therapy in hepatitis C virus infection with or without mixed cryoglobulinaemia: a prospective, controlled pilot study. Dig Liver Dis 2014;46(9):833e7. Saadoun D, Thibault V, Si Ahmed SN, Alric L, Mallet M, Guillaud C, et al. Sofosbuvir plus ribavirin for hepatitis C virus-associated cryoglobulinaemia vasculitis: VASCUVALDIC study. Ann Rheum Dis November 13, 2015;75. Sise ME, Bloom AK, Wisocky J, Lin MV, Gustafson JL, Lundquist AL, et al. Treatment of hepatitis C virus-associated mixed cryoglobulinemia with sofosbuvir-based direct-acting antiviral agents. Hepatology October 17, 2015;63. De Vita S, Quartuccio L, Isola M, Mazzaro C, Scaini P, Lenzi M, et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum March 2012;64(3):843e53. Sneller MC, Hu Z, Langford CA. A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis. Arthritis Rheum March 2012;64(3):835e42. Saadoun D, Resche Rigon M, Sene D, Terrier B, Karras A, Perard L, et al. Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood July 22, 2010;116(3):326e34. Dammacco F, Tucci FA, Lauletta G, Gatti P, De Re V, Conteduca V, et al. Pegylated interferon-alpha, ribavirin, and rituximab combined therapy of hepatitis C virus-related mixed cryoglobulinemia: a long-term study. Blood July 22, 2010;116(3):343e53. Sene D, Ghillani-Dalbin P, Amoura Z, Musset L, Cacoub P. Rituximab may form a complex with IgMkappa mixed cryoglobulin and induce severe systemic reactions in patients with hepatitis C virus-induced vasculitis. Arthritis Rheum December 2009;60(12):3848e55. Dammacco F, Sansonno D, Han JH, Shyamala V, Cornacchiulo V, Iacobelli AR, et al. Natural interferon-alpha versus its combination with 6-methyl-prednisolone in the therapy of type II mixed cryoglobulinemia: a long-term, randomized, controlled study. Blood November 15, 1994;84(10):3336e43. Casato M, Agnello V, Pucillo LP, Knight GB, Leoni M, Del Vecchio S, et al. Predictors of long-term response to high-dose interferon therapy in type II cryoglobulinemia associated with hepatitis C virus infection. Blood November 15, 1997;90(10):3865e73.

Chapter 11

Systemic Lupus Erythematosus M. Vilardell-Tarre´s, A. Selva-O’Callaghan and J. Ordi-Ros Vall D’Hebron General Hospital, Barcelona, Spain

1. INTRODUCTION Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a broad range of clinical manifestations. It is characterized by an immune system dysregulation resulting in the production of various autoantibodies and is considered a multifactorial disease with evidence of genetic susceptibility [1]. SLE affects several organ systems and leads to significant morbidity and mortality. Gastrointestinal (GI) manifestations caused by the disease per se or aggressive treatment regimens are not rare in SLE patients [2], but are seldom reported, likely being masked by other, more salient clinical features such as renal or central nervous system abnormalities. The incidence of GI symptoms attributable to the disease itself varies widely, ranging from 1.3% to 27.5% in the literature. Chronic intestinal pseudoobstruction (CIPO), protein-losing gastroenteropathy, and intestinal vasculitis are the most common identifiable SLE-related GI manifestations [3], which seem to occur more commonly in Asian populations. No specific autoantibodies associated with SLE-related gastroenteropathy have been identified to date. In this chapter, we describe the GI manifestations occurring in SLE patients. The liver manifestations of the disease are beyond the scope of this chapter and will be reviewed elsewhere.

2. OVERVIEW OF GASTROINTESTINAL MANIFESTATIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS Almost half of all lupus patients experience anorexia, nausea, and vomiting. These symptoms may result not only by GI involvement but also from the uremia associated with renal failure, or from the effects of cytostatic therapies, such as azathioprine and intravenous cyclophosphamide pulses, or the more recently used immunosuppressive drug, mycophenolate mofetil. The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00011-8 215 Copyright © 2017 Elsevier B.V. All rights reserved.

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Serositis (pleuritis, pericarditis, and less frequently, ascites) is a wellrecognized diagnostic criterion of SLE. It is present in 8e11% of patients and can be divided into inflammatory (true serositis) or noninflammatory serositis, mainly caused by the hypoalbuminemia resulting from nephrotic syndrome, liver cirrhosis, or protein-losing enteropathy. Chronic ascites due to lupus per se has a painless onset, progresses even in the absence of other signs of disease activity, and usually responds to corticosteroids or in refractory cases, cyclophosphamide [4,5]. GI symptoms are the first complaints in nearly one-third of lupus patients, although they can occur at any stage of the disease. It is important to be aware of these manifestations in SLE because misdiagnoses and delayed treatment can lead to unfavorable outcomes [3]. Abdominal pain is usually a nonspecific symptom, but it can be particularly important in lupus patients, occurring in adults with this condition [4] and in childhood-onset SLE [6]. Acute abdomen is always a challenging diagnostic and therapeutic problemdeven more so in SLE [7]dand the abdominal pain may also be caused by the complications of therapy or the disease, itself (Table 11.1). Immunosuppressive agents and corticosteroids, the usual treatments for SLE, may mask the classic symptoms of bowel perforation and ischemia, two of the main causes of acute abdomen. Nonsteroidal antiinflammatory drugs, azathioprine, calcineurin antagonists such as cyclosporine and tacrolimus, and mycophenolate mofetil can all cause abdominal pain to a greater or lesser extent. Evaluation of the patient’s disease activity using the

TABLE 11.1 Abdominal Pain in Systemic Lupus Erythematosus (SLE) SLE-Related

Treatment-Related

Non-SLE Causes

Renal vein thrombosis

Gastritis, duodenitis

Appendicitis

Mesenteric thrombosis

Pancreatitis (azathioprine)

Viral hepatitis

Acalculous cholecystitis

Sepsis

Biliary pancreatitis

Bowel perforation

Peptic ulcer

Diverticulitis

Vasculitis

Perforation

Surgical adhesions

Ectopic pregnancy

Enterocolitis

Pancreatitis

Salmonella infection

Serositis Splenic infarction Ischemic bowel disease Angioedema

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SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) may help physicians to choose the most effective approach. Intraabdominal vasculitis and mesenteric thrombosis, both severe abdominal complications of SLE, seem to be associated with higher scores on the SLEDAI [5] and other activity indices [8]. However, one study has reported that the SLEDAI is not reliable as a general marker of SLE-related GI manifestations [9]. Radiological examinations such as ultrasound and computed tomography (CT) scanning are essential to achieve the correct diagnosis; gastroscopy and colonoscopy, which can show ischemia and ulcers, are also of value. Prompt laparotomy is preferred in some cases, particularly acute abdomen with active SLE or a severe clinical presentation, because mortality is high in these patients [10,11]. Mesenteric insufficiency [4], sometimes referred to as intestinal angina, is a related complication that deserves special attention. It is well recognized that SLE patients are prone to premature atherosclerosis, affecting several vascular territories. In addition to the cerebral and coronary vessels, the splanchnic arteries may be affected, causing chronic intermittent abdominal pain, which should not be overlooked. The symptoms usually start after lunch and persist for 1e3 h. Weight loss and a fear of eating are common in patients with mesenteric insufficiency. Conventional angiography is the criterion standard diagnostic technique, but magnetic resonance imaging (MRI) and abdominal CT angiography are also useful in this regard and are less invasive. Longstanding disease, renal failure, long-term corticosteroid therapy, and the presence of classic cardiovascular risk factors such as hypertension, smoking, hyperlipidemia, and diabetes favor the development and progression of atherosclerosis in SLE. Healthy lifestyle habits and drug therapy (e.g., statins) are strongly recommended to control or minimize these factors. Therapeutic options include surgical revascularization and, in selected cases, percutaneous transluminal mesenteric angioplasty with or without stent placement. Anticoagulation therapy and antiplatelet therapy with aspirin or clopidogrel should be prescribed on an individual basis.

3. ORAL CAVITY, ESOPHAGUS, AND GASTROINTESTINAL ABNORMALITIES Oral ulcers are common in SLE, occurring in 6e52% of patients [2]. The lesions are usually painless and affect the hard palate, nasal cavity, and pharyngeal wall. As most lupus patients receive immunosuppressive therapy, infection should not be overlooked as a cause of oral ulcers. Candidiasis, herpes virus, and oral leukoplakia can produce oral ulcers or plaquelike lesions. Secondary sicca syndrome with dry mouth and dry eyes develops in almost 20% of lupus patients [12]. Dry mouth favors periodontal disease and aphthous ulcers, erythema, hemorrhage, and gingival overgrowth. Cyclosporine A treatment usually exacerbates gingival hypertrophy. Tissue biopsy may show

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lupus-specific histopathology similar to that seen in the skin. Histology and immunopathology of the oral lesions in these patients include an inflammatory perivascular lymphohistiocytic infiltrate, spongiosis, hyperkeratosis, and deposition of IgG/IgM, complement, or fibrinogen at the dermal/epidermal junction. The lesions may be difficult to distinguish from oral lichen planus or leukoplakia. Antimalarial agents (chloroquine and hydroxychloroquine) and topical corticosteroids are the treatments of choice for SLE-related oral lesions. Systemic steroids and/or azathioprine are generally used in severe cases. Thalidomide and cyclosporine A in Europe and methotrexate in the United States are used as second-line agents in the most refractory cases. To date, there are no evidence-based guidelines for systemic therapy of oral lesions in lupus patients. Sugar-free gum, artificial saliva, and systemic therapy with pilocarpine hydrochloride to increase salivation can be useful in cases of secondary Sjo¨gren syndrome. Esophageal symptoms in SLE include dysphagia and heartburn, but it cannot be assumed that these are due to the disease and not the therapy. The introduction of proton pump inhibitors has lowered the incidence of esophageal symptoms. Manometric abnormalities, particularly hypoperistalsis in the upper third of the esophagus, have been reported in almost two-thirds of lupus patientsdeven asymptomatic onesdand may be associated with CIPO, an uncommon GI complication discussed in the following text. Involvement of the lower esophageal sphincter is rare, and esophageal symptoms do not seem to correlate well with the manometry findings [7]. Conventional, symptomatic therapy (proton pump inhibitors and small, frequent meals) may be a better approach than immunosuppressive or antiinflammatory therapy. Nonetheless, if vasculitis or inflammation is seen on biopsy study, treatment of lupus itself is warranted, particularly when the disease is serologically and clinically active. Gastric disease is more often related to treatment complications [nonsteroidal antiinflammatory drugs (NSAIDs) and corticosteroids] than to the disease itself. Therefore patients on long-term NSAIDs may require a gastroprotective agent such as proton pump inhibitors. Clinicians should be aware of cytomegalovirus infection of the gastric mucosa, particularly in lupus patients receiving long-term treatment with mycophenolate mofetil, as this is a well-known complication in renal transplantation [13]. Gastric antral vascular ectasia, also referred to as watermelon stomach, is a rare vascular malformation that has been described in SLE. It can cause acute or chronic bleeding that, in turn, leads to persistent iron deficiency anemia. Moderate doses of prednisone are recommended, although transendoscopic treatment or antrectomy may occasionally be needed [14]. Colon and small bowel involvement includes pneumatosis cystoides intestinalis, an uncommon but important condition in which gas is found in a linear or cystic form in the submucosa or subserosa of the bowel wall [15]. The left colon and ileum are the bowel segments most often affected. There are a

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few reports of pneumatosis cystoides intestinalis in adults with systemic autoimmune diseases, especially systemic sclerosis and dermatomyositis, but it has been mainly described in SLE patients [7,16]. Several mechanisms have been proposed for the development of this condition, including breaks in the intestinal mucosa, infection, and ischemia due to vasculitis. Pneumatosis cystoides intestinalis is often asymptomatic and sometimes occurs with pneumoperitoneum, which is sterile and must be differentiated from a perforated viscus. Pneumoperitoneum should be considered a sign, not a disease, and its relevance should be interpreted within the overall clinical context. Differentiation between the benign variety, in which no intervention is indicated, and the life-threatening form, in which immediate surgery is necessary, is extremely important and sometimes challenging for the clinician. Radiologic study, mainly contrast-enhanced abdominal CT, usually assists the diagnosis. As a rule, bowel biopsies are not indicated in this benign pneumoperitoneum, although ischemic necrosis of the bowel wall due to vasculitis or thrombosis due to antiphospholipid antibodies (aPL) has been reported in SLE patients [17]. After excluding life-threatening illnesses such as bowel necrosis, perforation, and infections, patients whose symptoms are caused by the cysts themselves can be treated with oxygen or antibiotics. Because reports of pneumatosis cystoides intestinalis treatment are at best anecdotal, the decision to treat and the treatment chosen should be carefully balanced against the risks. In the absence of sepsis and peritonitis, treatment remains highly conservative [18]. Physicians should bear in mind the possibility that enteritis due to cytomegalovirus or Salmonella spp. infection may be the cause of the abdominal pain and diarrhea in immunocompromised lupus patients. Nearly 20% of patients with Salmonella bacteremia have underlying lupus disease.

4. MAIN IDENTIFIABLE LUPUS-RELATED GASTROINTESTINAL SYNDROMES 4.1 Lupus Mesenteric Vasculitis Lupus mesenteric vasculitis (LMV) is the main cause of acute abdominal pain and one of the most serious complications in SLE patients [9,19]. Acute, severe, and diffuse abdominal pain with a sudden onset is the clinical hallmark of the syndrome. In addition to abdominal pain, there is usually evidence of active disease in other organs, fever, acute-phase proteins elevation, and a high SLEDAI score. Occult blood in stool or even frank GI hemorrhage is also reported. Although the pathophysiology of LMV in these patients is not well defined, it seems that lupus cystitis, whether symptomatic or not, occurs simultaneously with LMV, perhaps due to immune complexemediated abdominal vasculitis. Data from a large study performed in China have suggested that leukopenia, hypoalbuminemia, and elevated serum amylase are

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negative prognostic factors in LMV, whereas cyclophosphamide therapy is associated with a better prognosis [20]. The small mesenteric vessels are usually affected, and pathology findings include both vasculitis and thrombosis, which would probably be related to the presence of aPL. The diagnosis is usually made on clinical criteria due to the difficulty in obtaining bowel specimens for pathology analysis. LMV is generally accompanied by bowel ischemia, which can lead to perforation and hemorrhage, with an associated mortality rate of almost 50%. Abdominal CT is extremely useful for establishing a prompt diagnosis, as it enables reliable visualization of the vasculature and can depict the bowel dilation, focal or diffuse bowel thickening with bowel wall enhancement (target sign), mesenteric edema (comb sign), and ascites commonly seen in this condition [19]. A clue to the diagnosis of LMV is involvement of several different vessels simultaneously. The most frequently affected anatomical structures are the jejunum and ileum, followed by the duodenum. Rectal involvement is fairly uncommon, even though this area is well supplied with blood. Improvement after intravenous glucocorticoid therapy (prednisolone pulses of 1 g/day for 3 days) may favor the diagnosis of reversible ischemic bowel disease caused by intestinal vasculitis. A differential diagnosis with inflammatory bowel disease is sometimes required. Glucocorticoids remain the therapy of choice and can be combined with immunosuppressive agents such as cyclophosphamide. Surgery is recommended when the patient’s general condition deteriorates [19,21].

4.2 Intestinal Pseudoobstruction CIPO is a rare, severe, and poorly understood GI complication of SLE. It has been defined as the presence of clinical features of intestinal obstruction without an identifiable organic obstructive lesion [22]. CIPO reflects a dysfunction of the visceral smooth muscle or the visceral autonomic nervous system. Ureterohydronephrosis and biliary tract abnormalities have been reported in association with CIPO, which indicate the existence of a smooth muscle motility problem [23,24] (Figs. 11.1 and 11.2). Interstitial cystitis resulting from immune complex deposition in the vessels of the bladder walls is present in one-third of cases. Nearly half the patients described are of Asian origin [24,25], which implies a genetic component, although studies to identify a specific related human leukocyte antigen have not been carried out. The clinical presentation is subacute, with mild abdominal pain and abdominal distension accompanied by very sluggish or absent peristalsis. Rebound tenderness is uncommon. CIPO can be the first manifestation of SLE, but it usually develops as a GI complication appearing during the course of the disease. Mortality is not related to CIPO itself, but instead to sepsis related to immunosuppressive treatment or to involvement of other major organs attributable to SLE. Most patients have a fluctuating course, with recurrent

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FIGURE 11.1 Abdominal magnetic resonance imaging with dilated urinary pelvicalyceal system and bilateral ureterohydronephrosis.

FIGURE 11.2 Magnetic resonance cholangiopancreatography showing dilatation of the extrahepatic common biliary tract and the pancreatic duct without extrinsic or intrinsic obstruction.

clinical relapses. The small bowel is affected more often than the large bowel [24,26]. Radiological examination, mainly ultrasonography and contrast-enhanced abdominal CT, often shows bilateral ureteral dilatation and decreased capacity of the urinary bladder. Chronic interstitial cystitis, a condition associated

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with immune complex deposition and a well-recognized complication of SLE, has been documented in some patients with CIPO [25e27]. The clinically suspected diagnosis is typically confirmed by antroduodenal manometry, which usually shows esophageal aperistalsis and intestinal hypomotility, which may be neurogenic or myogenic. Immune complexemediated vasculitis or a common autoantibody against the enteric nervous system or smooth muscle may be responsible for the symptoms of CIPO. Serositis, vasculitis, and bowel wall fibrosis are occasionally found on histopathological study. No specific autoantibodies have been consistently associated with CIPO, but most patients test positive to antinuclear antibodies and anti-Ro antibodies and have serology findings suggestive of active disease [22,25]. Antibodies against proliferating cell nuclear antigen have been reported in two lupus patients with chronic CIPO [28], although the clinical value of this finding is uncertain. The therapy of choice for CIPO in SLE is high doses of intravenous prednisone. Other immunosuppressive agents (e.g., azathioprine, cyclosporine A, and cyclophosphamide) have been successfully used as the initial treatment and as maintenance therapy in prednisone nonresponders. Broad-spectrum antibiotics, prescribed to decrease bacterial overgrowth, and promotility agents such as erythromycin are usually effective when combined with the immunosuppressive regimen. Octreotide, a long-acting somatostatin analog, and rituximab, an anti-CD20 monoclonal antibody, have been used successfully in isolated cases and may prove useful for refractory or severely ill patients. Early recognition of CIPO is important because it is potentially reversible when treated with immunosuppressive agents. Surgery should be avoided whenever possible.

4.3 Protein-Losing Enteropathy Lupus proteinelosing enteropathy (LUPLE) is a clinical syndrome characterized by hypoalbuminemia due to protein loss from the GI tract in the absence of significant loss from the kidneys, reduced protein intake, malnutrition, or severe liver disease [4]. Thus the diagnosis of LUPLE relies mainly on exclusion of other conditions. Nonetheless, the diagnosis should not be considered definite, because several GI abnormalities, such as intestinal lymphoma, lymphatic obstruction, lymphangiectasia, and malabsorption, can be responsible for a loss of proteins. The main symptoms of LUPLE are generalized edema, abdominal pain, and severe diarrhea. This disorder is a well-recognized, but uncommon, manifestation of SLE and can be the initial symptom of the disease. Moreover, as CIPO is also more frequent in Asian patients, specific genetic or environmental factors may play a role [29]. The pathogenesis of LUPLE is uncertain. Mesenteric vasculitis, which has occasionally been found in mucosal biopsies, may be a likely mechanism. Although no specific autoantibodies have been

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associated with this GI manifestation, it seems that an increase in mucosal capillary permeability as a result of complement deposition or cytokinemediated damage may be implicated in the pathogenesis [30]. The diagnosis of LUPLE should be confirmed by complementary examinations. Technetium 99melabeled human serum albumin scintigraphy is the criterion standard quantitative evaluation, and the alpha-1-antitrypsin stool test can be of value in the diagnosis. Other examinations such as endoscopy, barium studies, abdominal CT scanning, or the D-xylose absorption test may also be needed. Most LUPLE patients respond well to corticosteroid therapy, although intravenous pulse cyclophosphamide may be necessary in refractory cases. In one study, the combination of prednisolone and azathioprine proved effective and well tolerated for treating LUPLE in SLE patients [31]. A systematic review including 112 LUPLE patients has provided data that concur with most of the aforementioned concepts [32].

5. LUPUS-ASSOCIATED PANCREATITIS Pancreatitis is a rare complication of SLE. In the general population, choledocholithiasis, alcohol intake, and certain drugs are common causes of pancreatitis. However, some lupus patients develop pancreatitis of uncertain origin, which has been attributed to the disease itself. In the clinical approach to a patient with SLE-associated pancreatitis, the first step is to rule out the common causes, which can explain half the cases. The relationship between azathioprine and corticosteroids, which can cause drug-induced pancreatitis, is difficult to prove and remains elusive [33]. Although pancreatitis can be the presenting symptom of SLE [34], it is usually a complication of the disease and mainly related to SLE activity. The etiology is unknown, but several causes have been suggested, such as an autoimmune origin, vasculitis, aPL-related thrombosis, or exocrinopathy when sicca syndrome accompanies SLE. Autoimmune pancreatitis related to hyper-IgG4 syndrome has also been reported in lupus patients [35]. The usual clinical manifestations are seendsevere abdominal pain, nausea, and vomitingdbut mortality seems higher than in non-SLEeassociated pancreatitis [33]. Pancreatitis seems to be more common and severe in pediatric-onset SLE, and mortality is higher, likely in relation to a greater disease activity [36,37]. Steroid therapy combined with supportive measures seems to improve the prognosis of these patients.

6. OTHER SYSTEMIC LUPUS ERYTHEMATOSUSeRELATED GASTROINTESTINAL PROBLEMS Adult celiac disease, a chronic GI disorder characterized by mucosal atrophy due to gluten intolerance, has been associated with some autoimmune disorders, including SLE [38]. Antietissue transglutaminase antibodies are a

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serological hallmark of the disease. Although cases of SLE associated with Crohn disease are rare, the coexistence of these two diseases represents a conundrum for the treating clinician who may miss the Crohn disease diagnosis and fail to implement adequate therapy when needed [39]. Eosinophilic GI diseases, characterized by an inappropriate accumulation of eosinophils within the GI tract, have been related to allergic conditions and parasitic infections. However, as eosinophils act as modulators of the GI immune response, eosinophilic infiltration of the GI tract is also seen in connective tissue diseases, especially SLE [40]. It is important for clinicians to be aware of these associations in lupus patients with GI manifestations.

REFERENCES [1] Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus. Lancet 2014;384:1878e88. [2] Sultan SM, Ionnaou Y, Isenberg DA. A review of gastrointestinal manifestations of systemic lupus erythematosus. Rheumatology 1999;38:917e32. [3] Xu D, Yang H, Lai CC, Li P, Zhang X, Yang XO, et al. Clinical analysis of systemic lupus erythematosus with gastrointestinal manifestations. Lupus 2010;19:866e9. [4] Mok CC. Investigations and management of gastrointestinal and hepatic manifestations of systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2005;19:741e66. [5] Ebert EC, Hagspiel KD. Gastrointestinal and hepatic manifestations of systemic lupus erythematosus. J Clin Gastroenterol 2011;45:436e41. [6] Richer O, Ulinski T, Lemelle I, Ranchin B, Loirat C, Piette JC, et al. Abdominal manifestations in childhood-onset systemic lupus erythematosus. Ann Rheum Dis 2007;66:174e8. [7] Kishimoto M, Nasir A, Mor A, Belmont HM. Acute gastrointestinal distress syndrome in patients with systemic lupus erythematosus. Lupus 2007;16:137e41. [8] Yuan S, Lian F, Chen D, Li H, Qiu Q, Zhan Z, et al. Clinical features and associated factors of abdominal pain in systemic lupus erythematosus. J Rheumatol 2013;40:2015e22. [9] Lee CK, Ahn MS, Lee EY, Shin JH, Cho YS, Ha HK, et al. Acute abdominal pain in systemic lupus erythematosus: focus on lupus enteritis (gastrointestinal vasculitis). Ann Rheum Dis 2002;61:547e50. [10] Medina F, Ayala A, Jara LJ, Becerra M, Miranda JM, Fraga A. Acute abdomen in systemic lupus erythematosus: the importance of early laparotomy. Am J Med 1997;103:100e5. [11] Tian XP, Zhang X. Gastrointestinal involvement in systemic lupus erythematosus: insight into pathogenesis, diagnosis and treatment. World J Gastroenterol 2010;16:2971e7. [12] Andonopoulos A, Skopouli F, Dimou G, Drosos A, Moutsopoulos H. Sjo¨gren’s syndrome in systemic lupus erythematosus. J Rheumatol 1990;17:202e4. [13] Mathew TH. A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Tricontinental mycophenolate mofetil renal transplantation study group. Transplantation 1998;65:1450e4. [14] Hallegua DS, Wallace DJ. Gastrointestinal manifestations of systemic lupus erythematosus. Curr Opin Rheumatol 2000;12:379e85. [15] Heng Y, Schuffer MD, Haggitt RC, Rohrmann CA. Pneumatosis intestinalis: a review. Am J Gastroenterol 1995;90:1747e58.

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Cabrera GE, Scopelitis E, Cuellar ML, Silveira LH, Mena H, Espinoza LR. Pneumatosis cystoides intestinalis in systemic lupus erythematosus with intestinal vasculitis: treatment with high dose prednisone. Clin Rheumatol 1994;13:312e6. Alcocer-Gouyonnet F, Chan-Nunez C, Herna´ndez J, Guzma´n J, Gamboa-Domı´nguez A. Acute abdomen and lupus enteritis: thrombocytopenia and pneumatosis intestinalis as indicators for surgery. Am Surg 2000;66:193e5. Boerner RM, Fried DB, Warshauer DM, Isaacs K. Pneumatosis intestinalis. Two case reports and a retrospective review of the literature from 1985 to 1995. Dig Dis Sci 1996;41:2272e85. Ju JH, Min JK, Jung CK, Oh SN, Kwok SK, Kang KY, et al. Lupus mesenteric vasculitis can cause acute abdominal pain in patients with SLE. Nat Rev Rheumatol 2009;5:273e81. Yuan S, Ye Y, Chen D, Qiu Q, Zhan Z, Lian F, et al. Lupus mesenteric vasculitis: clinical features and associated factors for the recurrence and prognosis of disease. Semin Arthritis Rheum 2014;43:759e66. Grimbacher B, Huber M, von Kempis J, Kalden P, Uhl M, Ko¨hler G, et al. Successful treatment of gastrointestinal vasculitis due to systemic lupus erythematosus with intravenous pulse cyclophosphamide: a clinical case report and review of the literature. Br J Rheumatol 1998;37:1023e8. Mok MY, Wong RWS, Lau CS. Intestinal pseudo-obstruction in systemic lupus erythematosus: an uncommon but important clinical manifestation. Lupus 2000;9:11e8. Pardos-Gea J, Ordi-Ros J, Selva A, Perez-Lopez J, Balada E, Vilardell M. Chronic intestinal pseudo-obstruction associated with biliary tract dilatation in a patient with systemic lupus erythematosus. Lupus 2005;14:328e30. Wang JL, Liu G, Liu T, Wei JP. Intestinal pseudo-obstruction in systemic lupus erythematosus: a case report and review of the literature. Medicine (Baltimore) 2014;93:e248. Xu N, Zhao J, Liu J, Wu D, Zhao L, Wang Q, et al. Clinical analysis of 61 systemic lupus erythematosus patients with intestinal pseudo-obstruction and/or ureterohydronephrosis: a retrospective observational study. Medicine (Baltimore) 2015;94:e419. Narvaez J, Perez-Vega C, Castro-Bohorquez FJ, Garcia-Quintana AM, Biosca M, VilasecaMomplet J. Intestinal pseudo-obstruction in systemic lupus erythematosus. Scan J Rheumatol 2003;32:191e5. Kim HJ, Park MH. Obstructive uropathy due to interstitial cystitis in a patient with systemic lupus erythematosus. Clin Nephrol 1996;45:205e8. Nojima Y, Mimura T, Hamasaki K, Furuya H, Tanaka G, Nakajima A, et al. Chronic intestinal pseudo-obstruction associated with autoantibodies against proliferating cell nuclear antigen. Arthritis Rheum 1996;39:877e9. Meulders Q, Michel C, Marteau P, Grange JD, Mougenot B, Ronco P, et al. Association of chronic interstitial cystitis, protein-losing enteropathy and paralytic ileus with seronegative systemic lupus erythematosus: case report and review of the literature. Clin Nephrol 1992;37:239e44. Yazici Y, Erkan D, Levine DM, Parker TS, Lockshin MD. Protein-losing enteropathy in systemic lupus erythematosus: report of a severe, persistent case and review of pathophysiology. Lupus 2002;11:119e23. Mok CC, Ying KY, Mak A, To CH, Szeto ML. Outcome of protein-losing gastroenteropathy in systemic lupus erythematosus treated with prednisolone and azathioprine. Rheumatology 2006;45:425e9. Al-Mogairen SM. Lupus protein-losing enteropathy (LUPLE): a systematic review. Rheumatol Int 2011;31:995e1001.

