Rheumatology and Pulmonology 9781032421469, 9781032421452, 9781003361374, 1032421452

Table of contents :
Cover
Half Title
Series
Title
Copyright
Dedication
Contents
Preface
Acknowledgment
About the Editors
Contributors
Part I Approach to the Patient with Lung Disease
1 Approach to the Patient with Interstitial Lung Disease
2 Idiopathic Pneumonia with Autoimmune Features
3 Approach to the Patient with Pulmonary Vascular Disease
4 Approach to the Patient with Neuromuscular Weakness
5 Approach to the Patient with Pleural Disease
6 Approach to the Patient with Obstructive Airways Disease
7 General Care of the Patient with Pulmonary Manifestations of Rheumatic Diseases
Part II Approach to Pulmonary Manifestations of Specific Systemic Autoimmune Rheumatic Diseases
8 Pulmonary Manifestations of Rheumatoid Arthritis
9 Pulmonary Manifestations of Sjögren’s Disease
10 Pulmonary Manifestations of Systemic Lupus Erythematosus
11 Pulmonary Manifestations of the Idiopathic Inflammatory Myopathies
12 Pulmonary Manifestations of Systemic Sclerosis and Mixed Connective Tissue Disease
13 Pulmonary Manifestations of Systemic Vasculitis
14 Sarcoidosis
15 Pulmonary Manifestations of Axial Spondyloarthritis
16 Pulmonary Manifestations of IgG4-Related Disease
Part III Treatment-associated Pulmonary Complications
17 Pulmonary Toxicities of Medications Used for Treating Patients with Rheumatic Diseases
Index

Citation preview

INTERDISCIPLINARY RHEUMATOLOGY SERIES Edited by Jason Liebowitz and Philip Seo

INTERDISCIPLINARY RHEUMATOLOGY

RHEUMATOLOGY AND PULMONOLOGY EDITED BY

MARCY B. BOLSTER AND KRISTIN B. HIGHLAND CRC Press Taylor & Francis Croup

Interdisciplinary Rheumatology Rheumatology and Pulmonology

Certain diseases may involve organ systems that cross the boundaries of specialties. For instance, a patient with scleroderma can develop interstitial lung disease, or a patient with relapsing polychondritis can have the clinical manifestation of subglottic stenosis. This book represents a collaboration between specialties, helping clinicians recognize the implications of disease both within their own specialty and in the overlapping specialty. Here, leading experts from the fields of rheumatology and pulmonology provide a masterclass in the care of patients with systemic illnesses that involve the immune system and the lungs. Key Features: ■

Provides an evidence-based clinical approach to the patient with pulmonary manifestations of rheumatic disease

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Details cutting-edge research with input from the world’s leading experts

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Discusses possible future directions for research and advancement

Interdisciplinary Rheumatology Series Series Editors: Philip Seo and Jason Liebowitz Rheumatology and Gastroenterology Edited by: Reem Jan and Sushila Dalal Rheumatology and Cardiology Edited by: Vaneet K. Sandhu Rheumatology and Nephrology Edited by: Karina Torralba, Duvuru Geetha, and Anisha Dua Rheumatology and Pulmonology Edited by: Marcy B. Bolster and Kristin B. Highland

For more information on the Interdisciplinary Rheumatology Series, please visit https://www.routledge.com/ Interdisciplinary-Rheumatology/book-series/IRJL

Interdisciplinary Rheumatology Rheumatology and Pulmonology

Edited by

Marcy B. Bolster and Kristin B. Highland

Boca Raton London New York

CRC Press is an imprint of the Taylor & Francis Group, an informa business

Designed cover image: Designed Cover First edition published 2025 by CRC Press 2385 NW Executive Center Drive, Suite 320, Boca Raton FL 33431 and by CRC Press 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN CRC Press is an imprint of Taylor & Francis Group, LLC © 2025 selection and editorial matter, Marcy B. Bolster and Kristin B. Highland individual chapters, the contributors This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978–750–8400. For works that are not available on CCC please contact [email protected] Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. ISBN: 978-1-032-42146-9 (hbk) ISBN: 978-1-032-42145-2 (pbk) ISBN: 978-1-003-36137-4 (ebk) DOI: 10.1201/9781003361374 Typeset in Palatino by Apex CoVantage, LLC

This book is dedicated to Dr. Richard Silver, our mentor, trusted advisor, and friend. He has an unparalleled commitment to excellence in clinical medicine, scientific investigation, and in teaching the many next generations of learners. He consistently demonstrates his approach to medicine in terms of humanism, respect, patient–physician rapport, comfort with uncertainty, and pursuit of the difficult diagnosis. A truly special day is one in which either of us finds ourselves doing or saying something as Rick Silver may have done. Rick has a career-long commitment to promoting the professional development of his trainees and colleagues, and it is very fitting that he recently received the Award for Advancement of Women Faculty at the Medical University of South Carolina! It is a demonstration of our tremendous gratitude that we serve as co-editors for this book, assimilating shared knowledge between our specialties of rheumatology and pulmonary medicine.

Contents Preface������������������������������������������������������������������������������������������������������������������������������������������������������������ ix Acknowledgment��������������������������������������������������������������������������������������������������������������������������������������� x About the Editors�������������������������������������������������������������������������������������������������������������������������������������� xi Contributors����������������������������������������������������������������������������������������������������������������������������������������������� xii Part I  Approach to the Patient with Lung Disease��������������������������������������������������������������������1 1 Approach to the Patient with Interstitial Lung Disease��������������������������������������������������������������������2 Iazsmin Bauer Ventura, Kavitha Selvan, Mary E. Strek, and Lydia Chelala 2 Idiopathic Pneumonia with Autoimmune Features������������������������������������������������������������������������26 Apostolos Perelas and Darryn L. Winter 3 Approach to the Patient with Pulmonary Vascular Disease����������������������������������������������������������36 Josanna Rodriguez-Lopez and Daniel Alape Moya 4 Approach to the Patient with Neuromuscular Weakness��������������������������������������������������������������51 Aparna Bhat, Jason Dean, and Loutfi S. Aboussouan 5 Approach to the Patient with Pleural Disease����������������������������������������������������������������������������������66 Carlos E. Kummerfeldt, Amit Chopra, and John T. Huggins 6 Approach to the Patient with Obstructive Airways Disease����������������������������������������������������������89 Tessy K. Paul and Adam Q. Carlson 7 General Care of the Patient with Pulmonary Manifestations of Rheumatic Diseases ������������107 Jee Young You, Soumya Chatterjee, and Atul Mehta Part II Approach to Pulmonary Manifestations of Specific Systemic Autoimmune Rheumatic Diseases����������������������������������������������������������������������������������119 8 Pulmonary Manifestations of Rheumatoid Arthritis��������������������������������������������������������������������120 Robert K. Arao, Robert W. Hallowell, and Jeffrey A. Sparks 9 Pulmonary Manifestations of Sjögren’s Disease����������������������������������������������������������������������������137 Hassan Baig, Nancy Carteron, Paul Dellaripa, and Augustine Lee 10 Pulmonary Manifestations of Systemic Lupus Erythematosus ��������������������������������������������������151 Megan M. Lockwood, Isabel C. Mira-Avendano, Selvin Jacob, Christopher Jenkins, and Rosalind Ramsey-Goldman 11 Pulmonary Manifestations of the Idiopathic Inflammatory Myopathies����������������������������������172 Didem Saygin, Erin M. Wilfong, Chester V. Oddis, and Dana P. Ascherman 12 Pulmonary Manifestations of Systemic Sclerosis and Mixed Connective Tissue Disease������187 Denise G. Sese, Katherine C. Silver, Kristin B. Highland, and Richard M. Silver 13 Pulmonary Manifestations of Systemic Vasculitis ������������������������������������������������������������������������215 Laura C. Arneson, Lakshmi A. Jayaram, Sarah P. Cohen, Lynn A. Fussner, Sebastian E. Sattui, and Anisha B. Dua 14 Sarcoidosis��������������������������������������������������������������������������������������������������������������������������������������������235 Tarek Taha, Logan Harper, Patompong Ungprasert, and Manuel L. Ribeiro Neto vii

Contents

15 Pulmonary Manifestations of Axial Spondyloarthritis����������������������������������������������������������������253 Kiana Vakil-Gilani, Tomas Cordova, Daniel Seifer, and Atul Deodhar 16 Pulmonary Manifestations of IgG4-Related Disease��������������������������������������������������������������������265 Guy Katz, Amita Sharma, Yin P. Hung, and John H. Stone Part III  Treatment-associated Pulmonary Complications ��������������������������������������������������287 17 Pulmonary Toxicities of Medications Used for Treating Patients with Rheumatic Diseases����������������������������������������������������������������������������������������������������������������������������288 Emily Littlejohn and Kristine Keaton Index��������������������������������������������������������������������������������������������������������������������������������������������������������������299

viii

Preface The intersection of rheumatology and pulmonary medicine occurs in many diseases, and the collaborative approach to patient care enhances the care either specialty can provide alone. There are times when a patient is diagnosed with lung disease, and the nuances of history, physical examination, and/or laboratory evaluation, as conducted by the pulmonologist, raise the question of a potential underlying or associated rheumatic condition. Consultation with a rheumatologist uncovers a diagnosis of a systemic autoimmune rheumatic disease, thus bringing together the collaborative care of the pulmonologist with the rheumatologist. Similarly, the appreciation that many systemic autoimmune rheumatic diseases have parenchymal, airway, pleural, and/or vascular manifestations invites the deep knowledge and skillset of the pulmonologist into the collaborative care of the patient known to the rheumatologist. The matrix of determining the value of non-invasive imaging and functional testing, as well as invasive testing, including hemodynamic measures, bronchoscopy, and tissue biopsy, is best navigated with the guidance of a pulmonologist. Similarly, the interpretation of serologic testing with an assessment for autoimmunity and the diagnostic reasoning around multisystem diseases is the art of rheumatology. An interweaving of these skillsets brings together the specialties of rheumatology and pulmonary medicine for the best care of these complex patients. The first six chapters of the book are foundational for the evaluation of the patient with specific lung diseases. This is followed by a chapter addressing the general care of the patient with pulmonary manifestations of systemic disease such as prophylaxis against Pneumocystis jirovecii, vaccinations, and the importance of addressing bone health in the setting of glucocorticoid use. The next section of this book comprises content for learning about the many pulmonary complications associated with specific rheumatic diseases, including the approach to the care of the patient from a rheumatology and pulmonary perspective. Our last chapter addresses the pulmonary toxicities that can occur with various therapies used for systemic autoimmune rheumatic diseases. It is our hope that this book, Interdisciplinary Rheumatology: Rheumatology and Pulmonology, will provide educational value for students, trainees, and any clinical provider at the intersection of pulmonary and rheumatic diseases. In addition to providing learners at all levels of pulmonology and rheumatology expertise with a sound clinical approach to disease evaluation and management, it is our hope that this book underscores the value of the collaborative approach to the care of our patients.

ix

Acknowledgment We are grateful to our chapter authors for the knowledge, insight, and expertise they bring to interdisciplinary collaboration at the intersection of pulmonary and rheumatic diseases. We would like to acknowledge our patients who continually teach us as we strive for excellence in diagnostic and therapeutic approaches to their care. We would also like to acknowledge our publisher, Taylor & Francis Group, for their interest and support in publishing this valuable resource for clinicians.

x

About the Editors Marcy B. Bolster, MD is a rheumatologist, the Director of the Rheumatology Fellowship Training Program, and a member of the Scleroderma Program at the Massachusetts General Hospital (MGH)l, Boston, MA. She is a professor of medicine at Harvard Medical School. Her clinical interests lie in scleroderma and systemic autoimmune rheumatic diseases. She was a member of the core leadership group for the American College of Rheumatology Interstitial Lung Disease Guidelines working group. She additionally has a strong interest in medical education across the spectrum of learners, and she has helped train more than 70 rheumatology fellows. She is the recipient of the 2019 American College of Rheumatology Distinguished Program Director Award, the 2019 Partners (now Mass General Brigham) Outstanding Program Director Award, and the 2021 Arthritis Foundation Marian Ropes Lifetime Achievement Award. Kristin B. Highland MD, MSCR is Vice Chair of the Integrated Hospital Care Institute (Anesthesiology, Emergency Services, Hospital Medicine, Infectious Disease, and Pulmonary/ Critical Care) of the Cleveland Clinic and Director of the Rheumatic Lung Disease Program. Her clinical and research interests have focused on the pulmonary manifestations of rheumatic lung disease, with an emphasis on interstitial lung disease and pulmonary hypertension, particularly in the setting of scleroderma. She is a member of the scientific advisory council of the Pulmonary Hypertension Association and the Scleroderma Foundation and has been active in the American College of Chest Physicians. She has published more than 100 peer-reviewed articles and serves on the editorial board of several international journals, including Lancet Respiratory. She is also an associate editor of Respiratory Medicine.

xi

Contributors Loutfi S. Aboussouan, MD Department of Pulmonary and Critical Care Medicine Cleveland Clinic Cleveland, Ohio, USA Robert K. Arao, MD Division of Pulmonary and Critical Care Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, USA Laura C. Arneson, MD Division of Rheumatology Northwestern University Feinberg School of Medicine Chicago, Illinois, USA Dana Ascherman, MD Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, USA Hassan Baig, MD Pulmonary Medicine Mayo Clinic Jacksonville, Florida, USA Aparna Bhat, MD Department of Pulmonary and Critical Care Medicine Cleveland Clinic Cleveland, Ohio, USA Adam Q. Carlson, MD Division of Rheumatology University of Virginia Charlottesville, Virginia, USA Nancy Carteron, MD Division of Rheumatology University of California, Berkely and San Francisco San Francisco, California, USA Soumya Chatterjee Department of Rheumatology Cleveland Clinic Cleveland, Ohio, USA Lydia Chelala, MD Department of Radiology University of Chicago Chicago, Illinois, USA

xii

Amit Chopra, MD, FCCP Division of Pulmonary and Critical Care Medicine Albany Medical College Albany, New York, USA Sarah P. Cohen, MD Pulmonary, Critical Care and Sleep Medicine The Ohio State University College of Medicine Columbus, Ohio, USA Tomas Cordova, MD Division of Pulmonary Medicine Oregon Health & Science University Portland, Oregon, USA Jason Dean, CNP Department of Pulmonary and Critical Care Medicine Cleveland Clinic Cleveland, Ohio, USA Paul Dellaripa, MD Division of Rheumatology, Inflammation, and Immunity Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts, USA Atul Deodhar, MD Division of Arthritis and Rheumatic Diseases Oregon Health & Science University Portland, Oregon, USA Anisha B. Dua, MD, MPH Division of Rheumatology Northwestern University Feinberg School of Medicine Chicago, Illinois, USA Lynn A. Fussner, MD Pulmonary, Critical Care and Sleep Medicine The Ohio State University College of Medicine Columbus, Ohio, USA Robert W. Hallowell, MD Division of Pulmonary and Critical Care Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, USA Logan Harper, MD, MS Department of Pulmonary and Critical Care Medicine Cleveland Clinic Cleveland, Ohio, USA

Contributors

Kristin B. Highland, MD, MSCR Department of Pulmonary and Critical Care Medicine Cleveland Clinic Cleveland, Ohio, USA John T. Huggins, MD, FCCP Division of Pulmonary, Critical Care, Allergy & Sleep Medicine Medical University of South Carolina Charleston, South Carolina, USA Yin P. Hung, MD, PhD Department of Pathology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, USA Selvin Jacob, MD Divisions of Critical Care, Pulmonary and Sleep UT Health University of Texas Health Science Center at Houston-McGovern Medical School Houston, Texas, USA

Emily Littlejohn, MD Department of Rheumatology Cleveland Clinic Cleveland, Ohio, USA Megan M. Lockwood, MD Division of Rheumatology MedStar Georgetown University Hospital Georgetown University School of Medicine Washington, District of Columbia, USA Atul Mehta, MD Department of Pulmonary and Critical Care Medicine Cleveland Clinic Cleveland, Ohio, USA Isabel C. Mira-Avendano, MD Divisions of Critical Care, Pulmonary and Sleep UT Health University of Texas Health Science Center at Houston-McGovern Medical School Houston, Texas, USA

Lakshmi A. Jayaram, MD Immunology and Rheumatology Stanford University School of Medicine Palo Alto, California, USA

Daniel Alape Moya, MD Division of Pulmonary and Critical Care Medicine Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, USA

Christopher Jenkins, MD Division of Rheumatology MedStar Georgetown University Hospital Georgetown University School vof Medicine Washington, District of Columbia, USA

Chester V. Oddis, MD Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, USA

Guy Katz, MD Division of Rheumatology, Allergy & Immunology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, USA

Tessy K. Paul, MD Division of Pulmonary and Critical Care Medicine University of Virginia Charlottesville, Virginia, USA

Kristine Keaton, Pharm D Department of Rheumatology Department of Pharmacy Services Cleveland Clinic Cleveland, Ohio, USA Carlos E. Kummerfeldt, MD Baylor Scott & White Pulmonary and Critical Care Specialists of Dallas Baylor University Medical Center Dallas, Texas, USA Augustine Lee, MD Department of Critical Care Mayo Clinic Jacksonville, Florida, USA

Apostolos Perelas, MD Division of Pulmonary Disease and Critical Care Medicine Virginia Commonwealth University Richmond, Virginia, USA Rosalind Ramsey-Goldman, MD, DrPH Division of Rheumatology Northwestern University Feinberg School of Medicine Chicago, Illinois, USA Manuel L. Ribeiro Neto, MD Department of Pulmonary and Critical Care Medicine Cleveland Clinic Cleveland, Ohio, USA xiii

Contributors

Josanna Rodriguez-Lopez Division of Pulmonary and Critical Care Medicine Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, USA Sebastian E. Sattui, MD, MS Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, USA Didem Saygin, MD Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania, USA Daniel Seifer, MD Division of Pulmonary Medicine Oregon Health & Science University Portland, Oregon, USA Kavitha Selvan, MD Section of Pulmonary and Critical Care University of Chicago Chicago, Illinois, USA Denise G. Sese, MD Division of Pulmonary, Critical Care, Allergy and Sleep Medicine Medical University of South Carolina Charleston, South Carolina, USA Amita Sharma, MBBS Department of Radiology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, USA Katherine C. Silver, MD, MSCR Division of Rheumatology and Immunology Medical University of South Carolina Charleston, South Carolina, USA Richard M. Silver, MD, MSCR Division of Rheumatology and Immunology Medical University of South Carolina Charleston, South Carolina, USA Jeffrey A. Sparks, MD, MMSc Division of Rheumatology, Inflammation, and Immunity Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts, USA

xiv

John H. Stone, MD, MPH Division of Rheumatology, Allergy & Immunology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, USA Mary E. Strek, MD Section of Pulmonary and Critical Care University of Chicago Chicago, Illinois, USA Tarek Taha Division of Pulmonary and Critical Care Medicine University Hospitals Cleveland, Ohio, USA Patompong Ungprasert, MD Department of Rheumatology Cleveland Clinic Cleveland, Ohio, USA Kiana Vakil-Gilani, DO, MPH Division of Arthritis and Rheumatic Diseases Oregon Health & Science University Portland, Oregon, USA Iazsmin Bauer Ventura, MD, MSc Section of Rheumatology University of Chicago Chicago, Illinois, USA Erin M. Wilfong, MD, PhD Division of Rheumatology and Immunology and Allergy Division of Pulmonary and Critical Care Vanderbilt University Medical Center Nashville, Tennessee, USA Darryn Leslie Winter, DO Division of Pulmonary Disease and Critical Care Medicine Virginia Commonwealth University Richmond, Virginia, USA Jee Young You, MD Department of Pulmonary and Critical Care Medicine Cleveland Clinic Cleveland, Ohio, USA

PA R T I

APPROACH TO THE PATIENT WITH LUNG DISEASE

1

Interdisciplinary Rheumatology

1  Approach to the Patient with Interstitial Lung Disease Iazsmin Bauer Ventura, Kavitha Selvan, Mary E. Strek, and Lydia Chelala List of Abbreviations 6MWT 6-minute walk test ANA Antinuclear antibodies Anti-CCP Anti-cyclic citrullinated peptide ASyS Anti-synthetase syndrome BAL Bronchoalveolar lavage COPD Chronic obstructive pulmonary disease CPFE Combined pulmonary fibrosis and emphysema CT Computed tomography DLCO Diffusion capacity for carbon monoxide DM Dermatomyositis DMARD Disease-modifying antirheumatic drug FVC Forced vital capacity GAP Gender, age, physiology score GPA Granulomatous polyangiitis HP Hypersensitivity pneumonitis HRCT High-resolution computed tomography IIM Idiopathic inflammatory myopathy ILA Interstitial lung abnormality ILD Interstitial lung disease IPAF Interstitial pneumonitis with autoimmune features IPF Idiopathic pulmonary fibrosis MCTD Mixed connective tissue disease NSIP Nonspecific interstitial pneumonia OP Organizing pneumonia PFT Pulmonary functional test RA Rheumatoid arthritis RA-ILD Rheumatoid arthritis-associated interstitial lung disease RF Rheumatoid factor SARD Systemic autoimmune rheumatic disease SjD Sjögren’s disease SLB Surgical lung biopsy SLE Systemic lupus erythematosus SLE-ILD Systemic lupus erythematosus-associated interstitial lung disease SpA Spondylarthropathy SSc Systemic sclerosis SSC-ILD Systemic sclerosis-associated interstitial lung disease TBBX Transbronchial biopsy TBLC Transbronchial lung cryobiopsy TLC Total lung capacity UIP Usual interstitial pneumonia 1.1 CLINICAL AND LABORATORY EVALUATION OF A PATIENT WITH INTERSTITIAL LUNG DISEASE 1.1.1 Introduction Interstitial lung diseases (ILDs) encompass a large group of heterogenous diseases that affect primarily the interstitium of the lungs, the space between the alveolar epithelium and the capillary endothelium, where efficient gas exchange takes place (1). It is estimated that there are over 200 different types of ILDs that derive from a wide range of pathobiological processes, which reflects the variable clinical presentation and disease course in these rare lung diseases (Figure 1.1). Nonetheless, achieving a correct diagnosis early is critical to estimate prognosis and establish a therapeutic plan because treatments can differ depending on the underlying etiology. The diagnosis of ILD requires a detailed investigation that surpasses the boundaries 2

DOI: 10.1201/9781003361374-2

1 Approach to the Patient with Interstitial Lung Disease

Interstitial Lung Disease

Idiopathic Interstitial Pneumonias

Autoimmune Disease-Related ILDs

Idiopathic Pulmonary Fibrosis

Rheumatoid Arthritis

Exposure Related ILDs

ILDs with Cysts

Hypersensitivity Pneumonitis

Langerhans Cell Histiocytosis

Sarcoidosis

Occupational Systemic Sclerosis Other Idiopathic Interstitial Pneumonias

Lymphoproliferative Interstitial Pneumonia Drug Induced

Mixed Connective Tissue Disease Radiation Induced Myositis Spectrum of Diseases/ Antisynthetase Syndrome

Sjögren’s Syndrome

Pulmonary Alveolar Proteinosis

Post-infectious Lymphangioleiomyomatosis Smoking Related

Systemic Lupus Erythematosus

Figure 1.1  Most common interstitial lung disease subtypes. (Figure was adapted from [2].)

Figure 1.2  Diagnostic approach to patients with interstitial lung diseases. (Figure was adapted from [1].)

of a limited pulmonary assessment, for which a multidisciplinary effort is often indispensable (Figure 1.2). 1.1.2  Demographic Information The initial assessment of ILD starts with a simple review of demographic information (2). Older individuals, 60 years of age and above, are the main risk group for idiopathic pulmonary fibrosis 3

Interdisciplinary Rheumatology

(IPF), particularly males. Younger patients are more likely to be affected by non-IPF diagnoses, systemic autoimmune rheumatic diseases (SARDs), sarcoidosis, or pulmonary Langerhans’s cell histiocytosis, lymphangioleimyomatosis, for example. Female sex also increases the likelihood of these alternate diagnoses. Historically, there have been more men in industrial and labor workforces with a higher risk of occupational exposures and therefore pneumoconiosis, whereas women have traditionally been more exposed to domestic antigens, such as birds, one of the main recognizable antigens in hypersensitivity pneumonitis (HP). Epidemiologic data, albeit very useful, must be interpreted with its nuances. Although most SARDs affect women more than men, the male sex is associated with a higher risk of ILD in SARDs. Overall, men and individuals with an older age at diagnosis tend to have a worse prognosis for both IPF and non-IPF ILDs. These important signals have been validated in the GAP (gender, age, physiology) score, which predicts mortality across ILD subtypes (3). 1.1.3  Respiratory Symptoms and Cardiopulmonary Examination 1.1.3.1  Respiratory Symptoms Dyspnea and nonproductive cough are the most frequently reported symptoms in a patient with ILD and are often debilitating. Dyspnea is defined as the sensation of shortness of breath or breathlessness and is a nonspecific symptom in a variety of cardiopulmonary diseases. It usually involves several contributing factors, most prominently the neuromechanical dissociation when the demand signal from the cortex is disproportionate to the supply signal from the peripheral receptors of flow, pressure, stretch, and partial pressures of oxygen and carbon dioxide in the respiratory system due to restrictive and gas exchange changes in this population (4). Dyspnea has been shown to correlate significantly with quality of life, ILD severity, and prognosis (5). Other causes of dyspnea, such as heart failure, pulmonary hypertension, anemia, and thyroid dysfunction, should be considered. Cough, usually chronic (>8 weeks) and nonproductive, also has a significant negative impact on quality of life. It is hypothesized that vagal afferents, mostly unmyelinated C fibers, in close proximity to alveoli and neighboring airways may be activated by the local inflammatory and fibrotic mediators and architectural distortion (6). As with dyspnea, cough is a nonspecific symptom, and a careful evaluation must be conducted to investigate other etiologies, such as infection, ongoing environmental exposures, and comorbidities: obstructive lung disease such as asthma, gastroesophageal reflux disease, postnasal drip, and angiotensin-converting enzyme inhibitorassociated cough. Acute worsening or changes in pattern of both dyspnea and cough may be signs of ILD progression or exacerbation. Importantly, other causes, most commonly the decompensation of cardiovascular comorbidities and respiratory tract infections, should be promptly investigated. 1.1.3.2  Cardiopulmonary Examination Chest auscultation remains an important clinical tool in patients with pulmonary symptoms. Inspiratory crackles, usually “Velcro-like” in quality and bibasilar in distribution, are caused by the opening of collapsed alveolar spaces and have been shown to predict the presence of ILD and correlate with the presence and extension of fibrotic features in imaging studies (7, 8). The presence of elevated jugular venous pressure or hepatojugular reflux, a loud P2, right ventricular heave, ascites, and/or lower extremity edema suggests right-sided heart failure, which can occur in patients with ILD-associated pulmonary hypertension. This may be a result of chronic hypoxemia or vascular drop out related to fibrosis. (9, 10) 1.1.4  Exposure History 1.1.4.1 Smoking The lungs of patients with tobacco use disorder are chronically exposed to cytotoxic, mutagenic, and proinflammatory substances that have been linked to the development of respiratory disorders (11). It is not surprising that smoking is the most prevalent risk factor for chronic respiratory diseases worldwide (12). A detailed smoking history can help identify ILDs that are strongly associated with cigarette smoking: respiratory bronchiolitis-associated ILD, desquamative interstitial pneumonia, combined pulmonary fibrosis and emphysema, and adult pulmonary Langerhans’s cell histiocytosis. Cigarette smoking is also a risk factor for the development of rheumatoid arthritis-associated ILD (RA-ILD); nonspecific interstitial pneumonia (NSIP), which is often due to a SARD; and IPF in a dose-response fashion (13). Interestingly, smoking is negatively correlated 4

1 Approach to the Patient with Interstitial Lung Disease

with the development of HP and sarcoidosis, but it is associated with increased pulmonary fibrosis once HP has developed. Natural history longitudinal studies would be necessary to prove the association between second-hand smoking and the development of ILD. Nevertheless, it has been our experience that second-hand smoke exposure is frequently reported by patients with ILD, yet few cross-sectional studies support the association (13, 14). Cigarette smoking has a significant impact on the survival of patients with ILD due to either the disease itself or concomitant smoking-related comorbidities, such as emphysema, chronic obstructive pulmonary disease (COPD), and lung cancer (15). Smoking cessation should be recommended in all patients with ILD and is the cornerstone of treatment of all smoking-related ILDs. There is unequivocal evidence that the regular smoking of marijuana is not harmless, at least with respect to airways disease. Yet data on the relationship between regular marijuana smoking and ILD is lacking. Cautioning against regular heavy use of marijuana is prudent, as it could exacerbate respiratory symptoms in patients with ILD and is a risk factor for the development of pulmonary aspergillosis (16). Given the radiographic and clinical similarities between vaping product use-associated lung injury and HP, specific questioning on vaping should be included in the exposure history; regular use should also be discouraged (17). 1.1.4.2  Environmental and Occupational Exposures While some ILD subtypes are clearly attributable to certain exposures, as is the case with silicosis due to sandblasting, a growing body of evidence suggests that inhalational exposures are prevalent across the ILD spectrum and may contribute to the multiple-hit pathway that gives rise to ILDs in genetically predisposed individuals, including in patients with SARD-ILD (18, 19). While the future validation of exposure questionnaires is necessary and professional environmental assessment is encouraged when feasible, thorough history taking in the clinical setting, including lifetime occupational history, can aid in the identification of potentially significant exposures (Table 1.1) (18). The remediation of suspected offending exposures is recommended but is not always feasible, as it may require changing jobs or residences. 1.1.4.3  Medication and Radiation Exposure A detailed assessment of medication and radiation history is mandatory in the evaluation of a new case of ILD and when ILD exacerbation or progression is being considered (20). More than 400 drugs have been linked to the development of ILD, including antibiotics, antiarrhythmics, and the growing list of disease-modifying antirheumatic drugs (DMARDs) and antineoplastic/ immune checkpoint inhibitors. Drug-induced ILD is a heterogenous group of diseases that can have a subclinical to rapidly progressive and life-threatening presentation and are not characterized by a specific pattern on high-resolution computed tomography (HRCT) chest scans. Most patients develop drug-induced ILD within weeks to a few months after the culprit drug is initiated. Medication discontinuation is requisite, and subsequent improvement is the strongest diagnostic support favoring a drug-induced etiology, most often leading to a retrospective diagnosis. The Drug-Induced Respiratory Disease Website provides an updated list of culprit drugs (www. pneumotox.com).

Table 1.1: How to Elicit an Environmental and Occupational History Questions Do you have or have you ever had any pet birds? Have you worked with or been around birds in your life, in your home or other environments? Consider inquiring about other domestic organic exposures: mold, down bedding, hot tubs. Tell me what kinds of jobs you have had in your lifetime. What exactly did/do you do at your job site? Have you ever been exposed to dust, fumes, chemicals, or radiation at your workplace? Did/do you wear respiratory protection? Does your job require it? Did any of your co-workers get sick with breathing problems? Do your symptoms improve when you are at home? Are there any other inhaled exposures you can think of that I did not ask about, whether in a job, or at home, or a hobby? Source: Table was adapted from (19)

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Table 1.2: List of the Immunomodulatory Agents/Disease-Modifying Agents Most Frequently Associated with Drug-Induced Respiratory Diseases (DIRDs) as per www.pneumotox.com Immunomodulatory Agent

Overall Frequency of DIRDs

Methotrexate

+++++

Nonsteroidal antiinflammatory drugs Leflunomide

+++++

Hydroxychloroquine

+++

Anti-TNF alpha antagonists -Infliximab and etanercept > Others

++++

Rituximab

+++++

+++

Parenchymal Lung Disease (Frequency) —Acute and/or severe pneumonitis (+++++) —ILD with granulomatous component (+++) —Pneumonitis (++) —Pulmonary nodulosis (++) —ARDS (++) —Organizing pneumonia (+) —Pulmonary fibrosis (+) —Eosinophilic pneumonia (+++) —ARDS (+) —Acute and/or severe pneumonitis (+) —Pneumonitis (+) —Eosinophilic pneumonia (+) —Organizing pneumonia (+) —Diffuse alveolar damage (+) —Pulmonary alveolar proteinosis (+) —Pulmonary nodulosis (+) —Pneumonitis (+) —Eosinophilic pneumonia (+) —Pulmonary nodulosis (+++) —Pneumonitis (++) —Pulmonary fibrosis (++) —ILD with granulomatous component (++) —Acute and/or severe pneumonitis (++) —Pneumonitis (++) —Organizing pneumonia (++) —Diffuse alveolar damage (++) —ARDS (++) —Pulmonary fibrosis (+)

Exacerbation of Existing ILD —

— ++

— ++

—

Pulmonary toxicity has been reported with virtually all DMARDs (Table 1.2) (20). Methotrexate has been traditionally associated with pulmonary fibrosis, but most recent data has not supported these concerns; on the contrary, methotrexate has been shown to decrease the risk of ILD in patients with rheumatoid arthritis (RA) (21). Although rare, an acute hypersensitivity type of pneumonitis is the most common form of methotrexate-induced lung toxicity. This is characterized by rapidly progressive dry cough, chest pain, fever, and eosinophilia that typically occur within the first year of commencement of methotrexate therapy and should raise concern for acute interstitial pneumonitis. Bronchoalveolar lavage is a helpful tool in ruling out infections in this setting, with increased lymphocytes in the lavage fluid suggesting acute methotrexate pneumotoxicity (22). The prognosis of methotrexate-induced lung toxicity is favorable, and the discontinuation of methotrexate is usually sufficient for clinical improvement, but glucocorticoids may be necessary in cases of severe or progressive disease. 1.1.5  Family History Recent studies have reported that up to 20% of patients with ILD report a family history of ILD, and family history has become the strongest risk factor for ILD (23). Several genes, most being surfactant or telomere related, have been implicated in familial interstitial pneumonia syndrome, defined by the presence of ILD among two or more closely related individuals, including at least one with an idiopathic subtype. Notably, familial interstitial pneumonia can occur across a 6

1 Approach to the Patient with Interstitial Lung Disease

lifetime, from the neonatal period to late adulthood, and across different ILD subtypes. Similarly, familial autoimmunity, defined as the aggregation of diverse autoimmune diseases clustering in a nuclear family, is also a frequent occurrence, and family history should thus include questions about other autoimmune diseases (24). These familial patterns have significant implications beyond the affected individual, given the high risk of ILD among bloodline relatives, and argue in favor of ILD screening within families, aiming at ILD early detection. However, the best strategy for ILD screening in this population has yet to be established. 1.1.6  Extrapulmonary Manifestations It is the extrapulmonary manifestations that are often helpful in determining the etiology behind a patient’s ILD. The presence of extrapulmonary manifestations suggests the presence of an underlying systemic disease, and SARDs can be implicated in approximately one third of all ILD cases (25, 26). Additionally, ILD can complicate the course of SARDs in up to 80% of patients with antisynthetase syndrome or systemic sclerosis, for example, and ILD is a leading cause of morbidity and mortality in these populations (27). Consequently, a detailed rheumatic disease review of systems and careful physical examination for extrapulmonary manifestations of disease have become crucial in the ILD diagnostic investigation. Nonetheless, the rheumatic disease review of systems is often nonspecific and may require further investigation and/or rheumatology referral in order to properly diagnose an underlying SARD (Table 1.3).

Table 1.3: Rheumatic Disease Review of Systems for the Assessment of Extrapulmonary Manifestations in Patients with Interstitial Lung Disease Sign or Symptom Constitutional symptoms Fatigue Fever Weight loss

Inflammatory eye diseases Episcleritis Scleritis Uveitis Oral or nasal ulcers

Sicca symptoms Xerophthalmia Xerostomia

Characteristics

Comments Fatigue is a common symptom in ILD, and weight loss is a sign of poor prognosis in ILD; these symptoms can be also concerning for an active and severe SARD.

— Eye pain or tenderness associated with prolonged periods of eye redness — Blurry vision not corrected using corrective lenses — Photophobia — Frequent ulcers inside the nose or mouth, painful or nonpainful — Involvement of tongue, gingiva, or palate — Daily, persistent dry eyes for — Investigate medical >3 months history for other causes — Use of tear substitutes >3/day of sicca symptoms and — Sensation of sand or gravel in the medication list for eyes agents with — Daily, persistent dry mouth for anticholinergic >3 months properties. — Need to drink liquids frequently to swallow food — Poor dental health — Swelling in the lacrimal or salivary glands

Associated Diseases SLE, vasculitides, IIMs/ASyS, MCTD, severe RA, sarcoidosis

RA, GPA, SjD, SpA, sarcoidosis, Behcet

SLE, GPA, Crohn’s disease, IIMs, SjD, Behcet Primary or secondary (when associated with another SARD) SjD

(Continued )

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Table 1.3:  (Continued) Sign or Symptom

Characteristics

Raynaud phenomenon

— Digital color changes triggered by cold — Associated pain, numbness — Painful digital ulcers — Age of presentation — Associated puffy fingers, sclerodactyly

Inflammatory arthritis

— Joint pain distribution — Inflammatory signs: Swelling, warmth, erythema, loss of function — Prolonged morning stiffness — Responsiveness to glucocorticoids or nonsteroidal anti-inflammatory agents

Cutaneous manifestations

— Associated ulcers, pruritus, pain — Photosensitivity — Thickening or induration of the skin, particularly around fingers — Fissuring, roughness in the skin of the fingers or toes — Tender or ragged cuticles — Non-blanching red spots in weight-bearing or pressureexposed areas

Muscle weakness

— Proximal muscle weakness affecting the shoulder and hip girdles — Asymmetric foot, wrist drop

Comments — The triphasic (white– blue–red) changes are characteristic, but not all color changes are necessary for the diagnosis. — Secondary Raynaud phenomenon should be considered in patients over 30 years of age. — Examination of the nailfold capillaries can identify capillary enlargement and/or avascularity or “drop out”. — Joint stiffness is described as slowness or difficulty performing full range of motion of the affected joint, worse after periods of rest, usually after a night of sleep, and lasting at least 30 to 60 minutes in the morning. The cutaneous manifestations of SARDs are extensive. The specialist must be familiar with the most commonly encountered in systemic sclerosis, dermatomyositis, and antisynthetase syndrome given the high prevalence of ILD in these diseases. — Proximal muscle weakness is the hallmark manifestation of the inflammatory myopathies, but these diseases can be amyopathic. — Paresthesias, asymmetric foot/wrist drop can be signs of mononeuritis multiplex and small-vessel vasculitis.

Associated Diseases SSc, SLE, SjD, MCTD, IIMs/ASyS

RA, SLE, SjD, MCTD, SSc, IIMs/ ASyS

SSc, DM/ASyS, SLE, SjD, smallvessel vasculitis

IIMs/ASyS, MCTD, SjD, vasculitides

(Continued )

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1 Approach to the Patient with Interstitial Lung Disease

Table 1.3:  (Continued) Sign or Symptom

Characteristics

Comments

Associated Diseases

Gastroesophageal symptoms Reflux Dysphagia Serositis Pleuritis Pericarditis Cytopenias

— Hoarseness, heartburn, nasal regurgitation, need for drinking water to swallow

SSc, SLE, SjD, MCTD, IIMs/ ASyS, RA

— Pleurisy, pericardial effusions, multilead ST elevations

SLE, RA, SSc

Thromboembolic phenomena

— Unprovoked venous, arterial, or small-vessel thrombosis — Unexplained miscarriage >10 weeks — ≥3 unexplained miscarriages 25%, though mild neutrophilia may also be seen (42). The identification of significant eosinophilia or macrophages with smoking-related inclusions can effectively eliminate suspicion for SARD-ILD and prompt clinicians to consider alternative diagnoses (Figure 1.3). The utility of lung biopsy in the diagnosis of SARD-ILD is less clear. Transbronchial biopsy (TBBX) has been reported to have an overall low diagnostic yield of 30% at best, and while transbronchial lung cryobiopsy (TBLC) has been shown to increase the diagnostic confidence of suspected ILD diagnoses, its utility in SARD-ILD specifically is low (43). However, if pathology is obtained, certain features such as lymphoid hyperplasia, plasma cell infiltrate, and fibrinous pleuritis may be suggestive of SARD-ILD (43). Additionally, if present, alternative features in 12

1 Approach to the Patient with Interstitial Lung Disease

Figure 1.3  Bronchoalveolar lavage cellular analysis in interstitial lung disease. SARD-ILD: systemic autoimmune rheumatic disease-associated interstitial lung disease; IPF: idiopathic pulmonary fibrosis; HP: hypersensitivity pneumonitis; LIP: lymphocytic interstitial pneumonia; COP: cryptogenic organizing pneumonia; DIP: desquamative interstitial pneumonia; RB-ILD: respiratory bronchiolitis-interstitial lung disease; LCH: Langerhans cell histiocytosis. (Figure was adapted from [43].)

abundance, such as fibroblastic foci or loosely formed granulomas, may suggest alternative diagnoses, such as IPF and HP, respectively. In general, surgical lung biopsy (SLB) is not indicated for patients with confirmed SARD and ILD that could be consistent with known presentations of disease, as it has not been consistently shown to alter disease management. In cases where pulmonary disease is incompatible with the known SARD, SLB can be considered on a case-by-case basis after careful consideration of the patient’s underlying risk for anesthesia-related or procedural complications. When obtained, SLB has a diagnostic yield of greater than 90% but carries a 30-day mortality rate of up to 24% (44, 45). 1.3.1  Evaluation of Known SARD-ILD In addition to providing clarity in cases of suspected SARD-ILD, bronchoscopy can be a useful tool in the evaluation of patients with known SARD-ILD presenting with new radiographic infiltrates. As many of these patients require treatment with immunosuppression, drug-induced pneumonitis and infection are often major concerns. In such cases, BAL provides a diagnostic yield of approximately 17% for infection, with a high specificity and positive predictive value (46). A BAL cellular analysis with a neutrophil percentage greater than 50% is highly suggestive of infection, and additional cultures, stains, and studies may be sent from fluid to increase the diagnostic yield (42). Additionally, the presence of clinically relevant symptoms and ground-glass opacities or consolidation on imaging will also increase the diagnostic yield of BAL (44). Clinicians may choose to perform BAL alone or in combination with TBBX based on the degree of suspicion for infection and safety in the context of patient-specific factors (e.g. thrombocytopenia, pulmonary hypertension). Malignancy and other lymphoproliferative disorders may also complicate the course of patients with SARD-ILD, as the underlying SARD confers a heightened risk for both compared to the general population (43). Some neoplasms may present with radiologic changes that mimic ILD, such as in lymphangitic carcinomatosis or lymphoproliferative disorders, and in such cases, bronchoscopy with BAL and tissue biopsy can be instrumental in diagnosis (43). When tissue is required for definitive diagnosis, TBBX is often utilized, but recently, there has been a growing body of literature in support of TBLC in ILD. Studies have found that the diagnostic yield of TBLC 13

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is approximately 80%, compared to only 30% with TBBX (45, 47, 48). Additionally, TBLC has a lower mortality rate (0.1–0.5%) when compared to surgical lung biopsy (SLB) (approximately 2%) and a high level of agreement with SLB in histopathologic interpretation (45, 47–49). It is important, however, to note that complication rates with TBLC, specifically bleeding and pneumothorax, are relatively high, so individual patient factors should be considered in decision-making (43). In addition to providing diagnostic clarity, bronchoscopy may also be useful in guiding therapeutic management in patients with SARD-ILD. The treatment of SARD-ILD relies heavily upon glucocorticoids and other immunosuppressive agents that target active inflammation in the lungs. However, in patients with predominantly fibrotic disease, management is less clear and often shifts to the use of antifibrotic agents. It has been suggested that lymphocytosis on BAL may be associated with a higher likelihood of treatment response, which may prompt clinicians to reconsider ongoing treatment with immunosuppressive agents in patients with a HRCT pattern suggestive of fibrosis (44). Additionally, BAL cellular analysis may help guide prognostication. In both SSc-ILD and RAILD, neutrophilia can be associated with disease severity; however, the prognostic significance remains unclear and varies across published literature (43). 1.4 PULMONARY FUNCTION EVALUATION OF A PATIENT WITH INTERSTITIAL LUNG DISEASE Pulmonary function tests (PFTs) are utilized in patients with ILD to diagnose and quantitate the degree of reduction in lung function and to monitor disease progression and response to therapy. A complete set of PFTs includes lung volumes, especially total lung capacity (TLC), spirometry with a focus on the forced vital capacity (FVC), and the diffusion capacity for carbon monoxide (DLCO) performed according to society standards (50, 51). In addition, the 6-minute walk test (6MWT), where walk distance and oxygen saturation at rest and with exercise are measured, has been useful in measuring functional capacity, oxygen desaturation, and the need for oxygen therapy (52, 53). In patients with ILD, measurements of lung function and functional capacity have been most rigorously studied in patients with idiopathic interstitial pneumonias, especially IPF, but have also been found to be useful in patients with SARD-ILD (54, 55). 1.4.1  Outcome Measure in Clinical Trials Beginning with the first trials of therapy for IPF, FVC was chosen as the most reliable and obtainable marker of ILD progression and as a surrogate, not without initial controversy, for outcomes, including mortality (5). Later trials of anti-fibrotic therapy in patients with ILD with a progressive phenotype (INBUILD) also used change in %FVC as the primary outcome (56). The reliability and minimally clinically important difference in FVC at 12 months was found to be 3.0% to 5.3% for FVC% improvement and –3.0% to –3.3% for FVC% worsening utilizing data from patients participating in the Scleroderma Lung Studies I and II (55). 1.4.2  Measurement in Clinical Practice In clinical practice, the FVC has been utilized as the most accurate and reliable measurement of lung function abnormality in ILDs, including SARD-ILD. The DLCO is also considered a measurement of importance in assessing for the progression of ILD, although many factors other than lung function, such as anemia and pulmonary vascular disease, may affect this measurement. Recent guidelines proposing a definition for the entity of non-IPF progressive pulmonary fibrosis (PPF) utilize declines in FVC and DLCO as essential criteria for determining the progression essential to the definition of PPF (57). PPF encompasses patients with all forms of SARD-ILD with worsening pulmonary fibrosis. It is notable that these criteria utilize an absolute decline in FVC (greater than or equal to 5% over 1 year) rather than relative change. In patients with combined pulmonary fibrosis emphysema (CPFE), which can occur in the setting of SARD-ILD, lung volumes, FVC, and expiratory flows are often normal due to the balancing effect of the increased lung recoil from pulmonary fibrosis and the loss of lung recoil from emphysema, with the DLCO disproportionately reduced due to capillary loss from both processes. FVC may not decline as expected in CPFE; thus, reliance on symptoms and HRCT imaging becomes even more important in assessing ILD worsening (57). PFTs are uniquely suited to monitor ILD progression and response to therapy, as they are widely available, noninvasive, and complementary to respiratory symptoms and ILD on CT imaging. In the case of patients with inflammatory SARD-ILD, treatment with corticosteroids and immunosuppressive agents may result in improvements in lung function, including the TLC, FVC, and 14

1 Approach to the Patient with Interstitial Lung Disease

DLCO. Data on the time course of this improvement is lacking, but it generally occurs over weeks to months and plateaus by 12 months. The slowing of the decline in FVC, noted in the SENSCIS trial of nintedanib in SSc-ILD, began after 12 weeks (58). 1.4.3 Screening PFTs are used in conjunction with CT imaging to assess for the presence and severity of ILD. Numerous studies suggest that PFTs are not as sensitive as HRCT in patients with early or mild ILD; thus, CT chest imaging is the screening test of choice. PFTs should be performed at the diagnosis of ILD and periodically over time. In some SARDs such as SSc, where the prevalence of ILD is high, PFTs might be performed in all patients at SARD diagnosis. 1.5 IMAGING IN THE EVALUATION OF A PATIENT WITH INTERSTITIAL LUNG DISEASE Major radiologic advances and the increased utilization of CT in past decades have allowed for a better understanding of numerous disease processes. While much remains to be learned, HRCT has provided greater insight into various types of ILD, becoming an integral piece of the diagnostic work-up. In SARD-ILD, diverse imaging manifestations may coexist or overlap between various SARD entities. Occasional overlap with the classic usual interstitial pneumonia pattern (UIP) of IPF further adds to the complexity of the problem. However, the frequent association of some subtypes of ILD with SARD and the increased recognition of imaging clues for SARD-ILD in variant types of fibrosis are key in facilitating the diagnosis (Table 1.6) (59, 60). The role of HRCT in suggesting the diagnosis is especially critical in that SARD-ILD may precede extrathoracic manifestations and the clinical diagnosis of SARD in up to 25% of patients (61). Current and emerging concepts of SARD-ILD manifestations on HRCT are reviewed in this chapter. 1.5.1  High-Resolution Chest Tomography Patterns 1.5.1.1  Organizing Pneumonia Organization is a common pattern of response to lung injury, with a broad range of possible etiologies, including but not limited to SARD-ILD, infection, aspiration, and drug-related pneumonitis (61). When organization constitutes the dominant imaging pattern, the term organizing pneumonia (OP) is adopted on HRCT. While nonspecific, OP is a frequent manifestation of SARD-ILD, which should therefore always be considered in the diagnostic work-up (62). OP can have a wide variety of appearances on imaging. It typically presents with bilateral, diffuse lower lobe predominant opacities without fibrotic features. Opacities are characteristically peribronchovascular or peripheral with subpleural sparing and may be patchy or nodular in appearance (63). Less frequently, OP may be focal, presenting as a single nodular opacity. While OP may occasionally be suggested on initial presentation when typical features are present, findings may be nonspecific and difficult to discern from other common processes such as multifocal pneumonia. It is the longitudinal progression of these imaging findings that is most telling. Findings usually regress spontaneously or with treatment, with decreased attenuation and progressive central

Table 1.6: Radiologic Patterns in SARD-ILD RA SSc IIMs/ASyS SjD MCTD SLE

NSIP

UIP

OP

+ ++++ ++++ ++ ++ ++

++++ + + + + +

++ + ++++ + + +

LIP +

++++ +

DAD + + + + + ++

Note: The number of “+” signs indicates frequency of observed pattern (41) Abbreviations: RA: rheumatoid arthritis; SSc: systemic sclerosis; IIMs: idiopathic inflammatory myopathies; ASyS: antisynthetase syndrome; SjD: Sjögren’s disease; MCTD: mixed connective tissue disease; SLE: systemic lupus erythematosus; NSIP: nonspecific interstitial pneumonia; UIP: usual interstitial pneumonia; OP: organizing pneumonia; DAD: diffuse alveolar damage; LIP: lymphocytic interstitial pneumonia

15

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    Figure 1.4  78-year-old female with polymyalgia rheumatic and reverse halo sign. Cropped down axial (A) and coronal (B) HRCT images in lung window showing subtle right upper lobe ground-glass opacity with incomplete rim of greater attenuation (arrows, A–B) compatible with reverse halo sign.

Figure 1.5  44-year-old female with undifferentiated connective tissue disease and organizing pneumonia. Axial HRCT image in lung window showing lower lobe and peripheral consolidation. An arcade of subpleural clearance is seen in the right lower lobe (circle).

   Figure 1.6  58-year-old male with interstitial pneumonia and autoimmune features and nonspecific interstitial pneumonia (NSIP) fibrosis on HRCT. Axial (A) and coronal (B) HRCT images in lung window showing lower lobe predominant fibrosis with ground-glass opacity, fine reticulation, and traction bronchiectasis (arrows, A–B). There is mild relative subpleural sparing. Pattern is compatible with NSIP. and subpleural clearance. This pattern of evolution can result in the characteristic atoll or reverse halo signs defined as central ground-glass attenuation surrounded by consolidation (Figure 1.4). Arcades of subpleural clearance can also be seen with the presence of perilobular, arch-like peripheral opacities (Figure 1.5) (64). Recurrence is common, and the diagnosis can therefore be suggested in patients with recurrent opacities (65). 1.5.1.2  Nonspecific Interstitial Pneumonia Nonspecific interstitial pneumonia (NSIP) is the most common pulmonary manifestation of SARD-ILD (66). The possibility of SARD-ILD should therefore be explored in patients with NSIP on HRCT. NSIP typically presents with bilateral lower lobe and peribronchovascular predominant ground-glass opacity with subpleural sparing. Associated reticulation, traction bronchiectasis, and lower lobe predominant volume loss are distinguishing features from OP that underlie the presence of fibrosis (Figure 1.6). Findings are usually relatively symmetrical. While honeycombing 16

1 Approach to the Patient with Interstitial Lung Disease

Figure 1.7  44-year-old male with history of myositis and OP progressed to NSIP. Axial image in lung window from baseline HRCT (A) showing lower lobe predominant peribronchovascular consolidation suggestive of OP. Axial image in lung window from 2-month follow-up HRCT (B) showing decreased attenuation of opacity. Residual ground-glass opacity is associated with fine reticulation and mild traction bronchiectasis (arrow). Pattern is compatible with NSIP.

  

  

Figure 1.8  49-year-old female with history of myositis and OP progressed to mild NSIP. Axial HRCT images in lung windows at baseline (A) and 2-year follow-up (B) showing peripheral lower lobe opacities mildly sparing the subpleural parenchyma (circles, A–B). Findings are compatible with OP. Axial HRCT images in lung window 15 years after baseline (C) showing decreased mild residual ground-glass opacity (dashed circle) with subtle traction bronchiolectasis (arrow), compatible with progression to mild NSIP. and consolidation may occasionally be encountered, they are less common and should not constitute dominant features. OP and NSIP share striking similarities on HRCT. The imaging appearance of NSIP is somewhat of a progressed OP pattern (Figures 1.7 and 1.8). In a prior cohort of patients with OP, overlapping OP and NSIP portended adverse patient outcomes (67). Patients with persistent or residual OP were shown to most commonly progress to an NSIP pattern of fibrosis, suggesting that these two diagnostic patterns are often intertwined (68). 1.5.1.3  Usual Interstitial Pneumonia The 2018 Official ATS/ERS/JRS/ALAT Clinical Practice Guideline endorses the use of four diagnostic categories for the classification of pulmonary fibrosis on HRCT based on the level of suspicion for UIP (i.e. typical UIP, probable UIP, indeterminate, and alternative diagnosis) (69). Typical UIP on HRCT is defined as lower lobe predominant fibrosis comprising subpleural reticulation, honeycombing, and traction bronchiectasis. Honeycombing characterized by the presence of small subpleural cysts is lacking in probable UIP, which otherwise demonstrates a similar pattern of 17

Interdisciplinary Rheumatology

Figure 1.9  63-year-old male with rheumatoid arthritis and the “anterior upper lobe sign”. Axial HRCT image in lung window showing concentration of prominent honeycombing in the anterior upper lobes, a finding associated with systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD). The remainder of the upper lobes are relatively spared.

   Figure 1.10  68-year-old female with rheumatoid arthritis and variant usual interstitial pneumonia (UIP). Axial (A) and coronal (B) HRCT images in lung window showing exuberant predominant honeycombing, involving the near entirety of the lower lobes. On coronal reformat (B), the findings are sharply demarcated from the adjacent parenchyma without superior extension along the lateral chest walls, compatible with the “straight edge sign”.

Figure 1.11  65-year-old female with systemic sclerosis and the straight edge sign. Coronal HRCT image in lung window showing a sharp demarcation of lower lobe predominant fibrosis from the adjacent parenchyma and with a horizontal configuration laterally at the chest wall interface. abnormality to typical UIP. These higher-confidence UIP categories are trademarks of IPF in the appropriate clinical context. UIP on HRCT can also be associated with SARD-ILD in a subset of patients, thereby mimicking IPF (66, 70, 71). In these patients, discerning imaging clues and evolutional changes on HRCT may suggest an alternative diagnosis to IPF, supportive of the differences in clinical progression of these entities. 1.5.1.4  Variant UIP Fibrosis Variant patterns of fibrosis distinguishing IPF from SARD-ILD are increasingly described on HRCT. The recognition of these clues is critical in achieving timely diagnosis and optimizing patient outcomes. Previously described features include prominent anterior upper lobe involvement (i.e. “anterior upper lobe sign”), extensive honeycombing with >70% involvement of the fibrotic lung (i.e. “exuberant honeycombing”), and a relatively sharp horizontal delineation of fibrosis from the adjacent normal-appearing parenchyma on coronal reconstructions (i.e. “straight edge sign”) (Figures 1.9, 1.10, and 1.11) (72). Predominant involvement of the anterolateral upper lobes and superior lower lobes (i.e. “the four corner sign”) has also been described as a specific feature of systemic sclerosis-associated ILD (SSc-ILD), allowing for its differentiation from IPF (73). 18

1 Approach to the Patient with Interstitial Lung Disease

   Figure 1.12  63-year-old male with history of rheumatoid arthritis and island-like fibrosis. Axial (A) and sagittal (B) HRCT images in lung window showing multifocal, sharply demarcated, and wedge-shaped clusters of honeycombing (circles, A–B) termed “island-like fibrosis” and compatible with variant SARD-ILD.