226 SECTION j IV Gastrointestinal Involvement of Systemic Diseases [33] Nesher G, Breuer GS, Temprano K, et al. Lupus-associated pancreatitis. Semin Arthritis Rheum 2006;2006(35):260e7. [34] Essaadouni L, Samar E, Krati K. Pancreatitis as initial manifestation of systemic lupus erythematosus. Lupus 2010;19:884e7. [35] Kobayashi S, Yoshida M, Kitahara T, Abe Y, Tsuchida A, Nojima Y. Autoimmune pancreatitis as the initial presentation of systemic lupus erythematosus. Lupus 2007;16:133e6. [36] Limwattana S, Dissaneewate P, Kritsaneepaiboon S, Dendumrongsup T, Vachvanichsanong P. Systemic lupus erythematosus-related pancreatitis in children. Clin Rheumatol 2013;32:913e8. [37] Wang CH, Yao TC, Huang YL, Ou LS, Yeh KW, Huang JL. Acute pancreatitis in pediatric and adult-onset systemic lupus erythematosus: a comparison and review of the literature. Lupus 2011;20:443e52. [38] Freeman HJ. Adult celiac disease followed by onset of systemic lupus erythematosus. J Clin Gastroenterol 2008;42:252e5. [39] Yamashita H, Ueda Y, Kawaguchi H, et al. Systemic lupus erythematosus complicated by Crohn’s disease: a case report and literature review. BMC Gastroenterol 2012;12:174. [40] Lecouffe-Desprets M, Groh M, Bour B, Le Jeunne C, Pue´chal X. Eosinophilic gastrointestinal disorders associated with autoimmune connective tissue disease. Joint Bone Spine 2015. http://dx.doi.org/10.1016/j.jbspin.2015.11.006.

Chapter 12

Digestive Involvement in the Antiphospholipid Syndrome I. Rodrı´guez-Pinto´, G. Espinosa and R. Cervera Hospital Clı´nic, Barcelona, Spain

1. INTRODUCTION The antiphospholipid syndrome (APS) is a thrombophilic disorder characterized by arterial and venous thrombosis as well as pregnancy morbidity in patients with circulating antiphospholipid antibodies (aPL) [1]. aPL include a broad number of antibodies that react to anionic phospholipids. Their detection progressively evolved from false-positive Wasserman reaction for syphilis to three more specific markers: the lupus anticoagulant (LA), the anticardiolipin antibody (aCL), and the anti-b2 glycoprotein I antibody (ab2GPI). Although other aPL have been described thereafter, their clinical significance is not yet clear. Often APS occurs in association to other autoimmune diseases and, especially but not only, to systemic lupus erythematosus (SLE). When the APS is not associated to any other autoimmune disease, it is named primary APS. Thrombotic manifestations may involve any organ of the body giving rise to a wide variety of presentations. Deep venous thrombosis followed by lung embolism is the most frequent manifestation, followed by cerebrovascular accidents. However, many other clinical manifestations may occur. A small group of patients, accounting for up to 1% of cases of APS, develop a rare life-threatening clinical form of APS characterized by a widespread organ thrombosis that affects mainly the small vessels in a short period of time [2]. This clinical variety is named catastrophic APS (CAPS) or Asherson syndrome, to honor Ronald Asherson, the physician who first described this clinical condition [3]. In contrast to classic APS, medium to large venous or arterial blood vessel occlusion is uncommon in CAPS; instead, it is characterized by microthrombosis affecting small vessels throughout the body. The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00012-X 227 Copyright © 2017 Elsevier B.V. All rights reserved.

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Cumulative abdominal manifestations of APS were reported in up to 4.2% of patients with APS in the Euro-Phospholipid cohort, the largest cohort published so far [4]. However, the true incidence of abdominal involvement in APS might be underestimated because of the lack of general awareness and frequent asymptomatic clinical course of most abdominal manifestations. Thus if the clinician does not look for them, these thrombotic events will probably be missed. Furthermore, in CAPS, where screening tools are usually used due to the severity of the clinical situation, abdominal manifestations account for up to 50% of cases [5]. This chapter aims to review the digestive system clinical manifestations of APS in both its classic and catastrophic forms.

2. GASTROINTESTINAL INVOLVEMENT 2.1 Ischemic Gastrointestinal Involvement 2.1.1 Esophageal Involvement Esophagus involvement has infrequently been reported in patients with APS. Until now only two cases of esophageal disease have been related to the presence of aPL. The first one was published by Cappell et al. [6], and they observed extensive esophageal necrosis due to esophageal vascular thrombosis in a patient with APS. Recently, Naitoh et al. [7] reported a patient with recurrent spontaneous esophageal ruptures and elevated levels of LA and aCL. 2.1.2 Gastric Involvement Gastric involvement is very rare in APS. The rarity of stomach involvement is explained by its extensive blood supply that comes from five major vessels, and complete gastric vascular filling can be achieved by several major arteries. Thus ischemia to take place requires occlusion of all major vessels or the celiac trunk itself. Three cases of gastric involvement have been published so far, all of them showing wide microthrombosis of the stomach. Kalman et al. [8] described a man who developed a progressive gastric ulceration. Histopathological examination of the stomach showed a widespread vascular occlusive disease involving veins and small arteries and arterioles consistent with classic histological findings of CAPS. Recently, two more cases have been published. Both had a total gastrectomy with Roux-loop esophagojejunostomy performed [9]. Again, both cases showed extensive necrosis with microthrombosis without inflammation. In all cases, usually, treatment with high-intensity anticoagulation is indicated, when security postoperative time is over. Some authors would consider prescribing corticosteroids as well; however, their role in cases of APS with single organ involvement is not clear.

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2.1.3 Intestinal Involvement Several different forms of intestinal involvement have been described in APS. Intestinal manifestations of APS are reported in up to 1.5% of cases [4]. More than half of patients with intestinal involvement related to APS have an acute clinical presentation, whereas 14% had a subacute and 22% have chronic presentation. Mesenteric venous thrombosis is the most common clinical manifestation, accounting for up to 43% of cases, followed by acute arterial involvement, reported in 38% of patients [10]. Less frequently, subacute and chronic arterial ischemic forms have been described [10,11]. Intestinal involvement in the setting of APS is much more often described in patients with CAPS [10]. In this situation, histopathologic examination usually shows thrombosis of small vessels, while large vessel involvement is less often reported [10]. 2.1.3.1 Venous Mesenteric Bowel Disease The symptoms of mesenteric venous thrombosis are often nonspecific. Severity depends on the speed of thrombus formation, extend, and location. Acute thrombosis often presents with cramping abdominal pain that lasts for days or weeks sometimes with nausea and vomiting. Diarrhea and lowergastrointestinal bleeding is rare. It might be followed by mucosal barrier disruption, resulting in peritonitis and sepsis leading to hemodynamic instability and multiorgan failure [12]. In subacute and chronic mesenteric venous thrombosis, patients are usually asymptomatic or present with vague intermittent abdominal pain due to the presence of collateral vessels. Mesenteric venous thrombosis is seldom suspected by the clinician before ordering the computed tomography (CT). Usually, abdominal CT with intravenous contrast demonstrates extensive thrombosis of the portomesenteric system. When mesenteric venous thrombosis is demonstrated, a careful differential diagnosis should be undertaken to rule out thrombophilic disease because, often, several hemostatic diseases are uncovered. Special attention should be taken to myeloproliferative disorders prone to thrombosis development, such as polycythemia vera, essential thrombocythemia, or paroxysmal nocturnal hemoglobinuria [10]. Thus, most physicians search for activating JAK2 tyrosine kinase mutation V617F in blood cells or for a CD55þ clonal proliferation in a blood sample, as well as other inherited thrombophilic diseases such as G220210A prothrombin or metatetrahydrofolate reductase gene mutations, factor V Leiden deficiency, or low levels of S and C proteins. Treatment depends on the severity of symptoms and extension of bowel involvement. In severe cases, initial treatment includes bowel rest, nasogastric suction, intravenous fluids, and parental anticoagulation with intravenous unfractionated heparin. In patients with suspected chronic disease, sometimes only subcutaneous low-molecular-weight heparin is added to the treatment

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when patients were not under oral anticoagulants. In patients who were under anticoagulant treatment, the therapeutic strategy should be individualized because there is no consensus on which is the best option. Some authors would agree to increase target international normalized ratio range from 2e3 to 2.5e3.5. Other patients develop hemodynamic instability or are refractory to treatment; in these cases, fibrinolysis, thrombectomy, or bowel resection has been proposed, although there is no expert consensus on which would be the best treatment option. 2.1.3.2 Acute Ischemic Bowel Disease Classically, patients with acute superior mesenteric artery occlusion present with severe abdominal pain but with minimal findings on clinical examination. The often sudden onset of abdominal pain, usually, decreases in intensity to increase again afterward with the subsequent clinical deterioration associated to the peritonitis development [13]. CT examination can show bowel enhancement after contrast infusion as well as intravessel defects. In the absence of intestinal findings on the CT scans, the patient should undergo angiography. In APS, almost all reported cases of mesenteric acute arterial ischemia occur in patients with associated atherosclerotic disease or, at least, with known atherosclerotic risk factors, such as smoking, hypertension, hypercholesterolemia, or diabetes mellitus [10]. Furthermore, although still controversial, some patients with APS might develop an accelerated form of atherosclerosis [14e16]. Thus, several pathophysiological pathways seem to take place together in patient with APS, leading to the development of acute intestinal ischemia. Surgical procedures are generally mandatory in cases of acute ischemic disease. Thereafter, when not contraindicated, long-term oral anticoagulation is usually prescribed to prevent recurrent episodes of mesenteric artery thrombosis. 2.1.3.3 Chronic Mesenteric Arterial Ischemia Patients with chronic mesenteric arterial ischemia present classically with postprandial abdominal pain or intestinal angina. When the disease progresses, patients often complain of weight loss related to the eating evasion. Intestinal angina results from vessel narrowing associated to intravascular thrombosis, embolism, or atherosclerotic occlusion. It has usually an indolent course that results in collateral vascular recruitment. Symptoms occur when blood demand outweighs vessels capability. Diagnosis is usually made by noninvasive methods, such as CT angiography or abdominal magnetic resonance imaging (MRI) angiography and/or Doppler ultrasound. Sometimes, an invasive catheter angiography is required for diagnosis, thus allowing intravascular therapy in the same procedure. However, treatment depends on the extent and location of vascular disease. Treatment

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alternatives include surgical bypass, thrombolysis, or endovascular procedures; however, nowadays, percutaneous angioplasty with vascular stenting is usually undertaken. 2.1.3.4 Colon Ischemic Disease Colon involvement in APS has been much less frequently reported than small bowel disease. However, the prevalence of aPL has been demonstrated to be much higher in patients with colon ischemia than in healthy controls [11]. Until now very few cases of colon ischemic disease have been associated to the presence of aPL and in most of them other thrombophilic diseases are found simultaneously [10,11].

2.2 Inflammatory Bowel Disease and Antiphospholipid Syndrome A higher prevalence of aPL has been found in patients with inflammatory bowel disease, either Crohn disease or ulcerative colitis [17,18]. However, follow-up studies could not find a relationship between the presence of aPL and the development of thrombotic manifestations. Enhanced serum antibody formation is a well-known feature of inflammatory bowel disease [19]. Thus, the scientific community has understood the higher prevalence of aPL in these patients in the background of an unselective immunologic stimulation that usually takes place in inflammatory bowel disease or in the setting of immunological shift related to anti-TNF treatment [20]. However, no relation could be found between the development of aPL and the disease activity, either measured by C-reactive protein or by activity indexes [19].

3. HEPATIC INVOLVEMENT 3.1 Vascular Liver Disease 3.1.1 BuddeChiari Syndrome BuddeChiari syndrome (BCS) refers to a rare and potentially life-threatening clinical condition where hepatic venous outflow is obstructed due to venous thrombosis excluding sinusoidal obstruction syndrome (see the following text) and right-sided cardiac disease [21]. It is clinically characterized by right upper quadrant pain, hepatomegaly, and ascites. However, this classical triad of symptoms only accounts for up to two-third of cases [22]. BCS has been divided into primary or secondary depending on whether or not a space occupying lesion invading the hepatic venous outflow is found. Furthermore, a routine evaluation for thrombophilic states is recommended because more than one thrombotic risk factor is found in up to a quarter of cases [21,22]. The most frequent risk factors are myeloproliferative disorders, found in up to 50% of tested cases [22]. The aCL are found in about 10e30% of patients with

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BCS, whereas LA and ab2GPI antibodies are described in 4e5% [21,23]. However, since elevated aCL are found in a similar proportion in patients with chronic liver disease, some authors consider that aPL might be only an epiphenomenon. Thus the pathogenic role of aPL remains as a matter of discussion [21,24]. Nevertheless, APS should be considered in the differential diagnosis of suprahepatic vein thrombosis and measurement of aPL is recommended [21,23]. BCS in the patients with aPL is mainly described in females around their third to fourth decade of life. Most of them have primary APS, and BCS is their first clinical manifestation. Most authors agree to treat these patients with long-term anticoagulation sometimes linked to some kind of percutaneous procedures, either by angioplasty and stenting or by transjugular intrahepatic portosystemic shunt (TIPS) [23].

3.1.2 Sinusoidal Obstruction Syndrome Sinusoidal obstruction syndrome or hepatic venoocclusive disease is a rare disease characterized by hepatic sinusoid obstruction leading to liver dysfunction that occurs more commonly after myeloablative regimens used to prepare patients for hematopoietic stem cell transplantation [21]. Generally, these regiments include high-dose chemotherapy drugs, although some cases have been related to more conventional chemotherapy doses, chronic immunosuppression, and intake of herbal teas or food sources contaminated with pyrrolizidine alkaloids [21]. The association between aPL and hepatic venoocclusive disease has been documented in only three cases. However, a posterior case control study could not find a relation between the presence of circulating aPL in serum obtained during the transplant conditioning therapy and the development of hepatic venoocclusive disease during or after the treatment [25]. 3.1.3 Hepatic Thrombosis and Infarction The liver has a unique dual blood supply, with a compensatory relationship existing between the two sources, so that the arterial flow increases when the portal venous flow decreases. This dual hepatic blood supply of the liver (75% portal venous, 25% hepatic arterial) protects it against hepatic infarction; although rarely, some patients develop liver thrombosis, usually associated to surgical procedures or to underlying vascular disease and sometimes associated to classic APS [26,27]. Hepatic infarction results from either an insult to the hepatic artery or the portal vein thrombosis superimposed on hepatic arterial occlusion. It leads to a cell death and coagulation necrosis due to focal ischemia [27]. More frequently, liver thrombosis associated to aPL is seen after liver transplant (see the following text) or in pregnant women [28e32]. Hepatic infarctions are described in up to one-third of pregnant women with APS who develop a HELLP (hemolysis, elevated liver enzymes, low platelets)

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syndrome. In a review of 30 pregnancies with hepatic infarction, aPL was found to be positive in almost every tested women [32]. Additionally, one-third of patients with CAPS present some features of liver involvement. According to the CAPS registry, 20% of the patients in whom necropsy was performed showed histopathological features of hepatic infarction [5,33]. Clinically, patients with liver infarction complain of right abdominal pain, and laboratory tests reveal abnormal liver function. Usually, unenhanced tomographic examinations show peripheral wedge-shaped, rounded, or irregularly shaped tubular areas of low attenuation paralleling bile duct corresponding to the liver infarction [27]. Intravenous contrast administration allows the differential diagnosis with abscess or focal steatosis [27]. Thus APS should be considered as a possible cause of hepatic infarction, and measurement of aPL is warranted in some settings especially in pregnancy and after transplant [34].

3.2 Autoimmune Liver Disease 3.2.1 Nodular Regenerative Hyperplasia of the Liver Nodular regenerative hyperplasia of the liver is a rare condition characterized by widespread benign transformation of the hepatic parenchyma into small regenerative nodules. It may lead to the development of noncirrhotic portal hypertension. Definitive diagnosis is established by direct liver parenchyma examination where diffuse micronodular regeneration without fibrous septa is seen. The absence of connective tissue in the liver samples differentiates this entity from cirrhotic transformation Nodular regenerative hyperplasia is generally a slowly evolving progressive disease unless portal hypertension develops. The etiology is not clear. An unbalanced blood supply throughout the liver parenchyma might lead to apoptosis, and hepatocyte atrophy with adaptive hyperplasic hepatocyte reaction at the adjacent acini due to maintained or increased blood supply is thought to take place. Accordingly, nodular regenerative hyperplasia has been related to several thrombophilic states as well as to other autoimmune diseases where vasculitis leading to parenchyma ischemia state has been proposed. In this sense, several case reports have associated this rare entity to APS [35,36]. Klein et al. [37] reported that up to 77% of patients with histologically defined nodular regenerative hyperplasia have circulating aPL. The aCL were found in 46% of cases, while it was found in only 14% of patients with autoimmune liver diseases and healthy controls [37]. However, ab2GPI antibodies did not discriminate between nodular regenerative hyperplasia and autoimmune liver diseases. 3.2.2 Autoimmune Hepatitis Autoimmune hepatitis is a disorder of unknown etiology characterized by liver inflammation without a known trigger. Laboratory tests show elevated

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transaminase levels, circulating nonorganospecific autoantibodies, and hypergammaglobulinemia [38]. Autoimmune hepatitis is thought to arise from a failure of immune tolerance mechanisms in individuals with genetic predisposition leading to a T cellemediated immune attack on liver antigens [39]. Several studies have found an increased prevalence of aPL in patients with autoimmune hepatitis [40e43]. Additionally, an increased risk of thrombotic events has been proposed by some of them. A recent metaanalysis including four studies leading to the inclusion of 180 patients with autoimmune hepatitis and 415 controls confirmed an increased prevalence of aCL and ab2GPI antibodies in patients with autoimmune hepatitis, especially from the IgM and IgA isotype [44]. Unfortunately, the prevalence of LA positivity was not assessed. A chronic antigenic stimulus induced from hepatocyte membrane disruption and a cross-reactivity with other autoantigens have been proposed to explain the increased frequency of these aPL in these patients; however, their origin is not yet clear [45]. Nevertheless, an increased frequency of APSrelated clinical manifestations was not found in the metaanalysis, although patients showed a trend toward a higher prevalence of aPL-related thrombotic complications [44]. However, most studies were not designed to assess the clinical risk of thrombotic manifestation, and a vast amount of information was missing [44]. Thus, with this small amount of data, it is difficult to achieve definitive conclusions.

3.2.3 Primary Biliary Cholangitis Primary biliary cholangitis (PBC) (formerly known as primary biliary cirrhosis) is an autoimmune liver disease characterized by autoreactive B and T cell responses against 2-oxoacid dehydrogenase complex, a protein found in the inner mitochondrial membrane. It is characterized by the finding of antimitochondrial antibodies (AMA or anti-M2) in serum. Besides other autoantibodies, an increase in aPL prevalence has been described in patients with PBC and this fact can be of interest because microthrombosis has been postulated as a pathophysiologic pathway in PBC [46]. Several case control studies showed an increased prevalence of aPL in patients with PBC compared to patients with other liver diseases and healthy controls [37,46e51]. However, aPL prevalence was inconsistent between the studies what might be explained by studies methodological differences and powerful. Even though a cross-reactivity between AMA and aPL has been proposed, AMA found in PBC are type 2 AMA and not type 5, which seem to be the ones that have been found to cross-react with aCL [46,51]. Most studies addressed the prevalence of aCL and some addressed the prevalence of ab2GPI antibodies; however, none of them addressed the prevalence of LA independently. Again, although an increase in aPL seems evident, no study has been designed to address if these

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patients with aPL have an increased risk of APS clinical manifestations. Thus the clinical significance of aPL in patients with PBC is still a matter of debate.

3.2.4 Primary Sclerosing Cholangitis Similar to the situation described for PBC, some authors have reported an association between circulating aPL and primary sclerosing cholangitis. Primary sclerosis cholangitis is a chronic cholestatic liver disease characterized by progressive inflammation, destruction, and fibrosis of intrahepatic and extrahepatic bile ducts. It is best diagnosed by contrast cholangiography that reveals the characteristic diffuse involvement with multifocal strictures and focal dilatation leading to a beaded appearance [52]. Two case control studies including 151 patients and 452 controls demonstrated an increase in the prevalence of aCL in patients with primary sclerosing cholangitis [49,53]. Either IgG, IgM, IgA aCL or IgG, IgM, and IgA anti-b2-GPI antibody levels were shown to be increased in patients with primary sclerosing cholangitis, although most isotypes were tested only in one of these studies [44,49,53]. Angulo et al. [53] showed aCL in 66% of patients with primary sclerosing cholangitis and anti-b2GPI antibodies in 18%. Furthermore, the authors of this paper found the levels of aCL to be positively correlated to the Mayo risk score, especially in patients with associated inflammatory bowel disease; however, this finding was not repeated in the study from Zachou et al. [49,53]. The study from Zachou et al. [49] detected aCL in 26.8% of patients with primary sclerosing cholangitis. Nevertheless, unlike the study of Angulo et al., [53] only IgG and IgM aCL were tested. In this study, only one patient was tested positive for IgM anti-b2GPI antibodies. Furthermore, aCL levels in patients who were tested positive had low or medium titers and no association could be found between autoantibody positivity and APS-related clinical manifestations [49]. However, these studies were not designed to test the clinical significance of the increase of aPL. Thus authors do not agree on the relationship of these aPL with clinical disease.

3.3 Liver Cirrhosis An increased frequency of aPL has been demonstrated in patients with several chronic liver disease leading to liver cirrhosis (i.e., alcoholic liver disease, hepatitis C virus infection, and autoimmune hepatitis) and in patients with liver cirrhosis per se [24,44,54e56]. However, the clinical significance of these antibodies in individuals with liver diseases is not clear [24]. Specifically, it is not clear whether they represent an important dysregulation of the immune system or simply represent an epiphenomenon [24]. In this sense, a study that tried to analyze the relationship between aPL and thrombotic

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phenomena in patients with liver disease could not find any association [24]. Thus their role in cirrhotic patients is not clear and probably reflects only liver lesion rather than a real autoimmune disease [24,56e58]. Accordingly, a study showed aPL levels to be related to the degree of histological damage in patient with cirrhosis [24,58].

3.4 Liver Transplant Hepatic artery thrombosis and portal vein thrombosis are severe lifethreatening complications of liver transplantation that might lead to graft failure, leading to emergent transplant need, and that sometimes leads to patient death. It is one of the main causes of graft loss and mortality after liver transplantation. In this sense three patients showed to have aPL in a study 24 patients who had hepatic artery thrombosis after liver transplant. This finding prompted the authors to propose screening for aPL in pretransplant workup. However, the other study that tried to relate aPL with posttransplant hepatic artery thrombosis could not find any relation. Thus, caution management of patients with circulating aPL is warranted and prophylactic anticoagulation is suggested in posttransplant period.

4. SPLENIC INVOLVEMENT 4.1 Splenic Ischemic Disease Spleen infarcts have been generally described in patients with CAPS. However, few cases have been reported as first manifestations in patients with classic APS or associated to other intraabdominal vessel occlusions. Although infrequently reported, ischemic splenic involvement should be considered in the context of APS, especially in patients with CAPS [5,59e62].

4.2 Autosplenectomy or Functional Asplenia Similar to the loss of function seen in pediatric patients with sickle cell disease, several reports have linked functional asplenia to SLE. The diagnosis of functional asplenia is based on the absence of splenic uptake of radiolabeled colloids or HDRBC and on erythrocyte abnormalities (HowelleJolly bodies, increased number of pitted erythrocytes) indicative of impaired phagocytic function [63]. Autosplenectomy in SLE is associated with a high mortality rate due to Streptococcus pneumoniae sepsis, although vaccination seems to preclude severe sepsis [63,64]. A link between functional asplenia in SLE patients and aPL has been proposed, reasoning that repeated spleen infarction would lead to loss of function of spleen due to repeated episodes of infarction [63,65]. In this sense, a few cases of autosplenectomy in SLE have reported the presence of circulating aPL.

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5. PANCREATIC INVOLVEMENT Some authors have linked aPL with the development of pancreatitis [66e71]. Most cases of pancreatic manifestations in APS patients have been reported in the context of CAPS widespread organ thrombosis. Unlike autoimmune pancreatitis associated to SLE, where pancreatitis is attributed to local vasculitis, in APS, pancreatitis is thought to take place due to thrombotic vascular occlusion [72]. Pancreatic vessels are too thin to be explored with CT or MRI scans. However, thrombotic vessel occlusion was shown in patients who develop acute pancreatitis linked to APS [69]. The real prevalence of aPL in patients with pancreatitis is not known because aPL are not routinely assessed in patients with pancreatitis. Thus, there are no studies dealing with the prevalence of aPL in pancreatitis patients. Spencer [69] proposed routine checking for aPL in patients with idiopathic pancreatitis although Makol and Petri [73] could not find a relation between aPL and pancreatitis in SLE patients. Thus, the real significance of aPL in acute pancreatitis is not yet clear.

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Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346(10):752e63. [2] Cervera R, Rodrı´guez-Pinto´ I, Colafrancesco S, et al. 14th international congress on antiphospholipid antibodies task force report on catastrophic antiphospholipid syndrome. Autoimmun Rev 2014;13(7):699e707. [3] Asherson RA. The catastrophic antiphospholipid syndrome. J Rheumatol 1992;19(4):508e12. [4] Cervera R, Piette J-C, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46(4):1019e27. [5] Cervera R, Bucciarelli S, Plası´n MA, et al. Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the “CAPS Registry”. J Autoimmun 2009;32(3e4):240e5. [6] Cappell MS. Esophageal necrosis and perforation associated with the anticardiolipin antibody syndrome. Am J Gastroenterol 1994;89(8):1241e5. [7] Naitoh H, Fukuchi M, Kiriyama S, et al. Recurrent, spontaneous esophageal ruptures associated with antiphospholipid antibody syndrome: report of a case. Int Surg 2014;99(6):842e5. [8] Kalman DR, Khan A, Romain PL, Nompleggi DJ. Giant gastric ulceration associated with antiphospholipid antibody syndrome. Am J Gastroenterol 1996;91(6):1244e7. [9] Srivastava V, Basu S, Ansari M, Gupta S, Kumar A. Massive gangrene of the stomach due to primary antiphospholipid syndrome: report of two cases. Surg Today 2010;40(2):167e70. [10] Cervera R, Espinosa G, Cordero A, et al. Intestinal involvement secondary to the antiphospholipid syndrome (APS): clinical and immunologic characteristics of 97 patients: comparison of classic and catastrophic APS. Semin Arthritis Rheum 2007;36(5):287e96.

238 SECTION j IV Gastrointestinal Involvement of Systemic Diseases [11] Koutroubakis IE, Sfiridaki A, Theodoropoulou A, Kouroumalis EA. Role of acquired and hereditary thrombotic risk factors in colon ischemia of ambulatory patients. Gastroenterology 2001;121(3):561e5. [12] Russell CE, Wadhera RK, Piazza G. Mesenteric venous thrombosis. Circulation 2015;131(18):1599e603. [13] Acosta S. Mesenteric ischemia. Curr Opin Crit Care 2015;21(2):171e8. [14] Borba E. Primary antiphospholipid syndrome: absence of premature atherosclerosis in patients without traditional coronary artery disease risk factors. Lupus 2015:1e7. [15] Hahn B. Systemic lupus erythematosus and accelerated atherosclerosis. N Engl J Med 2003;349(25):2379e80. [16] Ames PRJ, Antinolfi I, Scenna G, Gaeta G, Margaglione M, Margarita A. Atherosclerosis in thrombotic primary antiphospholipid syndrome. J Thromb Haemost 2009;7(4):537e42. [17] Chiarantini E, Valanzano R, Liotta AA, et al. Hemostatic abnormalities in inflammatory bowel disease. Thromb Res 1996;82(2):137e46. [18] Aichbichler BW, Petritsch W, Reicht GA, et al. Anti-cardiolipin antibodies in patients with inflammatory bowel disease. Dig Dis Sci 1999;44(4):852e6. [19] Sipeki N, Davida L, Palyu E, et al. Prevalence, significance and predictive value of antiphospholipid antibodies in Crohn’s disease. World J Gastroenterol 2015;21(22):6952e64. [20] Atzeni F, Sarzi-Puttini P. Autoantibody production in patients treated with anti-TNF-alpha. Expert Rev Clin Immunol 2008;4(2):275e80. [21] DeLeve LD, Valla D, Garcia-Tsao G, American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology 2009;49(5):1729e64. [22] Darwish Murad S, Plessier A, Hernandez-Guerra M, et al. Etiology, management, and outcome of the BuddeChiari syndrome. Ann Intern Med 2009;151(3):167e75. [23] Espinosa G, Font J, Garcı´a-Pagan JC, et al. Budd-Chiari syndrome secondary to antiphospholipid syndrome: clinical and immunologic characteristics of 43 patients. Medicine (Baltimore) 2001;80(6):345e54. [24] Mangia A, Margaglione M, Cascavilla I, et al. Anticardiolipin antibodies in patients with liver disease. Am J Gastroenterol 1999;94(10):2983e7. [25] Fastenau DR, Haire WD, Schneider JR, Stephens LC, Faulk WP, McIntyre JA. The preconditioning incidence of antiphospholipid antibodies is not significantly increased in patients with bone marrow transplant-related organ dysfunction. Bone Marrow Transplant 1998;22(7):681e4. [26] Smith GS, Birnbaum BA, Jacobs JE. Hepatic infarction secondary to arterial insufficiency in native livers: CT findings in 10 patients. Radiology 1998;208(1):223e9. [27] Torabi M, Hosseinzadeh K, Federle MP. CT of nonneoplastic hepatic vascular and perfusion disorders. Radiographics 2008;28(7):1967e82. [28] Van Thiel DH, George M, Brems J, et al. Antiphospholipid antibodies before and after liver transplantation. Am J Gastroenterol 2003;98(2):460e5. [29] Collier JD, Sale J, Friend PJ, Jamieson NV, Calne RY, Alexander GJ. Graft loss and the antiphospholipid syndrome following liver transplantation. J Hepatol 1998;29(6):999e1003. [30] Mor F, Beigel Y, Inbal A, Goren M, Wysenbeek AJ. Hepatic infarction in a patient with the lupus anticoagulant. Arthritis Rheum 1989;32(4):491e5. [31] Kinoshita K. Hepatic infarction during pregnancy complicated by antiphospholipid syndrome. Am J Obstet Gynecol 1993;169(1):199e202.