  

  

Figure 1.13  65-year-old female with undifferentiated connective tissue disease and progression of SARD-ILD patterns. Axial image in lung window from baseline HRCT (A) showing lower lobe and peripheral predominant consolidation suggestive of OP. Axial image in lung window from 1-year follow-up HRCT (B) showing new subpleural sparing (circle) and traction bronchiectasis (arrow) associated with coarsened peribronchovascular opacity. Findings are compatible with progression of OP to NSIP. Axial image in lung window from HRCT 15 years after baseline (C) showing new clustered right basilar honeycombing (circle) and other scattered non-honeycomb cysts. There is a subpleural extension of associated reticular and ground-glass density. Pattern is compatible with mixed UIP/NSIP.

   Figure 1.14  44-year-old female with undifferentiated connective tissue disease and progression of SARD-ILD. Axial HRCT images in lung window at baseline (A) showing lower lobe peribronchovascular ground-glass opacity (circle) compatible with OP. There is associated mosaicism (arrow) and a patulous esophagus. Axial HRCT images in lung window at 13-year follow-up (B) showing development of numerous basilar honeycomb cysts compatible with progression to a variant UIP pattern. Occasionally, areas of sharply demarcated, wedge-shaped, UIP-like fibrosis may be seen, with prominent focal honeycombing and reticulation (Figure 1.12). Previous comparisons often reveal corresponding ground-glass or consolidative opacities. This “island-like” pattern of fibrosis was recently described in SLE-associated ILD (SLE-ILD), although its specificity has not yet been established (59, 60). 1.5.1.5  Longitudinal Progression A detailed assessment of prior available imaging is essential in assessing disease pathogenesis and evolution. The longitudinal progression from OP or NSIP to mixed UIP/NSIP, UIP, or UIPlike patterns is particularly telling of a non-IPF etiology (Figures 1.13 and 1.14). Mixed patterns with features of both UIP and NSIP can occasionally be encountered in SARD-ILD (61). In these patients, ground-glass and reticular opacity may be associated with honeycombing and/or scattered non-honeycomb, non-subpleural cysts of variable size (Figures 1.13 and 1.15). Increasingly prominent cystic changes may progressively replace the ground-glass abnormality (60). The recently described “heterogeneous lung destruction” in SLE-ILD likely represents an example of 19

INTERDISCIPLINARY RHEUMATOLOGY

Figure 1.15 20-year-old female with systemic lupus erythematosus and mixed UIP/NSIP fbrosis on HRCT. Axial (A, B) and sagittal (C) HRCT images in lung window demonstrating the presence of lower lobe predominant opacity and reticulation with subpleural sparing (double arrow, A), subtle traction bronchiectasis (arrow, C), and posteriorly displaced major fssures refective of lower lobe volume loss (dashed arrows, A–B). There is a subpleural extension of abnormality in the superior lower lobes with subpleural cysts on the left (circle, B). Findings are compatible with a mixed UIP/NSIP pattern and consistent with SARD-ILD.

Figure 1.16 37-year-old with antisynthetase syndrome (ASyS) and progression of SARD-ILD. Coronal HRCT image in lung window at baseline (A) demonstrating peripheral and lower lobe predominant ground-glass opacity and fne reticulation with subpleural sparing compatible with NSIP. Coronal HRCT image in lung window at 2-year follow-up (B) demonstrating new numerous cysts of variable shapes and sizes with reticulation and areas of continued subpleural sparing (circle). This appearance is consistent with the recently described “heterogeneous lung destruction” sign and compatible with progression of SARD-ILD.

Figure 1.17 50-year-old female with history of systemic lupus erythematosus and progression of SARD-ILD. Axial (A) and sagittal (B) HRCT images in lung window at baseline showing lower lobe predominant peribronchovascular ground-glass opacity with relative subpleural sparing (double arrow, B), subtle traction bronchiolectasis (arrow, A–B), and lower lobe volume loss as evidenced by posteriorly displaced major fssures (dashed arrows, A). Findings are compatible with NSIP. Axial (A) and sagittal (B) HRCT images in lung window at 10-year follow-up showing progression to a variant pattern of SARD-ILD. There is interval development of numerous nonhoneycomb cysts (circles, C–D) with continued subpleural sparing. Non-uniform cysts within areas of reticulation and architectural distortion are compatible with the “heterogeneous lung destruction” sign. There is progression of NSIP to a variant pattern of SARD-ILD. overlapping patterns, with combined variable cystic and ground-glass abnormalities (Figures 1.16 and 1.17) (60). In a subset of patients with SARD-ILD, the overlapping UIP/NSIP pattern conceivably constitutes a time point in the disease progression from OP/NSIP to exuberant UIP fbrosis. SARD-ILD should therefore be a diagnostic consideration in patients presenting with such overlapping features. 20

1 APPROACH TO THE PATIENT WITH INTERSTITIAL LUNG DISEASE

1.5.1.6 Interstitial Lung Abnormality Interstitial lung disease abnormality (ILA) is an increasingly recognized entity referring to CT chest fndings of possible unsuspected early ILD (74). ILA is defned as a non-dependent abnormality involving more than 5% of any of the lung zones. The inferior aortic arch and right inferior pulmonary vein delineate the upper, middle, and lower lung zones. ILA may manifest with ground-glass opacity, reticulation, honeycomb and non-emphysematous cysts, architectural distortion, and traction bronchiectasis. Depending on the axial distribution of abnormality, ILA is defned as subpleural or non-subpleural. ILA is termed fbrotic when architectural distortion, traction bronchiectasis, and/or honeycombing is identifed. The progression of CT abnormality occurs in a substantial minority of these patients (Figure 1.18) (61). Features associated with progression on imaging include the presence of reticulation, basilar predominant and subpleural non-fbrotic ILA, and fbrotic ILA compatible with probable or typical UIP (74). When the ILA diagnosis is uncertain on an initial CT chest, a dedicated HRCT is warranted. When high-risk CT features are present, a repeat HRCT in 12–24 months is recommended assuming clinical stability and the exclusion of signifcant ILD. Notably, preclinical interstitial abnormalities identifed during screening in higher-risk individuals, for example, those with RA and SSc, are not considered ILA (75). 1.5.1.7 Lymphocytic Interstitial Pneumonia Lymphocytic interstitial pneumonia (LIP) is an interstitial pneumonia and lymphoproliferative disorder well known to be associated with SARD. Patients with Sjögren’s disease (SjD) are particularly at risk (76). Diagnosis can be reached on HRCT, and familiarization with key imaging features is essential. LIP is characterized by a combination of cysts, ground-glass opacities, scattered nodules, air trapping, and bronchial wall thickening. The close evaluation of the distribution and the morphology of cysts is key in narrowing down the differential diagnosis. Cysts are typically lower lobe predominant and closely associated with bronchovascular bundles. While non-pathognomonic, a multiseptated appearance of these basilar predominant cysts is common and highly suggestive of the diagnosis (Figure 1.19) (77). Follicular bronchiolitis, considered a milder form of

Figure 1.18 63-year-old male with history of rheumatoid arthritis and interstitial lung abnormality (ILA) progression to variant pattern SARD-ILD. Axial image in lung window from abdominal CT (A) showing subtle peripheral lower lobe opacity with subpleural sparing (circles, A) and subtle right lower lobe traction bronchiolectasis. Findings were incidental and compatible with limited non-subpleural fbrotic ILA. Axial image in lung window from 10-year follow-up HRCT (B) showing new right basilar honeycombing (circle) and left lower lobe peribronchovascular, reticulation and non-honeycomb cystic change (arrow). Findings are compatible with progression of ILA to mixed UIP/NSIP.

Figure 1.19 39-year-old male with history of Sjögren’s disease and lymphocytic interstitial pneumonia (LIP). Axial (A) and coronal (B) HRCT images in lung window showing lower lobe predominant cysts closely associated with bronchovascular bundles (arrow, A) and superimposed on ground-glass attenuation. Several of the cysts have a characteristic multi-septate appearance. 21

Interdisciplinary Rheumatology

the same disease spectrum, may present with nonspecific small scattered nodules, with or without ground-glass opacity and air trapping. Cysts may be scarce or absent. In milder forms, findings can be subtle, and the diagnosis may be difficult to reach solely on the basis of imaging. 1.5.1.8 Summary ILD is a well-recognized complication of SARDs, and SARD-ILD has been increasingly identified as one of the most common subtypes of ILD. HRCT chest scan is the backbone of SARD-ILD diagnosis, but in select cases, bronchoalveolar lavage can be a useful tool, particularly when other causes of acute pneumonitis are being considered. PFTs and the 6-minute walk test are noninvasive procedures capable of reliably assessing disease progression and response to therapy. PFTs have been adopted as the preferred outcome measures in ILD clinical trials evaluating response to treatment. Despite the advantages of these tools, collaborative interdisciplinary discussion continues to be the gold-standard practice in the diagnosis and treatment of SARD-ILD. The multidisciplinary discussion meetings are an opportunity to engage pulmonologists, radiologists, pathologists, and rheumatologists in reviewing all patient data together: clinical history, physical examination findings, immunoserologies, radiographic findings, and histologic features. These meetings are the best example of the irreplaceable value of interdisciplinary collaborative medicine in the care of patients with complex multisystem disease. REFERENCES 1. Wijsenbeek M, Suzuki A, Maher TM. Interstitial lung diseases. Lancet. 2022;400(10354):769–86. 2. Kawano-Dourado L, Glassberg MK, Assayag D, Borie R, Johannson KA. Sex and gender in interstitial lung diseases. Eur Respir Rev. 2021;30(162):210105. 3. Ryerson CJ, Vittinghoff E, Ley B, Lee JS, Mooney JJ, Jones KD, et al. Predicting survival across chronic interstitial lung disease: The ILD-GAP model. Chest. 2014;145(4):723–8. 4. Collard HR, Pantilat SZ. Dyspnea in interstitial lung disease. Curr Opin Support Palliat Care. 2008;2(2):100–4. 5. Parisien-La Salle S, Abel Rivest E, Boucher VG, Lalande-Gauthier M, Morisset J, Manganas H, et al. Effects of pursed lip breathing on exercise capacity and dyspnea in patients with interstitial lung disease: A randomized, crossover study. J Cardiopulm Rehabil Prev. 2019;39(2):112–17. 6. Madison JM, Irwin RS. Chronic cough in adults with interstitial lung disease. Curr Opin Pulm Med. 2005;11(5):412–16. 7. Moran-Mendoza O, Ritchie T, Aldhaheri S. Fine crackles on chest auscultation in the early diagnosis of idiopathic pulmonary fibrosis: A prospective cohort study. BMJ Open Respir Res. 2021;8(1):e000815. 8. Sgalla G, Walsh SLF, Sverzellati N, Fletcher S, Cerri S, Dimitrov B, et al. “Velcro-type” crackles predict specific radiologic features of fibrotic interstitial lung disease. BMC Pulm Med. 2018;18(1). 9. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, et al. 2022 ESC/ ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2023;61(1):2200879. 10. Shellenberger RA, Imtiaz K, Chellappa N, Gundapanneni L, Scheidel C, Handa R, Bhat A. Physical examination for the detection of pulmonary hypertension: A systematic review. Cureus. 2021;13(9):e18020. 11. Margaritopoulos GA, Vasarmidi E, Jacob J, Wells AU, Antoniou KM. Smoking and interstitial lung diseases. Eur Respir Rev. 2015;24(137):428–35. 12. Soriano JB, Kendrick PJ, Paulson KR, Gupta V, Abrams EM, Adedoyin RA, et al. Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med. 2020;8(6):585–96. 13. Bellou V, Belbasis L, Evangelou E. Tobacco smoking and risk for pulmonary fibrosis: A prospective cohort study from the UK Biobank. Chest. 2021;160(3):983–93. 14. Vierikko T, Järvenpää R, Uitti J, Virtema P, Oksa P, Jaakkola MS, et al. The effects of secondhand smoke exposure on HRCT findings among asbestos-exposed workers. Respir Med. 2008;102(5):658–64. 15. Dawod YT, Cook NE, Graham WB, Madhani-Lovely F, Thao C. Smoking-associated interstitial lung disease: Update and review. Expert Rev Respir Med. 2020;14(8):825–34. 16. Joshi M, Joshi A, Bartter T. Marijuana and lung diseases. Curr Opin Pulm Med. 2014;20(2):173–9. 22

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42. Meyer KC, Raghu G, Baughman RP, Brown KK, Costabel U, du Bois RM, et al. An official American thoracic society clinical practice guideline: The clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med. 2012;185(9):1004–14. 43. Hetzel J, Wells AU, Costabel U, Colby TV, Walsh SLF, Verschakelen J, et al. Transbronchial cryobiopsy increases diagnostic confidence in interstitial lung disease: A prospective multicentre trial. Eur Respir J. 2020;56(6). 44. Tomassetti S, Colby TV, Wells AU, Poletti V, Costabel U, Matucci-Cerinic M. Bronchoalveolar lavage and lung biopsy in connective tissue diseases, to do or not to do? Ther Adv Musculoskelet Dis. 2021;13:1759720x211059605. 45. Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. In-hospital mortality after surgical lung biopsy for interstitial lung disease in the United States. 2000 to 2011. Am J Respir Crit Care Med. 2016;193(10):1161–7. 46. Sun XF, Liu YJ, Xiao Y, Xu WB. Role of bronchoalveolar lavage for diagnosing pulmonary infection in patients with rheumatic autoimmune diseases and lung infiltrates. J Clin Rheumatol. 2014;20(7):369–72. 47. Ravaglia C, Bonifazi M, Wells AU, Tomassetti S, Gurioli C, Piciucchi S, et al. Safety and diagnostic yield of transbronchial lung cryobiopsy in diffuse parenchymal lung diseases: A comparative study versus video-assisted thoracoscopic lung biopsy and a systematic review of the literature. Respiration. 2016;91(3):215–27. 48. Hutchinson JP, McKeever TM, Fogarty AW, Navaratnam V, Hubbard RB. Surgical lung biopsy for the diagnosis of interstitial lung disease in England: 1997–2008. Eur Respir J. 2016;48(5):1453–61. 49. Troy LK, Grainge C, Corte TJ, Williamson JP, Vallely MP, Cooper WA, et al. Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung disease diagnosis (COLDICE): A prospective, comparative study. Lancet Respir Med. 2020;8(2):171–81. 50. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. Standardization of spirometry 2019 update. An official American thoracic society and European respiratory society technical statement. Am J Respir Crit Care Med. 2019;200(8):e70–e88. 51. Graham BL, Brusasco V, Burgos F, Cooper BG, Jensen R, Kendrick A, et al. 2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung. Eur Respir J. 2017;49(1). 52. Holland AE, Spruit MA, Troosters T, Puhan MA, Pepin V, Saey D, et al. An official European respiratory society/American thoracic society technical standard: Field walking tests in chronic respiratory disease. Eur Respir J. 2014;44(6):1428–46. 53. Brown AW, Nathan SD. The value and application of the 6-minute-walk test in idiopathic pulmonary fibrosis. Ann Am Thorac Soc. 2018;15(1):3–10. 54. Karimi-Shah BA, Chowdhury BA. Forced vital capacity in idiopathic pulmonary fibrosis— FDA review of pirfenidone and nintedanib. N Engl J Med. 2015;372(13):1189–91. 55. Kafaja S, Clements PJ, Wilhalme H, Tseng CH, Furst DE, Kim GH, et al. Reliability and minimal clinically important differences of forced vital capacity: Results from the Scleroderma Lung Studies (SLS-I and SLS-II). Am J Respir Crit Care Med. 2018;197(5):644–52. 56. Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–27. 57. Cottin V, Selman M, Inoue Y, Wong AW, Corte TJ, Flaherty KR, et al. Syndrome of combined pulmonary fibrosis and emphysema: An official ATS/ERS/JRS/ALAT research statement. Am J Respir Crit Care Med. 2022;206(4):e7–e41. 58. Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380(26):2518–28. 59. White CS. Interstitial pulmonary fibrosis in systemic lupus erythematosus : Are there variants of the variant fibrotic patterns ? Radiol Cardiothorac Imaging. 2021;3(4):e210183. 60. Brady D, Berkowitz EA, Sharma A, Ackman JB, Bernheim A, Chung M, et al. CT morphologic characteristics and variant patterns of interstitial pulmonary fibrosis in systemic lupus erythematosus. Radiol Cardiothorac Imaging. 2021;3(4):e200625. 61. Yoo H, Hino T, Hwang J, Franks TJ, Han J, Im Y, et al. Connective tissue disease-related interstitial lung disease (CTD-ILD) and interstitial lung abnormality (ILA): Evolving concept of CT findings, pathology and management. Eur J Radiol Open. 2022;9:100419. 62. Capobianco J, Grimberg A, Thompson BM, Antunes VB, Jasinowodolinski D, Meirelles GS. Thoracic manifestations of collagen vascular diseases. Radiographics. 2012;32(1):33–50. 24

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63. Raghu G, Meyer KC. Cryptogenic organising pneumonia: Current understanding of an enigmatic lung disease. Eur Respir Rev. 2021;30(161). 64. Tiralongo F, Palermo M, Distefano G, Vancheri A, Sambataro G, Torrisi SE, et al. Cryptogenic organizing pneumonia: Evolution of morphological patterns assessed by HRCT. Diagnostics (Basel). 2020;10(5). 65. Cordier JF. Cryptogenic organising pneumonia. Eur Respir J. 2006;28(2):422–46. 66. Kim EA, Lee KS, Johkoh T, Kim TS, Suh GY, Kwon OJ, et al. Interstitial lung diseases associated with collagen vascular diseases: Radiologic and histopathologic findings. Radiographics. 2002;22(Spec No):S151–65. 67. Todd NW, Marciniak ET, Sachdeva A, Kligerman SJ, Galvin JR, Luzina IG, et al. Organizing pneumonia/non-specific interstitial pneumonia overlap is associated with unfavorable lung disease progression. Respir Med. 2015;109(11):1460–8. 68. Lee JW, Lee KS, Lee HY, Chung MP, Yi CA, Kim TS, et al. Cryptogenic organizing pneumonia: Serial high-resolution CT findings in 22 patients. AJR Am J Roentgenol. 2010;195(4):916–22. 69. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44–e68. 70. Corte TJ, Copley SJ, Desai SR, Zappala CJ, Hansell DM, Nicholson AG, et al. Significance of connective tissue disease features in idiopathic interstitial pneumonia. Eur Respir J. 2012;39(3):661–8. 71. Chung JH, Montner SM, Adegunsoye A, Lee C, Oldham JM, Husain AN, et al. CT findings, radiologic-pathologic correlation, and imaging predictors of survival for patients with interstitial pneumonia with autoimmune features. AJR Am J Roentgenol. 2017;208(6):1229–36. 72. Chung JH, Cox CW, Montner SM, Adegunsoye A, Oldham JM, Husain AN, et al. CT features of the usual interstitial pneumonia pattern: Differentiating connective tissue diseaseassociated interstitial lung disease from idiopathic pulmonary fibrosis. AJR Am J Roentgenol. 2018;210(2):307–13. 73. Walkoff L, White DB, Chung JH, Asante D, Cox CW. The four corners sign: A specific imaging feature in differentiating systemic sclerosis-related interstitial lung disease from idiopathic pulmonary fibrosis. J Thorac Imaging. 2018;33(3):197–203. 74. Hatabu H, Hunninghake GM, Richeldi L, Brown KK, Wells AU, Remy-Jardin M, et al. Interstitial lung abnormalities detected incidentally on CT: A position paper from the fleischner society. Lancet Respir Med. 2020;8(7):726–37. 75. Hatabu H, Hunninghake GM, Richeldi L, Brown KK, Wells AU, Remy-Jardin M, et al. Interstitial lung abnormalities detected incidentally on CT: A position paper from the fleischner society. Lancet Respir Med. 2020;8(7):726–37. 76. Egashira R, Kondo T, Hirai T, Kamochi N, Yakushiji M, Yamasaki F, et al. CT findings of thoracic manifestations of primary Sjogren syndrome: Radiologic-pathologic correlation. Radiographics. 2013;33(7):1933–49. 77. Flament T, Bigot A, Chaigne B, Henique H, Diot E, Marchand-Adam S. Pulmonary manifestations of Sjogren’s syndrome. Eur Respir Rev. 2016;25(140):110–23.

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2  Idiopathic Pneumonia with Autoimmune Features Apostolos Perelas and Darryn L. Winter List of Abbreviations ANA Antinuclear antibody ANCA Anti-neutrophil cytoplasmic antibodies Anti-CCP Anti-cyclic citrullinated peptide Anti-Scl-70 Anti-DNA topoisomerase I Anti-SSA Anti-Sjögren’s syndrome-related antigen A autoantibody, anti-Ro Anti-SSB Anti-Sjögren’s syndrome-related antigen B autoantibody, anti-L BMI Body mass index CRP C-reactive protein CT Computed tomography CXCL Chemokine (C-X-C motif) ligand DLCO Diffusion capacity for carbon monoxide EXR Erythrocyte sedimentation rate FVC Forced vital capacity HRCT High-resolution computed tomography IIP Idiopathic interstitial pneumonia IL Interleukin ILD Interstitial lung disease IPAF Interstitial pneumonia with autoimmune features KL-6 Krebs von den Lungen-6 LIP Lymphocytic interstitial pneumonia NSIP Nonspecific interstitial pneumonia OP Organizing pneumonia P2 Pulmonic valve closure PFT Pulmonary function test PH Pulmonary hypertension RF Rheumatoid factor RNP Anti-ribonucleoprotein SARD Systemic autoimmune rheumatic disease SARD-ILD Systemic autoimmune rheumatic disease-associated interstitial lung disease S2 Second heart sound SpO2 Oxygen saturation SSc Systemic sclerosis, scleroderma UIP Usual interstitial pneumonia 2.1 INTRODUCTION Interstitial pneumonia with autoimmune features (IPAF) is a subcategory of idiopathic interstitial pneumonia (IIP) that has clinical, serologic, and/or imaging features consistent with an autoimmune disease but does not meet criteria for a more well-defined connective tissue disease-associated interstitial lung disease (CTD-ILD). Many researchers have tried to study this disease entity utilizing varied criteria and terminology including “undifferentiated CTD-associated ILD”, “lungdominant CTD”, or “autoimmune-featured ILD” (1). The European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Diseases was developed in 2015 to provide internationally-recognized criteria for this patient population, which could then be utilized in further research (1). For the diagnosis of IPAF to be considered, several criteria need to be met. These include evidence of an IIP on high-resolution computed tomography of the chest (HRCT) or histopathologic findings from a lung biopsy, no other elucidated etiology after thorough evaluation, and the patient not meeting classification criteria for a CTD-ILD (1). Further evaluation of the patient is then categorized into three separate medical domains: clinical, serologic, and morphologic (Table 2.1). The clinical domain encompasses certain extrathoracic manifestations consistent with an underlying CTD such as mechanic’s hands, Raynaud phenomenon, or Gottron’s papules (Figure 2.1). The serologic domain incorporates autoimmune antibodies that are closely associated 26

DOI: 10.1201/9781003361374-3

2 Idiopathic Pneumonia with Autoimmune Features

Table 2.1: IPAF Diagnostic Domain Criteria Clinical Domain Distal Digital Fissuring (i.e. Mechanic Hands) Distal Digital Tip Ulceration Inflammatory Arthritis or Polyarticular Morning Joint Stiffness Lasting ≥60 min Palmar Telangiectasia Reynaud’s Phenomenon Unexplained Digital Edema Unexplained Fixed Rash on the Digital Extensor Surfaces (i.e. Gottron’s Sign)

Serologic Domain

Morphologic Domain

ANA ≥ 1:320 Titer, Diffuse, Speckled, Homogenous Patterns or ANA Nucleolar Pattern (any titer) or ANA Centromere Pattern (any titer)

Suggestive Radiology Pattern by HRCT: • NSIP • OP • NSIP with OP Overlap • LIP Histopathology Patterns or Features by Surgical Lung Biopsy: • NSIP • OP • NSIP with OP Overlap • LIP • Interstitial Lymphoid Aggregates with Germinal Centers • Diffuse Lymphoplasmacytic Infiltration (with or without Lymphoid Follicles) Multi-Compartment Involvement (in addition to the interstitial pneumonia): • Unexplained Pleural Effusion or Thickening • Unexplained Pericardial Effusion or Thickening • Unexplained Intrinsic Airways Disease (by PFT, imaging, or pathology) • Unexplained Pulmonary Vasculopathy

Rheumatoid Factor ≥2x Upper Limit of Normal Anti-CCP Anti-dsDNA Anti-Ro (SS-A) Anti-La (SS-B) Anti-ribonucleoprotein Anti-topoisomerase (Scl-70) Anti-Smith Anti-tRNA synthetase Anti PM-Scl Anti-MDA-5

Source: Adapted from 2015 ERS/ATS Statement

Figure 2.1  Gottron’s papules (A) in a 73-year-old female referred to our clinic for evaluation. Mechanic’s hands (B) in a 64-year-old female patient with ILD and positive PM/Scl antibodies. 27

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Figure 2.2  Imaging findings in two of our IPAF cases. (A) 69-year-old Caucasian female with Raynaud phenomenon, high titer ANA and NSIP on pathology. She has not differentiated into a defined SARD over a 7 year period. (B) 53-year-old African American female with organizing pneumonia on pathology and positive anti-Jo-1 antibodies with no other manifestation of a defined SARD.

with CTDs while intentionally excluding less specific markers such as low-titer antinuclear antibody (ANA), low-titer rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), antineutrophil cytoplasmic antibodies (ANCA), and C-reactive protein (CRP). Lastly, the morphologic domain is derived from imaging patterns on HRCT and/or histopathologic features, including the presence of lymphocytic infiltration and lymphoid aggregates or the presence of multicompartment involvement including airway, vascular, pleural, or pericardial abnormalities (Figure 2.2). The patient must fulfill the initial requirements and exhibit, at a minimum, one feature from at least two domains to meet the classification criteria for IPAF (1) in the absence of an alternative explanation. The introduction of IPAF, which has not been without controversy, sparked considerable interest, resulting in more than 250 scientific papers published on IPAF between 2015 and 2023. Although there remains a lot to be discovered, and we still have no randomized controlled trials, there has been tremendous progress in the understanding of the epidemiology, pathophysiology, prognosis, and treatment of this disease entity. The aim of this chapter is to provide a concise summary of what is known about IPAF while recognizing the limitations of a definition that may yet need further refinement. 2.2 EPIDEMIOLOGY With a unifying nomenclature and classification criteria, the characteristics of the IPAF patient population are amenable to study. The prevalence varies based on the population screened, with values ranging from 5% to almost 20% of the total ILD population (2, 3). However, most centers from Europe, Asia, Australia, and the United States report a prevalence of approximately 15% of all ILD cases (4–10). In our ILD clinic at the Virginia Commonwealth University, patients who fulfill IPAF criteria account for 14% of the total cohort. Consistently, patients with IPAF are diagnosed within the sixth or seventh decade of life (2, 11–13). There is a slight female predominance, accounting for between 55% and 65% of cases in most series (6, 11, 12). There has not been a clear predilection toward a specific racial group, but this has not been extensively studied. A smoking history is variably reported, with anywhere from 19.2% to 63.5% of the IPAF population having ever smoked, depending on the geographic area of origin (6, 12). When it comes to diagnosis, it is more common for patients to fulfill the morphologic and serologic criteria compared to the clinical criteria. In most of the published series, the prevalence of morphologic and/or serologic positivity is above 80%, whereas the clinical criteria are satisfied between 30% and 60% of the time (2, 13, 14). Among the morphologic criteria, imaging is more 28

2 Idiopathic Pneumonia with Autoimmune Features

commonly satisfied, with only a few patients undergoing surgical lung biopsy or demonstrating multicompartmental involvement. Nonspecific interstitial pneumonia (NSIP) is the most frequent morphologic pattern in most cohorts, with two notable exceptions where usual interstitial pneumonia (UIP) was the dominant feature (5, 14). Other patterns, such as organizing pneumonia (OP) and lymphocytic interstitial pneumonia (LIP), are significantly rarer. A positive ANA with a titer of 1:320 or higher is the most frequently encountered serologic criterion, followed by a positive RF and anti-SSA antibody (6). A relatively high prevalence of ANCA positivity has been reported, but this is not part of the original serological criteria for IPAF (1, 13). Among the clinical criteria, Raynaud phenomenon is the most common finding, with arthritis predominating in a minority of cohorts (2, 6, 13, 14). Nailfold capillary abnormalities are common, but nailfold capillaroscopy is rarely performed outside of a rheumatology clinic. Mechanic’s hands are less commonly seen, although there may be some degree of underrecognition. 2.3 PATHOBIOLOGY Although very little is known about the pathogenesis of IPAF, the activation of both fibrotic and inflammatory pathways has been demonstrated. More specifically, both the chemokine CXCL1 and its receptor CXCR2 are upregulated in patients with IPAF (15, 16). Moreover, similar trends have been demonstrated for the serum levels of the inflammatory cytokines IL-4, IL-6, IL-13, and IL-17 (15, 16). It is expected that this increase in inflammatory mediators results in tissue damage. Indeed, the level of Krebs von den Lungen-6 (KL-6), which is a major marker of alveolar epithelial cell injury and dysfunction, is elevated in the serum of patients with IPAF (17) and is correlated with disease severity as expressed by percent predicted diffusion capacity for carbon monoxide (DLCO[%]) or the extent of abnormalities on chest CT (18). The levels of surfactant protein A and surfactant protein D, large glycoproteins that act as indicators of alveolar epithelial cell dysfunction, are also increased (17) and correlate with disease severity as expressed by percent predicted force vital capacity (FVC[%]) (18). Genetic studies have demonstrated that markers important for other types of ILD remain relevant in IPAF. For example, short telomere length has been associated with a faster decline of lung function and shorter transplant-free survival in this population, similar to that seen in patients with idiopathic pulmonary fibrosis (IPF) (19). Moreover, the prevalence of MUC5B rs35705950, the most common allele associated with IPF, is high among patients with IPAF and has been associated with worse outcomes (19). Additional research is needed to investigate the pathophysiology of IPAF, determine diagnostic and prognostic biomarkers, and identify the similarities and differences between IPAF and other types of ILD. 2.4 EVALUATION Patients will usually seek medical attention either because of the pulmonary (shortness of breath, cough, chest pain) or the extrapulmonary manifestations (Raynaud phenomenon, arthritis, skin manifestations) of IPAF (13). These symptoms determine referrals to either a pulmonologist or a rheumatologist. After the initial assessment, the characteristic multisystem involvement is usually revealed, and in most cases, both specialists are integral to the care of the patient with IPAF. In detailing the patient’s history, questions should focus on joint symptoms; the presence of dry eyes, dry mouth, or poor dentition; joint swelling, stiffness, or pain; and skin changes. Exposures to tobacco smoke or vaping, medications, organic and inorganic dusts, mold, and birds or feather pillows/comforters should also be assessed. A family history of autoimmune disease, premature graying, ILD, bone marrow fibrosis, or liver cirrhosis should be actively sought. Physical examination could start with the hands, looking for evidence of skin pigment alteration, cold-induced color changes, digital pits, skin thickening, puffy fingers, fissuring or ulcerations of the fingers, finger or palmar telangiectasias, or swelling or tenderness of the joints (Figure 2.1). Auscultation of the lungs will reveal crackles in the majority of the cases, but it can be normal if the extent of disease is limited. Heart auscultation may reveal signs of pulmonary hypertension (PH), such as a loud P2 component of S2. Signs of right heart failure should be actively sought, including lower extremity edema, jugular venous distention, and the presence of hepatojugular reflux. The initial laboratory investigation should include nonspecific markers of inflammation (ESR, CRP), along with a complete blood count, creatine kinase, aldolase, urinalysis, and a comprehensive metabolic panel. “Basic” tests such as ANA, ANCA, anti-SSA, anti-SSB, rheumatoid factor, and anti-CCP antibodies should be performed in every patient on initial assessment. In the case of ANA positivity, additional testing for anti-dsDNA, anti-Smith, anti-ribonucleoprotein (RNP), anti-Scl-70, and anticentromere antibodies should be performed. Laboratory investigation 29

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for myositis-associated and myositis-specific antibodies, though relatively expensive, can be particularly useful, especially among patients who have no extrapulmonary manifestations of autoimmunity. Although a chest X-ray can be performed at most offices and is a reasonable first step, it lacks sensitivity and specificity, and it may be normal in the early stages of disease. Every patient in whom ILD is suspected should be evaluated with an HRCT, including inspiratory and expiratory images as well as prone imaging. This will allow for the identification of ILD and the extent and pattern of lung involvement while providing information about the status of the airways, the pleura, and the pericardium. Figure 2.2 demonstrates two patients who were referred to our ILD clinic after undergoing lung biopsies at outside institutions and were both found to satisfy IPAF criteria. Spirometry, DLCO, and lung volumes complement the chest CT; however, pulmonary function test (PFT) results can be affected by extraparenchymal factors—for example, muscle weakness may affect FVC measurements, and the presence of PH may result in a disproportionate reduction in the DLCO (20). Similarly, a 6-minute walk test, although useful as a crude estimate of exercise capacity, can also be affected by joint or muscle disease. Walking oximetry can be easily performed in the office setting to assess for the need for supplemental oxygen; however, the presence of Raynaud phenomenon can result in underestimation of the SpO2 obtained by a finger probe (21). In this setting, warming the extremities prior to testing or utilizing a forehead or earlobe probe is preferable. Tissue pathology is required in only a minority of patients and is typically performed in the case of atypical presentations or when a concomitant process, such as malignancy or infection, is suspected. Although surgical lung biopsy was previously the standard of care, transbronchial cryobiopsy has emerged as a reliable and safe modality despite the smaller specimen sizes (22). Other bronchoscopic modalities, such as bronchoalveolar lavage and forceps transbronchial biopsies, are less helpful. A number of pathology motifs can be seen in this population, including NSIP, OP, NSIP/OP overlap, LIP, lymphoid aggregates with germinal centers, diffuse lymphoplasmacytic infiltration, pleuritis, and pulmonary vasculopathy (1). Imaging, as well as functional testing, should be repeated at regular intervals to monitor for disease progression and to detect complications, most importantly pulmonary malignancy as well as PH. In our practice, we repeat spirometry and DLCO every 3–6 months and chest imaging once a year or with any symptomatic progression. A baseline echocardiogram is useful to screen for PH, ventricular function, and pericardial disease and can be repeated annually or biannually. We cannot overemphasize the value of cooperation between rheumatology and pulmonology during the evaluation and treatment of patients with IPAF. By combining expertise and working collaboratively, these two specialties can provide a holistic approach to patient evaluation and management while minimizing the risk for side effects and adverse events related to pharmacological interventions, as well as approaching patient care in a cost-effective manner. 2.5 PROGNOSIS Given the between-cohort variability when considering patient characteristics, morphological features, and serologies, it is not surprising that there seem to be discrepancies in the reported prognosis of patients with IPAF. In the landmark study by Oldham et al., the survival of patients with IPAF was found to be worse than for those with CTD-ILD and better than for IPF (14). However, this has not been verified universally, with some studies reporting similar outcomes to those of CTD-ILD (4, 6). This is most likely a result of the very high prevalence of UIP in the study by Oldham et al. (14). Median survival varies significantly from 5.5 years to more than 12 years, reflecting the heterogeneity of the populations examined (4). However, even among survivors, the majority of patients demonstrate some disease progression over time based on imaging and/or spirometry (23). Advanced age has been associated with worse outcomes, similar to that seen in other types of ILD such as IPF-ILD or systemic sclerosis (SSc)-ILD (5, 24). Other risk factors for mortality include male sex, a lower BMI, and a smoking history (5). Serologies also matter, with myositis-associated antibodies conferring a better outcome compared to anti-SSA or antibodies associated with SSc (8, 23). Other predictors of poor outcomes include the extent of lung involvement, as demonstrated by lower DLCO(%) and FVC(%), and the presence of PH (5, 13). Although exacerbations in IPAF are relatively uncommon, they are associated with a significant risk of death (4, 25). Despite the value of clinical parameters, morphology seems to be the strongest prognostic indicator. Among the different imaging patterns, the presence of organizing pneumonia (with or 30

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without NSIP) is linked to the best outcomes and excellent long-term prognosis (7). On the contrary, patients with a UIP pattern have a disease course similar to that of IPF (4, 8, 14, 26, 27) with a median survival of just 3–5 years (4, 14). Non-UIP IPAF has a prognosis that is similar to that reported in the general CTD-ILD population (14). In a study from the University of Chicago, the presence of honeycombing and pulmonary artery enlargement on chest CT were independent risk factors for mortality (28). 2.6 TREATMENT As of late 2023, there are no established guidelines addressing the management of IPAF. However, there is accumulating, mostly retrospective, data that suggests a role for both anti-inflammatory and antifibrotic agents. It is reasonable to manage asymptomatic patients with limited disease (preserved spirometry and/or DLCO(%), limited extent on imaging, asymptomatic or minimally symptomatic from a pulmonary standpoint) expectantly. However, when pulmonary symptoms are present or when there are risk factors for progression, treatment is warranted, and more than 80% of patients with IPAF receive pharmacotherapy (13). The standard approach is a combination of corticosteroids with a steroid-sparing agent, most commonly mycophenolate mofetil or azathioprine (27). Unfortunately, real-world data on the effectiveness of this approach is scarce; McCoy et al. reported a trend toward an improvement in FVC(%) and the stabilization of DLCO(%) in their series of patients with IPAF being treated with mycophenolate; however, the absolute benefit in pulmonary physiology seemed to be small (29). Similarly, Joerns et al. reported that the majority of individuals receiving prednisone and mycophenolate did not progress during follow up (30). Rituximab has been used in a minority of patients with IPAF, mostly among those with progressive or severe disease and an inflammatory pattern on imaging and/or pathology (NSIP or organizing pneumonia) (31). In a combined cohort from Mass General Brigham and the University of Chicago, almost 80% of patients remained stable or improved while receiving rituximab (31), usually in combination with corticosteroids. A smaller subgroup was on multimodality therapy with corticosteroids, mycophenolate mofetil or IVIG, and rituximab (31). There is limited data on cyclophosphamide, but it has been used in patients with refractory disease (32). The role of antifibrotics is still evolving. In the landmark INBUILD trial, nintedanib was shown to reduce the rate of FVC decline among patients with progressive fibrotic lung disease (33). Patients with autoimmune disease and “idiopathic NSIP” comprised about 40% of the population, and subsequent analysis confirmed the benefit of nintedanib in this subgroup (34). However, it needs to be emphasized that background immunosuppressive therapy was not allowed during this trial, and there is no data on nintedanib specifically among patients with IPAF. In the RELIEF study, pirfenidone was evaluated as a treatment for progressive fibrotic ILD (using criteria that were slightly different than those used in the INBUILD trial) (35). Again, a significant proportion of the participants had conditions with an autoimmune “flavor” (CTD-ILD or idiopathic NSIP); however, the study had to be terminated early because of poor recruitment (35). In the largest retrospective study to date specifically focusing on patients with IPAF, pirfenidone at a dose of up to 1800mg per day was associated with an improvement in the FVC(%) and DLCO(%) (36). A reduction in the need for immunosuppression was also seen as an additional benefit. Pirfenidone was combined with corticosteroids in more than 80% of individuals. The safety profile of pirfenidone was favorable over that seen in the IPF trials, with the majority of patients able to tolerate the full dose, and the discontinuation rates were less than 10% (36). Although PH is seen only in 10–15% of patients with IPAF, the timely identification and treatment of pulmonary vascular disease is important, since it is associated with significant morbidity and mortality (37). Dyspnea out proportion to the extent of fibrosis, profound desaturation on exertion, and a disproportionate drop in the DLCO(%) compared to the FVC(%) may suggest the presence of PH. Although specific guidelines for the treatment of PH in the setting of IPAF do not exist; these patients are expected to respond to inhaled treprostinil based on the results of the INCREASE trial (38), with an improvement in exercise capacity and a reduction in hospitalization risk. Nonpharmacologic therapies such as pulmonary rehabilitation and supplemental oxygen should be considered in patients with IPAF in a similar manner to how they are considered in patients with other types of ILD. Although rarely, patients with IPAF have been referred for lung transplantation; this option should be reserved for those with very severe or progressive disease despite intensified therapy (30). Referral to palliative care may be beneficial for most patients with severe symptoms; hospice is appropriate for those with terminal disease who are not candidates for lung transplantation. 31

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Figure 2.3  Our approach to management of patients with IPAF; CS: corticosteroids; MMF: mycophenolate mofetil; AZA: azathioprine; CYC: cyclophosphamide.

Our approach to the management of IPAF is shown in Figure 2.3. Immunosuppressive therapy remains first line, and it may be combined with antifibrotic therapy in cases of disease progression or in patients with profound fibrosis on imaging and limited physiologic reserve. Although it may be tempting to place patients with IPAF and a UIP pattern of ILD on antifibrotic therapy alone, there is retrospective data to suggest that anti-inflammatory therapy is the best initial therapy even in this population (27, 39). Early treatment is preferred, as this strategy may reduce the risk of IPAF exacerbations and may be linked to better clinical outcomes (25). 2.7 CONTROVERSIES—DISTINCT ENTITY OR CTD-ILD WITH A TWIST? Since its inception, the term IPAF has been controversial—should it be considered a specific clinical entity, or does it merely represent a prodromal stage of ILD associated with CTD in a patient where the other manifestations of CTD have yet to develop? Also, are there distinct subgroups within the IPAF category that would be more accurately classified as a different entity? There is data to suggest that IPAF is not just “incomplete” CTD-ILD. Indeed, despite followup periods of up to 7 years, a defined CTD developed in only 12–27% of individuals initially diagnosed with IPAF (7, 11, 40, 41). This suggests that more than 70% of these patients will never develop other manifestations of CTD; whether this is the result of the disease itself or the concomitant therapy they receive to treat their pulmonary disease is still under debate. Moreover, the natural history of IPAF is distinct; when examined as a group, patients with IPAF have a better prognosis than those with IPF and worse prognosis than those with CTD-ILD (14). However, there is considerable heterogeneity; indeed, patients with a UIP pattern on imaging or pathology have a much worse prognosis, suggesting a group with unique biological behavior. On the other hand, the non-UIP group behaves more like traditional CTD-ILD, and patients with IPAF who test positive for antisynthetase antibodies have a prognosis and response to therapy that is identical to that of those who fulfill antisynthetase syndrome criteria (8, 14, 42). Thus, it is possible that a number of different endotypes exist within the IPAF group, some of which may be better classified within other entities and potentially should be removed from the IPAF category altogether. For example, it has been proposed to remove myositis-specific antibodies from the IPAF criteria and instead manage these patients in a similar manner to those with antisynthetase syndrome (8). Our approach is somewhere in the middle between two extremes. IPAF is a useful concept that promotes the recognition and investigation of a unique group of patients who otherwise would not have been classified as having any specific disease and are suffering from significant morbidity and mortality. More importantly, the introduction of the term IPAF has allowed for the analysis of treatment data and the development of management strategies that have the potential to improve patients’ lives. As research into the pathogenesis and the subtypes of this condition is evolving, we can expect further refinement of the criteria used to describe the entity, which may result in the reclassification of some of today’s patients with IPAF into other disease categories. Collaboration between rheumatologists and pulmonologists, and perhaps the revision of some of the CTD criteria (none of which—with the exception of systemic sclerosis—include ILD as part of the clinical scoring systems) will be crucial to this end. 32

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elevation of the Th17 cytokine profile. J Clin Med [Internet]. 2020;9(5) [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih.gov/32384594/. 17. Wang J, Zheng P, Huang Z, Huang H, Xue M, Liao C, et al. Serum SP-A and KL-6 levels can predict the improvement and deterioration of patients with interstitial pneumonia with autoimmune features. BMC Pulm Med. 2020;20(1). 18. Miądlikowska E, Rzepka-Wrona P, Miłkowska-Dymanowska J, Białas AJ, Piotrowski WJ. Review: Serum biomarkers of lung fibrosis in interstitial pneumonia with autoimmune features-what do we already know? J Clin Med [Internet]. 2021;11(1) [cited 2023 Apr 23]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/35011819. 19. Newton CA, Oldham JM, Ley B, Anand V, Adegunsoye A, Liu G, et al. Telomere length and genetic variant associations with interstitial lung disease progression and survival. Eur Respir J [Internet]. 2019;53(4) [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm. nih.gov/30635297/. 20. Perelas A, Silver RM, Arrossi A V., Highland KB. Systemic sclerosis-associated interstitial lung disease. Lancet Respir Med. 2020;8(3):304–20. 21. Akdogan A, Kilic L, Dogan I, Karadag O, Bilgen SA, Kiraz S, et al. Effect of capillaroscopic patterns on the pulse oximetry measurements in systemic sclerosis patients. Microvasc Res [Internet]. 2015;98:183–6 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih. gov/24530379/. 22. Wu W Jue, Mo HY, Liu H. Transbronchial lung cryobiopsy for connective tissue diseaserelated interstitial lung disease and interstitial pneumonia with autoimmune features: A single center retrospective case series. Clin Rheumatol [Internet]. 2021;40(9):3765–72 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih.gov/33660082/. 23. Nagy A, Nagy T, Kolonics-Farkas AM, Eszes N, Vincze K, Barczi E, et al. Autoimmune progressive fibrosing interstitial lung disease: Predictors of fast decline. Front Pharmacol [Internet]. 2021;12:778649 [cited 2023 Apr 23]. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/35002713. 24. Kamiya H, Panlaqui OM. Systematic review and meta-analysis of the prognosis and prognostic factors of interstitial pneumonia with autoimmune features. BMJ Open [Internet]. 2019;9(12) [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih.gov/31831537/. 25. Murata O, Suzuki K, Takeuchi T, Maemondo M. The risk factors of exacerbation in interstitial pneumonia with autoimmune features: A single-center observational cohort study. Rheumatol Ther [Internet]. 2021;8(4):1693–710 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi. nlm.nih.gov/34536219/. 26. Yoshimura K, Kono M, Enomoto Y, Nishimoto K, Oyama Y, Yasui H, et al. Distinctive characteristics and prognostic significance of interstitial pneumonia with autoimmune features in patients with chronic fibrosing interstitial pneumonia. Respir Med. 2018;137:167–75. 27. Nieto MA, Sanchez-Pernaute O, Vadillo C, Rodriguez-Nieto MJ, Romero-Bueno F, LópezMuñiz B, et al. Functional respiratory impairment and related factors in patients with interstitial pneumonia with autoimmune features (IPAF): Multicenter study from NEREA registry. Respir Res [Internet]. 2023;24(1):19 [cited 2023 Apr 23]. Available from: https:// pubmed.ncbi.nlm.nih.gov/36653833/. 28. Chung JH, Montner SM, Adegunsoye A, Lee C, Oldham JM, Husain AN, et al. CT Findings, radiologic-pathologic correlation, and imaging predictors of survival for patients with interstitial pneumonia with autoimmune features. AJR Am J Roentgenol [Internet]. 2017;208(6):1229–36 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih. gov/28350485/. 29. McCoy SS, Mukadam Z, Meyer KC, Kanne JP, Meyer CA, Martin MD, et al. Mycophenolate therapy in interstitial pneumonia with autoimmune features: A cohort study. Ther Clin Risk Manag [Internet]. 2018;14:2171–81 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi. nlm.nih.gov/30464490/. 30. Joerns EK, Adams TN, Newton CA, Bermas B, Karp D, Batra K, et al. Variables associated with response to therapy in patients with interstitial pneumonia with autoimmune features. J Clin Rheumatol [Internet]. 2022;28(2):84–8 [cited 2023 Apr 23]. Available from: https://pubmed. ncbi.nlm.nih.gov/34897197/. 31. D’Silva KM, Ventura IB, Bolster MB, Castelino FV., Sharma A, Little BP, et al. Rituximab for interstitial pneumonia with autoimmune features at two medical centres. Rheumatol Adv Pract [Internet]. 2021;5(Suppl 2):II1–9 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi. nlm.nih.gov/34755024/.

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32. Wiertz IA, Van Moorsel CHM, Vorselaars ADM, Quanjel MJR, Grutters JC. Cyclophosphamide in steroid refractory unclassifiable idiopathic interstitial pneumonia and interstitial pneumonia with autoimmune features (IPAF). Eur Respir J [Internet]. 2018;51(4) [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih.gov/29496758/. 33. Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med [Internet]. 2019;381(18):1718–27 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih.gov/31566307/. 34. Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: A randomised, double-blind, placebocontrolled, parallel-group trial. Lancet Respir Med [Internet]. 2020;8(5):453–60 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih.gov/32145830/. 35. Behr J, Prasse A, Kreuter M, Johow J, Rabe KF, Bonella F, et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): A double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med [Internet]. 2021;9(5):476–86 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih. gov/33798455/. 36. Chen T, Li QH, Zhang Y, Yin CS, Weng D, Zhou Y, et al. The role of pirfenidone in the treatment of interstitial pneumonia with autoimmune features. Clin Exp Rheumatol [Internet]. 2022;40(3):560–7 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih. gov/33822701/. 37. Alzghoul BN, Hamburger R, Lewandowski T, Janssen B, Grey D, Xue W, et al. Pulmonary hypertension in patients with interstitial pneumonia with autoimmune features. Pulm Circ [Internet]. 2020;10(4) [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih. gov/33343878/. 38. Waxman A, Restrepo-Jaramillo R, Thenappan T, Ravichandran A, Engel P, Bajwa A, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med [Internet]. 2021;384(4):325–34 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm. nih.gov/33440084/. 39. Yamano Y, Kataoka K, Takei R, Sasano H, Yokoyama T, Matsuda T, et al. Interstitial pneumonia with autoimmune features and histologic usual interstitial pneumonia treated with anti-fibrotic versus immunosuppressive therapy. Respir Investig. 2023;61(3):297–305. 40. Sebastiani M, Cassone G, De Pasquale L, Cerri S, Della Casa G, Vacchi C, et al. Interstitial pneumonia with autoimmune features: A single center prospective follow-up study. Autoimmun Rev [Internet]. 2020;19(2) [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm. nih.gov/31838159/. 41. Enomoto N, Homma S, Inase N, Kondoh Y, Saraya T, Takizawa H, et al. Prospective nationwide multicentre cohort study of the clinical significance of autoimmune features in idiopathic interstitial pneumonias. Thorax [Internet]. 2022;77(2):143–53 [cited 2023 Apr 23]. Available from: https://pubmed.ncbi.nlm.nih.gov/34272335/. 42. Mejía M, Herrera-Bringas D, Pérez-Román DI, Rivero H, Mateos-Toledo H, Castorena-García P, et al. Interstitial lung disease and myositis-specific and associated autoantibodies: Clinical manifestations, survival and the performance of the new ATS/ERS criteria for interstitial pneumonia with autoimmune features (IPAF). Respir Med [Internet]. 2017;123:79–86 [cited 2023 Apr 24]. Available from: https://pubmed.ncbi.nlm.nih.gov/28137500/.

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3  Approach to the Patient with Pulmonary Vascular Disease Josanna Rodriguez-Lopez and Daniel Alape Moya List of Abbreviations 6MWT 6-minute walk test ACB Alveolar capillary bed ASIG Australian Scleroderma Interest Group BNP Brain natriuretic peptide BPA Balloon pulmonary angioplasty CCB Calcium channel blocker CI Cardiac index cMRI Cardiac magnetic resonance imaging CO Cardiac output COMPERA Comparative and Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension four-stratum risk score CPET Cardiopulmonary exercise testing CT Computed tomography CTEPH Chronic thromboembolic pulmonary hypertension CTPA Computed tomography pulmonary angiography DLCO Diffusion capacity DPG Diastolic pressure gradient ERA Endothelin receptor antagonist ERS European Respiratory Society ESC European Society of Cardiology FPHN French Pulmonary Hypertension Network FVC Forced vital capacity HfpEF Heart failure with preserved ejection fraction ILD Interstitial lung disease iNO Inhaled nitric oxide IPAH Idiopathic pulmonary arterial hypertension LAP Left atrial pressure LV Left ventricle MCTD Mixed connective tissue disease mPAP Mean pulmonary artery pressure NT-proBNP N-terminal pro-B-type natriuretic peptide OSA Obstructive sleep apnea PAH Pulmonary arterial hypertension PAOP Pulmonary artery occlusion pressure PASP Pulmonary artery systolic pressure PCA Prostacyclin receptor agonist PCH Pulmonary capillary hemangiomatosis PDE5I Phosphodiesterase-5 inhibitor Platelet-derived growth factor β PDGF-β PETCO2 End-tidal carbon dioxide tension PH Pulmonary hypertension PVR Pulmonary vascular resistance PTE Pulmonary thromboendarterectomy Peak oxygen uptake pVO2 PVOD Pulmonary veno-occlusive disease RA Rheumatoid arthritis RAP Right atrium pressure RHC Right heart catheterization RV Right ventricle RV S’ Right ventricular S’ velocity RVOT Right ventricular outflow tract RVSP Right ventricular systolic pressure 36

DOI: 10.1201/9781003361374-4

3 Approach to the Patient with Pulmonary Vascular Disease

SARD sGC SLE SSc SVR TAPSE TGF-β1 TKI TPG TRV TSH TTE VEGF-A VE/VCO2 V/Q WHO WU

Systemic autoimmune rheumatic disease Soluble guanylate cyclase stimulator Systemic lupus erythematosus Systemic sclerosis Systemic vascular resistance Tricuspid annular plane systolic excursion TGF-β1 transforming growth factor-beta 1 Tyrosine kinase inhibitor Transpulmonary gradient Tricuspid regurgitant jet velocity Thyroid stimulating hormone Transthoracic echocardiogram Vascular endothelial growth factor A Minute ventilation/carbon dioxide production relationship Ventilation/perfusion World Health Organization Wood units

3.1 DEFINITION PH is defined by a mean pulmonary arterial pressure (mPAP) > 20 mmHg on resting right heart catheterization (RHC) (1). An elevation of mPAP in isolation is not sufficient to define pulmonary vascular disease, as the elevated pressure can be due to other etiologies such as an increase in cardiac output (CO) and pulmonary artery occlusion pressure (PAOP). The definition of precapillary pulmonary hypertension due to vasculopathy, defined as an mPAP > 20 mmHg, with normal PAOP ≤ 15 mmHg and an elevated pulmonary vascular resistance (PVR) ≥ 2 Wood units (WU), was updated in 2022 by the European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension (PH) (2). Postcapillary PH, caused by left heart disease, is defined by an mPAP > 20 mmHg and an elevated PAOP > 15 mmHg. Combined pre- and postcapillary PH is defined as having an mPAP > 20 mmHg, PAOP > 15 mmHg, and an elevated PVR ≥ 2 WU (1, 2). 3.2 CLASSIFICATION It is important to understand all potential causes that can lead to an increased pressure in the pulmonary vasculature (Figure 3.1). The World Health Organization (WHO) classifies the etiologies into five groups. WHO Group 1 refers to pulmonary arterial hypertension (PAH). PAH is a proliferative pulmonary vasculopathy characterized by intimal hyperplasia, medial hypertrophy, adventitial proliferation, and in situ thrombosis of the pulmonary arteries (3). Among the causes of Group 1 PAH, idiopathic PAH (IPAH) is the most prevalent, accounting for up to 50% of patients, followed by PAH-associated SARD (PAH-SARD) (4, 5). The most common SARDs associated with PAH are scleroderma (SSc) and MCTD. However, it is crucial to acknowledge that PAH can be present in any SARD. There is a strong female predominance (female:male ratio 4:1), and mean age at diagnosis is 50 years (6). Other causes that can lead to PAH include genetic polymorphisms and associated conditions such as HIV, congenital heart disease, schistosomiasis, and portal hypertension. Also, exposure to drugs and toxins such as anorexigens and methamphetamines have been implicated in PAH (3). Another medication that has gained attention recently is leflunomide, a noncompetitive inhibitor of dihydroorotate dehydrogenase used for the treatment of rheumatoid arthritis. Leflunomide has been shown to have tyrosine kinase inhibitor (TKI) activity, which has been associated with the development of PAH. Nevertheless, a detailed analysis of the French PH Registry from 1999 to 2019 showed that PH associated with leflunomide is rare and usually associated with other risk factors (7). Unrecognized, untreated, or poorly controlled PAH has a mortality rate of up to 55% at 3 years from the initial diagnosis (8). The prognosis tends to be worse in patients with SARD-PAH compared to IPAH. A rare subset of Group 1 PAH is pulmonary veno-occlusive disease (PVOD). PVOD is defined histologically by intimal fibrosis and obstruction of the small veins and venules in addition to the arterial and arteriolar pathology seen in PAH (9). PVOD is difficult to distinguish clinically from PAH, but it responds poorly to PAH therapy, and prognosis is poor. It is underrecognized in patients with SSc with either PAH or PH associated with interstitial lung disease (ILD) (10). PVOD should be considered in patients with high oxygen requirements, very low diffusion capacity 37

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Figure 3.1  Clinical classification of pulmonary hypertension. ACB: alveolar capillary bed; EF: ejection fraction; LV: left ventricle; PA: pulmonary artery; PV: pulmonary vein; SARD: systemic autoimmune rheumatic diseases; SV: small veins; PVOD: pulmonary veno-oclusive disease; PCH: pulmonary capillary hemangiomatosis (2); RV: right ventricle.