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240 SECTION j IV Gastrointestinal Involvement of Systemic Diseases [50] Gabeta S, Norman GL, Gatselis N, et al. IgA anti-b2GPI antibodies in patients with autoimmune liver diseases. J Clin Immunol 2008;28(5):501e11. [51] Agmon-Levin N, Shapira Y, Selmi C, et al. A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis. J Autoimmun 2010;34(1):55e8. [52] Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995;332(14):924e33. [53] Angulo P, Peter JB, Gershwin ME, et al. Serum autoantibodies in patients with primary sclerosing cholangitis. J Hepatol 2000;32(2):182e7. [54] Al-Saeed A, Makris M, Malia RG, Preston FE, Greaves M. The development of antiphospholipid antibodies in haemophilia is linked to infection with hepatitis C. Br J Haematol 1994;88(4):845e8. [55] Chedid A, Chadalawada KR, Morgan TR, et al. Phospholipid antibodies in alcoholic liver disease. Hepatology 1994;20(6):1465e71. [56] Biron C, Andre´ani H, Blanc P, et al. Prevalence of antiphospholipid antibodies in patients with chronic liver disease related to alcohol or hepatitis C virus: correlation with liver injury. J Lab Clin Med 1998;131(3):243e50. [57] Gervais A, Czernichow B, Grunebaum L, et al. Serum cardiolipin antibodies in patients with alcoholic cirrhosis. Gastroente´rologie Clin Biol 1996;20(10):736e42. [58] Perney P, Biron-Andre´ani C, Joomaye Z, et al. Antiphospholipid antibodies in alcoholic liver disease are influenced by histological damage but not by alcohol consumption. Lupus 2000;9(6):451e5. [59] Salcedo J, Blanco JR, Ferna´ndez A. Splenic infarction as presentation form of antiphospholipid syndrome. An Med Intern 2000;17(4):218e9. [60] Choi BG, Jeon HS, Lee SO, Yoo WH, Lee ST, Ahn DS. Primary antiphospholipid syndrome presenting with abdominal angina and splenic infarction. Rheumatol Int 2002;22(3):119e21. [61] Obarski TP, Stoller JK, Weinstein C, Hayden S. Splenic infarction. A new thrombotic manifestation of the circulating lupus anticoagulant. Cleve Clin J Med 1989;56(2):174e6. [62] Cappell MS, Simon T, Tiku M. Splenic infarction associated with anticardiolipin antibodies in a patient with acquired immunodeficiency syndrome. Dig Dis Sci 1993;38(6):1152e5. [63] Santilli D, Govoni M, Prandini N, Rizzo N, Trotta F. Autosplenectomy and antiphospholipid antibodies in systemic lupus erythematosus: a pathogenetic relationship? Semin Arthritis Rheum 2003;33(2):125e33. [64] Uthman I, Soucy JP, Nicolet V, Sene´cal JL. Autosplenectomy in systemic lupus erythematosus. J Rheumatol 1996;23(10):1806e10. [65] Pettersson T, Julkunen H. Asplenia in a patient with systemic lupus erythematosus and antiphospholipid antibodies. J Rheumatol 1992;19(7):1159. [66] Chang L, Francoeur L, Schweiger F. Pancreaticoportal fistula in association with antiphospholipid syndrome presenting as ascites and portal system thrombosis. Can J Gastroenterol 2002;16(9):601e5. [67] Bird AG, Lendrum R, Asherson RA, Hughes GR. Disseminated intravascular coagulation, antiphospholipid antibodies, and ischaemic necrosis of extremities. Ann Rheum Dis 1987;46(3):251e5. [68] Chang KY, Kuo YC, Chiu CT, et al. Anti-cardiolipin antibody associated with acute hemorrhagic pancreatitis. Pancreas 1993;8(5):654e7. [69] Spencer HL. Primary antiphospholipid syndrome as a new cause of autoimmune pancreatitis. Gut 2004;53(3):468. author reply 468.

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Chapter 13

Gastrointestinal Involvement in Systemic Sclerosis A.B. Shreiner* and D. Khanna* *University of Michigan Medical School, Ann Arbor, MI, United States

1. INTRODUCTION Gastrointestinal (GI) tract involvement affects w90% of patients with systemic sclerosis (SSc). Every part of the GI tract from the mouth to the anus can be involved. The main pathological mechanism in SSc is dysmotility secondary to progressive GI tract fibrosis. Dysmotility can result in morbid symptoms, various local complications, and, ultimately, malnutrition. The goal of treatment is to improve motility, limit local complications, and maintain nutrition. This chapter provides a detailed discussion on the GI involvement in SSc and provides practical guidance on the diagnosis and treatment of this complex medical condition.

2. PATHOGENESIS OF GASTROINTESTINAL TRACT DYSMOTILITY Although the etiology is unknown, the pathophysiology of SSc is characterized by chronic inflammation and vascular damage, ultimately leading to fibrosis of the skin and various internal organs [1]. In the early stages of disease, neuropathy is present but the smooth muscle is still functional, and patients generally respond to prokinetic agents [1,2]. Autoantibodies against the muscarinic type-3 receptor may be involved, as a recent study showed that pooled immunoglobulins from SSc patients, but not healthy controls, bound the muscarinic type-3 receptor and interfered with cholinergic nerve stimulation, thereby diminishing smooth muscle contractility [3]. In the advanced stages, GI tract dysmotility is largely due to fibrosis, and physiological tests demonstrate both neuropathic and myopathic abnormalities of motility [4]. In this setting, progressive smooth muscle atrophy and fibrosis renders prokinetic The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00013-1 243 Copyright © 2017 Elsevier B.V. All rights reserved.

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agents ineffective [5]. Significant fibrosis of the GI tract wall is invariably found at autopsy in those with GI involvement [6].

3. ESOPHAGUS 3.1 Esophageal Dysmotility Esophageal dysmotility in SSc is characterized by decreased amplitude of esophageal peristalsis and decreased lower esophageal sphincter (LES) pressures (Fig. 13.1), resulting in dysphagia and a greatly lowered threshold for gastroesophageal reflux disease (GERD) [7]. Prospective studies have reported abnormalities on esophageal manometry in approximately 70e75% of SSc patients [8e10]. While one retrospective study reported that esophageal dysmotility was more common in diffuse cutaneous versus limited cutaneous SSc [11], another prospective study of almost 200 patients reported that esophageal dysmotility was not related to demographic features including age, duration, or skin extension [12]. Treatment of dysphagia secondary to dysmotility in SSc is generally supportive, and patients should be advised on dietary measures that include eating small bites, avoiding dry or fibrous foods, and taking plenty of water with solid food. One of the main objectives of evaluation is to exclude other causes of dysphagia. A barium esophagram can identify many structural abnormalities, including hiatal hernia, and provide information on motility and the presence of reflux. In patients with significant dysphagia indicated by an

FIGURE 13.1 Images of high-resolution esophageal manometry from a control subject (A) showing normal motility and a patient with systemic sclerosis (B) showing characteristic dysmotility. The vertical axis corresponds to the length of the catheter positioned in the esophagus to capture the upper esophageal sphincter (UES) and the lower esophageal sphincter (LES). Time of the recording is depicted on the horizontal axis. The normal peristaltic wave in the control subject propagates distally in the esophagus over time with a corresponding relaxation of the LES. The patient with SSc demonstrates absent peristalsis in the distal two-thirds of the esophagus, weak LES pressure, and normal upper esophageal motility.

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incomplete response to acid suppression, certain risk factors (e.g., advanced age, smoking), or alarm symptoms (e.g., pain, weight loss, progressive dysphagia to solids), an upper endoscopy is indicated to evaluate for malignancy and premalignant conditions, complications of GERD, and other alternative diagnoses, including benign stricture, infectious esophagitis, and eosinophilic esophagitis [13]. If another form of dysmotility is suspected, esophageal manometry can be helpful in distinguishing scleroderma-type dysmotility (i.e., weak peristalsis and weak LES pressure) from other forms of esophageal dysmotility.

3.2 Gastroesophageal Reflux Disease Although heartburn is the most common symptom of GERD, other symptoms may include acid reflux, dysphagia, odynophagia, water brash, substernal chest pain, and extraesophageal symptoms, such as chronic cough. In a study of patients newly diagnosed with SSc, 70% had reflux symptoms, 33% had reflux esophagitis on endoscopy, and 81% had increased acid reflux on 24-h pH study [8]. Complications of GERD are categorized as benign lesions, including esophagitis, bleeding, and strictures, or premalignant or malignant lesions, including Barrett esophagus and adenocarcinoma [14]. In addition, authors have noted an association between GERD and interstitial lung disease (ILD) in SSc, leading some to recommend early and aggressive therapy for GERD [15e19]. Nonetheless, these associations do not prove a cause and effect relationship between GERD and ILD. For a detailed discussion on the evaluation and treatment of GERD, readers are referred to association guidelines [20]. Empiric therapy with antisecretory agents is an appropriate initial approach, and proton-pump inhibitors (PPIs) are more effective than histamine type-2 receptor antagonists (H2RA) [21,22]. PPI should be taken 30e60 min before meals, and the dosage and frequency should be adjusted based on the severity of symptoms (Table 13.1). It should be noted that a number of studies, mostly observational, have raised concerns about the potential risk of long-term use of PPIs for pneumonia [23], Clostridium difficile infection [24], cardiovascular events in those taking clopidogrel [25], osteoporosis [26], chronic kidney disease [27], and dementia [28], but we should be cautious about overinterpreting these observational studies where it is inherently difficult to control for all factors. Diagnostic testing is generally to evaluate patients with “alarm symptoms” (e.g., dysphagia, weight loss, or epigastric mass), identify alternative diagnoses or complications of GERD, and investigate cases of failed empirical therapy [20]. Upper endoscopy is the initial test to evaluate for complications of reflux and rule out alternative diagnoses. If unrevealing, endoscopy can be followed by manometry to assess esophageal motility and/or pH/impedance monitoring to assess for acid reflex and a correlation with symptoms. If patients do not respond to “maximal” antisecretory therapy (i.e., high-dose twice-daily PPI and

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TABLE 13.1 Gastrointestinal Tract (GIT) Involvement With Recommended Testing and Treatment Problem

Test

Treatment

Gastroesophageal reflux disease

Barium swallow, upper endoscopy, esophageal manometrya, 24-h pH monitoringa

Antireflux measures Head of the bed elevated using wooden blocks under the feet at the head of bed or using wedge pillow Take frequent small meals (five to six per day) Avoid eating or drinking fluids 2 h before bedtime Stop smoking (if currently smoking) Avoid or minimize acid-producing foods (fat, chocolate, and coffee) Do not wear tight belts as they put pressure on the abdomen and the lower esophageal pressure sphincter Medications Antisecretory Proton-pump inhibitors (may require two to four times the FDA-approved doses), H2 blockers Promotility (take 30e60 min before meals) Metoclopramide, erythromycin, domperidoneb, cisapridec Surgical procedures Endoscopic dilatation of strictures, fundoplication

Gastroparesis

Gastric radionuclide emptying study, upper endoscopya

Antireflux measures Take frequent small meals (five to six per day). Avoid eating or drinking fluids 2 h before bedtime. Medications Antisecretory and promotility agents (see Section 3.2) Gastric electric stimulationd, jejunal feeding tube

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TABLE 13.1 Gastrointestinal Tract (GIT) Involvement With Recommended Testing and Treatmentdcont’d Problem

Test

Treatment

Watermelon stomach (irondeficiency anemia)

Upper endoscopy, colonoscopya, push enteroscopya, radiolabeled red blood scana, video capsule endoscopya

Medications Antisecretory agents Endosocopic procedures Argon laser ablation, argon plasma coagulation, Nd:YAG laser Surgical Antrectomy

Bacterial overgrowth syndrome

Intestinal pseudoobstruction

Serum iron, calcium, magnesium, alkaline phosphatase, serum carotene, vitamin B12 and methylmalonic acid, vitamin D, and prothrombin time, bone density measurement, glucose hydrogen breath testa, lactulose hydrogen breath testa, 14C-D-xylose breath testa, fecal fat quantificationa, bacterial and fungal culture from jejunal aspiratea

Medications

Plain radiographs of the chest (to rule out free air) and abdomen, CT of the abdomen

Bowel rest and intravenous nutrition support, total parenteral nutrition

Antibiotic therapy Amoxicillin, ciprofloxacin, metronidazole, doxycycline, neomycine, rifaximine (monthly rotating, intermittent, or continuous therapy) Vitamins Adequate calcium/vitamin D daily

Medications Promotility agents Octreotide, metoclopramide, erythromycin, domperidoneb, cisapridec

Constipation

Plain radiographs of the abdomen

Medications Stimulant laxatives Senna, lactulose, bisacodyl, polyethylene glycol (Golytely) Continued

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TABLE 13.1 Gastrointestinal Tract (GIT) Involvement With Recommended Testing and Treatmentdcont’d Problem

Test

Treatment

Diarrhea

Workup as recommended for bacterial overgrowth syndrome

Medications Bulking agents Citrucel Antidiarrheal agents Loperamide

Rectal incontinence

Anorectal manometry, endoscopic ultrasounda

Medications Bulking agents Citrucel Antidiarrheal agents Loperamide Other modalities Biofeedback Sacral nerve stimulation Surgery Repair for rectal prolapse

a

Recommended only if symptoms do not improve after initial treatment. Not FDA-approved in the United States. Available in the United States on compassionate basis (call 1-800-JANSSEN). d Not approved/studied for SSc. e Minimal systemic absorption. Adapted from Sallam H, McNearney TA, Chen JD. Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma). Aliment Pharmacol Ther 2006;23(6):691e712; Jaovisidha K, Csuka ME, Almagro UA, Soergel KH. Severe gastrointestinal involvement in systemic sclerosis: report of five cases and review of the literature. Semin Arthritis Rheum 2005;34(4):689e702. b c

high-doseH2RA at bedtime), baclofen, a GABA-B agonist, is a potential adjuvant therapy that works by enhancing LES function. In clinical trials, baclofen has demonstrated efficacy in the treatment of GERD [29,30], but there are no published studies in SSc patients. In general, prokinetic medications have limited benefit in the treatment of GERD [21] and are reserved for the treatment of delayed gastric emptying that can contribute to GERD. Surgery, particularly Nissen fundoplication, is a validated therapy for selected patients with GERD; however, it is relatively contraindicated in the presence of distal GI dysmotility, as is often the case in SSc. A number of new

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minimally invasive procedures intended to enhance the LES barrier seem promising but will require further validation [31].

3.3 Barrett Esophagus Barrett esophagus is a complication of long-standing GERD [32,33]. It is diagnosed on the basis of the endoscopic appearance of columnar epithelium extending proximally from the gastroesophageal junction in place of the typical squamous epithelium combined with pathologic findings of intestinal metaplasia. As in the general population, Barrett esophagus in SSc confers an increased risk for the development of adenocarcinoma [34]. In a retrospective study of 110 patients with SSc and GERD, 13% had Barrett esophagus and 21% of these patients had dysplasia, a subsequent step in the pathway to adenocarcinoma [35]. Dysplasia is the strongest risk factor for the progression to adenocarcinoma and, in the general population, other risk factors in addition to GERD for the development of Barrett esophagus and esophageal adenocarcinoma include older age, white race, male sex, obesity, tobacco use, and hiatal hernia [36]. In patients with SSc, Barrett esophagus is often discovered incidentally in the workup for dysphagia. Screening for Barrett esophagus among patients with GERD by upper endoscopy is controversial and currently recommended for patients with multiple risk factors, including white race, age >50, family history, long-standing reflux, smoking, and obesity(37); SSc per se is not a recognized risk factor. Recent guidelines for management of Barrett esophagus include recommendations for surveillance and therapy [37,38]. It is important to note that once-daily standard-dose PPI is recommended for those diagnosed with Barrett esophagus, but higher or more frequent doses are not indicated simply by the presence of Barrett. Endoscopic therapy for ablation of high-grade dysplasia is generally recommended, and several techniques are available.

4. STOMACH 4.1 Gastroparesis In SSc, dysmotility commonly affects the stomach as well. Alterations in gastric motility, myoelectric activity, and gastric emptying have been demonstrated in patients with SSc [2]. In a small, prospective study, gastric impairment was seen in w80% of patients with SSc on electrogastrography to measure myoelectric activity [39]. In two separate studies, delayed gastric emptying was found in 38e50% [10,39]. As a result of these disruptions in gastric motility, SSc patients often develop clinical symptoms of gastroparesis that include nausea, vomiting, early satiety, postprandial fullness, bloating, and abdominal pain.

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The diagnosis of gastroparesis is made by ruling out gastric outlet obstruction with endoscopy or imaging, screening for other causes of delayed gastric emptying (e.g., medications, diabetes mellitus, or thyroid disease), and confirming delayed gastric emptying with a nuclear medicine gastric emptying test [40]. Dietary measures and prokinetic medications are typical first-line therapies. Patients are instructed to eat smaller, more frequent meals, avoid eating several hours before lying down, and avoid high-fat or high-fiber foods. There are three main prokinetic medications available. Metoclopramide and domperidone are dopamine receptor antagonists that improve gastric emptying [41]. Metoclopramide carries a black-box warning for tardive dyskinesia, a neurological disorder of involuntary, repetitive movements that may not resolve with medication discontinuation [42]. For this reason, many gastroenterologists prefer to use domperidone as it does not cross the bloodebrain barrier or cause tardive dyskinesia, but it is not FDA-approved in the United States. So domperidone is available only through compounding pharmacies under special approval from the FDA or from outside the United States. Erythromycin is a macrolide antibiotic that acts as a motilin-receptor agonist to stimulate gastric emptying [43]. The long-term use of erythromycin is limited by tachyphylaxis, so it is used episodically as a “rescue” medication. For patients who do not improve with the aforementioned interventions, postpyloric enteral tube feeding, often with a gastric port for decompression, is often the next best option. If there is significant small intestinal dysmotility as well, then enteral feeding may not be tolerated either. Hospitalization is required for patients who are dehydrated and unable to tolerate an oral diet. The goal is to restore hydration and electrolyte levels, alleviate symptoms, and identify a route for nutrition. The oral route is preferred over enteral feeding, and parenteral nutrition is the last option.

4.2 Gastric Antral Vascular Ectasia Gastric antral vascular ectasia (GAVE), an important cause of iron-deficiency anemia in SSc, is a type of vascular malformation characterized by dilation of superficial mucosal blood vessels in the gastric antrum. The reported prevalence of GAVE in SSC ranged from 5% to 14% in earlier series [39,44e46], but a recent retrospective analysis of a European patient database identified GAVE in only 1% of patients with SSc [47]. Interestingly, GAVE seems to be more prevalent in SSc patients with antiRNA-polymerase III antibodies and less prevalent in those with antitopoisomerase I antibody [47e49], and it may be more prevalent in those with diffuse cutaneous SSc [50]. GAVE is identified on upper endoscopy that is indicated for the workup of iron-deficiency anemia. In addition to supportive treatment in the form of iron supplementation or blood transfusion, the definitive treatment of GAVE consists of endoscopic ablative therapy, typically argon plasma coagulation

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[51,52]. Most patients require more than one session, but the long-term outcomes are generally good. If this fails, antrectomy may be necessary [53].

5. SMALL INTESTINE 5.1 Intestinal Pseudoobstruction Intestinal dysmotility, characterized by delayed intestinal transit time with neuropathic and myopathic abnormalities, has been reported in 40e88% of patients with SSc [4,54e57]. Intestinal pseudoobstruction is the result of severe dysmotility that results in the failure of contents to progress through the small intestine (Fig. 13.2). It presents with symptoms such as abdominal pain, distention, nausea, vomiting, and absence of flatus. In spite of the high frequency of intestinal dysmotility in SSc, pseudoobstruction seems to be an uncommon complication. In a systematic review, intestinal pseudoobstruction was diagnosed in 3.9% of 1120 SSc patients [58]. In a retrospective study of a nationwide database including nearly 200,000 SSc patients admitted to US hospitals from 2002 to 2011, 5.4% of hospitalizations included a diagnosis of intestinal pseudoobstruction; the in-hospital mortality rate was 7.3% [59]. The initial management of intestinal pseudoobstruction usually requires admission to the hospital. The primary diagnostic task is to rule out mechanical small bowel obstruction with imaging. Once a diagnosis is made, the initial treatment includes bowel rest, intravenous fluids, correction of electrolyte abnormalities, and, typically, nasogastric tube decompression. It is important to discontinue medications that may contribute to dysmotility. Prokinetic agents to stimulate motility and antibiotics to decrease the bacterial load in the small intestine can be beneficial. Octreotide, a somatostatin analogue, improves intestinal motility and has demonstrated favorable results

FIGURE 13.2 Images from the same patient with systemic sclerosis (SSc) showing intestinal pseudoobstruction in an upright plain radiograph (A) and in cross section in a computed tomography scan (B).

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in the treatment of intestinal pseudoobstruction in SSc patients [5,60,61]. A combination of octreotide and erythromycin can be tried in resistant cases [62]. Surgery should be avoided but may be needed to exclude intestinal obstruction and for placement of venting and feeding tubes. Total parenteral nutrition may be required during prolonged recovery. In a retrospective study of patients with intestinal pseudoobstruction, lower mortality was associated with restoration of an oral diet and higher mortality was associated with a diagnosis of SSc [63]. In a large caseecontrol series, 70% of patients with SSc admitted for pseudoobstruction had spontaneous resolution with conservative management, whereas 9% required surgery and 25% required prolonged parenteral nutrition; the morality rate was 16% [64]. For patients with recurrent episodes of pseudoobstruction, octreotide at bedtime may be therapeutic and depot octreotide given monthly is available.

5.2 Small Intestinal Bacterial Overgrowth Small intestinal bacterial overgrowth (SIBO) refers to a condition wherein bacteria in the small intestine are increased in number. This can result from diminished antibacterial activity, altered anatomy, or decreased motility. SIBO is common in SSc as these patients often have multiple predisposing factors, including intestinal dysmotility, small bowel diverticula (likely secondary to dysmotility), and chronic PPI use. The symptoms include bloating, distention, abdominal discomfort, diarrhea, excessive flatulence, malabsorption, malnutrition, and weight loss. While diagnostic testing for SIBO is not ironclad, several different groups have reported the frequency of SIBO in patients with SSc as 36e56% [10,65e68], compared to 5e7% in controls [10,67]. Refractory SIBO can contribute to progressive malnutrition and weight loss necessitating the consideration of parenteral nutrition. The possibility of SIBO should be considered in SSc patients with characteristic symptoms as noted earlier and/or signs of malnutrition. Several serum tests can suggest SIBO: elevated folate that is produced by enteric bacteria, decreased vitamin B12 that is consumed by enteric bacteria, and anemia or other markers of malabsorption. Diagnostic testing for SIBO is quite controversial. The two most commonly used methods include culture of jejunal aspirate, a direct method, and glucose or lactulose breath tests, indirect methods. Jejunal aspiration requires upper endoscopy and is hampered by contamination during the procedure and the inability to culture many bacterial species. Breath tests rely on the ability of bacteria to digest radiolabeled sugar molecules liberate gases that are absorbed from the GI tract and exhaled into an instrument for measurement. It is difficult to assign sensitivity and specificity as there is no true gold standard for diagnosing SIBO, but the sensitivity and specificity of breath testing compared to jejunal culture is not very high [69,70]. If SSc patients have known GI tract involvement and symptoms consistent with SIBO, an empiric trial of antibiotics without testing is

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reasonable. Evidence for the efficacy of antibiotics for SIBO in SSc is limited to several small studies that vary in terms of antibiotic used, length of therapy, and method to determine eradication [66e68,71,72]. Based on these studies, it seems that the eradication rate of SIBO in SSc is about 50%. Rifaximin (a poorly absorbed antibiotic) and/or Flagyl are good choices as they do not increase the risk for C. difficile colitis, although a variety of other antibiotics have been used with success. If symptoms do not improve with a 10- to 14-day course of therapy, another antibiotic should be tried. If symptoms recur after a lengthy period of time, antibiotic courses can be repeated intermittently as needed. If symptoms recur soon after therapy, then a regimen of rotating antibiotics can be prescribed. In that case, patients are treated each month with a w10-day course of antibiotic, followed a month later with another antibiotic, and so on, rotating the two antibiotics. Probiotic therapy may have a role in the treatment of SIBO, but there is a lack of well-designed trials. Total parenteral nutrition needs to be considered if weight loss continues despite treatment.

5.3 Pneumatosis Cystoides Intestinalis Pneumatosis cystoides intestinalis, or air in the bowel wall, has been reported in SSc [73]. In this setting, it is a benign condition of no particular significance, although it may indicate more advanced disease. Rarely, the air-filled cysts in the bowel wall may rupture, leading to a benign pneumoperitoneum. As pneumatosis cystoides intestinalis and pneumoperitoneum are generally benign findings in the setting of SSc, no specific treatment is required [74]. This is in contrast with other conditions where bowel wall necrosis or viscus rupture can lead to similar radiographical findings that constitute a surgical emergency. A basic physical exam can easily distinguish between the benign conditions seen in SSc and a surgical emergency.

5.4 Malnutrition As discussed throughout this chapter, there are many potential contributors to malnutrition in the SSc patient with GI tract involvement. Some factors, such as oral involvement and gastroparesis, may primarily limit the ability to take food by mouth. Other conditions, such as intestinal pseudoobstruction and SIBO, also interfere with digestion and/or absorption in the small intestine. It is estimated that about 30% of SSc patients are at risk for malnutrition [75]. In addition to considering weight loss, it is important to assess serum levels of various nutrients in the evaluation for malnutrition (e.g., complete blood count, ferritin, folate, vitamin B12, vitamin D, vitamin A, and prealbumin). Nutrient deficiencies should be supplemented when detected, and a multivitamin is routinely advised. In general, it is best to deliver nutrition via the oral route, followed by the enteral route if needed, and, lastly, by the parenteral route if the GI tract does not allow for adequate nutrition [75]. The role of

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enteral and parental nutrition for SSc-related malnutrition was recently reviewed [76]. Notable adverse effects of parenteral nutrition include infection, thrombosis, and liver dysfunction. Although parenteral nutrition may be safe for the treatment of SSc patients [77], a recent report highlighted that SSc patients on home parenteral nutrition showed an increase in body mass index but a decrease in functional status score [78]. Consultation with a registered dietitian is prudent in the treatment of SSc patients with malnutrition.

6. COLON AND ANORECTAL DISORDERS 6.1 Colon Involvement Colon involvement is seen in 10e50% of patients with SSc [56,79,80]. Although many patients may be asymptomatic from colon involvement, constipation is the main problem related to colonic dysmotility. Similar to small intestinal pseudoobstruction, colonic pseudoobstruction can develop in the setting of severe colonic dysmotility. Diarrhea is also common in SSc, but it is more likely due to SIBO or fecal incontinence from anorectal involvement. Overflow diarrhea in the setting of fecal impaction, where only liquid stool can pass alongside solid impacted stool, is a possible source of diarrhea related to colonic involvement. The treatment of constipation secondary to colonic dysmotility can be quite challenging. Although it is reasonable to start with empiric therapy in most cases, it is important to also assess for structural lesions with colonoscopy and anorectal dysfunction according to patient age, family history, and response to therapy. The use of bulk forming laxatives, such as fiber, is generally not well tolerated or effective. If stool is firm, then a stool softener, such as polyethylene glycol, should be initiated and titrated to achieve soft stool. Oftentimes, patients with early dysmotility will benefit from stimulant laxatives, such as bisacodyl or senna, taken as needed or at bedtime. Newly developed enterokinetic agents and intestinal secretagogues have been used for patients with refractory constipation [81], but these medications have not been tested in SSc. Acute colonic pseudoobstruction is an urgent medical condition that usually requires in-hospital therapy. After exclusion of mechanical colon obstruction with imaging, patients are treated with bowel rest, intravenous fluids, and correction of electrolyte imbalances. If enemas or manual disimpaction are unsuccessful, then neostigmine, a cholinesterase inhibitor that promotes colonic motility, can be safe and effective for treatment [82].