(DLCO), and classic radiographic findings such as septal thickening, centrilobular ground-glass opacities, and pleural effusions despite a normal pulmonary artery occlusion pressure (PAOP). PVOD should also be considered if clinical deterioration and pulmonary edema occur after starting PAH-specific therapies. WHO Group 2 PH is the most common form of PH worldwide. It is caused by left heart failure and left-sided valvular heart disease, which result in pulmonary venous congestion and elevated PAOP. Over time, chronically elevated pressures transmitted from the left heart can lead to pulmonary vascular remodeling and injury, leading to worsening pulmonary hypertension. Patients with SARDs, particularly SSc and SLE, can also have myocardial involvement and are thus at risk 38

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for Group 2 PH (11). A right heart catheterization to measure pulmonary hemodynamics and left heart pressures is crucial to distinguish Group 1 from Group 2 PH. WHO Group 3 PH is pulmonary hypertension due to lung disease. Chronic hypoxemia activates growth factors in the pulmonary vasculature, including transforming growth factor-beta 1 (TGF-β1), vascular endothelial growth factor A (VEGF-A), and platelet-derived growth factor β (PDGF-β), which result in endothelial and smooth muscle cell remodeling and proliferation (12). Group 3 PH is common in SARD-associated ILD (SARD-ILD), such as that seen in SSc, RA, idiopathic inflammatory myopathies, and Sjögren’s syndrome. Patients with concomitant ILD and precapillary PH have reduced survival compared to patients with PAH (13). WHO Group 4 is PH associated with chronic thromboembolic disease or pulmonary artery obstruction. The incidence of chronic thromboembolic pulmonary hypertension (CTEPH) after a patient experiences a pulmonary embolism has been estimated to be around 0.57–3.8% (14, 15). Not all patients present with a prior history of thromboembolic disease, so CTEPH can be missed if appropriate screening tests are not performed. Some autoimmune conditions such as antiphospholipid syndrome have been associated with CTEPH. Interestingly, more than two-thirds of patients with CTEPH have no identifiable coagulopathy (16). WHO Group 5 encompasses etiologies with unidentified or multifactorial mechanisms such as sarcoidosis, sickle cell disease, and chronic myeloproliferative disease, among others (17). The incidence of PH in patients with sarcoidosis has been estimated to be 5–28% and as high as 75% in patients awaiting lung transplant (18, 19). Frequently, patients with a SARD have multifactorial PH that crosses groups, making diagnosis and management more challenging, which in part may explain why patients with SARD-PAH have worse survival than patients with idiopathic PAH. 3.3 PATIENT EVALUATION PH diagnosis is on average delayed by 2 years, due to both nonspecific symptoms and a lack of awareness among health care providers (16, 20). The most common symptoms include exertional dyspnea, fatigue, and progressive decline in functional status, which are often attributed to age, weight, deconditioning, or other existing comorbidities. In more advanced disease, symptoms can include presyncope, syncope, peripheral edema, abdominal bloating, and chest pain. Physical exam findings include low blood pressure, elevation of jugular venous pressure and/or hepatojugular reflux, tricuspid regurgitant murmur, right ventricle (RV) heave, loud second heart sound (in particular, the P2 component of S2), right-sided S3 and/or S4, hepatosplenomegaly, ascites, and lower extremity edema (21). 3.4 LAB TESTING Diagnostic assessment focuses on the correct classification of PH. Most patients will need a systematic evaluation, which includes laboratory and pulmonary function testing, imaging, and hemodynamic assessment. Recommended labs include the assessment of complete blood count, serum electrolytes, kidney function, liver function tests, iron status, thyroid stimulating hormone (TSH), and serological studies for hepatitis viruses and HIV. Antinuclear antibodies are recommended as a screening test for autoimmune disease. Additional specific serologies can be considered if suspicion for autoimmune disease is high. Brain natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are used as biomarkers in PH, as they correlate with right ventricular strain and independently predict mortality. They are also included in risk stratification scores and can be used to screen for PH in SARDs, specifically in SSc (22). Thrombophilia screening is not generally recommended unless the patient has confirmed CTEPH, for which autoantibodies associated with antiphospholipid syndrome are warranted (2). 3.5 ECHOCARDIOGRAPHY Transthoracic echocardiography (TTE) has become the screening test of choice for PH, as it is non-invasive and widely available. The ESC/ERS recommends using multiple echocardiographic parameters that assess RV function and estimate pressure to calculate the likelihood of PH (Figure 3.2). The most utilized echocardiographic measure to estimate RV systolic pressure (RVSP) is the tricuspid regurgitant jet velocity (TRV). TRV is obtained by measuring the peak TRV via Doppler, which then is added to an estimated right atrial pressure (RAP) utilizing the Bernoulli equation: RVSP = 4(TRV)2 + RAP. Although widely accepted, this equation is not perfect. There are several factors that can affect the accuracy of this measurement, including the amount of tricuspid regurgitation, the method used to measure RAP, and/or RV outflow obstructions. Studies have shown 39

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Figure 3.2  TTE image. Four-chamber view revealing right ventricular dilation, right atrial enlargement, and interventricular septum displacement.

Figure 3.3  Diagnostic algorithm for evaluating pulmonary hypertension (PH). Once the peak triscuspid regurgitation velocity is evaluated, we look for other transthoracic echocardigram (TTE) signs and risk factors to determine which patient will benefit from further testing such as right heart catheterization (RHC). TAPSE: Tricuspid annular plane systolic excursion; RV: right ventricle; RVOT: right ventricular outflow tract; LV: left ventricule (LV). (2, 23) that calculated RVSP by TTE can differ by >10 mmHg from pulmonary artery systolic pressure (PASP) on RHC up to 50% of the time. Therefore, RHC is still requisite for an accurate diagnosis (23). It is also needed to differentiate pre- and postcapillary pulmonary hypertension. Current guidelines recommend using the peak TRV (and not the estimated RVSP) as the key variable for assigning the echocardiographic probability of PH (2). The measurement of TRV should be used in conjunction with other echocardiographic markers of PH to determine which patients would benefit from further testing (Figure 3.3). Some proposed markers include tricuspid annular plane systolic excursion (TAPSE), right ventricular S’ velocity (RV S’), RV outflow tract acceleration time, flattening of the interventricular septum, RV/LV ratio, RV size, RV hypertrophy, and PA size (24). 40

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Another benefit of TTE includes the evaluation of left-sided function and valvular disease, which is important when suspecting Group 2 PH. TTE is also helpful for prognostic purposes. For instance, the presence of pericardial effusion, TAPSE values of 29 mm), PA-to-aorta ratio > 0.9, enlarged right heart chambers (RV-to-LV > 1), RVOT wall thickness ≥ 6 mm, and septal deviation ≥ 140° as predictors for PH (31). A CT scan can also clarify the underlying cause of PH like emphysema, ILD, CTEPH, or PVOD. PVOD can present with certain radiographic features, including mosaic attenuation, pleural effusions, septal thickening, lymphadenopathy, and centrilobular ground-glass opacities (32). However, it is important to note that these findings are not specific to PVOD alone and can be observed in other lung and heart conditions as well. Computed tomography pulmonary angiography (CTPA) is more helpful than regular CT chest if CTEPH is suspected. CTPA findings include chronic filling defects, pulmonary artery webs, PA dilatation, mosaic attenuation, and enlarged bronchial arteries (32). Although CTPA has high sensitivity and specificity in detecting chronic thromboembolic disease at the lobar and segmental level, it might have a limited ability to identify subsegmental disease (33). This limitation is reduced with the use of dual-energy CT scan, which may be as accurate as a ventilation/perfusion (V/Q) scan to detect CTEPH (34). This new CT modality has not yet been integrated into the PH diagnostic algorithm. 3.9 VENTILATION/PERFUSION (V/Q) SCAN A V/Q scan is a fundamental component of the diagnostic evaluation in PH, irrespective of whether the patient has a pre-existing diagnosis of a SARD. A V/Q scan should be done in all patients with suspected precapillary PH to rule out CTEPH, which could otherwise be missed. This image modality is more sensitive than CTPA for the detection of chronic pulmonary emboli, with a sensitivity of 90–100% (33). CTEPH is visualized on V/Q scan generally as large, often multiple bilateral mismatched ventilation/perfusion defects (Figure 3.4). Entities that can lead to false positive results include pulmonary artery sarcoma, vasculitis, veno-occlusive disease, fibrosing 41

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Figure 3.4  V/Q scan. (A) perfusion scan showing multiple bilateral moderate to large segmental perfusion defects. (B) Ventilation scan showing normal ventilation.

mediastinitis, congenital pulmonary vascular abnormalities, and lymphadenopathy leading to PA obstruction (35). 3.10 PULMONARY ANGIOGRAM A pulmonary angiogram should be performed in patients with an abnormal V/Q scan or when there is a high clinical suspicion for CTEPH. It can be performed at the same time as a RHC, by experienced operators, and can be used to confirm a diagnosis of CTEPH and identify potential targets for therapeutic intervention with surgical pulmonary thromboendarterectomy (PTE) or balloon pulmonary angioplasty (BPA) (16) (Figure 3.5). 3.11 SLEEP STUDY PH is uncommonly caused by obstructive sleep apnea (OSA) alone. Many conditions coexist in patients with sleep apnea, such as heart failure, COPD, or daytime hypoventilation, which may contribute to the development of PH. In view of the high prevalence of nocturnal hypoxemia and OSA in PH, patients with PH should be screened for sleep-disordered breathing by nocturnal oximetry and/or an overnight polysomnogram (36). Polysomnography should be considered in 42

3 Approach to the Patient with Pulmonary Vascular Disease

Figure 3.5  Pulmonary artery angiogram. Markedly decreased blood flow to the upper lobe suggesting a filling defect, which is consistent with CTEPH.

patients with symptoms and signs suggestive of sleep-disordered breathing such as loud snoring, morning headaches, nocturnal apneas, dry mouth, hypertension, and/or obesity. 3.12 CARDIAC MAGNETIC RESONANCE IMAGING (CMRI) More recently, the role of cMRI in the diagnosis of PH has expanded. cMRI can more accurately quantify RV size and function than echocardiography. This imaging technique provides morphologic and functional evaluation of the RV and PA, allowing for the estimation of stroke volume, RV mass index, and pulmonary artery systolic pressure. cMRI should be considered in cases when TTE images are suboptimal and non-diagnostic. Additionally, it can be useful in patients suspected of having primary cardiac involvement, which often can be seen in SARDs. The biggest limitations of cMRI are cost, availability, limited experience, patient tolerance (e.g., claustrophobia), and the lack of standardization of measurements (37). 3.13 EXERCISE TESTING—NON-INVASIVE AND INVASIVE The 6-minute walk test (6MWT) is the most widely used test to evaluate exercise capacity in patients with PH. The 6MWT has been validated in multiple risk stratification scores and is associated with survival (2). Many pivotal clinical trials in PAH have used six minute walk distance as the primary endpoint to evaluate for treatment efficacy, as it is accepted by the FDA as a surrogate for hemodynamics and survival. The main limitation of this test is that it is not very sensitive to detect changes related to treatment in patients with a high walking distance at baseline. Non-invasive cardiopulmonary exercise testing (CPET) can provide a physiologic evaluation of exercise limitation and dyspnea, which are the main symptoms in PH. CPET can be used in patients with intermediate risk of PH to further determine the likelihood of PH. It can also quantify the degree of functional impairment and disease severity, and it can assess the efficacy of interventions (38). In patients with lung disease and PH, it can help elucidate the major cause for the exercise limitation. Certain key CPET parameters, such as peak oxygen uptake (pVO2), end-tidal carbon dioxide tension (PETCO2), and the minute ventilation/carbon dioxide production relationship (VE/VCO2) can be prognostic tools in PH. Invasive CPET involves the additional insertion of pulmonary artery and radial artery catheters before exercise. This allows for complete cardiopulmonary hemodynamic and peripheral tissue O2 extraction analyses. The physiologic 43

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information obtained with invasive CPET is more comprehensive than that with conventional CPET alone (39). 3.14 PULMONARY HYPERTENSION SCREENING IN PATIENTS WITH SYSTEMIC AUTOIMMUNE RHEUMATIC DISEASE There have been efforts to develop early screening protocols for PH in patients with SSc, since the prevalence is as high as 19% and early diagnosis has been associated with better prognosis (2). However, traditional screening with echocardiography alone is limited by its cost and moderate sensitivity and specificity (71% and 69%, respectively), which can lead to underdiagnosis (40). The DETECT protocol uses a combination of PFTs, NT-proBNP, EKG, serum autoantibodies (anticentromere antibody), serum urate, and the presence of telangiectasias to guide the clinician to pursue further evaluation for PH, which would include TTE and subsequently RHC. However, this protocol is limited by its complexity and extensive testing. Alternatively, The Australian Scleroderma Interest Group (ASIG) calculator uses only PFTs and NT-proBNP to distinguish patients that would benefit from further evaluation with TTE and RHC. The 2022 ESC/ERS guidelines recommend that a multimodal approach using either the DETECT or ASIG algorithm should be used to determine which patients warrant evaluation with TTE and RHC (2, 41). Currently, there are no established guidelines for screening in other SARDs. 3.15 PRECAPILLARY VS. POSTCAPILLARY PULMONARY HYPERTENSION A useful framework for categorizing PH is to define the component of the pulmonary circulation involved based on pulmonary hemodynamics. PH due to the constriction, remodeling, occlusion, or destruction of the pulmonary arteries and arterioles (e.g., PAH, CTEPH, chronic lung disease) is defined as precapillary PH. PH due to left heart disease with an elevated PAOP or left atrial pressure (LAP) is defined as postcapillary PH. Precapillary and postcapillary PH can, and often do, coexist, and this condition is referred to as combined pre- and postcapillary PH. Of note, pulmonary veno-occlusive disease, while technically a disease of the pulmonary venules, is hemodynamically defined as precapillary PH given the PAOP is typically normal. In addition to obtaining hemodynamic data, the following maneuvers can be performed during RHC to provide additional clinical information: 1. Vasoreactivity testing with inhaled nitric oxide (iNO) or inhaled prostacyclins (e.g., iloprost and epoprostenol) should be performed in individuals with a higher likelihood of vasoreactive PAH such as suspected idiopathic, heritable, and drug-induced PAH. It is currently not required for patients with SARDs. The accepted criteria for vasoreactivity are a decline of more than 10mmHg in mPAP to a value less than 40 mmHg, without a drop in CO or systemic blood pressure. Patients who meet these criteria are candidates for calcium channel blocker (CCB) therapy (21). 2. A fluid challenge can be performed in patients with PAOP < 15 mmHg in whom left heart disease is suspected. There are pitfalls to this approach given the lack of standardization. An increase in PCWP to >18 mmHg after infusion with 500 cc normal saline over 5 minutes is suggestive of left heart dysfunction. Recent data suggest that passive leg raise during RHC also can be helpful to elucidate occult heart failure with preserved ejection fraction (HFpEF) (2). 3. Exercise challenge is helpful in patients who have exercise limitation, exertional dyspnea, and normal resting RHC values, where an abnormal increase in PA values during exercise is suspected. Exercise challenge is usually accompanied by a CPET using a ramp protocol. An invasive CPET can measure pulmonary hemodynamics while the patient exercises. An mPAP/ CO slope > 3 mmHg/L/minute with a PAOP/CO slope < 2 mmHg/L/minute is suggestive of exercise-induced precapillary pulmonary hypertension (2). Additionally, exercise challenge can be useful to identify occult left heart dysfunction, as it shows an increase in mPAP and PAOP (and mPAP/CO, PAOP/CO slope) during exercise (39). 3.16 RISK STRATIFICATION Risk assessment is crucial to determine severity, treatment, and prognosis in patients with PH. Several validated scores are available for the risk stratification of patients with Group 1 PAH. These include the French Pulmonary Hypertension Network (FPHN) registry risk equation; the Scottish composite score; the US Registry to Evaluate Early, Long-Term PAH Disease Management 44

3 Approach to the Patient with Pulmonary Vascular Disease

Table 3.1: WHO Functional Assessment for Pulmonary Hypertension Class I: No activity limitation Class II: Slight activity limitation, comfortable at rest Class III: Marked activity limitation, comfortable at rest Class IV: Unable to perform physical activity, may have dyspnea at rest and/or signs of right heart failure

Table 3.2: High-Risk Features High-risk features with prognostic significance based on three-stratum model Clinical evidence of right heart failure Rapidly progressive symptoms Repeated syncope 6MWT < 165 m CPET with peak VO2 < 35% predicted and VE/VCO2 slope 44 NT-proBNP > 1100 pg/mL TTE with RA area > 26 cm2 and/or presence of pericardial effusion RHC with RAP > 14 mmHg, CI < 2.0 L/minute/m2, and/or SvO2 < 60% Source: (2) Abbreviations: 6MWT: 6-minute walk test; CPET: cardiopulmonary exercise test; NT-proBNP: N-terminal pro-brain natriuretic peptide; TTE: transthoracic echocardiogram; RA: right atrium; TAPSE: tricuspid annular plane systolic excursion; RHC: right heart catheterization; CI: cardiac index; SvO2: cental venous gas.

(REVEAL) risk equation; and the Comparative and Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension four-stratum risk score (COMPERA). Risk calculators incorporate important subjective and objective parameters that have demonstrated significance in predicting outcomes. For the initial risk assessment, current guidelines recommend using a three-stratum model to categorize patients into low, intermediate, or high risk of death at 1 year. This model takes into account biomarkers, functional status (Table 3.1), echocardiographic findings, and hemodynamic variables (Table 3.2). After the initial stratification, patients can be followed by a simpler model called the four-stratum risk-assessment tool. This tool only uses three simple non-invasive factors: 6-minute walking distance, N-terminal pro-brain natriuretic peptide, and WHO functional class. Patients are then classified as low, intermediate–low, intermediate–high, or high risk. The observed 1-year mortality rates in these four risk categories are 0–3% in the low-risk, 2–7% in the intermediate–low-risk, 9–19% in the intermediate–high-risk, and 20% in the high-risk groups (2). Compared with the three-stratum model, the four-stratum model is more sensitive to changes in risk from baseline to follow-up, and it better discriminates patients within the intermediate-risk group, which helps guide therapeutic decision-making (42). An alternative approach is to use the REVEAL 2.0 calculator for initial diagnosis, which was found, in a US cohort, to have greater risk discrimination than the COMPERA and the noninvasive French criteria risk calculators (43). The REVEAL lite calculator, which excludes invasive parameters, can be used for risk assessment during follow-up visits. 3.17 REFERRAL TO A PULMONARY HYPERTENSION CENTER Expedited referral to a PH expert center plays a crucial role in early access to appropriate treatment and preventing disease progression. Fast-track referral is indicated in patients with a rapid progression of symptoms (over 3 months), presyncope or syncope, clinical signs of right heart failure, or echocardiographic evidence of RV dysfunction (2). Additionally, individuals who are pregnant or wish to become pregnant and who have PH risk factors should be seen in an expert center, as well as those with suspected CTEPH. It is also recommended that patients under consideration for PH-directed therapy should be comanaged with a PH expert for detailed risk stratification and drug selection (44). 45

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3.18 TREATMENT OPTIONS Medical management includes medications that function as pulmonary vasodilators and affect vascular remodeling. The use of these agents has mostly been studied in and is typically reserved for patients with PAH (Group 1 disease). Calcium channel blockers (CCBs) inhibit L-type calcium channels in vascular smooth muscle. These agents should only be utilized in patients with idiopathic, heritable, and anorexigeninduced PAH who meet criteria for vasoreactivity on RHC (21). Phosphodiesterase-5 inhibitors (PDE5Is) inhibit the degradation of cyclic GMP (cGMP), an enhancer of smooth muscle relaxation, via nitric oxide-mediated vasodilatory pathways. These agents should not be combined with nitrates or soluble guanylate cyclase (sGC) stimulators since this can cause profound hypotension. The two types of PDE5Is available in the US include sildenafil and tadalafil. Soluble guanylate cyclase stimulators (sGCs) also induce pulmonary vasodilation through the increased production of cGMP (11). The only current medication available from this group is riociguat, which has also been studied and approved for both PAH and inoperable CTEPH (2). Endothelin receptor antagonists (ERAs) block endothelin receptors on vascular smooth muscle, inhibiting vasoconstriction. ERAs have teratogenic effects and should not be used during pregnancy (45). Medications include bosentan, ambrisentan, and macitentan, and these agents are usually started in combination with PDE5Is in patients with idiopathic, heritable, or drug-associated PAH without cardiopulmonary comorbidities. Prostacyclin receptor agonists (PCAs) directly induce pulmonary vasodilation and have vascular remodeling effects, including the inhibition of inflammation, platelet activation, and smooth muscle proliferation. The most common side effects include headache, hypotension, jaw pain, diarrhea, and flushing (2). PCAs include: ■

Epoprostenol has a short half-life (3–5 minutes) and needs continuous intravenous infusion.

■

Treprostinil is available for subcutaneous, intravenous, inhaled, and oral administration. It has a longer half-life than epoprostenol. The inhaled formulation is the only option approved for Group 3 PH.

■

Iloprost is a prostacyclin analog approved for inhaled administration.

■

Selexipag is a nonprostanoid prostacyclin receptor agonist that is orally available.

Sotatercept is a new medication that functions as an activin and growth differentiation factor inhibitor. It acts as a ligand trap for members of the TGF-β super family. This particular medication has shown promising results in phase III clinical trials involving patients with idiopathic, hereditary, drug-induced, or SARD-associated PAH. Side effects include epistaxis, dizziness, telangiectasias, increased hemoglobin levels, thrombocytopenia, and increased blood pressure (46). In addition to PH-specific medications, other general measures are integral components of patient care. RV dysfunction is associated with systemic fluid retention, reduced renal blood flow, and activation of the renin–angiotensin–aldosterone system. To optimize RV function, it is important to have adequate management of volume status with diuretics. Another important management strategy is improving functional capacity through physical activity. Small studies have demonstrated positive effects of supervised exercise training on exercise capacity, muscular function, quality of life, RV function, and pulmonary hemodynamics (47). Supplemental oxygen reduces PVR and improves exercise tolerance in patients with PAH. Nevertheless, there is no data to suggest that long-term oxygen therapy has sustained benefits in patients with no, mild, or moderate DLCO reduction. Oxygen therapy should be considered only when there is evidence of correctable desaturation and severe DLCO impairment (48). Iron deficiency should be treated in patients with PAH since it has been associated with impaired myocardial function, dyspnea, and increased mortality (49). It is recommended that patients with PAH be vaccinated at least against influenza, Streptococcus pneumoniae, and SARS-CoV-2 (2). Additionally, patients should be counseled about avoiding pregnancy since this is associated with a high mortality rate. 3.19 MANAGEMENT OF GROUP 1 PAH 3.19.1  Treatment Initiation The PAH treatment algorithm outlined herein only applies to Group 1 PAH patients and not Groups 2–4. Vasoreactivity testing should be performed in idiopathic, heritable, or drug-related PAH. Only approximately 10% within that group may demonstrate vasoreactivity. If a patient demonstrates 46

3 Approach to the Patient with Pulmonary Vascular Disease

vasoreactivity and is of low to intermediate risk, CCBs can be used initially before considering other therapies. It is unlikely that a patient with a SARD would demonstrate vasoreactivity, so vasoreactivity testing is generally believed to be unnecessary in this group. The majority of low- or intermediate-risk patients who are not vasoreactive should be initiated on up-front combination therapy, most commonly with an ERA and PDE5I. Initial monotherapy is generally not recommended but can be considered in very mild disease or in patients with comorbidities (e.g., concomitant heart, lung, or liver disease). Patients with concomitant heart disease tend to not respond as well to PAH medications. They are both less likely to reach a low-risk status and have a higher mortality risk (50). High-risk patients should be initiated on combination therapy that includes a parenteral prostacyclin. IV epoprostenol is the only IV medication with favorable mortality data. Other acceptable options include IV or SQ treprostinil (51, 52). 3.19.2  Assessment of Treatment Response 3.19.2.1  Repeat Risk Stratification After the initiation of therapy, patients should be re-assessed within 3–6 months. During that follow-up visit, patients should be re-evaluated with repeat risk stratification to determine treatment response and next steps in therapy. In addition to a standard history and physical, follow-up visits should include 6-minute walk testing, BNP/NT-proBNP measurement, and an assessment of functional status. Echocardiograms should be done every 6–12 months to assess response to treatment and disease progression with low threshold to repeat right heart catheterization. Based on the four-stratum risk-assessment tool, patients who are low risk on reassessment after initial treatment should continue current therapy, with repeat evaluation in another 3–6 months. Patients in the intermediate category after initial treatment require an escalation of therapy. Patients who are intermediate–high or high risk after their initial treatment step should proceed to maximal medical therapy, which consists of triple combination therapy including a parenteral prostacyclin. Patients who fail to achieve a low-risk status after maximal therapy should be referred for lung transplantation evaluation (2). 3.19.2.2  Specific Approach for Patients with PH with SARD Patients with SARD-PH have high morbidity and mortality. In a meta-analysis including 2,244 patients with SSc-associated PH, the pooled 1-, 2-, and 3-year survival rates were 81%, 64%, and 52%, respectively (53). Therefore, it is important to start early treatment, as PAH is relentlessly progressive. Immunosuppression is not beneficial in IPAH, but its effect on SARD-PAH varies. Immunosuppressive medications may result in clinical improvement in patients with SLE or mixed connective tissue disease (MCTD)-associated PAH, while it does not have a clear benefit in PAH-SSc (54). 3.20 MANAGEMENT CONSIDERATIONS FOR PATIENTS IN WHO GROUPS 2–5 Group 2: Management should be focused on the optimization of heart disease with guidelinedirected therapy (beta blockers, renin–angiotensin–system-acting agents, mineralocorticoid receptor antagonists, and sodium-glucose transport protein 2 inhibitors). Multiple studies using pulmonary vasodilators in this population have been negative or have trended toward harm. It is unclear if there is a role for PH-specific therapy in carefully selected patients with combined pre/postcapillary PH. This is controversial and should be managed at an expert center. Group 3: Management centers on the optimization of the underlying lung disease. Inhaled treprostinil in patients with PH and ILD was recently approved, as it was shown to improve 6MWT and NT-proBNP levels and decrease the number of hospitalizations in this select patient group (55). Group 4: Patients with CTEPH need indefinite anticoagulation and should be evaluated at a CTEPH center for the consideration of pulmonary thromboendarterectomy. For patients who are not surgical candidates, balloon pulmonary angioplasty (BPA) and PH-specific therapy with riociguat can improve PVR. Riociguat given prior to BPA can decrease the rates of complications from the procedure (56, 57). Group 5: This is a heterogeneous group of patients whose treatment will be oriented toward the underlying disease process, and referral to a PH center should be considered. 47