6.2 Anorectal Dysfunction Anorectal involvement is common and reported in 50e70% of patients with SSc. These patients may present with fecal incontinence, difficulty with defecation, and rectal prolapse. Anorectal dysfunction is likely due to a

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combination of neuropathic and myopathic disorders. Manometric studies have demonstrated an absent or diminished rectoanal inhibitory reflex and lower voluntary squeeze pressure [83e86], and imaging studies have shown atrophy of the internal and external anal sphincters [83,87]. It is important to note that patients often do not volunteer information about problems with fecal incontinence, even though it may be a source of significant morbidity. A careful digital rectal examination is the first step in the evaluation. After colonoscopy to rule out structural lesions such as malignancy or proctitis, patients suspected of having anorectal dysfunction should be evaluated with functional tests, including anorectal manometry [88]. The first line of treatment for anorectal dysfunction involves biofeedback therapy [89]. Sacral nerve stimulation, a surgical procedure, has demonstrated some promise for the treatment of refractory fecal incontinence [90,91], but a recent study reported the lack of effect in patients with SSc [92]. Other surgical techniques can be considered for refractory, troublesome incontinence. Although the majority of anorectal disorders in SSc are related to neuromuscular dysfunction, barium defecography can identify structural causes of rectal outlet obstruction not identified by colonoscopy, for instance, a rectocele. Like rectal prolapse, these structural lesions may require surgical repair.

7. PATIENT-REPORTED OUTCOME MEASURES The majority of patients with SSc have multiple types of GI tract involvement with overlapping symptoms, making quantification of GI tract symptoms in SSc extremely challenging. In addition, the correlation between histological or physiological severity and GI tract symptoms has been poor in recent studies [2,39,56], stressing the need for a validated patient-reported instrument. The University of CaliforniaeScleroderma Clinical Trial Consortium Gastrointestinal Instrument (UCLA SCTC GIT 2.0) is a patient-reported outcome (PRO) measure to assess GI symptoms and their impact on social and emotional well-being in SSc [93]. This 34-item instrument has seven scales: reflux, distension/bloating, diarrhea, fecal soilage, constipation, emotional well-being and social functioning, and a total GI score. All scales are scored from 0.0 (better health-related quality of life) to 3.0 (worse healthrelated quality of life) except for the diarrhea and constipation scales that range from 0 to 2.0 and from 0 to 2.5, respectively. UCLA GIT 2.0 correlates well with the objective tests [94]. The instrument takes approximately 5e7 min to complete and is available free online in different languages at http://www.med.umich.edu/scleroderma/research/sctclanding.htm. The National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS) is a standardized set of PROs that cover physical, mental, and social health. Our team has recently developed the NIH PROMIS GI symptom measures [95]. The PROMIS GI symptom measures support eight scales: gastroesophageal reflux (13 items), disrupted

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swallowing (7 items), diarrhea (5 items), bowel incontinence/soilage (4 items), nausea and vomiting (4 items), constipation (9 items), belly pain (6 items), and gas/bloat/flatulence (12 items) and is valid in SSc [96].

8. CONCLUSION Involvement of the GI tract is seen in the great majority of patients with SSc. The primary pathogenesis of GI tract symptoms is related to progressive fibrosis causing neuropathic and myopathic dysfunction leading to dysmotility, and all sections of the GI tract can be involved. In general, a variety of treatments are available to target specific sites along the GI tract, and a comprehensive approach can limit the morbidity associated with GI tract involvement. In the most severe form, progressive involvement can lead to intestinal failure necessitating a consideration of parenteral nutrition and resulting in mortality in a small subset of patients with SSc. The management of these complex and challenging disease manifestations is best done in cooperation with a gastroenterologist and, in some cases, a registered dietitian.

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260 SECTION j IV Gastrointestinal Involvement of Systemic Diseases [64] Mecoli C, Purohit S, Sandorfi N, Derk CT. Mortality, recurrence, and hospital course of patients with systemic sclerosis-related acute intestinal pseudo-obstruction. J Rheumatol 2014;41(10):2049e54. [65] Di Stefano M, Veneto G, Malservisi S, Corazza GR. Small intestine bacterial overgrowth and metabolic bone disease. Dig Dis Sci 2001;46(5):1077e82. [66] Marie I, Ducrotte P, Denis P, Menard JF, Levesque H. Small intestinal bacterial overgrowth in systemic sclerosis. Rheumatology (Oxford) 2009;48(10):1314e9. [67] Parodi A, Sessarego M, Greco A, Bazzica M, Filaci G, Setti M, et al. Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of its eradication. Am J Gastroenterol 2008;103(5):1257e62. [68] Tauber M, Avouac J, Benahmed A, Barbot L, Coustet B, Kahan A, et al. Prevalence and predictors of small intestinal bacterial overgrowth in systemic sclerosis patients with gastrointestinal symptoms. Clin Exp Rheumatol 2014;32(6 Suppl. 86):S82e7. [69] Corazza GR, Menozzi MG, Strocchi A, Rasciti L, Vaira D, Lecchini R, et al. The diagnosis of small bowel bacterial overgrowth. Reliability of jejunal culture and inadequacy of breath hydrogen testing. Gastroenterology 1990;98(2):302e9. [70] Ghoshal UC, Ghoshal U, Das K, Misra A. Utility of hydrogen breath tests in diagnosis of small intestinal bacterial overgrowth in malabsorption syndrome and its relationship with oro-cecal transit time. Indian J Gastroenterol 2006;25(1):6e10. [71] Kaye SA, Lim SG, Taylor M, Patel S, Gillespie S, Black CM. Small bowel bacterial overgrowth in systemic sclerosis: detection using direct and indirect methods and treatment outcome. Br J Rheumatol 1995;34(3):265e9. [72] Marie I, Leroi AM, Menard JF, Levesque H, Quillard M, Ducrotte P. Fecal calprotectin in systemic sclerosis and review of the literature. Autoimmun Rev 2015;14(6):547e54. [73] Ejtehadi F, Chatzizacharias NA, Kennedy H. Pneumatosis intestinalis as the initial presentation of systemic sclerosis: a case report and review of the literature. Case Rep Med 2012;2012:987410. [74] Vischio J, Matlyuk-Urman Z, Lakshminarayanan S. Benign spontaneous pneumoperitoneum in systemic sclerosis. J Clin Rheumatol 2010;16(8):379e81. [75] Recasens MA, Puig C, Ortiz-Santamaria V. Nutrition in systemic sclerosis. Reumatol Clin 2012;8(3):135e40. [76] Bharadwaj S, Tandon P, Gohel T, Corrigan ML, Coughlin KL, Shatnawei A, et al. Gastrointestinal manifestations, malnutrition, and role of enteral and parenteral nutrition in patients with scleroderma. J Clin Gastroenterol 2015;49(7):559e64. [77] Brown M, Teubner A, Shaffer J, Herrick AL. Home parenteral nutritionean effective and safe long-term therapy for systemic sclerosis-related intestinal failure. Rheumatology (Oxford) 2008;47(2):176e9. [78] Jawa H, Fernandes G, Saqui O, Allard JP. Home parenteral nutrition in patients with systemic sclerosis: a retrospective review of 12 cases. J Rheumatol 2012;39(5):1004e7. [79] Govoni M, Muccinelli M, Panicali P, La Corte R, Nuccio Scutellari P, Orzincolo C, et al. Colon involvement in systemic sclerosis: clinical-radiological correlations. Clin Rheumatol 1996;15(3):271e6. [80] Poirier TJ, Rankin GB. Gastrointestinal manifestations of progressive systemic scleroderma based on a review of 364 cases. Am J Gastroenterol 1972;58(1):30e44. [81] Thayalasekeran S, Ali H, Tsai HH. Novel therapies for constipation. World J Gastroenterol 2013;19(45):8247e51. [82] Valle RG, Godoy FL. Neostigmine for acute colonic pseudo-obstruction: a meta-analysis. Ann Med Surg (Lond) 2014;3(3):60e4.

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Franck-Larsson K, Graf W, Eeg-Olofsson KE, Axelson HW, Ronnblom A. Physiological and structural anorectal abnormalities in patients with systemic sclerosis and fecal incontinence. Scand J Gastroenterol 2014;49(9):1076e83. Hamel-Roy J, Devroede G, Arhan P, Tetreault L, Duranceau A, Menard HA. Comparative esophageal and anorectal motility in scleroderma. Gastroenterology 1985;88(1 Pt 1):1e7. Massone C, Milone L, Parodi A, Pandolfo N, Rebora A. Anorectal involvement is frequent in limited systemic sclerosis. Acta Derm Venereol 2002;82(6):446e8. Thoua NM, Abdel-Halim M, Forbes A, Denton CP, Emmanuel AV. Fecal incontinence in systemic sclerosis is secondary to neuropathy. Am J Gastroenterol 2012;107(4):597e603. Thoua NM, Schizas A, Forbes A, Denton CP, Emmanuel AV. Internal anal sphincter atrophy in patients with systemic sclerosis. Rheumatology (Oxford) 2011;50(9):1596e602. Wald A, Bharucha AE, Cosman BC, Whitehead WE. ACG clinical guideline: management of benign anorectal disorders. Am J Gastroenterol 2014;109(8):1141e57 (quiz 058). Bharucha AE, Rao SS. An update on anorectal disorders for gastroenterologists. Gastroenterology 2014;146(1):37e45 e2. Hetzer FH, Hahnloser D, Clavien PA, Demartines N. Quality of life and morbidity after permanent sacral nerve stimulation for fecal incontinence. Arch Surg 2007;142(1):8e13. Kenefick NJ, Vaizey CJ, Nicholls RJ, Cohen R, Kamm MA. Sacral nerve stimulation for faecal incontinence due to systemic sclerosis. Gut 2002;51(6):881e3. Butt SK, Alam A, Cohen R, Krogh K, Buntzen S, Emmanuel A. Lack of effect of sacral nerve stimulation for incontinence in patients with systemic sclerosis. Colorectal Dis 2015;17(10):903e7. Khanna D, Hays RD, Maranian P, Seibold JR, Impens A, Mayes MD, et al. Reliability and validity of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument. Arthritis Rheum 2009;61(9):1257e63. Bae S, Allanore Y, Furst DE, Bodukam V, Coustet B, Morgaceva O, et al. Associations between a scleroderma-specific gastrointestinal instrument and objective tests of upper gastrointestinal involvements in systemic sclerosis. Clin Exp Rheumatol 2013;31(2 Suppl. 76):57e63. Spiegel BM, Hays RD, Bolus R, Melmed GY, Chang L, Whitman C, et al. Development of the NIH patient-reported outcomes measurement information system (PROMIS) gastrointestinal symptom scales. Am J Gastroenterol 2014;109(11):1804e14. Nagaraja V, Hays RD, Khanna PP, Spiegel BM, Chang L, Melmed GY, et al. Construct validity of the Patient-Reported Outcomes Measurement Information System gastrointestinal symptom scales in systemic sclerosis. Arthritis Care Res (Hoboken) 2014;66(11):1725e30.

Chapter 14

Gastrointestinal Involvement in Inflammatory Myositis M. Pe´rez-de-Lis Novo,* R. Pe´rez-A´lvarez,* L. Pallare´s-Ferreres,x J.J. Ferna´ndez-Martı´n,* M.-J. Soto Ca´rdenas{ and A. Selva-O’Callaghanjj

*Hospital A´lvaro Cunqueiro, Vigo, Spain; xHospital de Son Espases, Palma de Mallorca, Spain; { University of Ca´diz, Hospital Puerta del Mar, Ca´diz, Spain; jjUniversitat Auto`noma de Barcelona, Barcelona, Spain

1. INTRODUCTION Inflammatory myopathies (IMs) are a group of rare immune-mediated diseases characterized by proximal muscle weakness and mononuclear cell inflammation of the skeletal muscle [1]. IMs are the largest group of potentially treatable myopathies and form a heterogeneous group of disorders. We may classify them into five subtypes according to their clinicopathologic features: dermatomyositis (DM), polymyositis (PM), necrotizing autoimmune myositis, inclusion body myositis (IBM), and overlap myositis (OM). The precise diagnosis of the subtype and the differential diagnosis from other diseases that have similar signs and symptoms are fundamental, as each subtype has a different prognosis and therapeutic response [2,3]. The incidence of IM is between 3.7 and 7.7 cases per million, depending on the diagnostic inclusion criteria and population studied [4]. DM is the most common and affects both children and adults. PM is the least common and generally occurs after the second decade of life. IBM is the most frequent IM in patients over the age of 50. OM has only been recognized since 2005. The gastrointestinal (GI) complications of IM are often neglected, and few studies have been specifically focused on managing these patients [5].

2. DYSPHAGIA Dysphagia caused by pharyngeal and esophageal abnormalities has been reported in 32e84% of patients with myositis and may be the only symptom at the time of presentation [6]. The pharynx and upper esophageal sphincter are The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00014-3 263 Copyright © 2017 Elsevier B.V. All rights reserved.

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affected because, like peripheral muscle, they are composed of skeletal muscle. The causes of dysphagia in patients with IM are heterogeneous and may be related to an inadequate pharyngeal contraction, a poor relaxation of the cricopharyngeus muscle, or a reduced hyolaryngeal elevation. Videofluoroscopy (VF) often reveals hypopharyngeal and vallecular stasis and distention of the hypopharynx [7e10]. Although the highest incidence is reported in IBM, with 65e86% of IBM patients demonstrating dysphagic symptoms, it has been reported to affect 30e60% of PM patients and 18e20% of those with DM. As a result, the food bolus cannot be properly propelled into the esophagus. Dysphagia to both solids and liquids, together with heartburn, is the most common GI complaints. Other symptoms include nasal speech, hoarseness, nasal regurgitation and inability to swallow a food bolus while recumbent, discomfort in the sternal area, laryngitis, and coughing while eating. On physical examination, we may see tongue weakness, flaccid vocal cords, and poor palatal motion. In severe cases (aphagia), persistent sialorrhea is a bothersome manifestation. Proximal esophageal dysfunction is demonstrated by manometry with low amplitude⁄absent pharyngeal contractions and decreased upper esophageal sphincter pressure. Cine esophagram shows prolonged pharyngeal transit time with disorderly and decreased pharyngeal peristalsis, nasal reflux, tracheal aspiration, and retention of barium in the distended hypopharynx, valleculae, and atonic pyriform fossae [11,12].

3. GASTRIC INVOLVEMENT Gastric emptying can be delayed in PM and DM. This suggests malfunction of the smooth muscle of the upper GI tract [13]. These patients tend to have active disease, complain of reflux, and respond to antireflux measures and treatment of the myositis. Manometry may reveal a reduced distal esophageal sphincter resting pressure with normal relaxation and nonperistaltic lowamplitude simultaneous contraction. Endoscopy may reveal esophagitis or stricture formation [14]. When we assess gastric and esophageal emptying using scintigraphic techniques in patients with PM or DM, we may observe that they are significantly delayed. Nevertheless, we may also observe this in asymptomatic patients. Both gastric and esophageal emptying are correlated with the severity of the peripheral (skeletal) muscle weakness. Measurement of esophageal motility may help in monitoring the disease activity in PM/DM [15].

4. GASTROINTESTINAL VASCULITIS AND INFLAMMATION The association of juvenile DM with severe GI tract involvement due to vasculitis of the bowel wall is well known [16,17]. Few cases have been reported in adults [18]. DM may be associated with a vasculitis involving the GI

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tract. This may be a noninflammatory acute endarteropathy with arterial and venous intimal hyperplasia and occlusion of vessels by fibrin thrombi in the mucosa, submucosa, and serosal layers of the bowel. This narrowing and occlusion of small- and medium-sized arteries leads to ischemia. Patients present with abdominal pain, vomiting, constipation, and hematemesis with ischemic ulceration and perforation [19,20] and even acute acalculous cholecystitis [21]. Radiological features include widespread thickening of the mucosal folds and spiculation of the small intestine [22]. Severe GI inflammation in adult DM is neither widely recognized nor well defined. There are few case reports of inflammatory GI involvement in patients with DM, and these reports have variably included patients with mixed connective tissue disorder. This further hampers characterizing such an association [23]. The common histopathologic findings are severe, nonspecific acute and chronic inflammation with prominent vascular telangiectasia in the mucosa and submucosa of various parts of the alimentary tract, without vasculitis. These findings are seen macroscopically in endoscopic studies as edematous and hyperemic mucosa, with multiple erosions and ulcerative lesions [23].

5. PNEUMATOSIS CYSTOIDES INTESTINALIS Pneumatosis intestinalis (PI) has been associated with several autoimmune diseases, most commonly with systemic sclerosis, but has been also reported in patients with systemic lupus erythematosus, Sjogren’s syndrome, and IMs. The etiology of PI is often unclear although evidence exists for the contribution of increased intraluminal pressure due to GI dysmotility, overgrowth of anaerobic bacteria, retroperitoneal dissection of pulmonary gas, and disruption of mucosal integrity [24,25]. In patients with autoimmune diseases, mucosal integrity may be compromised by various factors including vasculitis, ischemic ulcers or peptic ulcer disease, and immunosuppressive therapy. The IMs in adults are renowned for their prominent upper GI involvement including dysmotility affecting the pharynx and esophagus, as well as delayed gastric emptying. Lower-GI tract involvement (including vasculitis with or without PI) is mainly reported in juvenile DM, although lower-GI tract dysmotility has also been reported in adult patients with PM [26,27]. PI can be an incidental radiological finding in adult patients with DM or PM. Its clinical significance needs to be evaluated according to the patient’s symptoms, physical examination findings, disease activity, immunosuppressive therapy, and potential risk factors for underlying ischemia, infection, and malignancy. PI may have a better prognosis in DM and PM than in other autoimmune diseases. We can often conservatively manage PI in adult DM and PM. Nonetheless, surgical intervention must be considered in patients with progressive symptoms, peritonitis, radiographic findings of inflammation, or associated neoplasia [28e30].

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6. OVERLAP WITH INFLAMMATORY BOWEL DISEASE The coexistence of IM with inflammatory bowel disease (IBD) has been reported in isolated cases [31]. IM is more commonly associated with Crohn disease (CD) than ulcerative colitis (UC). Both of them have many extraintestinal manifestations, but muscular involvement is infrequent. In patients diagnosed with UC, myositis may precede clinical expression of colitis and recur during acute exacerbations of IBD [32,33]. IM may be an infrequent extraintestinal complication in patients diagnosed with IBD. Patients with myositis and CD usually have colonic involvement. In general, the myositis follows the diagnosis of IBD; myalgias localized in both calves are the usual clinical manifestation in these patients. MRI and gastrocnemius muscle biopsy could be indicated in some cases [34]. It is usually associated with an acute exacerbation of IBD, but activity of the intestinal disease is not essential for the appearance or progression of the myositis [35,36]. Treatment with mesalazine (mesalamine) and/or corticosteroids leads to improvement of the muscle disease.

7. OVERLAP WITH COELIAC DISEASE Coeliac disease has been occasionally reported in patients with IMs. In 2007, Selva-O’Callaghan et al. evaluated the presence of celiac disease and related antibodies (antigliadin, antitissue transglutaminase, and antiendomysial antibodies) in 51 patients with IMs. Three (6%) patients showed jejunal biopsies diagnostic for coeliac disease, and all had histological normalization after a gluten-free diet. Seventeen patients (31%) were positive for antigliadin antibodies, and the frequency was higher in patients with inclusion body myositis in comparison with those with DM [37]. Hadjivassiliou et al. [38] reported similar results in a series of patients with myositis. In some patients, myositis could be an extraintestinal manifestation of celiac disease.

8. ASSOCIATION WITH CHRONIC VIRAL INFECTIONS The most frequent environmental etiopathogenic factors associated with myositis are infections. Hepatitis B virus (HBV) is associated with the development of several extrahepatic manifestations including vasculitis, glomerulonephritis, polyarthralgia and arthritis, PM, and DM [39,40]. Evidence of active HBV replication in the vascular endothelium of a patient with PM has been reported [41]. PM may be triggered by HBV. An acute exacerbation of HBV may be induced by withdrawal from steroids [42]. Lamivudine has good efficacy for this indication for prevention HBV reactivation in these patients [43e45]. An association between hepatitis C virus (HCV) infection and IM and IBM has been frequently reported. It has been suggested that the autoimmune

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reaction triggered by HCV infection causes myositis [46,47]. Furthermore, HCV-induced antibodies or circulating immune complexes could contribute to the pathogenesis of PM and DM [48,49].

9. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The diagnosis of IM-related GI involvement is based on the clinical aspects and complementary explorations such as endoscopy, cine esophagram, VF, and manometry [5,9,10]. There is a broad differential diagnosis, including certain muscular dystrophies, metabolic myopathies, drug- or toxin-induced myotoxicity, neuropathies, and infections [50,51]. An alternative diagnosis should be always considered in patients with PM, especially in those patients who showed a lack of response to immunosuppressive treatment. The most common diseases in the differential diagnosis of oropharyngeal dysphagia are neuromuscular disorders, including cerebral vascular accidents, motor neuron disease, myasthenia gravis, and PM [5,52]. Muscular dystrophies are generally hereditary, have a relatively early insidious onset, and slow progression. Dysphagia from myositis can be distinguished from that caused by cricopharyngeal muscle dysfunction [53]. Other etiologies that should be discarded include myopathies related to drugs or toxins (such as alcohol and penicillamine), endocrine diseases (such as hyper or hypothyroidism), metabolic abnormalities, and infections (such as human immunodeficiency virus and tuberculosis) [51]. Polymyalgia rheumatica has a normal creatine kinase and an absence of inflammatory histology.

10. THERAPEUTIC MANAGEMENT Corticosteroids are the mainstay of treatment, although their efficacy has not been fully established in randomized, placebo-controlled trials. Other immunosuppressive drugs that can be used include methotrexate, azathioprine, cyclophosphamide, and cyclosporin A [54]. Anti-TNF therapy may be considered in refractory PM/DM [55,56]. According to a double-blind, placebo-controlled study, intravenous immunoglobulin may be effective in muscle strength and rash in DM and provide dramatic improvement in patients with life-threatening steroid-resistant esophageal involvement [57]. It may also help in the dysphagia of IBM, although IBM generally responds poorly to corticosteroids and other immunosuppressive agents. Endoscopic balloon dilatation and botulinum toxin muscular injection can be a therapeutic option in some patients with cricopharyngeal achalasia [58,59]. Nevertheless, a long myotomy extending well into the constrictor muscle above and the esophageal musculature below may be useful [60]. Cricopharyngeal muscle obstruction is treated by myotomy rather than with steroids [61,62].

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270 SECTION j IV Gastrointestinal Involvement of Systemic Diseases [45] Thanapirom K, Aniwan S, Treeprasertsuk S. Polymyositis associated with hepatitis B virus cirrhosis and advanced hepatocellular carcinoma. ACG Case Rep J 2014;1(3):167e9. [46] Kee K-M, et al. Chronic hepatitis C virus infection associated with dermatomyositis and hepatocellular carcinoma. Chang Gung Med J 2004;27(11):834e9. [47] Mori N, et al. Hepatitis C virus (HCV) reactivation caused by steroid therapy for dermatomyositis. Intern Med (Tokyo, Japan) 2014;53(23):2689e93. [48] Agha B, et al. Hepatitis C virus infection, inflammatory myopathy, and pulmonary fibrosis: are they related? J Clin Rheumatol 2002;8(1):44e9. [49] Tsuruta Y, et al. Inclusion body myositis associated with hepatitis C virus infection. Fukuoka Igaku Zasshi 2001;92(11):370e6. [50] Baer AN, Wortmann RL. Noninflammatory myopathies. Rheum Dis Clin North Am 2013;39(2):457e79. [51] Michelle EH, Mammen AL. Myositis mimics. Curr Rheumatol Rep 2015;17(10):63. [52] Baer AN. Differential diagnosis of idiopathic inflammatory myopathies. Curr Rheumatol Rep 2006;8(3):178e87. [53] Dietz F, et al. Cricopharyngeal muscle dysfunction in the differential diagnosis of dysphagia in polymyositis. Arthritis Rheum 1980;23(4):491e5. [54] Fasano S, Alves SC, Isenberg DA. Current pharmacological treatment of idiopathic inflammatory myopathies. Expert Rev Clin Pharmacol 2016:1e12. [55] Anandacoomarasamy A, Howe G, Manolios N. Advanced refractory polymyositis responding to infliximab. Rheumatology (Oxford, England) 2005;44(4):562e3. [56] Moghadam-Kia S, Oddis CV, Aggarwal R. Modern therapies for idiopathic inflammatory myopathies (IIMs): role of biologics. Clin Rev Allergy Immunol 2016. [57] Marie I, et al. Intravenous immunoglobulins as treatment of life threatening esophageal involvement in polymyositis and dermatomyositis. Journal Rheumatol 1999;26(12):2706e9. [58] Liu LWC, Tarnopolsky M, Armstrong D. Injection of botulinum toxin A to the upper esophageal sphincter for oropharyngeal dysphagia in two patients with inclusion body myositis. Can J Gastroenterol 2004;18(6):397e9. [59] Nagano H, Yoshifuku K, Kurono Y. Polymyositis with dysphagia treated with endoscopic balloon dilatation. Auris Nasus Larynx 2009;36(6):705e8. [60] Houser SM, Calabrese LH, Strome M. Dysphagia in patients with inclusion body myositis. Laryngoscope 1998;108(7):1001e5. [61] Kagen LJ, Hochman RB, Strong EW. Cricopharyngeal obstruction in inflammatory myopathy (polymyositis/dermatomyositis). Report of three cases and review of the literature. Arthritis Rheum 1985;28(6):630e6. [62] Sanei-Moghaddam A, et al. Cricopharyngeal myotomy for cricopharyngeus stricture in an inclusion body myositis patient with hiatus hernia: a learning experience. BMJ Case Rep 2013;22:2013.

Chapter 15

Digestive Involvement in Primary Sjo¨gren’s Syndrome S. Retamozo,* P. Brito-Zero´n,x, { C. Morcillo,x B. Kostov,jj N. Acar-Denizli# and M. Ramos-Casals** *Institute University of Biomedical Sciences University of Co´rdoba (IUCBC), Co´rdoba, Argentina; x Hospital CIMA-Sanitas, Barcelona; {Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, Hospital Clı´nic, Barcelona, Spain; jjInstitut d’Investigacions Biome`diques August Pi i Sunyer, Barcelona and University of Barcelona; #Mimar Sinan Fine Arts University, Istanbul, Turkey; **Sjo¨gren Syndrome Research Group (AGAUR), Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, University of Barcelona, Hospital Clı´nic, Barcelona, Spain

1. INTRODUCTION Sjo¨gren’s syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes due to functional impairment of the salivary and lacrimal glands [1]. The histological hallmark is a focal lymphocytic infiltration of the exocrine glands, and the spectrum of the disease extends from an organ-specific autoimmune disease (autoimmune exocrinopathy) [2] to a systemic process with diverse extraglandular manifestations [3]. An estimated 2e4 million people in the United States have SS, and approximately 1 million of them have an established diagnosis [2]. The prevalence in European countries ranges between 0.60 [4] and 3.3% [5]. The incidence of SS has been calculated as 4 cases per 100,000 [6]. SS primarily affects Caucasian perimenopausal women, with a femaleemale ratio ranging from 14:1 [7,8] to 24:1 [9] in the largest reported series. The disease may occur at all ages but typically has its onset in the fourthesixth decades of life; although some cases are detected in younger female patients, especially in mothers of babies with congenital heart block [10]. When sicca symptoms appear in a previously healthy person, the syndrome is classified as primary SS. When sicca features are found in association with another systemic The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00015-5 271 Copyright © 2017 Elsevier B.V. All rights reserved.

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autoimmune disease, most commonly rheumatoid arthritis (RA), systemic sclerosis (SSc), or systemic lupus erythematosus (SLE), it is classified as associated SS. The variability in the presentation of SS may partially explain the delays in diagnosis of up to 9 years from the onset of the symptoms [1]. Although most patients present with sicca symptoms, various clinical and analytical features may indicate an undiagnosed SS. In addition, SS is a disease that may be expressed in many guises, depending on the specific epidemiological, clinical, or immunologic features. Epidemiologically, a lower frequency of autoantibodies is observed in male SS patients and those with an earlier onset [7]. Clinically, two main patterns of disease expression are observed: patients with only glandular involvement (sicca-limited disease), who have a low frequency of immunologic abnormalities and extraglandular features; and patients with a predominant systemic expression in addition to the sicca involvement [7]. Patients with positive immunologic features need a closer follow-up, paying special attention to the development of extraglandular manifestations. The therapeutic management of SS is mainly centered on the control of sicca features, using substitutive and oral muscarinic agents, while corticosteroids and immunosuppressive agents play a key role in the treatment of extraglandular features. Gastrointestinal involvement has been little studied in primary SS and may include altered esophageal motility, gastroesophageal reflux (GER), chronic gastritis, and, less frequently, malabsorption. More clinical data are available on pancreatic and liver involvements, which were first reported to be part of the extraglandular expression of SS by Bloch et al. [11].

2. ESOPHAGEAL INVOLVEMENT 2.1 Dysphagia Recent studies have analyzed esophageal involvement in patients with primary SS. Since adequate pharyngoesophageal transfer of the alimentary bolus requires saliva [12], its lack might contribute to the development of dysphagia in SS. However, Anselmino et al. [13], observed no differences in salivary flow rates of primary SS patients with and without dysphagia, while Grande et al. [14] found no relationship between dysphagia and the parotid saliva flow rate. Dysphagia has also been associated with esophageal motor dysfunction and upper esophageal webs [15]. Thus, Rosztoczy et al. [16] described decreased peristaltic velocity in the esophageal body of 11 (44%) out of 25 patients with primary SS. However, the majority of studies have found that the SS patients with and without dysphagia have similar function [13e15,17] and that dysphagia is independent of esophageal dysmotility [14,18,19]. Although some patients with primary SS may have altered manometric results, to date, studies have failed to describe any consistent pattern of esophageal dysfunction, and

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the motor disorders that some patients may present do not correlate with the presence of dysphagia. A recent study [20] has reported that 23 out of 193 patients with esophageal achalasia (12%) had an associated autoimmune disease, especially SS, with an odds ratio of 37 (95% CI 1.9e205).

2.2 Gastroesophageal Reflux Volter et al. analyzed the prevalence and clinical significance of GER in patients with primary SS, and its possible association with esophageal dysmotility [111] in 2004, and found abnormalities in motility in 21 patients with SS, which was associated with GER. The study found slow acid clearance in the esophagus of SS patients with GER, suggesting a prolonged duration of reflux. This extended exposure of the esophagus to refluxed acid may result either from defective acid neutralization by salivary bicarbonates or from altered esophageal motility [21e24]. Ho et al. [25] described a high frequency of tertiary waves in patients with markedly abnormal pH that were significantly associated with the total reflux time, suggesting a relationship between these contractions and prolonged exposure of the esophageal mucosa to low pH values. A caseecontrol study [26] compared the prevalence of dysphagia and dysmotility of the pharynx and esophagus in patients with primary SS, in whom a higher frequency of dysphagia (65% vs. 3%; p < .001), pharyngeal (45% vs. 7%; p < .01), esophageal (80% vs. 7%; p < .001), and GER (60% vs. 23%; p < .01) symptoms were reported in comparison with the control group. In a study done by [26], dysphagia was not associated with dysmotility but was found to be associated with a decreased E/I ratio; dysphagia does not correlate with video radiographical signs of dysmotility but could be related to an impaired parasympathetic function.

3. GASTRIC INVOLVEMENT 3.1 Chronic Gastritis Although earlier reports described chronic gastric inflammation with mucosal atrophy in nearly 80% of patients with SS [27e29], the prevalence of chronic gastritis has not been evaluated in recent studies. In clinical practice, patients frequently complain of gastric pain, although gastroscopic studies often show only mild gastric abnormalities. Some studies have analyzed the prevalence and clinical significance of anti-parietal cell gastric antibodies (anti-PCA) in primary SS. Nardi et al. [30] found positive anti-PCA antibodies in 90 (27%) out of 335 patients. These patients showed a higher prevalence of thyroiditis and autoimmune liver involvement, but no gastrointestinal involvement. El Miedany et al. [31] found

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anti-PCA antibodies in one-third of SS patients and controls. However, all SS patients with anti-PCA antibodies had Helicobacter pylori infection, in comparison with less than half of the autoantibody-positive controls. Likewise, only 22% of the autoantibody-positive controls had atrophic changes in gastric mucosa compared with 86% of those with SS. This study found a close association between anti-PCA antibodies and H. pylori infection, suggesting that this bacterium may induce a local hyperreactive/autoimmune response that might facilitate the induction of autoantibodies against the gastric mucosa of SS patients. Although anti-PCA antibodies have been associated with chronic atrophic gastritis and pernicious anemia, the two processes are only rarely described in patients with primary SS. Two cases were described in a recent review of hematologic manifestations in a cohort of 380 SS patients [32], with only four additional cases being reported [33e35], suggesting that chronic atrophic gastritis and pernicious anemia are very infrequent in primary SS.

3.2 Helicobacter pylori Infection 3.2.1 Prevalence and Clinical Significance A number of studies have analyzed the prevalence and clinical significance of H. pylori infection in primary SS, searching for a possible association with dyspepsia, gastritis, gastric ulcers or lymphoma, with controversial results. Theander et al. [36] found that SS patients have a similar H. pylori seroprevalence rate to controls, while Collin et al. [37] found that the seroprevalence of H. pylori infection in dyspeptic SS patients was similar to that of dyspeptic patients without SS. In contrast, other studies have described a higher prevalence of H. pylori antibodies in primary SS compared with controls [38e40]. El Miedany et al. [31] found both a significantly higher prevalence and higher serum titers of IgG and IgM anti-H. pylori antibodies in SS patients compared with both patients with other autoimmune diseases without sicca syndrome and healthy controls. This might reflect geographic differences in the prevalence of H. pylori infection, which is reported to be lower in Sweden than in other countries. Moreover, a recent study has shown that H. pylori was detected in gastric biopsies in 71% of Italian SS patients in comparison with 31% of Scandinavian patients [36]. Histologically, the severity of gastritis has been closely associated with the presence of H. pylori in primary SS. However, a recent study showed that eradication of H. pylori caused a significant regression of gastric mucosaassociated lymphoid tissue (MALT) and atrophy in controls but not in SS patients [41]. In addition, dyspepsia did not improve following bacterial eradication in the majority of SS patients, suggesting that H. pylori does not seem to play a role in the dyspeptic symptoms found in SS.

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3.2.2 Association With Gastric Lymphoma A possible relationship between H. pylori and gastric lymphomagenesis in SS has recently been postulated. Lymphoid accumulation in the gastric mucosa is common in SS, but full evidence for an antigen-driven B-cell expansion has not been demonstrated. De Vita et al. [38] described a low-grade gastric lymphoma concomitantly with H. pylori infection in a patient with SS. After H. pylori eradication, a dramatic regression of gastric lymphoma into chronic gastritis was observed, but no amelioration occurred in the parotid and nodal involvement. Multiple molecular analyses showed the expansion of the same B-cell clone in synchronous and metachronous lymph node, parotid, and gastric lesions before and after H. pylori eradication. Ferraccioli et al. [42] studied the gastric tissue in SS in order to define whether the presence of MALT in the stomach is associated with several infectious agents, and showed that H. pylori infection is not more frequent among patient with SS than in controls and that the abnormal accumulation of MALT may occur in the stomach even in the absence of H. pylori infection. Other studies performed on a limited number of SS patients with simple dyspepsia indicate that clonality may persist for up to 6 months after the eradication of H. pylori [43]. Thus, although H. pylori may play a crucial role in the local boosting of B-cell lymphoproliferation, the underlying B-cell disorder seems to be a nonmalignant process [38]. The regression of parotid MALT lymphoma after the eradication of H. pylori in SS patients has been reported in two patients [44,45]. However, and although SS and H. pylori infection are risk factors for developing MALT lymphoma, it is not yet clear if there is a causal association. Thus far there is no evidence that the coexistence of SS and H. pylori infection would play an additive role and lead to a much higher incidence of MALT lymphoma [46].

4. INTESTINAL INVOLVEMENT Intestinal involvement should be considered as one of the less-frequent, extraglandular manifestations of primary SS, with isolated cases of malabsorption or vasculitis being reported.

4.1 Association With Celiac Disease Several studies have analyzed the association of celiac disease (CD) in small series of patients with primary SS. Iltanen et al. [47] found that 5 (15%) out of 34 SS patients had CD, while Szodoray et al. [48] diagnosed CD in 5 (4.5%) out of 111 patients with SS, whereas the prevalence of CD is estimated to be 0.45% in the general population. In contrast [49] found 1 (0.9%) out of 114 patients with primary SS, and no case was found in a series including 400 patients [7]. In contrast with the opinion of other authors [50], these data suggest that CD should not be routinely evaluated in patients with primary SS.

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However, the close association of CD with other processes, that may also be observed in primary SS, such as primary biliary cirrhosis (PBC) or IgA deficiency, suggests that these patients should be tested for antiendomysial antibodies due to the increased risk of small bowel adenocarcinomas and lymphomas in patients with CD.

4.2 Gastrointestinal Vasculitis In patients with primary SS, systemic vasculitis only rarely involves the gastrointestinal tract. Of 19 reports of SS patients with systemic necrotizing vasculitis [51], 13 had the gastrointestinal tract involvement (Table 15.1). In addition, of the 19 reported deaths of SS patients due to vasculitis, the 2 main causes were CNS involvement in 6 and gastrointestinal perforation in 5. Cryoglobulins were determined in 12 of these patients and were positive in 10 (83%) cases. In spite of its rarity, gastrointestinal vasculitis, often related to cryoglobulinemia, should be considered as a life-threatening situation in patients with primary SS.

TABLE 15.1 Previous Reported Cases of Vasculitis Involving the Gastrointestinal Tract in Patients With Primary Sjo¨gren Syndrome [51] Number of Cases

Histology

Site of Vasculitic Involvement

1

Necrotizing

Ileum

2

Necrotizing

Gallbladder, spleen

3

Necrotizing

CNS, GI, kidney, pancreas

4

Necrotizing

Bowel

5

Necrotizing

Colonic ulcers

6

Necrotizing

Muscle, kidney, CNS, GI

7

Necrotizing

Muscle, parotid, bowel

8

Necrotizing

Colon ulcers

9

Leukocytoclastic

Rectum

10

Leukocytoclastic

Bowel

11

Leukocytoclastic

Ileum

12

Leukocytoclastic

Bowel

13

Leukocytoclastic

Gallbladder, appendix, mesentery

CNS, central nervous system; GI, gastrointestinal.

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4.3 Protein-Losing Gastroenteropathy Protein-losing gastroenteropathy (PLGE) is a rare complication in autoimmune diseases, especially in SS. The cause of PLGE is generally unknown, but when PLGE is associated with collagen diseases, an immune-mediated mechanism is suspected since corticosteroids or other immunosuppressive drugs are reported to be effective; further, patients often have low serum complement. Disturbance of vascular permeability by complement activation in the intestinal wall is speculated to be a mechanism of PLGE in autoimmune diseases, but complement deposition in the intestinal wall rarely has been confirmed [52]. Hsieh et al. [53] described the first two cases associated with the pSS successfully treated with glucocorticoids. Since then only five cases have been reported to date: [52,54e57]. All cases of pSS associated with PLGE have been reported from East Asia, particularly Japan, Taiwan, and China. More than a dozen cases of PLGE with SS have been reported in the Japanese-language literature [56].

5. PANCREATIC INVOLVEMENT In patients with primary SS, pancreatic involvement is usually asymptomatic and is demonstrated by altered pancreatic function tests, although some patients may present chronic pancreatitis. The prevalence of altered pancreatic function tests varies widely based on the tests used (Table 15.2). Fenster et al. [58] found a prevalence of altered secretin/ cholecystokinin test of 52% and Hradsky et al. [59] a prevalence of 36%, while Gobelet et al. [60] described a prevalence of 35% using the NBT-PABA test and Coll et al. [61] a prevalence of 63% using NBT-PABA test, serum immuno-reactive trypsin levels, and/or

TABLE 15.2 Prevalence of Altered Functional Pancreatic Tests in Patients With Sjo¨gren Syndrome Author

Pancreatic Tests

Prevalence of Altered Tests (%)

Fenster et al. [58]

Secretin

52

Hradsky et al. [59]

Secretin-cholecystokinin

36

Gobelet et al. [60]

N-Benzoyl-L-tyrosyl para- aminobenzoic acid (NBT-PABA) test, radioimmunoassay trypsinemia

35

Coll et al. [61]

NBT-PABA test, radio-immunoassay trypsinemia, and stool-fat measurements

63

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stool-fat measurement. All these studies, mainly performed in the 1970s and 1980s, suggested a high frequency of altered pancreatic function in primary SS, although no data were presented on the clinical impact of these altered tests in patients with primary SS. In contrast, the frequency of chronic pancreatitis is very low in large series of patients with primary SS (lower than 2%), although some patients may present with a cluster of autoimmune diseases including chronic pancreatitis, thyroiditis, and sclerosing cholangitis (SC) [62e64]. Autoimmune pancreatitis has recently been considered as an IgG4-related autoimmune disease, a novel group of diseases that includes other organspecific autoimmune diseases such as Riedel’s thyroiditis or tubulointerstitial nephritis [65,66]. Recent studies have described some Japanese patients with Mikulicz’s disease (MD), a disease closely related to SS [67,68]. These patients showed a higher frequency of males, higher levels of serum IgG4, lower titers of antinuclear antibodies (ANA) negative anti-Ro and anti-La antibodies, a predominance of IgG4þ cells in the salivary glands, and a close association with autoimmune pancreatitis in more than 50% of cases. The lack of reported cases outside Japan suggests that the association between MD and autoimmune pancreatitis might be related to local genetic or environmental factors. In all patients with SS presenting with chronic autoimmune pancreatitis, IgG4-RD must be investigated.

6. LIVER INVOLVEMENT Liver involvement was one of the first reported extraglandular manifestations of the systemic expression of SS, although new developments in the field of hepatic diseases have significantly changed the diagnostic approach. In the first studies on SS patients in the 1960s, liver involvement was evaluated by the presence of hepatomegaly, with a prevalence of 20%. In 1965, Bloch et al. found a 27% prevalence of liver involvement (hepatomegaly and/or raised alkaline phosphatase) in the first well-described series of patients with SS. In 1970, Golding et al. [69] reported a higher frequency of sicca syndrome in patients with diverse liver diseases including chronic active hepatitis, PBC, or cryptogenetic cirrhosis. Antimitochondrial antibodies (AMA) were included as a marker of liver disease in SS patients in the 1970s, with later studies finding a closer association between SS and PBC than with other types of autoimmune liver disease [70,71]. However, it was not until the 1990s when the spectrum of liver diseases in patients with primary SS, included the evaluation of clinical signs of liver disease, liver function, and a complete panel of autoantibodies [72,73]. Several studies have shown that liver function tests may be altered in 10e20% of patients with primary SS [74]. After discarding potentially hepatotoxic drugs, the main causes were chronic HCV infection (especially in

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geographic areas with a high prevalence) and PBC [75,76]. Some SS patients may present positive AMA with no clinical or analytical evidence of liver involvement, probably reflecting an early asymptomatic stage of PBC [77]. Less frequently, SS patients may present type-1 autoimmune hepatitis (AIH) and, even more rarely, autoimmune or SC.

6.1 Chronic Hepatitis C Virus Infection Chronic viral liver diseases have recently emerged as an additional cause of liver involvement in patients with SS (especially in some geographic areas), broadening the spectrum of hepatopathies that may affect these patients [76]. Chronic HCV infection was the main cause of liver involvement in patients with SS, with a prevalence of 13%, nearly threefold greater than that observed for autoimmune liver involvement [77]. This underlines the importance of chronic HCV infection as a cause of liver disease in SS patients from regions such as the Mediterranean, with a higher prevalence of HCV infection in the general population. Some experimental [78,79], virological [80,81], and clinical evidences [82e84] revealed a close association between HCV and SS and, in recent large multicenter studies [76,85], SS-HCV was indistinguishable in most cases from the primary form using the most recent sets of classification criteria. Two-thirds of SS-HCV patients presented cryoglobulinemia, which may be considered the key immunologic marker of SS associated with HCV and the main cause of vasculitis in these patients. How then should this SS be classified? Current evidence suggests that chronic HCV infection should be considered an exclusion criterion for the classification of primary SS, not because it mimics primary SS, but because it seems to be directly responsible for the development of SS in a specific subset of HCV patients [76]. SS-HCV patients should be considered as a separate subset from the primary form, and it would be more appropriate to classify these patients as having a “SS associated with HCV.” The term “SS secondary to HCV” might be used in those cases in which infection of salivary gland epithelium by HCV is directly demonstrated. In Mediterranean countries, chronic HCV infection is the main cause of liver involvement in patients with SS, with a prevalence of 13%dnearly threefold greater than that observed for autoimmune liver involvement [86]. A recent study [87] found a prevalence of sicca syndrome of 55% in 120 Egyptian patients with chronic HCV infection. We found HCV infection in 13% of a large series of Spanish patients with SS. The HCV-driven autoimmune response was characterized by a lower frequency of anti-Ro/La antibodies, an abnormal predominance of anti-La among anti-Ro antibodies, and a higher frequency of cryoglobulinemic-related immunological markers in comparison with patients without HCV infection. This immunological pattern may contribute to the poor outcomes found in patients with SS-HCV. This

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underlies the importance of chronic HCV infection as a cause of liver disease in SS patients from specific geographical regions that have high prevalences of HCV infection in the general population [88].

6.2 Chronic Hepatitis B Virus The association between SS and other types of chronic viral hepatitis is very infrequent. Only one case of chronic HBV infection was found in 475 SS patients, in comparison to 63 patients with chronic HCV infection [77]. Three additional cases [89e91] of HBV-related SS have been reported (one associated with HBV vaccination), compared to more than 300 cases of HCV-related SS [92]. Similarly, chronic HGV infection also plays an insignificant role in liver disease in SS patients. The predominant etiopathogenic role of HCV is probably due to its specific lymphotropism and sialotropism [78,93], which means it can infect and replicate in both circulating lymphocytes and epithelial cells from the salivary glands [94]. Recently, we reported a prevalence of chronic HBV infection of 0.83% in 603 patients with primary SS, a very similar prevalence to that found in the general population in Spain (0.7%) [95]. In spite of the few reported cases of HBV-related SS, a comparison between primary SS and HBV-related SS reveals some differences. The clinical expression of HBV-related SS is similar to that of primary SS with respect to the prevalence of sicca features, except for a higher percentage of patients with joint involvement. With respect to immunological expression, HBV-related SS patients had a higher radio frequency, but a lower frequency of some immunological features typically described in HCV-related SS patients, such as hypocomplementemia and cryoglobulinemia. In contrast to the close association between SS and HCV, chronic HBV infection is not associated with SS in our geographical area (Barcelona, Spain) with a ratio of HBV-related SS: HCV-related SS cases of 1:10. However, recent studies have suggested a different role of HBV in SS patients from Asian countries. Chen et al. [96] have recently reported a 10% prevalence of HBV infection in patients with primary SS from Taiwan. Although the prevalence of HBV infection in Taiwanese patients with SS was 10-fold higher than that found in European SS patients, the prevalence was lower than that found in the general population of Taiwan (10% vs. 17%, p < .001). In contrast, Kang et al. [97] have reported that Taiwanese patients with SS had a 2.3-fold higher risk of having associated HBV infection in comparison with the general Taiwanese population. The differing results obtained by these two studies suggest that further research is needed to evaluate whether the prevalence of HBV infection in Asian patients with primary SS is higher or lower with respect to the prevalence of HBV infection found in the general population of the same geographical area.

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6.3 Primary Biliary Cholangitis After discarding HCV infection, primary biliary cholangitis (formerly PBC) should be considered as the main cause of liver disease in patients with primary SS [72,73,77]. Although historically these patients have been considered as having a “secondary” SS, it seems more rational to use the term “SS associated with PBC,” due to the clinical-based evidence that SS is associated with (and not secondary to) other autoimmune diseases. The inclusion of AMA in the routine immunologic follow-up of SS patients should be recommended, independent of whether the analytical liver profile is altered or not, due to the strong association between AMA and the development of PBC.

6.3.1 Prevalence of Antimitochondrial Antibodies in Primary Sjo¨gren’s syndrome Several studies have analyzed the prevalence of AMA in patients with primary SS. Csepregi et al. [74] studied 180 patients and found 5 AMA positive patients (2 of whom developed symptomatic PBC), 3 patients with AIH and 1 with autoimmune cholangitis, while [98] found abnormal liver tests in 29 out of 59 (49%) patients, including 5 patients with positive AMA and 1 with AIH. Nardi et al. [30] found a prevalence of 8% of AMA, although only 50% of these SS-AMA positive patients had any clinical or analytical evidence of liver involvement, suggesting the existence of an incipient or incomplete PBC in some patients with primary SS. We have confirmed the broad spectrum of abnormalities in the analytical liver profile of SS patients with AMA-M2, including three patients with no clinical or analytical data suggestive of liver disease [77], as has been reported in five previous cases [72e74]. Previous studies on non-SS patients have shown that AMA-M2 patients with any clinical or analytical sign of liver involvement have a high risk of developing symptomatic PBC [99], underlining the key role of AMA-M2 as an early immunologic marker of PBC [75]. Although there are no therapeutic guidelines for these asymptomatic patients, early use of ursodeoxycholic acid can be considered, since some studies on non-SS patients with mild analytical abnormalities have suggested that treatment with ursodeoxycholic acid might prevent a possible evolution to liver cirrhosis [100]. 6.3.2 Prevalence of SS in Patients With Primary Biliary Cirrhosis Three studies have analyzed the prevalence of systemic autoimmune diseases in PBC [101e103]. Two of these studies found SS to be the most prevalent systemic autoimmune disease in patients with PBC [32,112]. Wang et al. [103] found that 36% of 322 patients with PBC had SS, followed by SLE

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with a prevalence of 4%. Gershwin et al. [101] found a lower prevalence of SS (10%) in 1032 patients with PBC. The same prevalence (10%) was found for RA. Finally, an Italian study including 170 PBC patients [18] found that SSc was the most frequently associated systemic autoimmune disease (12%), followed by SS (3.5%). Clinical expression of PBC in SS PBC and SS share several clinical, histological, and serological features. According to several studies, characteristic symptoms of SS such as dry mouth or dry eyes are also commonly found (47e73%) in PBC. In addition, objective findings of dry eyes or dry mouth (such as abnormal Schirmer test or diminished salivary flow rate) are also found in 30e50% of patients with PBC [104,105]. Furthermore, PBC patients frequently (26e93%) manifest histological changes in salivary gland biopsies that are compatible with a diagnosis of SS [71,106,107].

6.4 Autoimmune Hepatitis AIH was another autoimmune liver disease found in SS patients, although less frequently than PBC.

6.4.1 Type-1 Autoimmune Hepatitis Type-1 AIH is the second most frequently found autoimmune liver disease associated with SS. The frequency of AIH in primary SS ranges from 1% to 4% according to four studies (Table 15.3) [72,77,108,109]. Up to 2012, 69 cases of type-1 AIH had been reported in patients with primary SS [104]. A specific characteristic of AIH associated with primary SS is that two-thirds of the cases were reported from Asian countries. In addition, nearly 10% of AIH patients had positive AMA (AIHPBC overlap). These patients may have histological features compatible with both AIH and PBC, and a cholestatic biochemical pattern [104]. A recent study showed that SS was the systemic autoimmune disease most frequently reported to be associated with AIH-PBC overlap syndrome (6 out of 71 patients, 8%) [110]. A recent study [109] evaluated the prognostic implications of antibodies to Ro/SSA in patients with type-1 AIH, and reported that anti-Ro52 antibodies (alone or in combination with antibodies to soluble liver antigen) were independently associated with a poor prognosis. 6.4.2 Type-2 Autoimmune Hepatitis There are no reported cases of type-2 AIH in patients with primary SS, a fact consistent with the lack of positive anti-LKM-1 antibodies in SS. The prevalence of anti-LKM-1 antibodies has recently been evaluated in a large series of patients with primary SS, and none of the 335 patients tested had these autoantibodies [30].

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TABLE 15.3 Autoimmune Hepatitis Associated With Sjo¨gren Syndrome: 69 Reported Cases [77,108e114] Number of Cases

Year

Country

1

1991

Japan

2

1993

France

3e9

1995

Japan

10e11

1997

France

12

1997

Italy

13

1998

India

14e19

1998

China

20

1999

Japan

21

2000

Japan

22

2001

Spain

23

2001

Korea

24

2001

Japan

25

2002

Japan

26e28

2002

Hungary

29

2003

Japan

30

2003

France

31

2003

Korea

32e34

2004

Japan

35e42

2005

Japan

43e51

2006

Spain

52e53

2007

Mexico

54

2008

Greece

55

2010

USA

56e57

2010

Tunis

58e59

2010

Japan

60e63

2010

Germany

64e69

2012

France, Italy, Sweden, and Turkey (AIH/PBC)

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6.5 Other Autoimmune Liver Diseases 6.5.1 Sclerosing Cholangitis Other autoimmune liver diseases have infrequently been described in patients with primary SS (Table 15.4), including 14 cases of SC, 7 cases of autoimmune cholangitis, and 1 case of nodular regenerative hyperplasia of the liver [77,115]. Some characteristics of patients with SS and associated SC should be

TABLE 15.4 Other Autoimmune Liver Disease Associated With Sjo¨gren Syndrome [77,115] Liver Disease

Year

Country

Sclerosing cholangitis

1975

UK

Sclerosing cholangitis

1975

UK

Sclerosing cholangitis

1984

USA

Sclerosing cholangitis

1986

France

Sclerosing cholangitis

1989

Peru

Sclerosing cholangitis

1989

Japan

Autoimmune cholangitis

1989

Spain

Sclerosing cholangitis

1991

Spain

Nodular regenerative hyperplasia of the liver

1994

Spain

Autoimmune cholangitis

1995

Greece

Autoimmune cholangitis

1995

Japan

Sclerosing cholangitis

1996

Japan

Sclerosing cholangitis

1997

Finland

Autoimmune cholangitis

1998

Korea

Autoimmune cholangitis

2001

Korea

Sclerosing cholangitis

2002

Japan

Autoimmune cholangitis

2002

Hungary

Autoimmune cholangitis

2002

Rumania

Sclerosing cholangitis

2003

Switzerland

Sclerosing cholangitis

2004

Germany

Sclerosing cholangitis

2005

Japan

Sclerosing cholangitis

2009

Greece

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highlighted: a specific pattern of clinical features at presentation of SC (mainly abdominal pain, jaundice, and diarrhea), an overwhelming association with chronic pancreatitis in all but one case (with pancreatic masses demonstrated by CT abdominal scan), and an association with other autoimmune processes such as retroperitoneal fibrosis. These specific features may aid earlier diagnosis of this rare disease in patients with primary SS.

6.6 Evaluation of Altered Liver Profile in Patients With Sjo¨gren’s Syndrome Detection of an altered liver profile in a patient with SS requires a sequential diagnosis (Fig. 15.1). The first step is to discard processes not associated with SS, mainly the chronic use of potentially hepatotoxic drugs, steatosis, and congestive heart failure, all of which are frequently found in the elderly. The second step is to differentiate between autoimmune and viral liver diseases. Evaluation of epidemiological factors may be helpful. For example, HCV infection is more frequently found in SS patients from the Mediterranean area than in those from North Europe [116]. Likewise, HCV diagnosis is more frequent in older and male SS patients, while younger and female SS patients are more likely to have an associated autoimmune liver disease. The third step is the analytical liver profile, although in a recent study, this was not useful in differentiating between HCV- and autoimmune-related liver diseases [77]. The fourth step is the immunologic profile, which plays a key role in differentiating between the main etiologies: Patients with chronic HCV infection have a higher frequency of cryoglobulins and hypocomplementemia, while those with autoimmune liver disease present hypergammaglobulinemia and autoantibodies (ANA, SMA, Ro, and La) more frequently [88]. In SS patients with a

FIGURE 15.1 Sequential diagnosis of an altered liver profile in a patient with Sjo¨gren syndrome.

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suspected autoimmune liver disease, the existence of AMA with a specific M2 pattern indicates PBC, while high titers of ANA and anti-SMA suggest type-1 AIH. The differential diagnosis of liver disease in patients with primary SS (viral vs. autoimmune) is clinically important, since the two processes have a different therapeutic approach and prognosis.