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3.21 CONCLUSION Pulmonary hypertension is a complex condition encompassing multiple underlying etiologies that lead to elevated pressure in the pulmonary vasculature and right heart failure. Patients typically present with exertional dyspnea and fatigue and can develop signs of right heart failure as the disease progresses. Individuals with SARDs face a higher risk of developing PH compared to the general population. Specific PH screening algorithms exist for scleroderma, but for other SARDs, screening should be considered based on risk factors and symptoms. Patients suspected of having PH need to undergo extensive diagnostic testing to confirm the diagnosis and identify the underlying cause. The diagnostic work up includes blood work, PFTs, CTPA, V/Q scan, sleep study, TTE, and RHC. After confirming PH, patients should be referred to specialized centers with expertise in PH for appropriate classification, risk stratification, and treatment. The regular reassessment of risk stratification is necessary at the time of diagnosis and during follow-up visits after the initiation of PH-specific therapy. Medical management for PH primarily targets Group 1 pulmonary hypertension and consists of medications including CCBs, PD5Is, ERAs, soluble guanylate cyclase stimulators, and prostanoids. For patients who do not respond optimally to maximum PH therapy, careful evaluation for lung transplantation is warranted as a potential therapeutic option. REFERENCES 1. Maron BA, Brittain EL, Hess E , et al. Pulmonary vascular resistance and clinical outcomes in patients with pulmonary hypertension: A retrospective cohort study. Lancet Respir Med. 2020;8(9):873–84. 2. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS guidelines for pulmonary hypertension: Key points. Eur Heart J. 2022;61(1):2200879. 3. Prins KW, Thenappan T. World Health Organization group I pulmonary hypertension: Epidemiology and pathophysiology. Cardiol Clin. 2016;34(3):363–74. 4. McGoon MD, Miller DP. Reveal: A contemporary US pulmonary arterial hypertension registry. Eur Respir Rev. 2012;21(123):8–18. 5. Humbert M, Chaouat A, Bertocchi M, et al. Pulmonary arterial hypertension in France: Results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023–30. 6. Coghlan JG, Denton CP, Grünig E, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: The DETECT study. Ann Rheum Dis. 2014;73(7):1340–9. 7. Lacoste-Palasset T, Chaumais MC, Weatherald J, et al. Association between leflunomide and pulmonary hypertension. Ann Am Thorac Soc. 2021;18(8):1306–15. 8. Chang KY, Duval S, Badesch DB, et al. Mortality in pulmonary arterial hypertension in the modern era: Early insights from the pulmonary hypertension association registry. J Am Heart Assoc. 2022;11(9):e024969. 9. Gupta S, Gupta A, Rehman S, et al. Pulmonary veno-occlusive disease is highly prevalent in scleroderma patients undergoing lung transplantation. ERJ Open Res. 2019;5(1):00168–2018. 10. Haque A, Kiely DG, Kovacs G, et al. Pulmonary hypertension phenotypes in patients with systemic sclerosis. Eur Respir Rev. 2021;30(161):210053. 11. Hansdottir S, Groskreutz DJ, Gehlbach BK. WHO ‘s in second? A practical review of World Health Organization group 2 pulmonary hypertension. Chest. 2013;144(2):638–50. 12. Singh N, Dorfmüller P, Shlobin OA, et al. Group 3 pulmonary hypertension: From bench to bedside. Circ Res. 2022;130(9):1404–22. 13. Launay D, Montani D, Hassoun PM, et al. Clinical phenotypes and survival of pre-capillary pulmonary hypertension in systemic sclerosis. PLoS ONE. 2018;13(5):e0197112. 14. Klok FA, van Kralingen KW, van Dijk AP, et al. Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism. Haematologica. 2010;95(6):970–5. 15. Pengo V, Lensing AW, Prins MH, et al. Thromboembolic pulmonary hypertension study group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350(22):2257–64. 16. Kim N. Group 4 pulmonary hypertension. Chronic thromboembolic pulmonary hypertension: Epidemiology, pathophysiology, and treatment. Cardiol Clin. 2016;34(3):435–41. 17. Kalantari S, Gomberg-Maitland M. Group 5 pulmonary hypertension: The Orphan’s orphan disease. Cardiol Clin. 2016;34(3):443–9. 48

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18. Handa T, Nagai S, Miki S, et al. Incidence of pulmonary hypertension and its clinical relevance in patients with sarcoidosis. Chest. 2006;129(5):1246–52. 19. Shorr AF, Davies DB, Nathan SD. Predicting mortality in patients with sarcoidosis awaiting lung transplantation. Chest. 2003;124(3):922–8. 20. Kiely DG, Lawrie A, Humbert M. Screening strategies for pulmonary arterial hypertension. Eur Heart J Suppl. 2019;21(Suppl K): K9–K20. 21. Rich JD, Rich S. Clinical diagnosis of pulmonary hypertension. Circulation. 2014;130(20):1820–30. 22. Lewis RA, Durrington C, Condliffe R, et al. BNP/NT-proBNP in pulmonary arterial hypertension: Time for point-of-care testing? Eur Respir Rev. 2020;29(156):200009. 23. Fisher MR, Forfia PR, Chamera E, et al. Accuracy of doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179(7):615–21. 24. Cordina RL, Playford D, Lang I, et al. State-of-the-art review: Echocardiography in pulmonary hypertension. Heart Lung Circ. 2019;28(9):1351–64. 25. Forfia PR, Fisher MR, Mathai SC, et al. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med. 2006;174(9):1034–41. 26. Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39(7):1214–19. 27. Hoeper MM, Lee SH, Voswinckel R, et al. Complications of right heart catheterization procedures in patients with pulmonary hypertension in experienced centers. J Am Coll Cardiol. 2006;48(12):2546–52. 28. Tea I, Hussain I. Under pressure: Right heart catheterization and provocative testing for diagnosing pulmonary hypertension. Methodist Debakey Cardiovasc J. 2021;17(2):92–100. 29. Hoda D, Mohamed-Hussein AA. Evaluation of FVC/DLCO ratio as a predictor for pulmonary hypertension in patients with interstitial lung diseases. Eur Respir J. 2017;50(suppl 61):PA861. 30. Hachulla E, Gressin V, Guillevin L, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: A French nationwide prospective multicenter study. Arthritis Rheumatol. 2005;52(12):3792–800. 31. Swift AJ, Dwivedi K, Johns C, et al. Diagnostic accuracy of CT pulmonary angiography in suspected pulmonary hypertension. Eur Radiol. 2020;30(9):4918–29. 32. Lewis G, Hoey ET, Reynolds JH, et al. Multi-detector CT assessment in pulmonary hypertension: Techniques, systematic approach to interpretation and key findings. Quant Imaging Med Surg. 2015;5(3):423–32. 33. Gopalan D, Delcroix M, Held M. Diagnosis of chronic thromboembolic pulmonary hypertension. Eur Respir Rev. 2017;26(143):160108. 34. Masy M, Giordano J, Petyt G, et al. Dual-energy CT (DECT) lung perfusion in pulmonary hypertension: Concordance rate with V/Q scintigraphy in diagnosing chronic thromboembolic pulmonary hypertension (CTEPH). Eur Radiol. 2018;28(12):5100–10. 35. Narechania S, Renapurkar R, Heresi GA. Mimickers of chronic thromboembolic pulmonary hypertension on imaging tests: A review. Pulm Circ. 2020;10(1):2045894019882620. 36. Kholdani C, Fares WH, Mohsenin V. Pulmonary hypertension in obstructive sleep apnea: Is it clinically significant? A critical analysis of the association and pathophysiology. Pulm Circ. 2015;5(2):220–7. 37. Wessels JN, de Man FS, Vonk Noordegraaf A. The use of magnetic resonance imaging in pulmonary hypertension: Why are we still waiting? Eur Respir Rev. 2020;29(156):200139. 38. Weatherald J, Farina S, Bruno N, et al. Cardiopulmonary exercise testing in pulmonary hypertension. Ann Am Thorac Soc. 2017;14(Supplement_1):S84–S92. 39. Maron BA, Cockrill BA, Waxman AB, Systrom DM. The invasive cardiopulmonary exercise test. Circulation. 2013;127(10):1157–64. 40. Coghlan JG, Denton CP, Grünig E, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: The DETECT study. Ann Rheum Dis. 2014;73(7):1340–9. 41. Weatherald J, Montani D, Jevnikar M, et al. Screening for pulmonary arterial hypertension in systemic sclerosis. Eur Respir Rev. 2019;28(153):190023. 42. Boucly A, Weatherald J, Savale L, et al. External validation of a refined four-stratum risk assessment score from the French pulmonary hypertension registry. Eur Respir J. 2022;59(6):2102419. 43. Benza RL, Kanwar MK, Raina A, et al. Development and validation of an abridged version of the REVEAL 2.0 risk score calculator, REVEAL Lite 2, for use in patients with pulmonary arterial hypertension. Chest. 2021;159(1):337–46. 49

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44. Maron BA. Revised definition of pulmonary hypertension and approach to management: A clinical primer. J Am Heart Assoc. 2023;12(8):e029024. 45. Xing J, Cao Y, Yu Y, Li H, et al. In vitro micropatterned human pluripotent stem cell test (µP-hPST) for morphometric-based teratogen screening. Sci Rep. 2017;7(1):8491. 46. Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388(16):1478–90. 47. Grünig E, Eichstaedt C, Barberà JA, et al. ERS statement on exercise training and rehabilitation in patients with severe chronic pulmonary hypertension. Eur Respir J. 2019;53(2):1800332. 48. Farber HW, Badesch DB, Benza RL, et al. Use of supplemental oxygen in patients with pulmonary arterial hypertension in REVEAL. J Heart Lung Transplant. 2018;37(8):948–55. 49. Sonnweber T, Nairz M, Theurl I, et al. The crucial impact of iron deficiency definition for the course of precapillary pulmonary hypertension. PLoS ONE. 2018;13(8):e0203396. 50. McLaughlin VV, Vachiery JL, Oudiz RJ, et al. Patients with pulmonary arterial hypertension with and without cardiovascular risk factors: Results from the AMBITION trial. J Heart Lung Transplant. 2019;38(12):1286–95. 51. Barst RJ, Rubin LJ, Long W, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996. PMID: 8532025. http://doi.org/10.1056/NEJM199602013340504. 52. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: A double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165(6):800–4. 53. Lefèvre G, Dauchet L, Hachulla E, et al. Survival and prognostic factors in systemic sclerosisassociated pulmonary hypertension: A systematic review and meta-analysis. Arthritis Rheumatol. 2013;65(9):2412–23. 54. Sanchez O, Sitbon O, Jaïs X, et al. Immunosuppressive therapy in connective tissue diseasesassociated pulmonary arterial hypertension. Chest. 2006;130(1):182–9. 55. Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med. 2021;384(4):325–34. 56. Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319–29. 57. Jaïs X, Brenot P, Bouvaist H, et al. Balloon pulmonary angioplasty versus riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension (RACE): A multicentre, phase 3, open label, randomised controlled trial and ancillary follow-up study. Lancet Respir Med. 2022;10(10):961–71.

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4 Approach to the Patient with Neuromuscular Weakness

4  Approach to the Patient with Neuromuscular Weakness Aparna Bhat, Jason Dean, and Loutfi S. Aboussouan List of Abbreviations ACCP The American College of Chest Physicians ALS Amyotrophic lateral sclerosis ATS American Thoracic Society CT Computer tomography DM Dermatomyositis EMG Electromyography FRC Functional residual capacity FVC Forced vital capacity HFCWO High-frequency chest wall oscillation IBM Inclusion body myositis IIP Idiopathic inflammatory myopathies ILD Interstitial lung disease MEP Maximal expiratory pressure MIP Maximal inspiratory pressure NAM Necrotizing autoimmune myopathy NIPPV Noninvasive positive pressure ventilation NMD Neuromuscular diseases Pdi Transdiaphragmatic pressure PFTs Pulmonary function tests PM Polymyositis REM Rapid eye movement RV Residual volume SLE Systemic lupus erythematosus SLS Shrinking lung syndrome TLC Total lung capacity VC Vital capacity 4.1 INTRODUCTION Neuromuscular diseases (NMDs) are a broad group of disorders that impair or damage peripheral nerves or muscles. The disorders could originate in the spinal cord, motor neurons, motor nerves, neuromuscular junction, or the muscle itself and can progress to respiratory and expiratory dysfunction with the impairment of ventilation and compromise of cough and secretion clearance. Many of these diseases have respiratory implications, and serious adverse events, including death, can be directly attributed to pulmonary complications from respiratory muscle involvement, associated thoracic cage abnormalities, or aspiration risk. Representative diseases are shown in Table 4.1. Specific conditions in which neuromuscular impairment may be noted in autoimmune/ rheumatic diseases include restrictive lung disease in systemic lupus and inflammatory myopathies. A thorough evaluation including patient history, clinical assessment, and the timely implementation of therapeutic interventions can have a favorable impact on the morbidity and mortality of those disorders and will be reviewed here. 4.2 PATIENT EVALUATION 4.2.1  Clinical Presentation In addition to general symptoms of dyspnea at rest and on exertion, the clinician should elicit features of respiratory and diaphragm muscle weakness including orthopnea, difficulty breathing when bending down, or trepopnea (which reflects asymmetric diaphragm involvement with greater difficulty breathing with the healthier side down). Shortness of breath when lifting or reaching up may occur because of the diversion of accessory muscles of respiration to a different task, or when immersed in water due to the load imposed by water weight. In contrast to orthopnea, some patients with quadriplegia, spinal muscular atrophy, or multiple sclerosis may have difficulty breathing in the sitting or semi-recumbent position (platypnea) (1, 19). As the disruption of sleep may be an early marker of respiratory muscle weakness, symptoms may include DOI: 10.1201/9781003361374-551

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Table 4.1: Selected Neuromuscular Diseases with Respiratory Muscular Manifestations Representative Diseases Spinal cord injury Motor Neurons Postpolio syndrome Amyotrophic lateral sclerosis Spinal muscular atrophy Motor Nerves Guillain–Barré syndrome Charcot–Marie– Tooth Diaphragm paralysis

Description, Course of Disease, and Respiratory Muscular Involvement Permanent traumatic injury to the spinal cord. High lesions (C1–3) require mechanical ventilation. May be associated with platypnea (1).

New/slowly progressive disease, decades after acute poliomyelitis, due to the instability and degeneration of reinnervated, enlarged motor units (2) and spinal gray matter atrophy (3). Respiratory impairment in those with respiratory involvement in initial infection (4). Rapidly progressive loss of upper and lower motor neurons with muscle and bulbar weakness. Median survival 2–5 years after onset (5), with death from respiratory complications including respiratory failure or aspiration (6). Autosomal recessive, progressive disease from survival motor neuron gene 1 (SMN1) mutations (7). Reduced disease severity with more copies of paralogous SMN2 gene. SMA1: Death/respiratory failure ≤ 2 years. SMA2: scoliosis and respiratory muscle weakness. Potentially treatable acute polyneuropathy after respiratory or gastrointestinal infection reaching maximal severity by 4 weeks. Respiratory failure for days to months in 25% (8). Very slowly progressive group of hereditary demyelinating or axonal disorders of peripheral nerves with various forms of inheritance. Prolonged phrenic nerve conduction in over 96%, and 30% have FVC of < 80% (9). Potentially reversible phrenic nerve injury. Can be idiopathic, post-surgical, after neck mani­ pulations, or from neuralgic amyotrophy. May manifest with orthopnea or trepopnea (10).

Neuromuscular Junction Myasthenia gravis Autoimmune, complement-mediated postjunctional membrane damage from antibodies against nicotinic acetylcholine receptor, muscle-specific tyrosine kinase receptor, or lowdensity lipoprotein 4. Crisis episodes can occur spontaneously; with concurrent infection; after surgery, pregnancy, childbirth; or from medications (aminoglycosides, quinolones, macrolides, magnesium, beta blockers, procainamide, or quinidine) with 12% mortality (11). Lambert Eaton Reduced presynaptic release of acetylcholine due to antibodies against voltage-gated calcium channel. Can be paraneoplastic (almost all from small cell cancer and less often thymic tumors) or non-paraneoplastic (12). Toxins Includes botulism: Mortality of 8% is due to respiratory failure. Some pulmonary impairment may persist for > 1 year in survivors (13). Muscle Dystrophies

X-linked Duchenne muscular dystrophy: Absence of dystrophin from out-of-frame or nonsense mutations. Becker’s muscular dystrophy: Partially functional dystrophin from in-frame and missense mutations.

Inflammatory myopathies Metabolic myopathies Post-paralysis myopathy

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Other types: Congenital, distal, limb girdle, facioscapulohumeral, Emery–Dreifuss, myotonic, and oculopharyngeal. Respiratory failure is major cause of death (14). Include dermato- and polymyositis, inclusion body myositis, and necrotizing autoimmune myopathy. Respiratory muscle weakness can be present in up to 75% (15). Treatment is breathing support and immunosuppressive therapy (16). Defects in glycogen, lipid, adenine nucleotides, or mitochondrial metabolism. Respiratory weakness mostly in infantile and late-onset Pompe disease (IOPD and LOPD) from mutations causing complete or partial acid alpha-glucosidase (GAA) deficiency. 30% of asthmatics on steroids and paralytics in ICU had muscle weakness associated with prolonged ventilation (17, 18).

4  Approach to the Patient with Neuromuscular Weakness

unexplained nocturnal awakenings, morning headaches (from disrupted sleep or hypercapnia), or daytime sleepiness. Finally, for conditions associated with bulbar weakness (myasthenia gravis, amyotrophic lateral sclerosis [ALS], Guillain–Barré syndrome), close attention should be given to the ability to handle loose and thick secretions. 4.2.2  Physical Exam Direct observation can assess for accessory muscle use (i.e., sternocleidomastoids, scalenes, external intercostals), ineffective cough, or impaired speech (slurring of speech, low-volume speech, inability to complete a sentence in one breath). An assessment of diaphragm excursion by percussion can be made in a sitting position, with a normal excursion of about 2–3 fingerbreadths. Auscultation can reveal the asymmetry of breath entry as a marker of unilateral diaphragm impairment, or crackles from atelectasis or aspiration. There may be inspiratory abdominal paradox in the supine position in diaphragm weakness (20), though an inspiratory chest paradox may be noted in spinal muscular atrophy due to greater weakness of intercostals relative to the diaphragm (19). An oral exam should assess for the pooling of loose or thick secretions, atrophy or fasciculation of the tongue, and reduced gag reflex. A voluntary cough may also be assessed for strength. The clinician can also assess nutritional status (temporal wasting, enophthalmos) and findings of neuromuscular weakness (strength of extremities, interossei, thenar, hypothenar wasting). 4.2.3  Pulmonary Function Testing Forced vital capacity (FVC) is the most commonly used value in monitoring respiratory function in NMD. The FVC effectively assesses inspiratory and expiratory capacity since the test depends on forced expiration after maximal inspiration (21). Additionally, a drop in FVC of greater than 25% in the supine position has a 90% specificity and 79% sensitivity for diaphragmatic weakness (22, 23). In bilateral diaphragm involvement or paralysis, a drop in FVC of 40–50% when supine would be expected (24). In the general population, a sitting-to-supine drop in FVC of 5–7% would be considered normal, though a normative 95% confidence limit may be as high as 19% (25). The American College of Chest Physicians (ACCP) clinical practice guidelines recommends baseline pulmonary function tests (PFTs) in NMD at the time of diagnosis and at least every 6 months to track progress of respiratory involvement in progressive NMD (26). Measures of respiratory muscles weakness in NMD include maximal inspiratory and expiratory pressure (MIP and MEP) (27). The MIP is measured from residual volume (RV) and tests the strength of the diaphragm and other inspiratory muscles. A value < 60 cmH2O is 86% sensitive as a surrogate marker of nocturnal hypoxia (28). MEP is measured from total lung capacity (TLC) and tests the abdominal and other expiratory muscles, with values < 60 cmH2O suggesting ineffective cough (29). The MIP and MEP may over diagnose inspiratory and/or expiratory muscle weakness, as they are voluntary maneuvers. When MIP values are combined with other tests such as sniff testing, 27.4% fewer patients are found to have global inspiratory weakness when compared to using MIP alone. Similarly, when MEP values are combined with coughing strength, the relative reduction in diagnosis of expiratory muscle weakness is 56.4% (30). The American Thoracic Society (ATS) defines restrictive ventilatory defect by a reduction in TLC (31). However, the TLC is relatively preserved in the early stages of neuromuscular weakness (32), and the vital capacity (VC) may be more sensitive in predicting the progression of respiratory involvement compared to the TLC (32) (Figure 4.1). The residual volume (RV) is increased due to the reduced expiratory muscle strength and the outward elastic recoil of the chest wall. In NMD, the functional residual capacity (FRC) may be unchanged initially but reduces with disease progression due to the reduced chest wall recoil from muscular involvement and diaphragm weakness (32, 33). Nocturnal oximetry is a noninvasive and convenient method to assess the integrity of ventilation during the dual challenge of the supine position and sleep state, and it may be predictive of survival (34). Blood gas, end-tidal, or transcutaneous CO2 measurements can be helpful in the evaluation of hypoventilation in NMD, though changes in PaCO2 can lag and be near normal in the early stages of neuromuscular weakness (21). Transdiaphragmatic pressure (Pdi) is the gold standard diagnostic test for diaphragmatic paralysis and is measured as the difference between the pressure at the level of the lower third of the esophagus just above the diaphragm and that in the stomach, obtained at rest and during tidal 53

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8

7

6

5

4

3

2

1

0 NMD

Normal RV

ERV

TV

IRV

Figure 4.1  Comparison of individual lung volumes in normal vs. neuromuscular disease. Note that the reduction in vital capacity is more from an increase in the residual volume than from a decrease in the total lung capacity. The FRC is variable but generally preserved, and the expiratory reserve volume is significantly reduced.

breathing. The Pdi correlates well with less invasive tests including the supine FVC (23), the magnitude of FVC drop in the supine position (22), and the sniffed nasal inspiratory pressure (35, 36). 4.2.4 Imaging A chest radiograph can identify the position of the patient’s diaphragm and the presence of hypo-inflation or a thoracic process such as kyphoscoliosis. An elevated diaphragm is nonspecific and may represent diaphragm weakness, paralysis, or eventration. In diaphragm weakness or paralysis, there is partial or total loss, respectively, of the diaphragm strength required to generate adequate ventilation, usually following injury to the phrenic nerve (37). In contrast, eventration represents a developmental or acquired weakness with thinning causing regional elevation of the affected portion while maintaining normal attachments to the costal margins, which are best seen on the lateral radiograph (38). The chest radiograph has high sensitivity (90%) but low specificity (44%) for the diagnosis of unilateral hemidiaphragm paralysis (37). Clinical correlation with history, pulmonary function tests, and dynamic imaging are therefore important. The computer tomographic (CT) scan, though not commonly used in the workup of neuromuscular weakness, may help assess diaphragm muscle integrity (39) or parenchymal causes of restriction. Magnetic resonance imaging (MRI) can assess muscle health in degenerative muscular disease, such as Duchenne muscular dystrophy. In the idiopathic inflammatory myopathies, dynamic MRI can assess respiratory function (39), though chest fluoroscopy and ultrasound are more commonly used dynamic techniques. Chest fluoroscopy captures images of the diaphragm muscle contracting during breathing. Patients are asked to perform a variety of breathing sequences, including a forceful inspiratory “sniff” under fluoroscopy. This effort will cause the paralyzed diaphragm to move paradoxically in a cephalad direction, while the functional diaphragm moves in a caudal direction (40). While sniff fluoroscopy can be helpful when assessing diaphragm dysfunction, it should not be relied 54

4 Approach to the Patient with Neuromuscular Weakness

Figure 4.2  M-mode ultrasound of the diaphragm using a high-frequency linear probe placed in an anterior axillary line at the ninth intercostal space. This image demonstrates normal thickening of the diaphragm with breathing. (A) Thickness with inspiration. (B) Thickness with expiration.

upon as the sole objective measure. Sniff can yield a 20% false positive result. When sniff is used in patients with bilateral dysfunction, it can often be interpreted as a normal test due to the equal reduction in motion. Ultrasound is a noninvasive method to assess the diaphragm function at two functionally important areas: the zone of apposition and the dome of the diaphragm. The zone of apposition is where the diaphragm is in direct contact with the rib cage, and the dome is the central tendon of the diaphragm that is innervated by the phrenic nerve. Ultrasound uses linear and phased array probes to image the right and left hemidiaphragm through specific windows allowing for the visualization of the downward excursion of the diaphragm dome and the thickening of the muscle itself (Figure 4.2) (40). In general, normal diaphragm values (41, 42) are: ■

Diaphragm thickness > 1.5 mm at the end of a tidal breath

■

≥ 20% thickening with deep inspiration

■

≤ 3.3 mm variation in thickening between sides

■

> 1 cm excursion of the diaphragm dome with quiet breathing

■

≥ 3.6 cm excursion in females with deep breathing

■

≥ 4.7 cm excursion in males with deep breathing

4.2.5  Diaphragm Electromyography and Phrenic Nerve Conduction Diaphragm electromyography (EMG) with phrenic nerve stimulation evaluates the integrity of the phrenic nerve–diaphragm axis. The procedure involves electrical (or magnetic) stimulation of the phrenic nerve posterior to the sternocleidomastoid or in the supraclavicular fossa, as well as the measurement of diaphragm EMG (compound muscle action potential, latency, duration, and area) through surface, esophageal, or intramuscular electrodes (43). The most common application of this procedure in NMD is to help select candidates for diaphragm pacing or phrenic nerve reconstruction. There may be technical challenges in phrenic nerve stimulation, including the contamination of signals, especially with surface electrodes, and the risk of pneumothorax or injury to the liver and spleen with needle electrodes. EMG of the diaphragm with normal breathing can help distinguish between neuropathic and myopathic diaphragm impairment but is rarely done for that purpose, especially as diagnostic features in systemic NMD may not require diaphragm EMG (44). 55

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4.2.6 Polysomnography Polysomnography with measurements of CO2 and respiratory effort is invaluable for the detection of sleep hypoventilation, the characterization of the types of potential sleep disordered breathing events in neuromuscular disorders (pseudocentral, obstructive, and central events), and for the titration to optimal settings of noninvasive positive pressure ventilation (NIPPV) to prevent ineffective ventilation and asynchronies, which are associated with reduced survival and quality of life (20, 45, 46). Rapid eye movement (REM) sleep is a particularly vulnerable period for patients with neuromuscular disorders due to the “perfect storm” combination of a normally reduced contribution of the rib cage to the tidal volume from REM atonia and a pathologically weakened diaphragm (Figure 4.3) (20). From a practical standpoint, patients with NMD rarely undergo polysomnography due to reduced mobility, challenges in accommodating disabilities, a lack of specific protocols, a lack of CO2 monitoring, and poor familiarity with the goals of NIPPV titration for NMD in many sleep laboratories. In a randomized trial that included predominantly patients with NMD, NIPPV titration via polysomnography compared to sham titration had only modest benefits with improved

Figure 4.3  Polysomnogram in a patient with amyotrophic lateral sclerosis. Four 30-second epochs are shown, numbered 267 to 270, representing sleep stages N2, REM (R), wake (W), and N1 respectively. E2-M1 and E2-M2 are right and left eye activity referenced to their contralateral mastoid. CHIN1 is the chin electromyogram (EMG). Subsequent channels from F4-M1 to O1-M2 represent the electroencephalogram (EEG) from scalp electrodes: frontal (F), vertex (C), and occipital (O) (right followed by left referenced to the contralateral mastoid). NASAL-TR, CHEST, and ABDOMEN are the nasal pressure transducer, chest, and abdominal belts, respectively. SAO2 is oxygen saturation percent, and ETCO2 is end-tidal CO2 in mmHg. The latter two channels demonstrate significant hypoxemia and hypercapnia, respectively, from hypoventilation during sleep. The onset of REM in epoch 268 is demonstrated by the sharp out-of-phase eye movements, sudden attenuation of the chin EMG activity, and presence of sawtooth waves in the frontocentral EEG leads (best seen just after the transition from epoch 268 to epoch 269). A sleep disordered breathing event promptly follows the onset of REM sleep, with near complete loss of excursion in the NASAL-TR, CHEST, and ABDOMEN signals, most likely representing pseudocentral apnea. This event is promptly followed by further desaturation and an awakening. The decrease in the ETCO2 signal is an artifact related to apnea itself (no end-tidal CO2 to sample). 56

4 Approach to the Patient with Neuromuscular Weakness

asynchronies (specifically ineffective efforts) and increased daily use of NIPPV in those with poor initial adherence, but with no difference in arousal index, nocturnal gas exchange, or sleep quality (47). A randomized trial demonstrated the noninferiority of a device with self-adjusting expiratory positive airway pressure relative to manual adjustments (48). However, polysomnography is considered a gold standard for the diagnosis of sleep disordered breathing in pediatric NMD (49). Further, practice parameters recommend polysomnography in NMD to guide treatment decisions in the assessment of symptoms that remain undiagnosed after evaluation including PFTs and nocturnal oximetry (26, 50). 4.3 NEUROMUSCULAR DISEASE IN AUTOIMMUNE/RHEUMATIC DISEASE 4.3.1  Systemic Lupus Erythematosus Pulmonary manifestations occur in about 7% of patients with systemic lupus erythematosus (SLE) and include interstitial lung disease (ILD), acute pneumonitis, pulmonary hypertension, pulmonary infarction, embolic disease, pleural disease, alveolar hemorrhage, and shrinking lung syndrome (SLS) (51). SLS was described by Hoffbrand and Beck in 1965 to represent a progressive loss of lung volume, restrictive lung disease, and the progressive elevation of the diaphragm in the absence of interstitial lung disease (Figure 4.4) (52). SLS is rare and was found in only four of 626