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[90] Iakimtchouk K, Myrmel H, Jonsson R. Serological screening for hepatitis B and C and human herpesvirus 6 in Norwegian patients with primary Sjogren’s syndrome. J Rheumatol 1999;26:2065e6. [91] Toussirot E, Lohse A, Wendling D, Mougin C. Sjogren’s syndrome occurring after hepatitis B vaccination. Arthritis Rheum 2000;43:2139e40. [92] Ramos-Casals M, Loustaud-Ratti V, Zeher M. Hepatitis C virus and autoimmune diseases. In: Ramos-Casals M, Garcı´a-Carrasco M, Rosas J, Calvo J, Font J, editors. Enfermedades Autoinmunes Siste´micas y Reumatolo´gicas. Barcelona: Masson; 2005. p. 742e58. [93] Ramos-Casals M, Garcia-Carrasco M, Cervera R, Font J. Is hepatitis C virus a sialotropic virus? Am J Pathol 2001;159:1593e4. [94] Ramos-Casals M, Font J. Extrahepatic manifestations in patients with chronic hepatitis C virus infection. Curr Opin Rheumatol 2005;17:447e55. [95] Marcos M, Alvarez F, Brito-Zero´n P, Bove A, Perez-De-Lis M, Diaz-Lagares C, SanchezTapias JM, Ramos-Casals M. Chronic hepatitis B virus infection in Sjogren’s syndrome. Prevalence and clinical significance in 603 patients. Autoimmun Rev 2009;8:616e20. [96] Chen MH, Hsiao LT, Chen MH, Tsai CY, Huang YH, Chou CT. Clinical significance of chronic hepatitis B virus infection in patients with primary Sjo¨gren’s syndrome. Clin Rheumatol 2012;31:309e15. [97] Kang JH, Lin HC. Comorbidities in patients with primary Sjo¨gren’s syndrome: a registrybased case-control study. J Rheumatol 2010;37:1188e94. [98] Kaplan G. Hepatite virale, VHC et syndrome de Gougerot-Sjogren. L’Actualite´ Rhumatologique 1993. Paris: Expansion Scientifique Francaise; 1993. p. 11e8. [99] Prince MI, Chetwynd A, Craig WL, Metcalf JV, James OF. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut 2004;53:865e70. [100] Beswick DR, Klatskin G, Boyer JL. Asymptomatic primary biliary cirrhosis. A progress report on long-term follow-up and natural history. Gastroenterology 1985;89:267e71. [101] Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, Lindor KD, Kaplan MM, Vierling JM, USA PBC Epidemiology Group. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005;42:1194e202. [102] Marasini B, Gagetta M, Rossi V, Ferrari P. Rheumatic disorders and primary biliary cirrhosis: an appraisal of 170 Italian patients. Ann Rheum Dis 2001;60:1046e9. [103] Wang L, Zhang FC, Chen H, Zhang X, Xu D, Li YZ, Wang Q, Gao LX, Yang YJ, Kong F, Wang K. Connective tissue diseases in primary biliary cirrhosis: a population-based cohort study. World J Gastroenterol 2013;19:5131e7. [104] Fragoulis GE, Skopouli FN, Selmi C, Gershwin ME. Liver involvement in primary Sjo¨gren syndrome. In: Ramos-Casals M, Stone J, Moutsopoulos H, editors. Sjo¨gren syndrome. Diagnosis and therapeutics. London: SpringerVerlag; 2012. p. 237e46. [105] Selmi C, Meroni PL, Gershwin ME. Primary biliary cirrhosis and Sjo¨gren’s syndrome: autoimmune epithelitis. J Autoimmun 2012;39:34e42. [106] Kaplan MJ, Ike RW. The liver is a common non-exocrine target in primary Sjogren’s syndrome: a retrospective review. BMC Gastroenterol 2002;2:21. [107] Uddenfeldt P, Danielsson A, Forssell A, Holm M, Ostberg Y. Features of Sjogren’s syndrome in patients with primary biliary cirrhosis. J Intern Med 1991;230:443e8. [108] Karp JK, Akpek EK, Anders RA. Autoimmune hepatitis in patients with primary Sjogren’s syndrome: a series of two-hundred and two patients. Int J Clin Exp Pathol 2010;3:582e6.

292 SECTION j IV Gastrointestinal Involvement of Systemic Diseases [109] Montan˜o-Loza AJ, Crispin-Acun˜a JC, Remes-Troche JM, Uribe M. Abnormal hepatic biochemistries and clinical liver disease in patients with primary Sjo¨gren syndrome. Ann Hepatol 2007;6:150e5. [110] Efe C, Wahlin S, Ozaslan E, Berlot AH, Purnak T, Muratori L, Quarneti C, Yu¨ksel O, Thie´fin G, Muratori P. Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome and associated extrahepatic autoimmune diseases. Eur J Gastroenterol Hepatol 2012;24:531e4. [111] Debbeche R, Maamouri N, Ajmi S, Azzouz MM, Ben Mami N, Dougui MH, Filali A, Ghorbel A, Khedhiri F, Krichene MS, Najjar T, Saffar H, Zouari B. Autoimmune hepatitis in Tunisia. Retrospective multicenter study of 83 cases. Tunis Med 2010;88:834e40. [112] Stefanidis I, Giannopoulou M, Liakopoulos V, Dovas S, Karasavvidou F, Zachou K, Koukoulis GK, Dalekos GN. A case of membranous nephropathy associated with Sjo¨gren syndrome, polymyositis and autoimmune hepatitis. Clin Nephrol 2008;70:245e50. [113] Takahashi A, Abe K, Yokokawa J, Iwadate H, Kobayashi H, Watanabe H, Irisawa A, Ohira H. Clinical features of liver dysfunction in collagen diseases. Hepatol Res 2010;40:1092e7. [114] Teufel A, Weinmann A, Kahaly GJ, Centner C, Piendl A, Wo¨rns M, Lohse AW, Galle PR, Kanzler S. Concurrent autoimmune diseases in patients with autoimmune hepatitis. J Clin Gastroenterol 2010;44:208e13. [115] Katsanos KH, Saougos V, Kosmidou M, Doukas M, Kamina S, Asproudis I, Tsianos EV. Sjogren’s syndrome in a patient with ulcerative colitis and primary sclerosing cholangitis: case report and review of the literature. J Crohns Colitis 2009;3:200e3. [116] Ramos-Casals M, Jara LJ, Medina F, Rosas J, Calvo-Alen J, Man˜a´ J, Anaya JM, Font J, HISPAMEC Study Group. Systemic autoimmune diseases co-existing with chronic hepatitis C virus infection (the HISPAMEC registry): patterns of clinical and immunological expression in 180 cases. J Intern Med 2005;257:549e57.

Chapter 16

Gastrointestinal Involvement in Systemic Vasculitis L. Quartuccio and S. De Vita University of Udine, Udine, Italy

1. INTRODUCTION Gastrointestinal (GI) manifestations of systemic vasculitides (SVs) are a challenge for the clinician because of the variety and severity of individual vasculitis ranging from isolated involvement (e.g., small mucosal lesions) to life-threatening disease related to massive intestinal disease (e.g., acute mesenteric ischemia or infarction) (Table 16.1) [1]. When considering the

TABLE 16.1 Gastrointestinal Involvement in Primary Systemic Vasculitis Type of Primary Vasculitis

Frequency of Gastrointestinal Involvement (%)

Chronic periaortitis

80

Polyarteritis nodosa

30e50

Eosinophilic granulomatosis with polyangiitis (ex Churg-Strauss syndrome)

25e50

Granulomatosis with polyangiitis (ex Wegener granulomatosis)

5e10

Takayasu arteritis

47

Giant cell arteritis

11

HenocheScho¨nlein purpura

50e90

Mixed type II cryoglobulinemia

50 years of age [41]. TABLE 16.2 Characteristics of Giant Cell Arteritis and Takayasu Arteritis Findings

Giant Cell Arteritis

Takayasu Arteritis

Female-to-male ratio

3:2

7:1

Age at onset

>50 years

1 g/day, peak creatinine 158 mmol/ L, cardiomyopathy, GI tract involvement, and central nervous system involvement. This score has been recently updated, some factors being significantly associated with higher 5-year mortality, which include age >65 years, cardiac symptoms, gastrointestinal involvement, and renal insufficiency. Ear, nose, and throat (ENT) symptoms, affecting patients with WG and CSS, were associated with a lower relative risk of death [81]. Since 1950s, the introduction of corticosteroids has dramatically improved the outcome, from 87% of a 5-year mortality to 50%, and long-term follow-up studies have described 5-year survival of up to 85%. Survival is better among those with cutaneous disease and limited organ involvement. GI tract involvement, HBV infection, and age >65 years are associated with increased mortality [82]. Clinical trials of therapeutic strategies over the last 10 years have optimized the use of cyclophosphamide and the best administration (continuous oral versus pulsed intravenous) or treatment duration [83]. The FFS should drive the introduction of cyclophosphamide in the treatment of patients with poor prognosis. Patients with FFS 1 should receive cyclophosphamide in the induction phase of treatment. Cyclophosphamide, as a dosage of 2 mg/kg/d, is used orally as intravenous infusions every 2 weeks for three doses, then monthly, at 0.6 g/m2 for 4e12 months. Pulse cyclophosphamide is better than daily oral cyclophosphamide because of the best safety profile [84]. Also, severe organ involvement not included in the FFS, such as

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mononeuritis multiplex, may benefit from a strong immunosuppression [43]. Azathioprine or methotrexate is advised once remission is achieved. Maintenance therapy with steroid-sparing agents still remains an open issue (CHUSPAN 2 trial, ClinicalTrials.gov NCT00647166). Pulse steroid therapy can be introduced among patients with severe lifethreatening involvement or progression of mononeuritis multiplex. Plasma exchange may be helpful in refractory cases. Surgery may be required in disease complications (gastrointestinal perforation or ischemia, or hemorrhage). First-line monotherapy with antiviral agents is indicated only in mild HBV-positive cases. In the other cases, antiviral agents should be administered with corticosteroids and plasma exchange until antiviral therapy becomes effective.

3.2 Kawasaki’s Disease KD is an MVV affecting children. This is a febrile illness of childhood that usually occurs before 5 years. The most definite feature is the mucocutaneous lymph node syndrome, which includes fever, polymorphous erythematosus skin rash, oropharyngeal erythema, redness or fissuring of the lips, indurative edema of the extremities, desquamation, conjunctivitis, and nonsuppurative lymphadenopathy. Coronary arteries are often involved and represent the most important involvement affecting the morbidity and mortality in this setting. Pathologically, the arteritis of KD shows less fibrinoid necrosis than that observed in PAN and more medial edema. Involvement of the bowel or gallbladder is relatively uncommon [85]. The reported GI manifestations comprise surgically acute abdomen caused by paralytic ileus, vasculitic appendicitis, hemorrhagic duodenitis, or bloody or nonbloody diarrhea. A course of intravenous immunoglobulins (2 g/kg in total) given in the first 10 days in addition to aspirin (50e80 mg/kg) led to a faster resolution of fever and clinical signs and to a shorter hospitalization [86]. Corticosteroids may be useful in patients who failed intravenous immunoglobulins [87]. A randomized trial failed to demonstrate an advantage when a single pulsed dose of intravenous methylprednisolone was added to conventional intravenous immunoglobulin therapy for the routine primary treatment of children with KD [86]. Rarely, KD occurs in adults, with a high frequency of cardiac involvement and complications. Diagnosis and treatment should not be delayed, and early IVIG treatment seems to improve the outcome [88].

4. SMALL-SIZED VESSELS VASCULITIS Small-sized vessels vasculitis (SVV) has a predilection for capillaries and venules, but arterioles and small arteries may be involved. SVV can be divided

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into two immunopathologic categories: immune complex-mediated vasculitis, such as HenocheScho¨nlein purpura (HSP) and cryoglobulinemia, and pauciimmune SVV, such as antineutrophil cytoplasmic autoantibody (ANCA)associated vasculitis.

4.1 HenocheScho¨nlein Purpura and Leukocytoclastic Vasculitis HSP is a vasculitis of small vessels, secondary to an immune process that generates circulating immune complexes containing significant amounts of IgA, which precipitate in the skin, joints, kidneys, and bowel. In fact, clinical features include a palpable purpura, arthritis, acute glomerulonephritis, and abdominal pain. The typical histologic lesion in the skin biopsy is leukocytoclastic angiitis affecting postcapillary venules, capillaries, and arterioles. The most specific pathologic finding for HSP, which can differentiate HSP from other leukocytoclastic vasculitis, such as cryoglobulinemia, WG, CSS, or micropolyangiitis, is the deposition of IgA-dominant immune complexes in vessel walls [89]. Although the etiology is unknown, immunization, insect bites, medications, and infections may play a role in its development. HSP occurs predominantly in younger patients, but it can also affect the adult patients, in which the disease course seems to be more aggressive or resistant to corticosteroids. In a Spanish study, more than 30% of children with HSP presented with abdominal pain alone or in association with other manifestations, and during the follow-up, 70.5% developed bowel angina and about 31% developed GI bleeding [90]. There is a wide spectrum of involvement of the bowel in HSP, GI manifestations having been related to edema and intramural hemorrhage. GI hemorrhage is mostly confined to the mucosa and submucosa, whereas full-thickness necrosis and perforation of a bowel loop are rare. The GI findings described in the course of HSP include intussusception (2e5%, the most serious complication), bowel ischemia and infarction, intestinal perforation, fistula formation, acute appendicitis, massive upper GI hemorrhage, pancreatitis, hydrops of the gallbladder, and pseudomembranous colitis. Noncharacteristic radiological findings are seen, although upper GI barium studies as well as CT scans are useful to identify mural thickening, thickened folds, and ulcerations [91]. Treatment for HSP has been essentially supportive, a benign course being the most frequent outcome. Corticosteroids have been widely and successfully used in the acute phase of the disease to treat abdominal pain and arthralgias/ arthritis in children [92]. In refractory cases, mycophenolate mofetil, cyclophosphamide, intravenous immunoglobulins, plasma exchange, immunosuppressive treatment (mainly in leukocytoclastic vasculitis other than HSP), and tonsillectomy have been utilized in open-label study. In adult HSP, treatment of severe involvement, including severe gastrointestinal complications or proliferative glomerulonephritis, remains controversial, with no evidence that

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corticosteroids or immunosuppressive agents improved long-term outcome. Prospective, randomized, controlled trials are thus needed [93]. Isolated localized GI vasculitis is a rare entity that is very difficult to distinguish from HSP, and it can occur in association with HSP. The absence of IgA deposits on an intestinal biopsy specimen in the context of a leukocytoclastic vasculitis is crucial for the diagnosis. The course of this disease appears more aggressive and difficult to treat than that observed in HSP, requiring immunosuppressors, such as cyclophosphamide and/or plasma exchange, or surgical intervention [94].

4.2 ANCA-Associated Small-Vessel Vasculitis The ANCA-associated small-vessel vasculitides (ASVs) comprise a group of disorders characterized by necrotizing small-vessel vasculitis with a paucity of immune deposits, in conjunction with autoantibodies directed against neutrophil cytoplasmic constituents, in particular, proteinase 3 (PR3) and myeloperoxidase (MPO). A common feature is glomerulonephritis with crescent formation and fibrinoid necrosis [95,96]. The ASVs include Granulomatosis with polyangiitis (ex Wegener Granulomatosis, WG), microscopic polyangiitis, and Eosinophilic granulomatosis with polyangiitis (ex Churg-Strauss syndrome, CSS). ANCA positivity is often observed in WG patients, usually PR3-ANCA, and most patients with microscopic angiitis display MPO-ANCA, whereas only 35e50% of CSS patients are positive for ANCA, generally MPO-ANCA [97]. These findings, together with substantial clinical, histologic, and biologic differences among these three entities, have opened some debate when considering WG, CSS, and microscopic angiitis either as three distinct disorders or, more generally, as different aspects of a unique type of vasculitis. A putative role of ANCA, in particular MPO-ANCA, in the pathogenesis of ASV represents the basis of the hypothesis of an ANCA-associated vasculitic syndrome and the rationale of novel B-cell depletion treatment [98]. The ASV often present with malaise, myalgias, arthralgias, fever, rash, and neuropathy. WG and microscopic angiitis commonly present with acute renal and pulmonary disease. A hypereosinophilia and history of asthma characterize CSS, while the upper respiratory tract (typically ear, nose, throat) is the common target of WG and the granulomatous inflammation is the pathologic hallmark [99]. Generally, abdominal pain, diarrhea, or bleeding occurs in 30e60% of patients. Bowel perforation is one of the major causes of death. Granulomas and/or vasculitis are more often recorded in the small intestine or colon. GI involvement in the course of CSS is frequent, more common than in the remaining ASV, ranging from 25% to 50%. In a French study, about 30% of CSS patients had GI symptoms during the course of their disease and 2/23 died because of mesenteric infarct [100]. Other documented manifestations include

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melena, hematemesis, esophageal gastric, small intestine and colonic perforation, cholecystitis, bowel ischemia, ischemic colitis, and omental hematoma. In some patients, several of the intestinal vessels can be affected causing lifethreatening organ failures [101]. An Italian study group retrospectively followed 75 patients after diagnosis: 36 with WG, 23 with CSS, and 16 with microscopic polyangiitis. GI involvement was associated with an increased risk of relapse, mainly in patients with CSS, whereas renal disease and perinuclear antineutrophil cytoplasmic antibody positivity were correlated with a lower risk of relapse. Older age, renal and hepatic involvement, ESR >100 mm/h and serum creatinine levels >1.5 mg/dl were all related to higher risk of death in univariate analysis. However, only cerebral and hepatic involvement and serum creatinine level >1.5 mg/dl were independently correlated with an unfavorable prognosis for survival [102]. Similarly, French groups found that GI involvement represents a poor prognostic sign in CSS or PAN patients, in particular in those patients with bleeding, perforation, infarction, or pancreatitis [103], and they should receive a prompt aggressive immunosuppressive treatment. Interestingly, microscopic polyangiitis resembles CSS in many aspects, showing a similar spectrum of GI symptoms. GI involvement in WG appears to be a rare event, usually resulting in granulomatous colitis and gastritis. WG case reports with bowel infarction, esophageal ulceration, cholecystitis, gallbladder infarction, pancreatitis and pancreatic mass, bloody diarrhea, small and large bowel perforation, and spontaneous splenic hemorrhage are recorded in the literature. Isolated intestinal vasculitis sometimes occurred as the only manifestation and with a severe course [104]. The introduction of cyclophosphamide and corticosteroids in combination has drastically improved the overall survival in ASV, especially in WG, with 85% of patients achieving temporal or persistent remission. Cyclophosphamide, methotrexate, azathioprine, and glucocorticoids all have a role in the treatment of ASV. However, despite strong immunosuppressive regimen, many patients do not reach remission and up to 50% relapse; in addition, these regimens may result in high rate of morbidity and mortality. Thus several randomized controlled trials have been recently published or are now ongoing to optimize the use of immunosuppressants both in the remission induction and the maintenance regimen. Anti-CD20 therapy (rituximab) has been licensed for the induction phase of treatment of ASV, and it is considered a valid option in particular in patients with relapsing disease despite induction with cyclophosphamide, also for severe manifestations [105e107]. Encouraging results were also reported in the maintenance phase with this agent, if compared to azathioprine [108]. By contrast, etanercept, a soluble receptor of TNF, proved to be ineffective in the WG etanercept trial (WGET), in addition to the immunosuppressive standard regimen (Wegener’s Granulomatosis Etanercept Trial [109], increasing the risk of cancer [110]. More aggressive treatments, such as lymphocyte depletion with antithymocyte globulin or alemtuzumab (CAMPATH 1-H), or autologous stem cell transplantation, have been used in

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very refractory and life-threatening diseases [111]. In ASV patients with refractory or relapsing disease, despite current treatments, or in patients at very high risk of infection, even with ongoing infections, IVIG showed clinical benefit as an adjunctive therapy, with an acceptable tolerance profile [112,113].

4.3 Mixed Cryoglobulinemia, Hepatitis C Virus Infection, and Gastrointestinal Involvement The cryoglobulinemic vasculitis or syndrome is a systemic vasculitis usually associated with hepatitis C virus (HCV) infection and characterized by nonneoplastic B-cell lymphoproliferation in the large majority of cases, but with an increased risk of B-cell lymphoma development [114e116]. Among the HCV-negative cryoglobulinemic syndrome group, many cases with type II serum mixed cryoglobulinemia (MC) also present Sjo¨gren’s syndrome, an autoimmune and lymphoproliferative disorder primarily involving the salivary and lachrymal glands, leading to glandular damage, dysfunction, and sicca syndrome [117e119]. MC syndrome may rarely complicate with lifethreatening abdominal vasculitis, possibly involving the stomach and the small and the large bowel (Figs. 16.3A and B) [114,120e123]. In noninfectious MC vasculitis, gastrointestinal tract involvement accounts for 5% of the patients [124]. Vague and diffuse abdominal complaints may be referred at first. Thus this organ manifestation must be primarily suspected and specifically investigated in its early stages. In a panarteritis-like subset of MC syndrome, necrotizing vasculitis may lead to the small aneurysm findings (mesenteric, coeliac,

FIGURE 16.3 Large bowel intestinal vasculitis (panel A, 20 magnification, panel B 40 magnification) in a 74-year-old woman affected by Hepatitis C Virus-related mixed cryoglobulinemia syndrome and Sjo¨gren’s syndrome, who presented severe, diffuse abdominal pain, bloody diarrhea leading to hypovolemic shock. High-dose corticosteroids, cyclophosphamide, and azathioprine were ineffective, while this disease manifestation responded to rituximab (Quartuccio, L. 2010).

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hepatic, as well as renal) by abdomen arteriography [121,125], as seen in classical panarteritis nodosa, whereas colic mucosa biopsy may show nonspecific pathologic findings. A picture of acute abdomen and bowel infarctual lesions may then follow, although it may also develop ab initio. Finally, colitis pseudomembranosa may superimpose if the patient has been treated with large-spectrum antibiotics in our experience, and this further complicates the diagnostic and treatment approach. Although rare, such severe intestinal vasculitic complications of MC syndrome must be diagnosed and treated promptly, and mortality is high in any case. Therapy includes highdose steroids and cyclophosphamide. We also protect the patient from superimposed infections with antibiotic plus antifungal therapy in the period of high- to medium-dose steroids combined with cyclophosphamide, and periodically assess Clostridium difficile infection. Plasmapheresis is another treatment option as an induction therapy, whereas rituximab is currently not recommended as first-line option for abdomen vasculitis in MC syndrome, as well as in ANCA-associated vasculitis, although its efficacy and safety in other severe manifestations of MC syndrome has been clearly demonstrated in randomized controlled trials [126e128]. The latency for clinical efficacy of rituximab might be too long, usually more than 1 month, despite the usual early B-cell depletion [129,130]. However, rituximab may also prove effective in MC-related intestinal vasculitis based on personal preliminary experience, either in the context of induction or as maintenance therapy [131]. Thus additional investigation is required. GI bleeding due to peptic ulcer, MC-unrelated, or esophageal varices associated with portal hypertension in HCV-related cirrhosis [114] should always be considered in the differential diagnosis. The association of proteinlosing enteropathy and cryoglobulinemia was recently reported in one patient [132]. A 79-year-old woman with HCV-related MC syndrome diagnosed in 2001 was successfully treated by our group with combined standard antiviral therapy, with subsequent virus RNA (genotype 5a) clearance from serum and disappearance of systemic vasculitis features and bone marrow low-grade B-cell lymphoma by morphologic analyses. Interferon and ribavirin were, however, suspended after 1 year, as they were no longer tolerated. Two months after suspension of antiviral therapy, the patient was admitted to our hospital because she had developed fever and diarrhea. HCV-RNA was still negative. She developed an intractable wasting syndrome concomitantly with MC syndrome reactivation including active nephritis and cutaneous vasculitis. Infectious diseases, lymphoproliferative intestinal diseases, and coeliac disease were all excluded by tissue biopsies and radiological studies. High-dose steroid therapy was ineffective and the patient worsened developing hepatic failure and, finally, died because of multiorgan failure syndrome. Another patient with MC syndrome and chronic diarrhea, possibly due to intestinal vasculitis, has been reported [133]. Of note, intestinal vasculitis also developed during interferon plus ribavirin therapy [134].

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Abnormal acquisition of mucosa-associated lymphoid tissue (MALT) in the gastric mucosa represents an additional and much more frequent clinical manifestation both in HCV-related MC syndrome and chronic HCV infection without MC, as well as in Sjo¨gren’s syndrome with or without MC. This gastric MALT accumulation may lead to different pictures of chronic gastritis lymphoid infiltration, i.e., sparse, follicular, or lymphoepithelial lesions [135,136] and might favor gastric lymphoproliferation and eventually the development of low-grade gastric B-cell lymphoma of MALT. Such a subset of MALT lymphoma is usually linked with Helicobacter pylori infection, but in the case of MC syndrome and Sjo¨gren’s syndrome, H. pylori infection likely represents only a possible pathogenetic cofactor. By contrast, the “background” of lymphoproliferation is likely linked to the underlying autoimmune disease [119,136,137] (Fig. 16.4). As a first issue, HCV may localize in the gastric mucosa, both in HCV-infected individuals without MC and HCV-related MC syndrome. HCV gastric localization was shown by strong and unequivocal reactivity of the cytoplasm of glandular cells by immunohistochemistry, while the nuclei were completely negative. Results were concordant with the viral findings obtained by PCR in whole RNA from the same samples, while HCV in situ hybridization could not be employed [136]. When also considering the possible contribution of autoimmunity in chronic gastritis [138,139] and the evidence of intragastric clonal B-cell expansion in Sjo¨gren’s syndrome also in the absence of H. pylori infection [135], the role of other gastric local triggers (including HCV) and cofactors in the predisposed individual can be hypothesized. Secondly, HCV infection appears to increase the risk of gastric lymphoma, as the rate of HCV infection was increased in unselected cases of gastric lymphomas and in HCV-related lymphomas in Sjo¨gren’s syndrome [140e142]. This increased occurrence of HCV-positive cases was also found in what concerns primary hepatic and major salivary gland B-cell lymphomas [140]. Strikingly, HCV shows a tropism not only for the liver but also for the salivary epithelium [143], and a role of HCV as a trigger of MALT lymphoproliferation in the local microenvironment has been hypothesized. Thirdly, gastric low-grade B-cell lymphoma did not regress despite eradication of local H. pylori infection, as assessed by repeated metachronous gastric biopsies after effective antibiotic therapy, whereas HCV RNA was detected by sensitive PCR analyses in the same tissue lesions. Of note, HCV localization in the cytoplasm of the residual glandular epithelium was shown by in situ studies within the lymphomatous lesion, with no substantial differences in staining intensity if compared to results obtained in chronic gastritis in HCV-positive individuals. Frequently, positive cells could be observed within the center and the invasion front of the tumor, and positive residual glandular cells were found within the homogeneously HCV-negative lymphoma cells. Of note, sequence analyses of the immunoglobulin-rearranged genes of the neoplastic B-cell clone in the gastric lymphoma sample obtained after H. pylori eradication still showed the presence of intraclonal heterogeneity, indicating the persistence of antigenic stimulation in the

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FIGURE 16.4 Low-grade gastric B-cell lymphoma of mucosa-associated lymphoid tissue, Helicobacter pyloriepositive (panel A) occurring in a patient with Sjo¨gren’s syndrome, persistent parotid swelling due to myoepithelial sialadenitis, and nonmalignant lymphadenopathy. Gastric lymphoma regressed to chronic gastritis after H. pylori eradication with antibiotics (panel B). However, as shown in panel C (agarose gel stained with ethidium bromide showing VDJ-PCR products) and as confirmed by DNA sequencing, the same B-cell clone Sjo¨gren’s syndromerelated, as detected in the gastric fundus (F0), lymph node (L0), and parotid (P0) at baseline (monoclonal single band), was still present in the gastric fundus chronic gastritis (F1) and in nonmalignant lymph node (L1) in repeated biopsies after H. pylori eradication. The patient developed a gastric high grade B-cell lymphoma, H. pylori-negative, in the subsequent follow-up. Lanes A0 and A1 in panel C show a polyclonal pattern in the patient’s gastric antrum uninvolved by lymphoma, and in control reactive lymph node from another case (lane R). Lane B: positive control with amplified B-cell leukemia DNA; lane M: molecular weight markers; lane N: negative PCR control without DNA.

gastric mucosa [136]. This also argues against a fully deregulated B-cell neoplastic proliferation. Lastly, gastric B-cell lymphoproliferation in HCV-related Sjo¨gren’s syndrome and in MC syndrome showed significant deduced amino acid sequence homology both with immunoglobulin sequences encoding for rheumatoid factors (RFs) and with sequences encoding for anti-HCV

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antibodies, i.e., antibodies related to HCV infection [136,144]. These early results led to subsequent studies by our group that better explained a relevant mechanism by which HCV infection may preferentially favor the proliferation of RF-positive B-cell clones, i.e., HCV linking to RF B-cell receptor itself [145]. As concerns the acquisition of gastric MALT and vasculitis in HCV-unrelated MC syndrome and Sjo¨gren’s syndrome, it should be noticed that among the many extraglandular features that may be observed in the course of Sjo¨gren’s syndrome, MC occurs in a minority of cases [118,119] but has been consistently associated with the development of a B-cell lymphoma [118], which is in turn a well-known complication in MC syndrome secondary to HCV infection. By integrated clinical, pathological, and molecular studies, we recently highlighted that MC has a different biologic background in Sjo¨gren’s syndrome if compared to chronic HCV infection [146]. MC is polyclonal in the bone marrow and is associated with salivary MALT lymphoma in SS, consistent with the primary role of salivary MALT chronic inflammation and lymphoproliferation as a predisposing factor to lymphoma in this disease, which is rarely associated with HCV infection. By contrast, MC in the course of HCV infection is primarily a liver and bone marrow autoimmune and lymphoproliferative disorder, and malignant lymphoproliferation of salivary MALT is rarer in this setting. Overlapping features of Sjo¨gren’s syndrome and MC vasculitis may, however, occur in HCV-positive patients. Interestingly, as reported earlier, abnormal acquisition of gastric MALT may occur both in Sjo¨gren’s syndrome and in MC syndrome. Thus, the study of the gastric microenvironment, in conjunction with that of the bone marrow, liver and salivary glands, may be relevant for future research aimed to clarify the mechanisms leading to preferential RF-positive B-cell expansion in these diseases, and, in general, to better explain the various components of gastric lymphomagenesis. Besides local antigenic stimulation, the mechanisms by which HCV infection and other local triggers may favor gastric acquisition of MALT and, more generally, chronic inflammation and B-cell expansion, remain elusive. With regard to this issue, local cytokine networks are likely implicated. Recent results pointed out the role of HCV infection in upregulating the expression of BAFF [147], a relevant growth factor implicated in autoimmunity and B-cell lymphoproliferation. Recently, MALT lymphoma of salivary glands associated with cryoglobulinemic vasculitis in the course of Sjo¨gren’s syndrome has been successfully treated with belimumab, a human monoclonal antibody, which targets soluble BAFF, and rituximab sequential therapy [148]. Thus the therapeutic value of targeting the local trigger of chronic inflammation, autoimmunity, and lymphoproliferation versus other biologic targets should be better explored as well in the future.