Figure 4.4  Chest radiograph of shrinking lung syndrome in a patient with systemic lupus erythematosus (SLE). (A) Reduced lung volumes. The forced vital capacity was 23% predicted with a 27% drop in the supine position, and maximum inspiratory pressure was 57%. (B) The same patient several years later while on treatment for her SLE. The lungs are well expanded and the vital capacity is now 51%, with a 13% drop in the supine position; maximal inspiratory pressure is 98%. 57

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patients (0.6%) of a longitudinal cohort (51), though the prevalence may be as high as 6% in patients with severe refractory SLE manifestations (53). While SLS is well defined, its pathophysiology is uncertain and may be multifactorial, including neuromuscular causes from respiratory muscle weakness and phrenic neuropathy or impaired diaphragm excursion from pleuritis and adhesions (54). Factors that support diaphragm dysfunction as a contributing factor include a postmortem report documenting diffuse diaphragmatic fibrosis (55), findings of reduced transdiaphragmatic and maximal inspiratory pressures (56, 57), and reduced diaphragm thickness and excursion on ultrasound (58). Phrenic nerve involvement has also been described as possibly related to a vasculitic or autoimmune neuropathy (54). However, a more critical evaluation suggests that, in the majority of patients, pleuritic inflammation rather than diaphragm dysfunction may be a significant contributor to SLS (54, 56), with magnetic resonance imaging confirming pleuritis (59). Volitional tests of respiratory muscle function, such as PFTs, are likely confounded by the presence of pleurisy and pleuritic pain. For instance, studies that involve nonvolitional testing show normal transdiaphragmatic pressures and phrenic nerve function in the majority of patients with SLS after direct electrical or magnetic stimulation of the phrenic nerve (60, 61). This would not preclude diaphragm dysfunction from an autoimmune neuropathy or pleural inflammation causing the reflex inhibition of diaphragmatic function (54). In addition to supportive treatment of the restrictive pulmonary impairment described herein, the escalation of immunosuppressive therapy may objectively improve pulmonary restriction and measures of respiratory muscle strength in some patients (Figure 4.4) (54). 4.3.2  Idiopathic Inflammatory Myopathies Idiopathic inflammatory myopathies (IIMs) include polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), and necrotizing autoimmune myopathy (NAM) (Table 4.1). While ILD is the major pulmonary finding, IIM can be associated with additional pulmonary complications of pulmonary arterial hypertension, parenchymal disease, pulmonary infections, malignancy, or respiratory muscle weakness (16). ILD may start before muscular findings in roughly 20% of cases (16). ILD can often obscure the impact of IIM on respiratory strength due to its inherent restrictive presentation. Respiratory muscle weakness in IIM was thought to be very rare (16), but a systematic evaluation of mouth pressures in response to phrenic nerve stimulation identified diaphragm dysfunction in 78% of IIM, with the lowest mouth pressures in DM, followed by IBM, and then PM (15). Diaphragm thickening, as measured by ultrasound, is another advanced method to assess diaphragm function in IIM, and this technique similarly documents diaphragm weakness in at least 45% of patients with IBM (62). The early detection of diaphragm muscle weakness can be imperative for survival in this patient population (16). Critical criteria should trigger hospital admission and close monitoring, including: FVC < 15 mL/kg or < 55% predicted or MIP < 30% predicted (16). Restrictive lung disease related to myopathies treated with glucocorticoids or immunosuppressive drugs have been shown to reach full remission in most cases (16). 4.4 TREATMENT APPROACH 4.4.1  Noninvasive and Invasive Ventilation Patients with NMD account for 35% of domiciliary invasive and noninvasive mechanical ventilation, with 24% of those on ventilation via tracheostomy and the remainder via a noninvasive interface (63). NMD comprises 81% of indications for long-term home noninvasive ventilation in a survey from the European Respiratory Society, and the most common NMD was amyotrophic lateral sclerosis (ALS) (78% of cases) (64). Criteria in the United States for the coverage of noninvasive ventilation in progressive NMD include any of the following: an FVC ≤ 50% predicted, hypercapnia (PaCO2) ≥ 45 mmHg, MIP ≤ 60 cmH2O, or nocturnal oxygen saturation ≤ 88% for ≥ 5 minutes of recording time (65). Symptoms are a significant reason for initiating noninvasive ventilation (66) but are not considered in the reimbursement criteria. International guidelines and a recent technical expert report recommend more liberal criteria, including the use of noninvasive ventilation for the alleviation of symptoms (26, 67). Noninvasive positive pressure ventilation improves survival, relieves symptoms of chronic hypoventilation, and improves sleep and quality of life in patients with NMD (68–70). Mechanisms 58

4 Approach to the Patient with Neuromuscular Weakness

of benefit include support of hypoventilation, control of sleep disordered breathing, decrease in arousals, improvement in daytime hypercapnia and increased ventilatory response to CO2 (71), reduced oxygen cost of breathing (72), and improved lung compliance (73). Over 90% of patients with NMD on NIPPV continue using it 3 years after initiation (74). Negative-pressure ventilation options include the iron lung, rocking bed, poncho wrap, or cuirass ventilation (75, 76). The cuirass ventilator generates a suction to expand the chest (75) and remains the most common negative-pressure ventilation option, with other options either rarely used or no longer manufactured. It can be a primary option, an alternative option to NIPPV, or implemented for patients with NIPPV contraindications (intolerance, facial injuries, deformities, skin breakdown, or surgery). Contraindications to the cuirass include sleep apnea, severe obesity, kyphoscoliosis, rib fractures, or prior abdominal surgery. Modern devices also have a positive pressure applied during expiration to facilitate expiration and may have a high-frequency chest wall oscillation feature to facilitate secretion clearance. Advantages are the preservation of speech, swallowing, feeding, and expiratory function. Disadvantages include musculoskeletal pain, discomfort, glottic closure, and compromise of the upper airway due to the negative pressure with the possibility of worsening sleep disordered breathing (75, 77). 4.4.2  Support of Expiratory Function 4.4.2.1  Mechanical Insufflator–Exsufflator Coughing involves a coordinated effort between inspiratory, expiratory, and upper airway muscles, all of which can be compromised in NMD with an increased risk of atelectasis, pneumonia, and respiratory failure. The functional efficacy of cough can be indirectly assessed using maximal inspiratory pressure and maximal expiratory pressure, or peak cough flow. If the cough is deemed to be weak (such as peak cough flows < 270 L/minute) (78), treatment options include a mechanical insufflator–exsufflator device, which delivers positive pressure via a facial mask to maximally inflate the lungs followed by negative pressure to assist in the expulsion of secretions out of the respiratory tract. The device effectively increases peak cough flows in patients with respiratory muscle weakness (79). An ACCP clinical practice guideline recommends the mechanical insufflator–exsufflator device in patients with NMD and reduced cough effectiveness when alternative techniques are inadequate (26). 4.4.2.2  Oscillatory Devices Airway clearance also depends on the mobilization of secretions from the small airways. Oscillatory devices generate vibrations to mobilize mucous and come in two forms: intrathoracic oscillations generated with positive expiratory pressure devices (Flutter®, Acapella®, Aerobika®, and RC-Cornet®), or extrathoracic wearable vests that generate high-frequency chest wall oscillation (HFCWO). HFCWO applies high-frequency (5–20 Hz) pressure impulses externally to the chest wall. It is typically used for 20–30 minutes up to three times daily. Primarily, the evidence for using this device has been in those with cystic fibrosis, as these patients have impaired mucociliary function (80). A small prospective study of HFCWO in patients with ALS receiving NIPPV showed no improvement in survival and no impact on the rate of decline in vital capacity as compared to NIPPV alone (81). Alternatively, a review of insurance claims showed that HFCWO in NMD reduced medical costs, hospitalizations, and pneumonias (82). An ACCP clinical practice guideline recommends HFCWO for secretion mobilization in those with NMD and difficulties with secretion clearance (26). 4.4.3  Other Options Aerosolized albuterol or hypertonic saline can be used in addition to the support of expiratory function to help with the clearance of thick adherent secretions that would otherwise be difficult to mobilize for patients with NMD. Sialorrhea is a disabling symptom in NMD and is primarily due to an impaired swallowing function with facial muscle weakness rather than from increased saliva production. The impact of sialorrhea can range from psychological stress and embarrassment to the exacerbation of dysarthria, inability to utilize NIPPV, and increased risk of aspiration, especially when there is impaired cough strength (83). The treatment of sialorrhea has been considered of high priority by an ACCP clinical practice guideline and can be achieved by pharmacologic and nonpharmacologic therapies. Anticholinergic agents, including amitriptyline, hyoscine, scopolamine, and atropine, are used with varying efficacy. Botulinum injection in the parotid 59

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and/or submandibular glands is tolerated and generally used in refractory cases of sialorrhea. If pharmacologic interventions are ineffective, then radiation therapy to the salivary glands may be considered (26). 4.4.4  Surgical Options While surgery is often not an option for most NMDs, diaphragm dysfunction from phrenic nerve injury may be an outlier. Three major surgical interventions impacting diaphragm dysfunction are diaphragm plication, diaphragm pacing, and phrenic nerve reconstruction. 4.4.4.1  Surgical Plication Diaphragm elevation in unilateral diaphragm paralysis causes symptoms by reducing thoracic volume, which is further compromised by maneuvers that increase the abdominal pressure (supine position, bending down). Surgical diaphragm plication is an irreversible process of pleating the diaphragm muscle with sutures to pull the paralyzed diaphragm into a more physiologic position and expand the thoracic cavity. Diaphragm plication improves FVC by about 20–40% and improves quality of life (84–86). The procedure effectively prevents the excursion of the diaphragm and is therefore reserved for patients with no potential for diaphragm recovery, if there has been no recovery after at least 1 year from onset (84), and potentially with the failure of other techniques, including supportive care, NIPPV, diaphragm pacing, and phrenic nerve reconstruction. Another caveat is that one study showed progressive a loss of benefit after 18 months and return of lung function to preoperative levels by 4 years (86). This may reflect scarring around the suture site or a progressive reduction in diaphragm thickness. These patients may continue to need supportive interventions, such as NIPPV, weight management, or elevated sleeping position. 4.4.4.2  Diaphragm Pacing The most appropriate candidates for diaphragm pacing are patients with spinal cord injury above the third cervical level, as they have preserved phrenic motor neurons (which extend from C3 to C5) and intact phrenic nerves. Such high vertebral levels generally comprise 40% of spinal cord injuries (87). Diaphragm pacing involves phrenic nerve stimulation either through a cervical/ thoracic approach with phrenic nerve electrodes or a diaphragmatic approach with diaphragm electrodes, with both techniques helping decrease dependence on mechanical ventilation in those with spinal cord injuries (88–90). Diaphragm pacing has been extended to other conditions with functional phrenic nerves (generally identified with nerve conduction studies demonstrating a stimulable diaphragm) (91), with the intervention credited with improved quality of life (87). Diaphragm pacing is not recommended in ALS, as two randomized trials found an association between pacing and reduced survival (92, 93). 4.4.4.3  Phrenic Nerve Reconstruction Phrenic nerve reconstruction aims to re-innervate the diaphragm through phrenic nerve decompression, grafting/bypass, or nerve route transfer (85). All of these approaches are dependent on the presence of motor unit potentials as determined by electromyography on nerve conduction studies (85). Studies demonstrate a 14% increase in FVC when compared to a nonintervention cohort (85). There may be a slightly higher improvement in FVC with plication relative to phrenic nerve reconstruction, though this does not preclude additional gradual improvement in the reconstruction cohort (85). Phrenic nerve reconstruction can have incremental benefits when combined with diaphragm pacing (94, 95). 4.5 CONCLUSION The morbidity and mortality of NMDs can often be attributed to the respiratory complications, most notably hypoventilation and aspiration. Systemic autoimmune rheumatic diseases in which diaphragmatic and neuromuscular dysfunction may most notably occur include systemic lupus erythematosus and the idiopathic inflammatory myopathies. An evaluation with clinical history, physical exam, exercise testing, imaging, and polysomnographic testing can help identify early respiratory compromise, to achieve a goal of getting the “right device to the right patient at the right time” (96). In addition to the management of the underlying disorder, treatment includes invasive and noninvasive ventilation, support of expiratory function, and surgical options in some cases. Benefits in survival and quality of life have been documented with these interventions. 60

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95. Kaufman MR, Elkwood AI, Aboharb F, Cece J, Brown D, Rezzadeh K, et al. Diaphragmatic reinnervation in ventilator-dependent patients with cervical spinal cord injury and concomitant phrenic nerve lesions using simultaneous nerve transfers and implantable neurostimulators. J Reconstr Microsurg. 2015;31(5):391–5. 96. Gay PC, Owens RL, Panel OTE. Executive summary: Optimal NIV medicare access promotion: A technical expert panel report from the American college of chest physicians, the American association for respiratory care, the American academy of sleep medicine, and the American thoracic society. Chest. 2021;160(5):1808–21.

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5  Approach to the Patient with Pleural Disease Carlos E. Kummerfeldt, Amit Chopra, and John T. Huggins List of Abbreviations ADA Adenosine deaminase ANA Antinuclear antibody ANCA Anti-neutrophil cytoplasmic antibody AxSpA Axial spondyloarthritis BD Behcet’s disease DM Dermatomyositis EGPA Eosinophilic granulomatosis with polyangiitis GPA Granulomatosis with polyangiitis HLA Human leukocyte antigen IgG4-RD IgG4-related disease IIP Idiopathic interstitial pneumonia Interleukin-1 beta IL-1β IPC Indwelling pleural catheter LDH Lactate dehydrogenase LE Lupus erythematosus MCTD Mixed connective tissue disorder MPA Microscopic polyangiitis PM Polymyositis PPFE Pleural parenchymal fibroelastosis RA Rheumatoid arthritis RF Rheumatoid factor RPE Rheumatoid pleural effusion SARDs Systemic autoimmune rheumatic diseases SLE Systemic lupus erythematosus SS Sjögren’s syndrome SSc Systemic sclerosis Tumor necrosis factor α TNF-α 5.1 INTRODUCTION Systemic autoimmune rheumatic diseases (SARDs) are a heterogeneous group of diseases characterized by immune-mediated inflammation. Although the exact prevalence of pleural disorders in SARDs is unknown, this group of diseases is often associated with pleural involvement, which is the focus of this chapter. The most common pleural manifestations of SARDs include pleuritic chest pain and exudative inflammatory effusions. However, pleural effusions are often small and may not cause symptoms, in which case the prevalence of pleural disease may be underestimated. Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are the two most common SARDs associated with pleural effusions. Other SARDs, such as systemic sclerosis, mixed connective tissue disease, and polymyositis/dermatomyositis are rarely associated with pleural effusions. In this chapter, we will review the pathophysiology and clinical aspects of pleural disorders in patients with various SARDs. 5.2 RHEUMATOID ARTHRITIS 5.2.1 Pathogenesis Rheumatoid pleural effusions (RPEs) are thought to form as a result of: 1) increased capillary permeability, 2) direct pleural injury, 3) lymphatic drainage obstruction in the parietal pleura, and 4) the rupture of necrotic rheumatoid pleural nodules into the pleural space. Increased capillary permeability occurs when immune complexes produced by monocytes in patients with rheumatoid arthritis (RA) deposit in the subpleural space or directly in the capillaries. This leads to complement activation and endothelial injury that allows passage of protein-rich fluid into the interstitium and pleural space (1). Pleural injury occurs when lysozymes, chemotaxins, proteolytic enzymes, and free oxygen radicals are released from leukocytes and macrophages. The resultant inflammatory environment also induces fibroblast migration and the formation of fibrosis, which 66

DOI: 10.1201/9781003361374-6

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further damages the pleura (2). The parietal pleura develops acute and chronic inflammation, which causes obstruction of the lymphatics and thus prevents pleural fluid reabsorption (3). When subpleural necrotic rheumatoid nodules cavitate, they create a direct communication into the pleural space and allow cellular necrotic debris to accumulate (4). 5.2.2 Epidemiology Pleural involvement, including inflammation and effusions, has been documented in up to 50–70% of patients with RA at autopsy (5, 6). Approximately 3–24% of patients with RA have radiographic evidence of a pleural effusion at some time during their disease course (7–9). RPEs are more prevalent in men than in women (9) and in those with rheumatoid nodules, a positive rheumatoid factor, active articular disease, and systemic manifestations of RA (10, 11). The HLA antigen, HLA-B8, dw3, has been strongly associated with the development of pleural effusions (12). RPEs typically occur several years after the initial presentation of RA (13, 14). However, in some cases, an effusion may precede the onset of articular disease or be present upon initial clinical presentation (10, 13, 15, 16). See Table 5.1 for a comparison with other SARDs. 5.2.3  Clinical Presentation Most patients with RPEs are asymptomatic and have small pleural effusions (17–19). The effusions can be unilateral or bilateral (10). There is a predilection for unilateral left effusions in more than 70% of cases (10, 13). RPEs can cause dyspnea and pleuritic-type chest pain when they are larger and occupy at least one-third to one-half of the hemithorax (20). Symptoms derive from a combination of parietal pleura inflammation, underlying lung disease, and/or compromised lung function (21). About 30–50% of patients develop pleuritic-type chest pain (10). A third of patients can develop fever (22). A large RPE leading to respiratory failure and requiring chest tube drainage is uncommon but has been reported (23). 5.2.4  Pleural Fluid Characteristics The pleural fluid appearance can be cloudy, greenish-yellow, opalescent, straw-colored, and purulent and is non-odorous (13, 24). RPEs can also have a milky or chylous appearance when there are either cholesterol crystals or lipid-containing inclusions in leukocytes (25–29). Although rare, bloody-appearing RPEs have been reported (30). RPEs are exudative and contain high protein levels, > 4.0 g/dL (24). During the initial phase of inflammation, which lasts about 7–11 days, the predominant cell type is polymorphonuclear cells including neutrophils. After the inflammatory period, the predominant cell type is mononuclear including lymphocytes (31). An eosinophilic predominant cell type has also been reported but is less common (15, 32). Thus, the timing of a thoracentesis in relation to the initial RPE may yield different types of cell counts accordingly (33). During the initial phase of inflammation, the glucose, pH, and LDH levels can be normal (31). As time elapses, the pH decreases (can be < 7.30), and the glucose becomes very low (< 30 mg/ dL; pleural fluid-to-serum glucose ratio of < 0.5), and the LDH very high (15, 29, 31). The mechanisms for low pH and glucose in RPEs are thought to be due to: 1) a selective block in glucose transfer from the blood to the pleural fluid due to an inflamed and/or thickened pleural surface, 2) increased glucose use by pleural tissue, and 3) a selective block in glucose metabolite products such as lactate and carbon dioxide from pleural fluid to blood due to abnormalities in the pleural surface (31, 34). Elevated LDH levels (> 700 IU/L) are thought to be due to increased LDH-4 and LDH-5 isoenzyme activity from activated white blood cells (21). Chronic RPEs can result in high pleural fluid cholesterol and lipid levels > 1000 mg/dL with a milky or chylous appearance (35). The fluid can also have an “opalescent sheen” appearance due to cholesterol crystal formation (29, 36). The mechanism of such high cholesterol and lipid levels is thought to be due to chronic cellular breakdown in the presence of a thickened pleura that prevents the reabsorption of debris (29, 31, 33). However, RPEs resulting in cholesterol effusions without pleural thickening have been reported (37). Chylothorax with the presence of chylomicrons and high triglyceride levels can also occur due to intrinsic lymphatic obstruction from RA-related amyloidosis (28, 38, 39). When available, pleural fluid rheumatoid factor (RF), measured in RPEs, can be higher than serum values (10, 22). However, it is not considered a diagnostic test, as the presence of RF has been identified in other non-RPE effusions (40). Low C3 and C4 complement levels occur in RPEs due to activation of the classic and alternate complement cascade pathways (41). RPEs can also have high levels of ferritin, beta-2-microglobulin, angiotensin-converting enzyme, neuronspecific enolase, hyaluronan, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), 67

Table 5.1: Pleural Characteristics of the Different Systemic Autoimmune Rheumatic Diseases (SARDs) CTD

RA

SLE

PM/DM

SSc

MCTD

AS

Sjögren’s GPA, Syndrome EGPA, MPA

Behcet’s Disease

IgG4-Related Disease

Prevalence of effusion Onset of effusion Clinical presentation

3–24%

40–70%

UKN, rare

7%

50%

UKN, rare < 1%

5–29%

UKN, rare

4%

IP; 5–15 years after active RA disease M > F; with active disease

DADS

DADS

DADS

DADS

DADS

IP or DADS

IP in some; DADS

ASM; dyspnea Pleurisy ASX when moderate Unilateral Small effusions Unilateral

Unilateral

Pleurisy, dyspnea; concurrent pericardial effusion Unilateral Bilateral

Fluid appearance

Cloudy, greenishyellow, opalescent, straw-colored, milky

SC, yellow

SC, yellow

Overlap with other CTD Unilateral or bilateral SC

Pleurisy, dyspnea

Small, unilateral

ASX; dyspnea when moderate to large Bilateral

IP or with other organs M>F

Imaging

Anytime during disease During flare; fever, pleuritic chest pain, dyspnea, cough Unilateral or bilateral Serous, turbid or bloody

SC

SC, milky

PFA

↓↓ pH and glucose; ↑LDH; PMN or

↑protein and

Exudate

Transudate or PMN or Exudate lymphocytic exudate

Exudate

Lymphocytic PMN, Lymphocytic, rarely predominant lymphocytic eosinophilic; exudate; exudate or eosinophilic chylothorax exudate

Lymphocytic exudate

ND

ND

ND

ND

ND

ND; absence of vasculitis in pleural biopsies

ND

ND

CS or other IMM

IMM

CS

CS

CS or other IMM

CS or other IMM

UKN

Spontaneously UKN in majority Pneumome­ PTX diastinum PTX

With therapy With therapy

AC if evidence of SVC, CS SV or innominate vein thrombosis; immunosuppression With therapy With therapy

PTX, rare

Refractory chylothorax ND

Cytology

Treatment

Resolution Compli­ cations

normal glucose;

lymphocytic; ↑LDH; PMN or chylothorax if chronic lymphocytic Giant multinucleated LE cells macrophages, elongated “tadpole” macrophages, granular debris Majority ASX; CS if CS or other IMM SXS

SPN in 3–4 months or 2 months UKN up to 1 year Empyema; PTX; lung Lung entrapment SPN PTX, entrapment pneumo-medi­ astinum and subcutaneous emphysema

SPN PTX

SC

SC

PTX, rare

SC

Abbreviations: AC: anticoagulation; AS: ankylosing spondylitis; ASX: asymptomatic; DADS: during active disease; EGPA: eosinophilic granulomatosis with polyangiitis; CS: corticosteroids; F: female; GPA: granulomatosis with polyangiitis; IgG4: IgG4-related disease; IMM: immunosuppression; IP: initial presentation; LDH: lactate dehydrogenase; MCTD: mixed connective tissue disease; M: male; MPA: microscopic polyangiitis; ND: not described; PMN: polymorphonuclear; PTX: pneumothorax; RA: rheumatoid arthritis; PFA: pleural fluid analysis; PM/DM: polymyositis/dermatomyositis; SC: straw-colored; SSc: systemic sclerosis; SLE: systemic lupus erythematosus; SXS: symptomatic; SPN: spontaneous; SV: subclavian vein; SVC: superior vena cava; UKN: unknown

5 Approach to the Patient with Pleural Disease

Figure 5.1  Cytology of a chronic rheumatoid effusion is shown. An elongated macrophage and a background of granular debris and/or amorphous material are shown and are diagnostic of RPE in the appropriate clinical context. The elongated macrophages are also multinucleated and appear to have a pointed tail, resembling a tadpole.

hydroxyproline, and adenosine deaminase (ADA) (15, 42–47). However, these pleural markers are neither readily available nor specific for diagnosing RPEs. 5.2.5  Fluid Cytology The triad finding of giant multinucleated macrophages, elongated macrophages, and a background of granular debris and/or amorphous material is virtually diagnostic of RPEs in the appropriate clinical context (1, 40, 48). The elongated macrophages are also multinucleated and appear to have a pointed tail or resemble a tadpole (Figure 5.1) (40). Other findings include cholesterol crystals and clefts, reactive mesothelial cells, chronic inflammatory cells, and rheumatoid arthritis (RA) cells (1, 14, 24, 40). RA cells, also known as “ragocytes”, were first described in synovial fluid samples of patients with RA (49). RA cells are leukocytes that contain cytoplasmic inclusions, and they have been identified in tuberculous and malignant effusions and therefore are not specific for RPEs (50, 51). 5.2.6 Pathology Blind and/or percutaneous pleural punch biopsies show nonspecific inflammatory changes, and their value in RPEs is to exclude other diseases like pleural tuberculosis (10). Thoracoscopy evaluation shows a granular, frozen, or “gritty” appearance of the parietal pleura and nonspecific inflammation of the visceral pleura (13, 52). The parietal pleura is thickened and covered with numerous small vesicles or granules that measure about 0.5 mm in diameter (Figure 5.2). Biopsies of the parietal pleura show that the mesothelial cell layer is replaced by a pseudostratified layer of epithelioid cells. The epithelioid cells focally form multinucleated giant cells. The inner stroma is fibrous and has features of chronic inflammation. No granuloma or necrosis is identified. Biopsies of the visceral pleura show nonspecific inflammatory changes (13). Microscopically, visceral and parietal pleural biopsies show three layers of cells that resemble 69

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Figure 5.2  (A) Medical thoracoscopic view of the parietal pleura of a patient with a rheumatoid pleural effusion. Parietal pleural biopsy demonstrates rheumatoid nodules. (B) The parietal pleura will show that the mesothelial cell layer is replaced by a pseudostratified layer of epithelioid cells. The epithelioid cells focally form multinucleated giant cells. The inner stroma is fibrous and has features of chronic inflammation. No granuloma or necrosis is identified. Biopsies of the visceral pleura show nonspecific inflammatory changes. (Reproduced courtesy of: Yalen Rose, Wikimedia Commons.)

the central zone of a rheumatoid nodule: 1) the outermost, consisting of a fibrin or fibrinoid necrotic layer, has necrotic nuclear debris and is of varying thickness; 2) the middle layer, which is composed of palisading cells and histiocytes with their long axis perpendicular to the surface; and 3) the inner layer, which has vascular granulation fibrous tissue, is infiltrated by 70