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Chapter 17

Mixed Connective Tissue Disease J. Romero-Dı´az and J. Sa´nchez-Guerrero Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Me´xico City, Me´xico

1. INTRODUCTION Mixed connective tissue disease (MCTD) was first described in 1972 by Sharp et al. as a disease with overlapping features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and polymyositis associated with high titers of hemagglutinating antibody to the ribonuclease-sensitive component (ribonucleoprotein(RNP)) of extractable nuclear antigen. The combination of these features may occur simultaneously or in sequence [34], and the diagnosis is based on clinical, pathological, and serological criteria. Since the description of this distinct entity, different sets of classification criteria have been proposed, being those by Sharp, Alarco´n-Segovia, Kasukawa, and Kahn. As previously mentioned, these criteria include both serologic and clinical features. Alarco´n-Segovia and Cardiel [3,4] analyzed the first three and found high correlation among them. Amigues et al. [1] analyzed the performance of the four sets of criteria in 45 patients in France and concluded that Alarco´nSegovia’s and Kahn’s criteria were the best to identify patients having MCTD. Recognition of gastrointestinal manifestation in patients with MCTD is important because they may have special diagnostic, therapeutic, and prognostic implications that require consideration of appropriate management [35]. For a long time, this entity had not gained widespread recognition despite having distinct clinical, serological, and immunoregulatory profiles [5,39,46]. This may explain the scarcity of studies focused on clinical manifestations, particularly gastrointestinal in MCTD patients. In the initial descriptions of the disease they included abnormal esophageal motility as one of its main clinical characteristics, similar to that found in scleroderma; however, a notable difference with scleroderma is the potential benefit of corticosteroids over esophageal dysmotility in MCTD patients [8]. The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00017-9 321 Copyright © 2017 Elsevier B.V. All rights reserved.

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Subsequent studies included descriptions of sialadenitis, malabsorption, colonic, and small bowel perforations due to vasculitis, chronic active hepatitis, acute pancreatitis, protein-loosing enteropathy, and acute pneumatosis intestinalis (PI), reflecting that any area of the gastrointestinal tract may be affected in MCTD. On the other hand, some gastrointestinal manifestations may overshadow other aspects of the disease, because they may derive from complications of the initial symptoms or adverse effects of medication (e.g., esophageal structure).

2. ARE GASTROINTESTINAL FEATURES A COMMON MANIFESTATION OF MIXED CONNECTIVE TISSUE DISEASE? Involvement of the gastrointestinal tract has been reported in most of the rheumatic diseases. Concerning MCTD, radiological evidence of esophageal dysmotility has been recognized as a feature in more than 50% of the patients. There are no recommendations for the follow-up period, these data being important in a disease with manifestations that tend to drift over time. The sensitivity of the different tests used varies considerably from report to report, contributing to the variation of clinical manifestations (Table 17.1). Gastrointestinal symptoms are quite common, affecting 66e74% of the patients (Burdt, Marshall, and Doria). The most frequently reported, heartburn in 48% and dysphagia in 38% of the patients, result from esophageal involvement (Table 17.2). A review of 80 patients from our department revealed a high frequency of diarrhea (36%) and malabsorption (20%), and in two patients occlusive episodes were observed [3,4]. On the other hand, in a retrospective cohort study of 98 MCTD patients who fulfill Alarcon-Segovia’s criteria we found that 69% of them had gastrointestinal involvement distributed as follows: dysphagia, gastroesophageal disease, and esophagitis in 48%, 46%, and 20%, respectively [27]. TABLE 17.1 Cumulative Gastrointestinal Findings According to Length of Disease Evolutiona Esophageal Dysmotility References

At Onset

At Diagnosis

Cumulative (Years of Follow-up)

[8]

9

47

66 (15)

[32,40]

57

e

43 (8)b

[43]

e

e

100 (9.3)

a

The values are presented as percentage of patients. In this study, evidence of esophageal dysmotility was slightly less frequent. The authors thought that this might be explained by lack of radiographic or manometric studies on reevaluation.

b

TABLE 17.2 Gastrointestinal Symptoms in Patients With Mixed Connective Tissue Disease Gutierrez et al. [18]

Marshall et al. [31]

Doria et al. [12]

Tiddens et al. [43]

Leal-Alanis et al. [27]

Number of patients

17

61

21

14b

98

Mean of follow-up (years)

8

7.7

9.3

10

Dysphagia (%)

53

38

19

40

48

Heartburn or regurgitation

59

48

23.8

20

46

Dyspepsia

65

20

e

e

e

Vomiting

e

2

e

e

e

6.3

a

Esophageal dysmotility (abnormal esophageal manometry)

91

60

85

100

e

Diarrhea

e

5

e

e

e

Constipation

e

3

e

e

e

Malabsorption

e

e

e

Other Conditions Pancreatitis

e

1

e

e

e

Chronic active hepatitis

e

1

e

e

e

Spontaneous perforations associated with vasculitis

e

1

e

e

e

Ten of 11 patients studied had abnormal results. Patients with juvenile onset of MCTD.

b

323

a

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Features

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3. ORAL MANIFESTATIONS As in other connective tissue disease, Sjo¨gren’s syndrome (SS) may be present in MCTD. According to Alarco´n-Segovia [2], 12 out of 25 patients with MCTD had xerostomia and/or ocular symptoms of keratoconjunctivitis sicca. Setty et al. [37] determined longitudinally the prevalence of clinical and serological features of SS in a cohort of MCTD patients. This study summarizes the clinical and serological features of 55 patients followed during 30 years who fulfilled the criteria for MCTD of whom 23 (42%) had sicca symptoms; no association was found with anti-SSA/Ro antibodies. Out of 19 patients with MCTD, 17 had focal sialadenitis determined with clinical manifestations, unstimulated and stimulated whole saliva, and minor salivary gland biopsy. Sixty-one percent had decreased salivary secretion and 74% had oral symptoms. The mean duration of the disease at the study was 10.6 years and only 11 (58%) patients had positive anti-RNP autoantibodies [19]. Usuba et al. [44] determined the prevalence of sicca symptoms, dry eye, and secondary SS in a cross-sectional study of 44 patients with MCTD. They found a similar prevalence to that previously reported (38.6%) in the literature. They also determined the frequency of secondary SS according to the revised American European Consensus Group (AECG) Classification Criteria, which was 31.8% of MCTD patients and 7 (50%) did not have the diagnosis prior to the study (p < .001). This study suggests that SS is often underdiagnosed, and efforts should be established to ensure detection and treatment intervention. In the retrospective MCTD cohort studied by Leal-Alanis et al., 46(47%) of patients had oral ulcers and 33(34%) were found with xerostomia [27]. Konttinen et al. [24] described the signs and symptoms in the masticatory system. All the 10 patients with MCTD included showed clinical dysfunction, and 7 had additional radiographic changes of the temporomandibular joints. Sialopenia was observed in 70% of the patients and sialadenitis with a focus score >1 in the labial salivary gland biopsy of nine patients. Only one patient had clinically detectable mucosal lesion. In 83% of patients with normal appearing mucosa, histological examination revealed chronic inflammation. The authors concluded that as it occurs in other connective tissue disease, MCTD patients should be treated on a multidisciplinary basis [7].

4. ESOPHAGEAL DYSFUNCTION Despite the heterogeneity of the rheumatic diseases in terms of symptoms and prognosis, most of them share some gastrointestinal manifestations. According to these observations, several investigators have thought that the features in MCTD are similar to those found in scleroderma but of milder degree. Nonetheless, it is clear that esophageal dysfunction is a much more

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common feature in scleroderma and MCTD than in the other connective tissue disease (92% and 88%, respectively) [31]. The motor disorders affecting the esophagus are found not only in SSc, but also in SLE and other connective tissue diseases. The simultaneous involvement of the esophageal body and the lower esophageal sphincter (LES) is discriminant among scleroderma, MCTD, polymyositis, and undifferentiated connective tissue disease, and SLE [25,26]. A study of esophageal motility in 37 patients with progressive SSc, 12 patients with MCTD, and 40 healthy controls without rheumatologic symptoms reported that MCTD patients were similar to PSS patients. Half of the MCTD patients had dysphagia, four patients had abnormal motility, and in only two patients motility was normal. LES pressure was low in seven patients, and in only one patient the pressure was similar to that of the controls. Involvement of the upper esophagus was unusual [10]. Manometry and radiological examinations have also been used to evaluate the esophageal disorders. Lapadula and colleagues studied the performance of these methods in the evaluation of esophageal motility; their data showed a higher sensitivity of esophageal manometry (EM) over the usual radiographic examination of the esophagus (ERE)d72.7 versus 40.7. Manometry was able to detect early motility disorders, such as a lower LES pressure and reductions in peristaltic waves amplitude, which are difficult to recognize by ERE (Table 17.3). Dinsmore et al. [11] described the presence of air on conventional chest roentgenograms within the intrathoracic portion of the esophagus in 12 out of 16 patients with SSc, proposing that an air esophagogram is strongly suggestive of SSc. In 1998, Lock et al. assessed systematically the diagnostic significance of an air esophagogram in 51 patients with connective tissue diseases and esophageal involvement, and 47 controls by comparing the

TABLE 17.3 Esophageal Involvement Studied by Esophageal Radiographic Examination (ERE) and Esophageal Manometry (EM) References

Patients With Abnormal ERE (%)

Patients With Abnormal EM (%)

[26]

70.6

88.2

[28]

31.4

45.1

[41]

e

83.3

[12]

e

71

[18]

e

94

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findings in chest roentgenogram with EM as the gold standard of esophageal motility testing. The presence of air in one or more esophageal segments had a sensitivity of 52% and a specificity of 68% for esophageal dysfunction compared to that of EM. They concluded that the radiological sign of air in the esophagogram is neither sensitive nor specific enough to omit esophageal motility studies in patients with connective tissue diseases. Regarding the pathophysiology of esophageal dysmotility, Stevens and colleagues [42] demonstrated the association between Raynaud’s phenomenon (RP) and aperistalsis, suggesting that the esophageal dysfunction may result from an abnormality of the autonomous nervous system, rather than sclerosis of the esophagus. On the contrary, Lapadula et al.’s [26] study did not demonstrate a consistent correlation between esophageal motility disorders and RP in 150 patients evaluated, suggesting that esophageal dysfunction and RP do not have the same neurogenic origin. They proposed that RP constitutes a parallel but independent phenomenon. Uzuki et al. [45] made a histological analysis of esophageal muscular layers from 27 autopsy cases with MCTD. They found severe degeneration of muscular tissue and fibrosis in the muscular layer, which was sustained primarily in the inner circular muscular layer of the lower portion of the esophagus. They also found in three of four cases that IgG extracted from MCTD patients reacted with smooth muscle cells in the muscularis mucosa, venous wall, muscular layer, and ganglionic cells in Auerbach’s plexus (did not react in the upper esophagus). This may suggest that esophageal muscle atrophy may be induced by serum factors reacting with esophageal smooth muscles. Previous studies have indicated that autoantibodies directed against smooth muscle cells in SLE, SSc, rheumatoid arthritis, and other connective tissue diseases might induce such histological changes in the esophagus. It’s also important to consider that patients with MCTD who have motor esophageal impairment may also have other organ and systems affected, which may interpose other comorbidities to these patients. Fagundes et al. [14] evaluated the relationship between esophageal dysfunction and interstitial lung disease (ILD) in patients with MCTD. In many patients with idiopathic pulmonary fibrosis, abnormal acid gastroesophageal reflux is quite common; however, it is not yet possible to consider it as a risk factor. In their study they found that the prevalence of ILD on computed tomography was significantly higher in patients with esophageal dilatation (92% vs. 45%; p ¼ .001). Their findings suggested that ILD may be associated with food reflux in MCTD patients, because it was more common in those with esophageal dilatation on computed tomography scan and with severe esophageal dysfunction on manometry. As a result, this study may strengthen the recommendation to screen patients for pulmonary involvement, especially those MCTD patients with esophageal motor impairment.

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5. BOWEL MANIFESTATIONS PI is an uncommon manifestation in scleroderma; however, it has also been reported in patients with MCTD. These reports included patients between 18 and 77 years of age and variable length of the disease [13,16,17,30,36,47]. In patients with SLE, PI is thought to result from isquemic necrosis of the bowel wall due to vasculitis; however, in SSc and MCTD, the mechanism of this manifestation is poorly understood. It is thought that an increase of the intraluminal pressure allows the passing of air within the intestinal wall. The usual clinical manifestations are abdominal pain and diarrhea, but patients can also be asymptomatic. Radiographs show a collection of air within the intestinal wall that delineates it longitudinally, and intraperitoneal air can also be seen. The authors concluded that PI should be suspected in patients known to have SSc-type involvement of the esophagus and the small bowel, and who present with abdominal distension. It may not only occur early in the course of the disease and resolve rapidly through medical intervention but also has been associated with poor survival. No surgical treatment is recommended unless the condition is complicated by perforation. Malabsorption is another symptom observed in scleroderma and less frequent in MCTD. Sometimes it may constitute a major management issue; several mechanisms have been proposed for its occurrence, but intestinal stasis with secondary bacterial overgrowth appears to be the main factor [3,4]. Protein-loosing enteropathy is a rare manifestation, and there is only one case report of this condition associated with MCTD [33]. Protein-loosing enteropathy should be suspected when diarrhea and severe hypoalbuminemia without proteinuria are found. Histological findings include atrophy of villi, polymorphonuclear infiltrate, and edema of the submucosa in the absence of vasculitis. The increased protein loss from the bowel can be documented by an increase of fecal excretion with intravenous radiolabeled albumin. Diagnosis is important because most patients improve with corticosteroids treatment. Megacolon is another rare manifestation and is typically observed radiographically as wide-mouthed diverticular sacculations. Symptoms secondary to this complication are rare but occasionally serious, such as impaction of barium or feces [15]. Spontaneous perforation associated with vasculitis has also been reported. Gastrointestinal bleeding may be due to fibrinoid necrosis of blood vessels of the small and large intestine [9,20].

6. OTHER CONDITIONS In the group of MCTD patients described by Marshall et al. [31], only one of them had identifiable pancreatic disease with subsequent pseudocyst and abscess formation. MCTD was presumed to be the cause of the pancreatitis,

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although a medication-related etiology could not be completely excluded. Also, one patient with chronic active hepatitis is the only instance of clinically significant liver disease in the same series of patients.

7. THERAPEUTIC CONSIDERATIONS As mentioned earlier, in contrast to scleroderma, esophageal dysfunction was noted to improve following corticosteroid therapy in MCTD patients [29]. The results from manometry studies carried out in 10 patients before and after treatment suggest that esophageal dysfunction in MCTD may be responsive to corticosteroids. These patients had received an average of 67 week of steroid therapy (range 44e154 week) at the time when the follow-up manometry was performed. Initially, most of the patients received 1 mg/kg of prednisone and the average dose during the course of their treatment was 25 mg/day. The improvement in the LES pressure was statistically significant (p < 0.05). No differences in distal and proximal esophageal peristaltic pressures were found; however, an improvement in upper esophageal sphincter hypotension and a reduction in the frequency of associated aspiration events were observed [31]. Similar results were not shown by Gutierrez et al. [18]. They studied 14 MCTD patients who had received steroids for a mean of 6.9 years (range 1e11 years), and esophageal peristalsis was abnormal in all of them; however, this study did not include an evaluation before the corticosteroid treatment. Probably the two series included patients with different degrees of severity of the disease, and probably in patients with less severe disease and predominantly inflammatory reaction in the esophageal muscles, steroids may reverse the inflammatory reaction, whereas in patients with fibrosis this response is not possible. According to these results, a course of corticosteroid therapy (15e30 mg/ day) may be considered in some cases of esophageal dysfunction with short disease evolution that are refractory to conventional treatment and have a short disease evolution. The conventional treatment consists upon proton-pump inhibitors, H2 receptor antagonists, antacids, and lifestyle modifications. Esophageal pH monitoring in patients who have persistent reflux symptoms are important to determine if high-dose therapy is needed. Endoscopic dilatations in severe cases of dysphagia related to structures, and fluids, fiber, and exercise in some cases of constipation should be considered. Severe manifestations such as pseudoobstruction and PI may require hospitalization for bowel rest [23]. A surgical approach is not recommended as it is associated with a poor prognosis. In some MCTD patients with diarrhea, the cause of this symptom may be unclear and symptomatic treatment may be indicated. Patients with malabsorption may require cyclic broad-spectrum antibiotic treatment to control colonic bacterial overgrowth [5]. Among 62 patients (46 SSc, 8 MCTD, and 8 polymyositis and SSc overlap), 12 (19%) required total parenteral or enteral nutrition. This may reflect severe

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gastric or intestinal involvement in SSc and related disorders; however, the possibility of tertiary referral bias may partially explain these results as patients were hospitalized to receive nutritional support [48].

8. CONCLUSION According to the available information, almost any segment of the gastrointestinal tract can be involved in patients with MCTD, particularly the esophagus. Until now, few studies have evaluated the gastrointestinal manifestations in this disease. Unfortunately, the few studies available differ in some characteristics, such as number of patients included, length of disease duration, diagnostic criteria used, etc., which may influence the results. Proof of this is that the largest study [31], which included 61 patients, is the one in which rare gastrointestinal manifestations such as pancreatitis, chronic active hepatitis, and spontaneous perforations due to vasculitis were described. The single study that assessed gastrointestinal manifestations at varying periods of disease evolution showed the variability in their prevalence [8]. In addition, although the four sets of criteria available [6,21,22,38] identify most MCTD patients in 80 MCTD patients evaluated in our department, the former three sets of criteria ruled out MCTD in most patients with other connective tissue disease except the criteria for possible MCTD included as part of Sharp’s set of criteria that identified as such 10 patients with SLE, 36 with scleroderma, 13 with polymyositis/dermatomyositis, and 2 with SS [3,4]. In summary, gastrointestinal manifestations in patients with MCTD are frequent, especially those related to esophageal symptoms due to dysmotility described as hypomotility or aperistalsis. The most affected structures are twothirds of the esophageal body and the LES, as it is seen with high frequency in SSc [31]. Autoimmune hepatitis, pancreatitis, and gastrointestinal vasculitis have been reported. Some patients with PI and protein-loosing enteropathy have also been reported. To evaluate esophageal dysfunction, manometry is a more sensitive and specific test than chest X-ray. The initial therapeutic approach includes conventional treatments such as proton-pump inhibitors, H2 receptor antagonists, antacids, lifestyle modifications, and esophageal pH monitoring in patients who have persistent reflux symptoms. A course of steroid therapy (15e30 mg/day) may be considered in some cases of esophageal dysfunction that are refractory to conventional treatment and have a short-time disease evolution.

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[2]

Amigues J, Cantagrel A, Mazieres B. Comparative study of 4 diagnosis criteria sets for mixed connective tissue disease in patients with anti-RNP antibodies. J Rheumatol 1996;23(12):2055e62. Alarco´n-Segovia D. Symptomatic Sjo¨gren’s syndrome in mixed connective tissue disease. J Rheumatol 1976;3:191e5.

330 SECTION j IV Gastrointestinal Involvement of Systemic Diseases [3] Alarco´n-Segovia D, Cardiel MH. Comparisons between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol 1989a;16:328e34. [4] Alarco´n-Segovia D, Cardiel MH. Connective tissue disease and the bowel. Baillier’s Clin Rheumatol 1989b;3(2):371e92. [5] Alarco´n-Segovia D, Cardiel MH. Mixed connective tissue disease. In: Current therapy in allergy, immunology and rheumatology. USA: Nosby Year Book; 1991. p. 202e6. [6] Alarco´n-Segovia, Villarreal M. Classification and diagnostic criteria for mixed connective tissue disease. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue disease and antinuclear antibodies. Amsterdam: Elsevier; 1987. p. 33e40. [7] Alfaro-Giner A, Pen˜arrocha-Diago M, Baga´n-Sebastia´n JV. Orofacial manifestations of mixed connective tissue disease with an uncommon serologic evolution. Oral Surg Oral Med Oral Pathol 1992;73:441e4. [8] Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum 1999;42(5):899e909. [9] Cooke CL, Lurie HI. Case report: fatal gastrointestinal hemorrhage in mixed connective tissue disease. Arthritis Rheum 1977;20(7):1421e7. [10] Dantas RO, Villanova MG, de Godoy RA. Esophageal dysfunction in patients with progressive systemic sclerosis and mixed connective tissue disease. Arq Gastroenterol 1985;22(3):122e6. [11] Dinsmore RE, Goodman D, Dreyfuss JR. The air esophagogram a sign of scleroderma involving the esophagus. Radiology 1966;87:348e9. [12] Doria A, Bonavina L, Anselmino M, et al. Esophageal involvement in mixed connective tissue disease. J Rheumatol 1991;18(5):685e90. [13] Essalah AA, Eddy AA. Pediatr Nephrol 1999;13(1):54e6. [14] Fagundes M, Caleiro M, Navarro-Rodriguez T, Baldi B, Kavakama J, Salge J, Carvalho C. Esophageal involvement and interstitial lung disease in mixed connective tissue disease. Resp Med 2009;103:854e60. [15] Ferreiro JE, Busse JC, Saldana MJ. Megacolon in a collagen vascular overlap syndrome. Am J Med 1986;80(2):307e11. [16] Gessner C, Kaltenhauser S, Borte G, Keim V. Pneumatosis custodies intestinalis, a rare complication of mixed connective tissue disease. Dtsch Med Wochenschr 2001;126(40): 1099e102. [17] Goulet JR, Hurtubise M, Senecal JL. Retropneumoperitoneum and pneumatosis intestinales in 2 patients with mixed connective tissue disease and the overlap syndrome. Clin Exp Rheumatol 1988;6(1):81e5. [18] Gutierrez F, Valenzuela JE, Ehresmann GR, et al. Esophageal dysfunction in patients with mixed connective tissue disease and systemic lupus erythematosus. Dig Dis Sci 1982;27(7):592e7. [19] Helenius LMJ, Hietanen JH, Helenius I, et al. Focal sialoadenitis in patients with ankylosing spondylitis and spondyloarthropathy: a comparison with patients with rheumatoid arthritis or mixed connective tissue disease. Ann Rheum Dis 2001;60:744e9. [20] Hirose W, Nakane H, Misumi J, et al. Duodenal hemorrhage and dermal vasculitis associated with mixed connective tissue disease. J Rheumatol 1993;20:151e4. [21] Kahn MF, Appeboom T. Syndrome de sharp. In: Kahn MF, Peltier AP, Meyer O, Piette JC, editors. Les Maladies Systemiques. 3rd ed. Paris: Flammarion; 1991. p. 545e56.

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[25]

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Kasukawa R, Tojo T, Miyawaki S. Preliminary diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue disease and antinuclear antibodies. Amsterdam: Elsevier; 1987. p. 41e7. Kim P, Grossman JM. Treatment of mixed connective tissue disease. Rheum Dis Clin North Am 2005;31:549e65. Konttinen YT, Tuominen TS, Piirainen HI, et al. Signs and symptoms in the masticatory system in ten patients with mixed connective tissue disease. Scand J Rheumatol 1990;19:363e73. Kotajima L, Aotsuka S, Sumiya M, et al. Clinical features of patients with juvenile onset mixed connective tissue disease: analysis of data collected in a nationwide collaborative study in Japan. J Rheumatol 1996;23:1088e94. Lapadula G, Moulo P, Semeraro F, et al. Esophageal motility disorders in the rheumatic disease: a review of 150 patients. Clin Exp Rheumatol 1994;12:515e21. Leal-Alanis A, Hermann M, Nunez-Alvarez C, Romero-Diaz J. Clinical presentation and organ involvement in a large simple of patients with mixed connective disease who fulfill Alarcon-Segovia’s criteria. J Rheumatol 2016 (Suppl.). Lock G, Strotzer M, Straub RH, Scholmerih J, et al. Air oesophagogram: a frequent, but not a specific sign of oesophageal involvement in connective tissue diseases. Br J Rheumatol 1998;37:1011e4. Lundberg IE. The prognosis of mixed connective tissue disease. Rheum Dis Clin North Am 2005;31:535e47. Lynn J, Gossen G, Miller A, Russell J. Pneumatosis intestinales in mixed connective tissue disease: two case reports and literature review. Arthritis Rheum 1984;27(10):1186e9. Marshall JB, Krestschmar JM, Gerhadt DC, et al. Gastrointestinal manifestations of mixed connective tissue disease. Gastroenterology 1990;98(5 Pt 1):1232e8. Nimelstein SH, Brody S, Mcshane D, Holman HR. Mixed connective tissue disease: a subsequent evaluation of the original 25 patients. Medicine 1980;59(4):239e48. Nosho K, Takahashi H, Ikeda Y, et al. A case of protein-losing gastroenteropathy in association with mixed connective tissue disease which was successfully treated with cyclophosphamide pulse therapy. Ryumachi 1998;38:818e24. Piirainen HI, Kurki PT. Clinical and serological follow-up of patients with polyarthritis, Raynaud’s phenomenon, and circulating RNP antibodies. Scand J Rheumatol 1990;19:51e6. Pope JE. Other manifestations of mixed connective tissue disease. Rheum Dis Clin North Am 2005;31:519e33. Samach M, Brandt LJ, Bernstein LH. Spontaneous pneumoperitoneum with pneumatosis cystoids intestinalis in a patients with mixed connective tissue disease. Am J Gastroenterol 1978;69(4):494e500. Setty YN, Pittman CB, Mahale AS, et al. Sicca symptoms and anti-SSA/Ro antibodies are common in mixed connective tissue disease. J. Rheumatol 2002:29,487e489. Sharp GC. Diagnostic criteria for classification of MCTD. In: Kasukawa R, Sharp GC, editors. Mixed connective tissue disease and antinuclear antibodies. Amsterdam: Elsevier; 1987. p. 23e32. Sharp GC. MCTD: a concept which stood the test of time. Lupus 2002;11:333e9. Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue diseasedan apparently distinct rheumatic disease syndrome associated with specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972;52(2):148e59.

332 SECTION j IV Gastrointestinal Involvement of Systemic Diseases [41] Stacher G, Merio R, Budka C, et al. Cardiovascular autonomic function, antiantibodies, and esophageal motor activity in patients with systemic sclerosis and mixed connective tissue disease. J Rheumatol 2000;27:692e7. [42] Stevens MB, Hookman P, Siegel CI, et al. Aperistalsis of the esophagus in patients with connective-tissue disorders and Raynaud’s phenomenon. N Engl J Med 1964;270(23): 1218e22. [43] Tiddens H, Van der Net J, Graeff-Meeder E, et al. Juvenile-onset mixed connective tissue disease: longitudinal follow-up. J Pediatr 1993;122:191e7. [44] Usuba F, Barros J, Fuller R, Hisae J, Ruiz M, Gofinet S, Caleiro M. Sjogren’s syndrome: an underdiagnosed condition in mixed connective tissue disease. Clinics 2014;69(3):158e62. [45] Uzuki M, Kamataki A, Watanabe M, Sasaki N, Miura Y, Sawai T. Histological analysis of esophageal muscular layers from 27 autopsy cases with mixed connective tissue disease (MCTD). Pathol Res Pract 2011;207:383e90. [46] Vanables PJW. Mixed connective tissue disease. Lupus 2006;15:132e7. [47] Wakamatsu M, Inada K, Tsutsumi Y. Mixed connective tissue disease complicated by pneumatosis cystoids intestinalis and malabsorption: case report and literature review. Pathol Int 1995;45(11):875e8. [48] Weston S, Thumshirn M, Wiste J, Camilleri M. Clinical and upper gastrointestinal motility features in systemic sclerosis and related disorders. Am J Gastroenterol 1998;93:1085e9.

Chapter 18

Gastrointestinal Manifestations of Rheumatoid Arthritis R.A. Ferrandiz* and G.S. Alarco´nx *Hospital Nacional Cayetano Heredia and Universidad Peruana Cayetano Heredia, Lima, Peru´; x The University of Alabama at Birmingham, Birmingham, AL, United States

1. INTRODUCTION Rheumatoid arthritis (RA) is a chronic, multisystemic disease that may manifest beyond the articular structures. Gastrointestinal (GI) disease in RA can take on many forms, although iatrogenesis is its most common cause. GI involvement due to the disease per se occurs, in general, in patients with a long-standing history of untreated RA and it may be fatal. Dysphagia, hepatotoxicity, bleeding, infarction, and perforation should be considered on the differential diagnosis in patients with RA. Likewise, manifestations of associated syndromes such as Felty and Sjo¨gren may also occur and need to be considered. Physicians should carefully monitor patients on nonsteroidal antiinflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and biologics for the occurrence of GI adverse events. Finally, it should be noted that numerous diseases affect the GI tract and articular surfaces in close temporal relationship, and a careful history remains essential to properly sort them out. In this chapter, the GI pathology and associated clinical manifestations that may occur in patients with RA are examined [1,2]. First, manifestations described as a direct result of the disease are discussed; this is followed by the GI manifestations that occur as a complication of RA therapy. Finally, diseases that can mimic the presentation of RA in the GI system are covered. This outline is depicted in Table 18.1.

2. MANIFESTATIONS DIRECTLY DUE TO RHEUMATOID ARTHRITIS RA is a chronic, systemic, and progressive inflammatory condition, mediated by self-reactive T and B lymphocytes. RA occurs worldwide and affects w1% The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00018-0 333 Copyright © 2017 Elsevier B.V. All rights reserved.

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TABLE 18.1 The Gastrointestinal (GI) System in Rheumatoid Arthritis (RA): Chapter Outline 1. Manifestations directly due to RA Upper GI tract involvement Rheumatoid arteriolitis in the gut Felty syndrome Secondary amyloidosis Secondary Sjo¨gren syndrome 2. Gastrointestinal disease resulting from RA therapeutics GI toxicity due to NSAIDs GI toxicity due to glucocorticoids GI toxicity due to DMARDs GI toxicity due to biologics 3. Mimics of gastrointestinal disease in RA Reactive or postinfectious arthritis Whipple disease 4. Conclusions NSAIDs, nonsteroidal antiinflammatory drugs; DMARDs, disease-modifying antirheumatic drugs.

of the North American and European population [3e6].It is characterized by inflammation of the synovium and surrounding structures, which may lead to significant joint destruction. The disease is not limited to the joints; in fact, there are many nonarticular complications that are also mediated by the inflammatory process [7e9]. RA leads to a predominance of the CD4þ T-helper lymphocyte subset 1 (Th1)-type immune response, with most cytokines secreted from this class type, i.e., TNF-a, IFN-g, and IL-1 [10,11]. Systemic manifestations of RA such as rheumatoid vasculitis and Felty syndrome are understood now to originate from progressive inflammation, such as that of large and small vessels. Sustained articular and extraarticular inflammation may be followed by premature or accelerated atherosclerosis. In turn, accelerated atherosclerosis leads to an increased morbidity and mortality from cardiovascular and cerebrovascular disease [12e14]. Other GI manifestations such as amyloidosis, secondary Sjo¨gren syndrome, and liver dysfunction are also present in RA, but their exact pathophysiology is poorly understood [15e17]. Currently, GI involvement in RA occurs rarely because it is a late extraarticular manifestation of untreated disease of more than 5 years in duration, a situation which is uncommon now [18]. An overview of GI disease in RA and its pathophysiology can be found in Table 18.2. Upper GI tract involvement in RA may occur because of impaired chewing [19], which results from temporomandibular joint involvement; in turn, this may lead to abnormal esophageal motility with low peristaltic pressure in the lower two-thirds of the esophagus and reduced pressure in the loweresophageal sphincter. These esophageal abnormalities may be associated

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TABLE 18.2 Secondary Gastrointestinal Syndromes in Rheumatoid Arthritis: Manifestations and Pathogenesis Disease Manifestation

Pathogenesis

Ulceration of the stomach (peptic ulcer disease), small intestine, and colon, with perforation as a possible sequela

Luminal injury as a result of drug toxicity, such as NSAIDs or glucocorticoids, or as a consequence of rheumatoid vasculitis

Temporomandibular joint arthritis that prevents adequate chewing

Inflammation of the synovium and surrounding structures, due to T-cell response

Dysphagia

Atlantoaxial subluxation

Dysmotility of the esophagus and lower-esophageal sphincter

Secondary Sjo¨gren syndrome

Chronic diarrhea and protein-wasting enteropathy

Secondary amyloidosis (SAA) of the small intestine

Hepatic diseasednodular regenerative hyperplasia

Felty syndrome

Pancreatic exocrine insufficiency and sicca syndrome

Secondary Sjo¨gren syndrome

NSAIDs, Nonsteroidal antiinflammatory drugs.

with heartburn, dysphagia, and esophagitis. Significant atlantoaxial subluxation may also result in dysphagia, which may be associated with other signs of spinal cord compression; endoscopy is a high-risk procedure in such patients. Rheumatoid vasculitis, although observed less frequently nowadays than in the past, is a nonarticular manifestation of RA in which microvascular lesions develop throughout different organ systems; in the GI tract, the small bowel is predominantly affected [20]. Rheumatoid arteriolitis in the gut may cause multiple ischemic ulcers and perforation, while vasculitis of larger vessels results in segmental or extensive bowel infarction. Vasculitis of the colon may present as pancolitis clinically similar to ulcerative colitis [19]. Rheumatoid vasculitis causes acute abdominal pain and can present as upper or lower GI bleeding, ulceration, ischemia or infarction, or intestinal perforation [21e23]. Rheumatoid vasculitis, whether involving the GI tract or not, is not a common presentation of RA; instead, it is frequently associated with a protracted course and a long history of erosive arthritis [24] with high levels of rheumatoid factor and subcutaneous nodules. It is less frequent in patients who have had earlier or more intensive therapeutic interventions; flares of rheumatoid vasculitis, however, tend to accompany a more quiescent phase of articular disease [25,26]. The prognosis is poor and the outcome is frequently fatal if not suspected and managed properly [27].

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Felty syndrome is a recognized complication of RA. The syndrome’s triad consists of splenomegaly, leucopenia in the setting of seropositive, and nodular and destructive RA [28]. As with rheumatoid vasculitis, it is rarely seen nowadays. Portal hypertension with gastroesophageal varices [29,30] and hepatic fibrotic disease [31] such as nodular regenerative hyperplasia [32] can occur as secondary manifestations of this rare syndrome. Secondary amyloidosis usually occurs in the setting of chronic inflammatory conditions such as RA, which leads to the progressive deposition of protein fibrils of serum amyloid A (SAA) [33]. These fibrils are deposited throughout the body, but have the most obvious clinical consequences when deposited in renal, GI, or cardiac tissues [34,35]. The distribution of secondary amyloidosis in the context of RA varies worldwide; the majority of cases have been described not in North America or Europe, but rather in other parts of the world such as Central and East Asia [36,37]. Secondary amyloidosis of the GI tract may involve any portion of the GI tract and may have different clinical presentations such as anorexia, nausea, vomiting, abdominal fullness, diarrhea (that may be intractable) [38], localized ulcerations, achalasia-type dysmotility, or a protein-wasting enteropathy [20]. Although Sjo¨gren syndrome is more commonly recognized in its primary form, it can also occur secondary to a preexisting autoimmune disease, and it is likely that 13 of the 19 patients that Sjo¨gren included in his original caseseries definition had secondary disease due to RA [39]. Primary or secondary Sjo¨gren syndrome involves lymphocytic infiltration and damage of exocrine glands; it has classically been recognized as involving the ocular and salivary glands but GI, cutaneous, renal, vascular, neurologic, and respiratory involvement is also well documented [40]. Pancreatic exocrine deficiency has been noted, but is an uncommon complication [41]. Severe sicca manifestations may be observed with secondary Sjo¨gren syndrome, leading to problems with deglutition and overall patient comfort [42], while both Sjo¨grenassociated and primary-RAeassociated esophageal disease can range from primary dysmotility to lower-esophageal sphincter [43e45]. Primary RA hepatotoxicity, unrelated to any therapeutic intervention, has been noted more often in past years rather than in the current literature. It was often described as a functional pathology, with steatosis and evidence of hepatocellular degeneration and elevated serum transaminase levels, with some cases progressing to impaired synthetic function [46e48]. Overall, such cases are seen less frequently now, with therapeutic interventions currently occurring earlier in the course of the disease.

3. GASTROINTESTINAL DISEASE RESULTING FROM RHEUMATOID ARTHRITIS THERAPEUTICS Both glucocorticoids and NSAIDs are frequently used in the management of inflammation and the symptoms associated with it, pain in particular. Although

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these drugs are useful for analgesia and improvement of function in cases of significant synovitis, NSAIDs have a limited role in altering the course of the disease, whereas low-dose glucocorticoids have been recognized to have a significant disease-modifying effect [49e52]. Both glucocorticoids and NSAIDs can lead to significant GI toxicity. GI toxicity in the NSAID-treated patient is a serious problem, with the risk of serious GI complications such as GI bleeding, ulcer perforation, obstruction, dyspepsia, nausea, vomiting, and heartburn [53,54] estimated in one study at 13 per 1000 RA patients treated with these drugs [55]. Of the subset of patients who are hospitalized with upper GI bleeding, secondary to NSAID ulceration, mortality is calculated at 5.6% [56]. An estimated 16,500 deaths have occurred each year in North America, secondary to GI toxicity since the mid-1990s to the early 2000s, but more recent data are not available [57,58]. NSAIDs act through either the selective (isoenzyme 2) or the nonselective (isoenzymes 1 and 2) inhibition of cyclooxygenase (COX), leading to either a total inhibition of synthesis of prostanoids (PGD2, PGE2, PGH2, PGI2, and TxA2) with the nonselective COX inhibitors or a selective decrement in PGE2 with the COX-2 inhibitors [59]. Although it was originally believed that this selective inhibition would lead to equal analgesic efficacy and reduced risk for gastric toxicity, this original model has been challenged by clinical trial results showing little to no improvement in the rates of gastric ulceration, an increase in the rates of cardiovascular complications, compared to nonselective COX inhibitors, and a loss of any GI protective effects if concurrent aspirin therapy is used [60e62]. The mechanism for the GI toxicity of both selective and nonselective NSAIDs is incompletely understood, but there is consensus on the basic principles. In the inhibition of the eicosanoid precursors transformed into prostaglandins (the end products of the arachidonic acid pathway), the protective prostaglandin, PGI2, among others inhibited, is thought to be inhibited by only nonselective NSAIDs, while the proinflammatory prostaglandin PGE2 is inhibited by both [53,63,64]. Additionally, inhibition of the COX enzymes seems to have an as-yet-uncharacterized effect on wound healing that prevents already developed ulcers from healing [65]. Overall, treatment with NSAIDs increases the risk of developing gastritis and peptic ulcer disease, with the subsequent risks of bleeding and perforation [65,66], as mentioned earlier. Glucocorticoids have multiple, complex mechanisms of action, but are currently understood to act at both the transcriptional level (NF-kB) and through proteineprotein inhibitory interactions such as IkB-NF-kB and functional inactivation of cytosolic phospholipase A2 (cPLA2). All of these processes lead to decrease in the production of proinflammatory cytokines and consequently reduction of inflammation [67]. Additionally, glucocorticoids are associated with gastritis, peptic ulcer disease, and GI bleeding, although not to the same degree as NSAIDs [68].

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Methotrexate is a DMARD, which is frequently prescribed as initial therapy for RA. The mechanism of methotrexate is irreversible inhibition of dihydrofolate reductase, preventing the formation of reduced folate metabolites and inhibiting the synthesis of purines [69e71]. The therapeutic value of methotrexate, however, is often hampered by its various systemic toxicities; the hepatic toxicity has been discussed here. Other drug-related toxicities, including pulmonary fibrosis and hematopoietic abnormalities, while not discussed here, are understood to have as a common underlying mechanism the intracellular accumulation of polyglutaminated methotrexate aggregates [72]. Specific methotrexate hepatotoxicity can result in histological patterns including steatosis, stellate cell hypertrophy, anisonucleosis, and hepatic fibrosis [73,74]. Exposure to other hepatotoxic drugs, alcohol, and hepatic infections can increase the risk of methotrexate liver damage, although the risk for cirrhosis resulting from methotrexate is small [75,76]. The American College of Rheumatology has published guidelines for the monitoring of patients with RA receiving methotrexate therapy that are designed to minimize the risk of toxicity [77]. A less commonly used DMARD is leflunomide, the inactive oral prodrug of the active metabolite A77-1726 [78]. A77-1726 acts as a noncompetitive inhibitor of dihydroorotate dehydrogenase, thus inhibiting the de novo synthesis of pyrimidines [79,80]. It is brought to attention here because of concerns of hepatotoxicity. The European Union Medicines Control Agency (EUMCA) undertook a study of leflunomide hepatotoxicity and found 296 total and 129 serious events among patients taking leflunomide over 104,000 patient-years. Of those 129 serious events, 101 (78%) occurred in patients who were taking “other hepatotoxic medications” (not specifically defined). Among the conclusions reached was that although confounding factors exist, a causal relationship could not be excluded, and the use of leflunomide in patients with preexisting liver disease was contraindicated. Additionally, the use of this agent with other potentially hepatotoxic medicines is discouraged, and the commission urges its use to be restricted to experienced specialists [81]. The vast majority of patients who had presumed leflunomide-associated hepatotoxicity had previously received hepatotoxic regimens, including methotrexate. As such, the biochemical and histological patterns of injury that have been documented have been difficult to assign to this single agent. The Food and Drug Administration and the North American and European professional rheumatologic societies have not endorsed these recommendations and have not introduced a black box warning on this product. In recent years, biologic compounds such as antitumor necrosis factor (anti-TNF) drugs, non-anti-TNF drugs, and Janus kinase inhibitor have emerged as agents in the treatment of patients with RA who are refractory to conventional treatment modalities [82]. Besides GI compromise due to bacterial infections, these drugs have been reported to cause GI involvement in some cases such as nausea, mild elevation

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of liver enzymes, constipation, and abdominal pain. More severe but very rare adverse events include cholecystitis, pancreatitis, GI hemorrhage, appendicitis, GI perforation, and liver failure [82e92]. The mechanism and side effects of various RA therapeutics modalities are summarized in Table 18.3.

4. MIMICS OF GASTROINTESTINAL DISEASE IN RHEUMATOID ARTHRITIS Although one of the most common associations of bowel disease and inflammatory arthritis or spondylitis is found in inflammatory bowel disease, it will not be discussed in this chapter because there is a separate chapter in this volume devoted entirely to this topic. Reactive or postinfectious arthritis may have a similar presentation to that of RA GI disease [93]. Dysentery resulting from infectious agents such as Yersinia enterocolitica, Yersinia pseudotuberculosis, and Chlamydophila spp. (formerly Chlamydia spp.) is associated with reactive arthritis [94e96]. If the clinical timeline is uncertain, the bloody stools may be seen as a later part of the patients’ illness, rather than the precipitating event. Delineation of the patient’s history can often determine if the underlying issue is primarily GI or rheumatologic in nature. A more complicated, although admittedly rare, disease is Whipple disease; although first described in 1907, it is still very difficult to diagnose. It consists of progressive wasting, chronic diarrhea, and polyarticular arthritis, followed by neurologic deterioration and, if untreated, death [97]. Long-term treatment with trimethoprim-sulfa seems to be curative, with little risk of a relapse. The etiologic organism Tropheryma whipplei has only been recently identified, while seropositivity and carriage of the organism seem to be frequent [98]. The prevalence of Whipple disease has been reported as very low, with only w1000 cases reported to date and an autopsy prevalence of less than 0.1%. Due to the wide variability in symptoms, the large seropositive or carrier population, and the difficulty in culturing the organism, the true prevalence of the disease is unknown at this time. It is known that misdiagnosis of Whipple disease for RA and treatment with corticosteroids can lead to an accelerated course and progression of GI disease and a potentially fatal outcome [99].

5. CONCLUSION GI disease in RA can take on many forms, although the primary cause of GI manifestations at this time is iatrogenic. Physicians should be vigilant in their prescribing habits and carefully monitor patients on NSAIDs, DMARDs, and biologics. In addition to this, health-care providers should remain aware that RA is a chronic, multisystemic disease that manifests itself beyond the

TABLE 18.3 Gastrointestinal (GI) Toxicities of Medications Used to Treat Rheumatoid Arthritis (RA) Mechanism

Manifestations

NSAIDs

Differential inhibition of cyclooxygenase isoforms; downregulation of cytoprotective prostaglandins, and impaired healing of mucosal ulcerations.

Development and progression of gastric and enteric ulcers. An enhanced likelihood of progression to perforation with frank hemorrhage or infection.a

Glucocorticoids

Pleiotropic actions, including indirect inhibition of the NF-kB transcription factor, cytosolic phospholipase A2a (cPLA2a), and mitogen-activated protein kinase (MAPK), through several pathways. They are antiinflammatory/immunosuppressive.

Development and progression of gastric and enteric ulcers.

Methotrexate

Polyglutamation of intracellular methotrexate. Their accumulation can result in toxicity.

Hepatocellular steatosis, fibrosis, and rarely, cirrhosis.b

Sulfasalazine

Potent inhibitor of the NF-kB transcription factor resulting in antiinflammatory actions.

Nausea, vomiting, and diarrhea are common. Idiosyncratic hypersensitivity hepatitis is uncommon. Rechallenge must not be attempted.cee

Hydroxychloroquine

Neutralization of acidic lysosomes; modification of innate immune response through toll- like receptor interaction.

Frequent GI disturbance due to muscular contractions caused by drugs; infrequent hepatocellular damage, which may be worsened in the setting of preexisting viral hepatitis.fei

Gold salts

Exact mechanism uncertain; it may involve dissociation of antigeneMHC complexes.

Gold salt preparations rarely cause enterocolitis; parenteral preparations cause more severe disease than oral compounds. Gold salts can also rarely cause cholestatic jaundice and pancreatitis.jel

D-Penicillamine

Exact mechanism uncertain; it may involve interruption of T-celleantigen-presenting cell interaction. It also complexes with circulating IgM rheumatoid factor.

Nausea and vomiting are common side effects. Dysgeusia, gingivostomatitis, and reactivation of preexisting ulcers have also been described.m,n

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Drug or Drug Class

Anti-TNF compounds

Varies by agent; etanercept consists of a soluble p75 TNFaR:Ig fusion molecule that binds to and inactivates free TNF-a.

Golimumab is a human IgO 1K, monoclonal antibody specific for human tumor necrosis factor alpha (TNF-a); it was developed using genetically engineered mice resulting in an antibody with human-derived antibody variable. Certolizumab pegol is a TNF blocker. Is a recombinant, humanized antibody Fab’ fragment, with specificity for human tumor necrosis fa`ctor alpha (TNF-a), conjugated to an w40 kDa polyethylene glycol. A human fusion protein of CTLA4 (CD154) and the Fc portion of IgG1. It inhibits the costimulatory signal between CD28 and CD80/ CD86 necessary for T-cell activation.

In 1955 subjects enrolled in placebo-controlled trials and reported by the manufacturer, there were no significant GI events. A PubMedMEDLINE search in April 2007 revealed no reports of GI toxicity resulting from abatacept.

Rituximab

A murine-human chimeric mAb (IgG1k) against CD20, an antigen found on pre B cells, mature B cells.

Worsening or unmasking of preexisting viral hepatitis (B not C).q

341

Abatacept

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Both infliximab and adalimumab are mAb directed against TNFaR (p55 and p75). They differ in Fc and route of administration. Infliximab is human-murine chimeric and is administered intravenously; adalimumab is a human mAb and is administered subcutaneously.

Etanercept has shown little significant GI toxicity. Infliximab has the risk of liver damage, with several cases of idiosyncratic hepatitis reported. Adalimumab has shown potential to cause a hypersensitivity reaction that can affect the GI tract, with the liver most commonly involved. With golimumab, patients may present constipation. No specific adverse reactions have been reported in patients with RA, but patients with Crohn disease, may present elevated liver enzymes and hepatitis. o,p

Continued

Drug or Drug Class

Mechanism

Manifestations

Tocilizumab

Tocilizumab, a recombinant humanized antihuman interleukin-6 (IL-6) receptor monoclonal antibody, binds specifically to both soluble and membrane-bound IL-6 receptors, and has been shown to inhibit IL6emediated signaling through these receptors. It has a molecular weight of w148 kDa.

Patients treated with tocilizumab presenting new onset of abdominal symptoms should be promptly evaluated for early identification of GI perforation, specially diverticular perforation. Treatment with tocilizumab was associated with a higher incidence of transaminase elevations.

Tofacitinib

Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit signals arising from cytokine or growth factorereceptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs. Tofacitinib citrate has a molecular weight of 504.5 Daltons.

GI perforation has been reported in clinical studies with tofacitinib in RA patients, although the role of JAK inhibition in these events is not known. Confirmed increases in liver enzymes greater than three times the upper limit of normal were observed in patients treated with tofacitinib. Finally, tofacitinib may cause diarrhea.

NSAIDs, nonsteroidal antiinflammatory drugs. a Armstrong CP, Blower AL. Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut 1987;28(5):527e32. b Gispen JG, Alarcon GS, Johnson JJ, Acton RT, Barger BO, Koopman WJ. Toxicity of methotrexate in rheumatoid arthritis. J Rheumatol 1987;14(1):74e9. c Box SA, Pullar T. Sulphasalazine in the treatment of rheumatoid arthritis. Br J Rheumatol 1997;36(3):382e6.

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TABLE 18.3 Gastrointestinal (GI) Toxicities of Medications Used to Treat Rheumatoid Arthritis (RA)dcont’d

d

Smedegard G, Bjork J. Sulphasalazine: mechanism of action in rheumatoid arthritis. Br J Rheumatol 1995;34(Suppl. 2):7e15. Wahl C, Liptay S, Adler G, Schmid RM. Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Invest 1998;101(5):1163e74. f Kyburz D, Brentano F, Gay S. Mode of action of hydroxychloroquine in RA-evidence of an inhibitory effect on toll-like receptor signaling. Nat Clin Pract Rheumatol 2006;2(9):458e9. g Gladman DD, Urowitz MB, Senecal JL, Fortin PJ, Petty RE, Esdaile JM, et al. Aspects of use of antimalarials in systemic lupus erythematosus. J Rheumatol 1998;25(5):983e5. h Scherbel AL, Harrison JW, Atdjian M. Further observations on the use of 4-aminoquinoline compounds in patients with rheumatoid arthritis or related diseases. Cleve Clin Q 1958;25(2):95e111. i Mok MY, Ng WL, Yuen MF, Wong RW, Lau CS. Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis. Clin Exp Rheumatol 2000;18(3):363e8. j Fam AG, Paton TW, Shamess CJ, Lewis AJ. Fulminant colitis complicating gold therapy. J Rheumatol 1980;7(4):479e85. k Eisemann AD, Becker NJ, Miner Jr PB, Fleming J. Pancreatitis and gold treatment of rheumatoid arthritis. Ann Intern Med 1989;111(10):860e1. l Conaghan PG, Brooks P. Disease-modifying anti-rheumatic drugs, including methotrexate, gold, antimalarials, and D-penicillamine. Curr Opin Rheumatol 1995;7(3):167e73. m Stein HB, Patterson AC, Offer RC, Atkins CJ, Teufel A, Robinson HS. Adverse effects of D-penicillamine in rheumatoid arthritis. Ann Intern Med 1980;92(1):24e9. n Fries JF, Williams CA, Ramey D, Bloch DA. The relative toxicity of disease-modifying antirheumatic drugs. Arthritis Rheum 1993;36(3):297e306. o Menghini VV, Arora AS. Infliximab-associated reversible cholestatic liver disease. Mayo Clin Proc 2001;76(1):84e6. p Michel M, Duvoux C, Hezode C, Cherqui D. Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an adult onset still’s disease. J Rheumatol 2003;30(7):1624e5. q Tsutsumi Y, Kanamori H, Mori A, Tanaka J, Asaka M, Imamura M, et al. Reactivation of hepatitis B virus with rituximab. Expert Opin Drug Saf 2005;4(3):599e608. e

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articular structures. Bleeding, infarction, and perforation from primarily affected bowel sites should be considered on the differential diagnosis in the care of patients with RA, while hepatotoxicity and esophageal varices and dysmotility can occur either directly as a result of RA or as manifestations of rheumatic syndromes such as Felty and Sjo¨gren, secondary to RA. Finally, it should be remembered that numerous diseases affect the GI tract and articular surfaces in close temporal relationship, and a careful history remains essential.

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346 SECTION j IV Gastrointestinal Involvement of Systemic Diseases [41] Kauppi M, Kankaanpaa E, Kautiainen H. Exocrine dysfunction of the pancreas in patients with chronic polyarthritis. J Clin Rheumatol 2001;7(3):166e9. [42] Moutsopoulos HM, Chused TM, Mann DL, Klippel JH, Fauci AS, Frank MM, et al. Sjogren’s syndrome (sicca syndrome): current issues. Ann Intern Med 1980;92(2 Pt 1):212e26. [43] Bassotti G, Gaburri M, Biscarini L, Baratta E, Pelli MA, Del Favero A, et al. Oesophageal motor activity in rheumatoid arthritis: a clinical and manometric study. Digestion 1988;39(3):144e50. [44] Volter F, Fain O, Mathieu E, Thomas M. Esophageal function and Sjogren’s syndrome. Dig Dis Sci 2004;49(2):248e53. [45] Ebert E. Gastrointestinal and hepatic manifestations of Sjogren syndrome. J Clin Gastroenterol January 2012;46(1):25e30. [46] Sullivan S, Hamilton EB, Williams R. Rheumatoid arthritis and liver involvement. J R Coll Physicians Lond 1978;12(5):416e22. [47] Lefkovits AM, Farrow IJ. The liver in rheumatoid arthritis. Ann Rheum Dis 1955;14(2):162e9. [48] Whaley K, Goudie RB, Williamson J, Nuki G, Dick WC, Buchanan WW. Liver disease in Sjogren’s syndrome and rheumatoid arthritis. Lancet 1970;1(7652):861e3. [49] Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. N Engl J Med 1995;333(3):142e6. [50] De Jong PH, Hazes JM, Han HK, et al. Randomised comparison of initial triple DMARD therapy with methotrexate monotherapy in combination with low-dose glucocorticoid bridging therapy; 1-year data of the tREACH trial. Ann Rheum Dis 2014;0:1e9. [51] Cutolo M, Spies CM, Buttgereit F, et al. The supplementary therapeutic DMARD role of low-dose glucocorticoids in rheumatoid arthritis. Arthritis Res Ther 2014;16(Suppl 2):S1. [52] Bijlsma JWJ. Disease control with glucocorticoid therapy in rheumatoid arthritis. Rheumatology 2012;51:iv9e13. [53] Sostres C, Gargallo CJ. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Prac Res Clin Gastroenterol 2010;24:121e32. [54] Brun J, Jones R. Non-steroidal anti-inflammatory drug-associated dyspepsia: the scale of the problem. Am J Med 2001;110:12Se3S. [55] Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl 1999;56:18e24. [56] Lanas A, Perez-Aisa MA, Feu F, Ponce J, Saperas E, Santolaria S, et al. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am J Gastroenterol 2005;100(8):1685e93. [57] Singh G. Recent considerations in nonsteroidal anti- inflammatory drug gastropathy. Am J Med 1998;105(1B):31Se8S. [58] Fries JF, Murtagh KN, Bennett M, Zatarain E, Lingala B, Bruce B, et al. The rise and decline of nonsteroidal antiinflammatory drug-associated gastropathy in rheumatoid arthritis. Arthritis Rheum 2004;50(8):2433e40. [59] Steinmeyer J. Pharmacological basis for the therapy of pain and inflammation with nonsteroidal anti-inflammatory drugs. Arthritis Res 2000;2(5):379e85.

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Chapter 19

Spondyloarthritis and Gastrointestinal Involvement F. Atzeni,* R. Talotta,x I.F. Masala{ and P. Sarzi-Puttinix

*IRCCS Galeazzi Orthopedic Institute, Milan, Italy; xUniversity Hospital L. Sacco, Milan, Italy; { Santissima Trinita` Hospital, Cagliari, Italy

1. INTRODUCTION The term spondyloarthritis (SpA) covers a broad spectrum of inflammatory axial joint rheumatic diseases that are often associated with extraarticular conditions such as psoriasis, uveitis, and colitis. In 2010, the international Assessment of SpondyloArthritis Society (ASAS) classified all forms with radiographically documented sacroiliitis or positivity for human leukocyte antigen (HLA)-B27 plus one or two articular or extraarticular manifestations as SpAs [1], which led to ankylosing spondylitis (AS), reactive arthritis, and psoriatic arthritis (PsA) being reclassified as SpAs because of their common pathogenesis, overlapping signs and symptoms, and similar treatment. The gastrointestinal tract plays a role in the development of SpAs, which are often associated with inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn’s disease (CD); furthermore, cases of asymptomatic colitis have also been described. The pathogenetic role of the dysbiosis of commensal aerobic and anaerobic bacterial flora has also recently been investigated because the overgrowth of some bacterial species can drive an altered immune response and favor the initiation of an autoimmune process. The aim of this chapter is to evaluate the prevalence, epidemiology, pathogenesis, and treatment of gastrointestinal involvement in patients with SpA.

2. PREVALENCE AND EPIDEMIOLOGY The overall estimated prevalence of SpA is 0.01e2.5% and its incidence is 0.48e63/100,000 [2]. However, prevalence varies widely depending which The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00019-2 349 Copyright © 2017 Elsevier B.V. All rights reserved.

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diagnosis and classification criteria are used: the European Spondyloarthropathy Study Group (ESSG) [3] and Amor criteria [4] are not recommended for the identification of SpA patients because they are less sensitive than the ASAS classification criteria [5], which may, nevertheless, overestimate the prevalence of SpA in subjects with chronic back pain aged