5 Approach to the Patient with Pleural Disease

lymphocytes and plasma cells, is of varying thickness, and is similar to the “equivalent zone” of a rheumatoid nodule (53). Rheumatoid nodules can also be identified with pleural biopsies and help establish the diagnosis of RA (53). 5.2.7  Empyema and Pneumothorax The concomitant development of empyema along with RPE has been well documented and is associated with increased morbidity (10, 54, 55). Empyema may occur in the presence of active RA alone with no evidence of prior RPEs (55). The precise incidence and prevalence of empyema along with RPEs or in patients with RA who have no evidence of prior RPEs is unknown. Sterile empyema, defined as pus aspirated from the pleural cavity without the isolation of any microorganisms on Gram stain and culture, has been documented (56, 57). It is theorized that when patients are taking immunosuppressive medications for RA, such as glucocorticoids, the possible source of infection is masked. As such, the pleural fluid cultures become sterile (3, 58). There are six proposed mechanisms related to the development of empyema in patients with RA and RPEs: 1) when present, necrotizing subpleural nodules are colonized with microbes and then rupture, creating an infected bronchopleural fistula (54, 59, 60); 2) when present, sterile necrotizing subpleural nodules rupture without evidence of microbial colonization and result in the massive accumulation of cellular necrotic debris (56, 57, 61); 3) immunosuppression from medications to treat RA increases susceptibility to infections (3, 62, 63); 4) the pleural space environment in patients with RPEs, characterized by chronic inflammation with low complement levels and anaerobic milieu, increases bacterial translocation (64); 5) RArelated parenchymal lung disease such as nodules, interstitial lung disease, bronchiectasis, and airways disease as well as vasculitis increase the risk of infection; and 6) repeat diagnostic and therapeutic thoracentesis provides a direct portal of entry into the pleural space (63). The empyema can be the result of an individual microorganism or may be polymicrobial (54, 55, 62, 65, 66). Spontaneous pneumothorax in patients with RA or RPEs has been described and is thought to occur by one of two mechanisms: 1) the rupture of cavitating subpleural nodules, creating a bronchopleural fistula (67–70), or 2) the rupture of small blebs that form when advanced interstitial fibrosis distorts bronchi and alveolar spaces (59). Spontaneous pneumothorax in the absence of cavitating subpleural nodules, underlying advanced interstitial fibrosis, parenchymal lung disease has been reported (71). Spontaneous pneumomediastinum with subcutaneous emphysema due to RA-associated interstitial lung disease has also been reported (72–74). The mechanism for pneumomediastinum and subcutaneous emphysema development is unknown (72–74). Concomitant empyema and pneumothorax (pyopneumothorax) have been described (55). Concomitant cholesterol effusions and pneumothorax have also been described (75–77). Visceral pleural inflammation, as seen in patients with RPE and pleurisy, can result in development of an unexpandable lung due to lung entrapment and with time lead to trapped lung (78). 5.2.8  Clinical Course and Treatment The majority of RPEs are asymptomatic and do not require evaluation by thoracentesis or other specific management. A majority of RPEs resolve within 3 months (10). In about 20% of cases, the RPE is persistent or recurs and results in the development of an unexpandable lung due to lung entrapment (27). Thoracentesis should be considered if there is suspicion of underlying infection or malignancy, or if the effusion is large and the patient is symptomatic (21). Periodic repeat thoracentesis may be required and sufficient. The use of an indwelling pleural catheter (IPC) to manage a recurrent RPE can be considered, though there is only anecdotal use, and currently no reported cases of its use in RPEs are described in the literature. The rate of spontaneous pleurodesis achieved after IPC insertion in a recurrent symptomatic RPE is unknown. Talc pleurodesis via chest tube or IPC to manage recurrent RPEs has not been described in the literature. Treatment with nonsteroidal anti-inflammatory agents can sometimes be effective when there is evidence of pleuritis with or without RPEs (79). Some RPEs resolve with systemic glucocorticoid treatment (10, 36), and others do not or even may recur (5, 80). Intrapleural glucocorticoids have been used, but results are mixed and therefore not routinely recommended (81, 82). If the RPE does not respond to glucocorticoid treatment, or if the patient has evidence of pleural thickening that suggests the development of lung entrapment, then surgical decortication is indicated (59, 83). 71

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5.3 SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) 5.3.1 Pathogenesis Pleuritis and pleural effusion formation in SLE are due to direct immune complex deposition and complement activation that result in damage to the pleural capillary beds and connective tissue (84–86). This direct immune reaction increases pleural capillary permeability. In addition, lymphocytic and plasma cell infiltration reduce pleural fluid reabsorption and induce fibrin deposition with resultant fibrinous pleuritis, pleural thickening, and restriction (87, 88). 5.3.2 Epidemiology During the course of their disease, it is estimated that approximately 40–70% of patients with SLE develop pleuritis and/or pleural effusion. In 1–5% of patients, it is the initial manifestation of the disease (79, 89–94). Pleural involvement has been shown to occur in more than 65% of patients with SLE at autopsy (95). See Table 5.1 for comparison with other SARDs. 5.3.3  Clinical Presentation The majority of patients are symptomatic at the time of presentation (96). Symptoms include pleuritic pain, dyspnea, fever, and cough. A pleural rub may be auscultated on physical examination. The majority of the effusions are bilateral and small to moderate in size. However, large and massive effusions can also occur (96–98). In some cases, the effusions are due to other systemic manifestations of SLE such as nephrotic syndrome, uremia from renal failure, pulmonary embolism, or infection (1, 8). Drug-induced lupus as well as therapies used to treat lupus can produce effusions (99, 100). 5.3.4  Pleural Fluid Characteristics The pleural fluid appearance may be serous, turbid, or bloody (90, 96). SLE effusions can also present as a hemothorax (101–103). SLE effusions are exudative typically with a high protein > 3.5 g/ dL and a moderately elevated LDH < 500 g/dL (96). The pleural fluid glucose is generally > 60 mg/ dL and the pH > 7.30 (22, 96). The predominant cell type depends on the timing of the thoracentesis in relation to the appearance of the effusion. If pleural fluid is sampled early, the predominant cell type is the neutrophil, whereas later in the course of the effusion, the predominant cell type is the lymphocyte (1, 96). Although rare, eosinophil predominant cell counts have been reported in SLE effusions as well (104). When available, the measurement of pleural fluid antinuclear antibody (ANA) is useful if the titer is > 1:160 or if the ratio of pleural fluid to serum ANA is > 1 (96, 105). However, ANA can also be found in other pleural effusions and is therefore not specific for SLE (106–109). For example, a positive ANA has been detected in malignant effusions (106, 110). The measurement of pleural fluid C3 and C4 complement levels, which are often low in the serum of patients with SLE, are of minimal clinical utility, as RPEs and other types of effusions can also have low complement levels (84, 111). 5.3.5 Cytology When identified, lupus erythematosus (LE) cells are virtually diagnostic of SLE effusions (96). First identified in bone marrow and blood (112–114), LE cells are macrophages or neutrophils that have phagocytosed the nuclear material of other cells. After intracellular penetration, ANA and complement C3b induce apoptosis and create apoptotic bodies that contain cell nuclei with depolymerized DNA (115, 116). These apoptotic bodies are then phagocytosed by macrophages or neutrophils and create LE cells. When seen under the microscope, LE cells contain dense homogeneous nuclear material (hematoxylin bodies) engulfed by neutrophils and macrophages (114). LE cells have been identified in SLE effusions and blood where serum ANA is negative, as well as in patients with drug-induced lupus and pleural effusions (Figure 5.3) (117, 118). 5.3.6 Pathology Thoracoscopy shows visceral pleural nodules. When biopsied, the nodules contain immunoglobulin deposits detected on immunofluorescent staining (119, 120). Pleural biopsies demonstrate diffuse and speckled patterns during the immunofluorescent staining of cell nuclei with anti-IgG, anti-IgM, or anti-C3 (85, 86). 5.3.7  Clinical Course and Treatment Unlike RPEs, SLE pleural effusions and pleurisy resolve quickly after starting immunosuppressive treatment with glucocorticoids or other immunosuppressive agents. The majority of the effusions 72

5 Approach to the Patient with Pleural Disease

Figure 5.3  Classic LE cells are shown on light microscopy Wright stain. When identified, LE cells are pathognomonic for systemic lupus erythematous. LE cells are only seen in about onethird of patients with lupus pleuritis.

resolve within 2 months and, when small, sometimes resolve spontaneously without therapeutic intervention (8, 91). When pleural effusions are due to a medication, the discontinuation of the offending agent results in complete resolution (121). SLE effusions refractory to glucocorticoids and immunosuppression have been successfully treated with pleurodesis or in extreme circumstances pleurectomy (122–126). In one reported case of refractory SLE effusion, spontaneous pleurodesis was achieved 3 months after the insertion of an IPC (127). This may indicate a potential role of IPC in the management of recurrent SLE effusions when talc or tetracycline pleurodesis fails and surgical treatment is contraindicated or not desired. 5.4 POLYMYOSITIS/DERMATOMYOSITIS (PM/DM) Pleural disease is rare in PM/DM. In an autopsy study, none of 65 patients with PM or DM had clinical evidence of pleural effusions (128). In the same study, only eight patients showed pleuritis (128). However, cases of massive and moderate-sized pleural effusions have been described (129– 131), and treatment with glucocorticoids and immunosuppressive medications led to the resolution of the effusions (129–131). Patients with PM/DM can develop spontaneous pneumothorax, pneumomediastinum, and subcutaneous emphysema (132–139). Pneumothorax, pneumomediastinum, and subcutaneous emphysema are thought to occur in patients with PM/DM as a result of underlying interstitial lung disease and small subpleural pulmonary infarctions due to vasculitis that lead to increased intra-alveolar pressure with subsequent rupture and fistula formation (132). The medical treatment of PM/DM with immunosuppression results in rapid resolution of pneumomediastinum and subcutaneous emphysema (135, 140). Pneumothorax, regardless of size, is routinely treated with chest tube insertion with close observation and immunosuppression (132, 133, 141). 5.5 SYSTEMIC SCLEROSIS Pleural effusions and pleural disease are rare in patients with limited and diffuse cutaneous systemic sclerosis (SSc). In a study looking at the frequency of pleural effusions in patients with limited and diffuse SSc, only 7% of patients had an effusion (142). Pleural effusions can be either transudative or exudative (143, 144). When a transudative pleural effusion occurs, an evaluation for cardiac involvement should be considered. Pleural effusions can also occur in overlap syndrome such as with PM and SLE (145). The mechanism of how pleural effusions form in patients with SSc is unknown. Spontaneous pneumothorax can also occur in patients with SSc (146–151). The mechanism is due to the formation of subpleural cysts that rupture into the pleural cavity. The subpleural cysts form as a result of lung fibrosis and visceral pleural thickening (150). Prolonged air leaks 73

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are usually seen, and chemical or surgical pleurodesis may be contraindicated or declined in the setting of underlying interstitial lung disease and poor lung function. In such cases, autologous blood-patch pleurodesis can be considered as an alternative treatment. Another option would be endobronchial valve placement if the air leak is isolated with balloon occlusion (152). 5.6 MIXED CONNECTIVE TISSUE DISEASE (MCTD) Pleural involvement including pleurisy and pleural effusions occurs in approximately 50% of patients with MCTD (153). The majority of the pleural effusions are small and resolve spontaneously (153, 154). Approximately 40% of patients will develop pleuritic-type chest pain (155). With pleural fluid sampling, the effusion is either a neutrophilic or lymphocytic predominant exudate and thought to occur due to serositis (156, 157). Concurrent pleural and pericardial effusions have been reported (158, 159). Treatment with glucocorticoids results in the resolution of the pericardial and pleural effusions as well as the alleviation of pleurisy (156, 158). Pneumomediastinum and pneumothorax have also been described in patients with MCTD (160–162). In the few reported cases, treatment has been with glucocorticoids, immunosuppressive medications, chest tube insertion, and surgical pleurectomy (160–162). 5.7 AXIAL SPONDYLOARTHRITIS Pleural effusions and pleurisy are very rare in patients with axial spondyloarthritis (AxSpA), and only a few cases have been reported in the literature (163–167). The effusions are exudative, have normal pH and glucose levels, and typically resolve with glucocorticoid treatment (165–167). Spontaneous pneumothorax has been reported and is also rare (166, 168–171). The development of apical fibrosis and bullous disease is thought to result in the development of spontaneous pneumothorax in patients with AxSpA (169, 172). Chest tube insertion and chemical or surgical pleurodesis are effective treatments. 5.8 SJÖGREN’S SYNDROME (SS) Pleural involvement is rare in SS, and the incidence of effusions is < 1% (173–183). The presence of pleural involvement should prompt evaluation for concomitant RA or SLE, as an overlap condition can occur (184). Pleural effusions can be bilateral or unilateral (175, 177) and are thought to occur as a consequence of pleuritis. Activated polyclonal B lymphocytes produce autoantibodies that are then recognized by CD4+ T lymphocytes as autoantibody-HLA class II complexes. The deposition of these complexes on the pleural surface leads to inflammation (177). Pleural fluid analysis shows a lymphocytic predominant exudate with normal glucose levels. When measured, ANA can be 1:160 or greater. Anti-SS-A and anti-SS-B antibody levels in the pleural fluid can be elevated, and C3, C4, and total complement levels may be low (185). Thoracoscopic pleural biopsies show fibrotic pleural thickening and lymphocytic infiltration and are performed when trying to exclude malignancy or tuberculosis (175, 179, 185, 186). When measured, ADA can be high (185). The majority of effusions in patients with SS respond well to glucocorticoids or immunosuppressive therapy (181, 183). There is one reported case of spontaneous pneumothorax due to SS that was initially treated with chest tube insertion. The pneumothorax recurred, and therefore the patient underwent surgical intervention that showed a ruptured left apical bulla and bronchopleural fistula that was repaired (187). 5.9 GRANULOMATOSIS WITH POLYANGIITIS (GPA), EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA), AND MICROSCOPIC POLYANGIITIS (MPA) Pleural effusions occur in approximately 5–12% of patients with GPA (188, 189). Pleuritic-type chest pain typically occurs (190). Pleural fluid shows a non-bloody neutrophilic or lymphocytic predominant exudate (188, 189, 191–193). Pleural effusion may be the initial manifestation of the disease, and these effusions are typically small in size, (192, 194) mostly unilateral, and associated with underlying pulmonary infiltrates and cavitating and non-cavitating lung nodules (189, 194). A massive pleural effusion has been described in one case that occurred after bronchopleural fistula formation while the patient was receiving treatment with glucocorticoids. The effusion and bronchopleural fistula resolved following treatment with intravenous cyclophosphamide (195). The mechanism of pleural fluid formation in GPA remains unclear (196). Pleural biopsies show dense inflammatory infiltrates in the periphery of blood vessels that are composed of lymphocytes and plasma cells. However, there is no evidence of true pleural vasculitis (192). The presence of necrotizing granulomatous vasculitis and necrotic lesions in the underlying lung parenchyma 74

5 Approach to the Patient with Pleural Disease

of patients with concomitant pleural effusions suggests that the rupture of these lesions into the pleural space may contribute to pleural effusion formation (192, 193, 197). In rare instances, pneumothorax can also occur (194). Immunosuppressive treatment results in the resolution of the pleural effusions and underlying pulmonary infiltrates and lesions (192, 195, 198). Pleural effusions occur in approximately 9–29% of patients with EGPA (199–202) and are more common in patients with EGPA who have a negative ANCA compared to those with a positive ANCA (202). Pleural fluid analysis shows an eosinophilic predominant exudate with low glucose levels and low pH (< 7.30) (203, 204). Pleural biopsies show pleural thickening, eosinophilic infiltration, and necrotizing granulomas (205). The effusions respond to treatment with glucocorticoids (204). Pleural effusions in MPA are quite rare (206). Pleural effusion has however been reported to precede other manifestations of the disease (207, 208). The incidence and prevalence are unknown. Pleural fluid analysis shows a lymphocyte predominant exudate (208, 209). Thoracoscopy shows visceral and parietal pleural thickening with fibrosis and no evidence of pleural vasculitis (209). Elevated pleural fluid myeloperoxidase-ANCA titers have been reported but are not routinely measured unless the diagnosis of MPA is suspected (210). Treatment with high-dose glucocorticoids, IVIG, and/or other immunosuppressive medications results in the resolution of pleuritis and pleural effusions (207–209). 5.10 BEHCET’S DISEASE (BD) Pleural effusions in BD are rare (211). Pleural fluid sampling reveals lymphocytic predominant exudative effusions (212). An eosinophilic predominant effusion has also been described in one case (213). Concomitant chylothorax can also occur if there is superior vena cava, left innominate, and/or subclavian vein thrombosis (214, 215). The thrombosis of such veins causes obstruction of the thoracic duct, which increases intraluminal pressure and results in the leakage of chyle via communicating vessels and pleural lymphatics into the pleural space (215–217). Concurrent pleural and pericardial effusions are often seen when there is thrombosis of the superior vena cava, left innominate, and/or subclavian vein (216–218). Pleural biopsies show inflammatory cell infiltration and fibrosis, as well as vasculitis with thrombus formation in the small vessels (219). Thus, contrary to the other discussed systemic vasculitis syndromes, in patients with BD, pleural effusions can also result from direct pleural injury due to small-vessel vasculitis and pulmonary infarction (219, 220). If measured, pleural fluid ADA levels can be elevated (219). Thus, thoracoscopic pleural biopsies may be needed in order to exclude tuberculosis, another cause of elevated pleural fluid ADA levels. When present, chylothorax can be refractory and therefore requires a multimodality stepwise treatment approach to address the underlying thrombosis and mechanical obstruction of the lymphatic duct. First, the underlying venous system thrombosis should be treated with anticoagulation. Second, immunosuppression should be initiated to target the underlying BD. Third, thoracic duct embolization or ligation should be attempted. Fourth, if embolization or ligation fails, then chemical pleurodesis should be attempted. Fifth, if chemical pleurodesis fails, then surgical pleurodesis with lung decortication should be considered (214). The role of IPC in the management of pleural effusions and chylothorax due to BD remains unknown. A few cases of pneumothorax related to BD have been described and are usually effectively managed with chest tube insertion or surgical pleurodesis (221, 222). 5.11 IgG4-RELATED DISEASE IgG4-related disease (IgG4-RD) can affect the lungs in up to 13–35% of cases (223–228). However, pleural involvement is only seen in approximately 4% of these patients (226, 229). The majority of patients with IgG4-RD and pleural effusion are male and between 60 and 65 years old (230, 231). Pleural effusions and pleuritis can occur as the sole manifestation or with other concomitant organ involvement (232–237). The majority of patients present with bilateral effusions, and the fluid shows a lymphocyte predominant exudate (231, 238). A case of spontaneous hemothorax has been described in the literature (239). Pleural fluid IgG4 levels can be elevated, and cytology can show IgG4 cells on immunohistochemical cell-block staining and sometimes eosinophils as well (232, 233, 240). Because pleural fluid can also demonstrate an elevated ADA level (232–234) and imaging can reveal pleural thickening and nodularity, thoracoscopic pleural biopsies are needed to exclude tuberculosis or malignant mesothelioma (241, 242). During thoracoscopy, IgG4-RD pleuritis is characterized by: 1) observation of milky pleural plaques due to hyalinized collagen fiber deposits; 2) diffuse inflammatory pleural thickening; and 3) presence of small (2–3 mm) parietal pleural nodules (243). In rare instances, the visceral and parietal pleural surfaces can also appear normal (233, 244). Pleural biopsies show lymphoplasmacytic infiltrates with storiform 75

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(irregularly whorled) fibrosis and obliterative phlebitis that stain positive for IgG4 plasma cells, as is characteristic of the pathologic features in other organs involved by this disease. Pleural eosinophilic infiltration can also be seen (245–248). Semiquantitative analysis during immunohistochemical staining should identify a percent of IgG4 plasma cells relative to IgG plasma cells of at least 40–50% and greater than 10 IgG4 plasma cells per high-power field (246, 249, 250). Distinction between diffuse large B-cell lymphoma and IgG4-RD is made by the sole presence of T lymphocytes in IgG4-RD, whereas in large B-cell lymphoma, there are B- and T-cell lymphocytes (246, 247). Although Castleman’s disease and RA can also have elevated IgG4 levels in pleural biopsies, the characteristic histopathological features of IgG4-RD are absent in such diseases (246). In the majority of cases of IgG4-RD isolated to the pleura, without any other systemic manifestations, treatment with glucocorticoids alone results in the improvement and resolution of pleuritis and pleural effusions (230, 233, 234). However, if a chylothorax is also present, then the addition of rituximab is recommended in order to achieve resolution of the effusion (231). There have been no reported cases of spontaneous pneumothorax due to IgG4-RD. 5.12 PLEURAL PARENCHYMAL FIBROELASTOSIS Pleural parenchymal fibroelastosis (PPFE) is categorized as a rare form of idiopathic interstitial pneumonia (IIP). IIPs are a subset of diffuse parenchymal lung diseases of unknown cause associated with an inflammatory infiltrate as well as with fibrosis and the proliferation of fibroblasts resulting in increased collagen deposition. PPFE is characterized by fibrosis of the pleura, subpleural parenchyma, traction bronchiectasis, and upper lobe volume loss. PPFE can also occur in the setting of a bone marrow transplant, chemotherapy toxicity, and connective tissue disease (251). On histopathology, lung pathology shows changes of intra-alveolar fibrosis, elastosis, and visceral pleura thickening. The distribution of disease is upper lobe predominant. Idiopathic and secondary cases, described in both RA and SSc, will have a mild histologic difference where fibroblastic foci are common in idiopathic cases and more alveolar septal thickening are seen with secondary causes. To date, there are no reported cases of pleural effusions associated with idiopathic or secondary causes of PPFE. However, there are reported cases of secondary spontaneous pneumothorax reported, and this is a major respiratory complication of this condition. In a retrospective multicenter study involving 89 patients with PPFE, pneumothorax occurred unilaterally or bilaterally (252) (Figure 5.4).

Figure 5.4  Posteroanterior chest radiograph in a patient previously diagnosed with diffuse systemic sclerosis shows upper lobe parenchymal scarring with associated upper lobe pleural thickening and bilateral secondary spontaneous pneumothoraxes. Because of persistent air leaks after the placement of tube thoracoscopy, the patient underwent video-assisted thoracic surgery (VATS) with talc poudrage. VATS surgical lung biopsy confirmed pleural parenchymal fibroelastosis (PPFE). The patient died of chronic hypoxic respiratory failure approximately 4 years after her diagnosis of PPFE. (Image courtesy of: Dhiraj Baruah MD, Associate Professor, Department of Radiology and Radiological Science, Medical University of South Carolina.) 76

5 Approach to the Patient with Pleural Disease

5.13 CONCLUSION Pleural involvement has been described with all of the SARDs. In many instances, it can precede the onset of disease or be its sole manifestation. Therefore, a high clinical suspicion is often needed to establish a diagnosis. Thoracentesis with pleural fluid analysis, including cytologic evaluation, can assist in establishing the correct diagnosis. In some instances, where the differential diagnosis includes tuberculosis or other granulomatous infectious processes and pleural fluid analysis evaluation alone cannot distinguish between the suspected SARDs, then thoracoscopic pleural biopsies may be needed. Therefore, recognition of the pleural fluid characteristics, cytology, and pleural biopsy pathology findings for each of the SARDs is imperative to enhance diagnosis and treatment. REFERENCES 1. Joseph J, Sahn SA. Connective tissue diseases and the pleura. Chest. 1993;104(1):262–70. http:// doi.org/10.1378/CHEST.104.1.262. 2. Roster FT, McGregor DD, Mackaness GB. The mediator of cellular immunity: II. Migration or immunologically committed lymphocytes into inflammatory exudates. J Exp Med. 1971;133(2):400–9. http://doi.org/10.1084/jem.133.2.400. 3. Sahn SA. The pleura. Am Rev Respir Dis. 1988;138(1):184–234. http://doi.org/10.1164/ ajrccm/138.1.184. 4. Davies D. Pyopneumothorax in rheumatoid lung disease. Thorax. 1966;21(3):230–5. http://doi. org/10.1136/THX.21.3.230. 5. Hunninghake GW, Fauci AS. Pulmonary involvement in the collagen vascular diseases. Am Rev Respir Dis. 1979;119(3):471–503. http://doi.org/10.1164/arrd.1979.119.3.471. 6. Pathol ABA, 1943 undefined. Visceral lesions associated with chronic infectious (rheumatoid) arthritis. ci.nii.ac.jp [cited 14 Jan 2023]. https://ci.nii.ac.jp/naid/10007010623/. 7. Horler AR, Thompson M. The pleural and pulmonary complications of rheumatoid arthritis. Ann Intern Med. 1959;51:1179–203. http://doi.org/10.7326/0003-4819-51-6-1179. 8. Cohen M, Sahn SA. Resolution of pleural effusions. Chest. 2001;119(5):1547–62. http://doi.org/ 10.1378/chest.119.5.1547. 9. Jurik AG, Davidsen D, Graudal H. Prevalence of pulmonary involvement in rheumatoid arthritis and its relationship to some characteristics of the patients. A radiological and clinical study. Scand J Rheumatol. 1982;11(4):217–24. http://doi. org/10.3109/03009748209098194. 10. Walker WC, Wright V. Rheumatoid pleuritis. Ann Rheum Dis. 1967;26(6):467–74. http://doi. org/10.1136/ARD.26.6.467. 11. Highland KB, Heffner JE. Pleural effusion in interstitial lung disease. Curr Opin Pulm Med. 2004;10(5):390–6. http://doi.org/10.1097/01.MCP.0000134390.27904.A9. 12. Hakala M, Tiilikainen A, Hämeenkorpi R, et al. Rheumatoid arthritis with pleural effusion includes a subgroup with autoimmune features and HLA-b8, dw3 association. Scand J Rheumatol. 1986;15(3):290–6. http://doi.org/10.3109/03009748609092595. 13. Faurschou P, Francis D, Faarup P. Thoracoscopic, histological, and clinical findings in nine case of rheumatoid pleural effusion. Thorax. 1985;40(5):371–5. http://doi.org/10.1136/ THX.40.5.371. 14. Cabot RC, Scully RE, Mark EJ, et al. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 44–1994. A 38-year-old woman with chronic rheumatoid arthritis and a new pleural effusion. N Engl J Med. 1994;331(24):1642–7. http:// doi.org/10.1056/NEJM199412153312408. 15. Pettersson T, Klockars M, Hellstrom PE. Chemical and immunological features of pleural effusions: Comparison between rheumatoid arthritis and other diseases. Thorax. 1982;37(5):354–61. http://doi.org/10.1136/thx.37.5.354. 16. Ip H, Sivakumar P, McDermott EA, et al. Multidisciplinary approach to connective tissue disease (CTD) related pleural effusions: A four-year retrospective evaluation. BMC Pulm Med. 2019;19(1). http://doi.org/10.1186/s12890-019-0919-2. 17. Chou CW, Chang SC. Pleuritis as a presenting manifestation of rheumatoid arthritis: Diagnostic clues in pleural fluid cytology. Am J Med Sci. 2002;323(3):158–61. http://doi. org/10.1097/00000441-200203000-00008. 18. Graham WR. Rheumatoid pleuritis. South Med J. 1990;83(8):973–5. http://doi.org/10.1097/ 00007611-199008000-00030. 77

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205. Hirasaki S, Kamei T, Iwasaki Y, et al. Churg-Strauss syndrome with pleural involvement. Int Med. 2000;39(11):976–8. http://doi.org/10.2169/internalmedicine.39.976. 206. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: Clinical and laboratory findings in eighty-five patients. Arthritis Rheumatol. 1999;42(3):421–30. http://doi. org/10.1002/1529-0131(199904)42:33.0.CO;2-6. 207. Hara A, Kinoshita Y, Hosoi K, Okumura Y, Song M, Min K. Pleural vasculitides of microscopic polyangiitis with asbestos-related plaques. Respirol Case Rep. 2015;3(4):148–50. http:// doi.org/10.1002/rcr2.133. 208. Shibuya H, Sano H, Osamura K, Kujime K, Hara K, Hisada T. Microscopic polyangiitis accompanied by pleuritis as the only pulmonary manifestation of occupational silica exposure. Intern Med. 2010;49(10):925–9. http://doi.org/10.2169/INTERNALMEDICINE.49.3046. 209. Ishimaru N, Ohnishi H, Fujii M, Yumura M, Yoshimura S, Kinami S. Microscopic polyangiitis presented with biopsy-confirmed pleuritis. Monaldi Arch Chest Dis. 2018;88(2):897. http:// doi.org/10.4081/monaldi.2018.897. 210. Ishimaru N, Ohnishi H, Fujii M, Yumura M, Yoshimura S, Kinami S. Microscopic polyangiitis presented with biopsy-confirmed pleuritis. Monaldi Arch Chest Dis. 2018;88(2):897. http:// doi.org/10.4081/monaldi.2018.897. 211. Chae EJ, Do KH, Seo JB, et al. Radiologic and clinical findings of Behçet disease: Comprehensive review of multisystemic involvement. Radiographics. 2008;28(5):1–56. http://doi. org/10.1148/rg.e31. 212. Alkhurassi HF, Ocheltree MR, Alsomali A, Alqunfoidi RA, Saadallah A. Pleural effusion presenting in a young man with Behcet’s disease. Cureus. 2020;12(9):e10273. http://doi. org/10.7759/cureus.10273. 213. Bal SK, Gupta R, Irodi A, et al. To immunosuppress or not: Behcet’s syndrome presenting as an eosinophilic pleural effusion. Lung India. 2017;34(5):457–60. http://doi.org/10.4103/lungindia.lungindia_471_16. 214. Das S, Cherian SV, Chava S, Allam FA, Manta DN, Lenox RJ. Bilateral pleural effusions in a 23-year-old man: A clinical puzzle. QJM. 2015;108(7):577–9. http://doi.org/10.1093/qjmed/ hct004. 215. Coplu L, Emri S, Selcuk ZT, et al. Life threatening chylous pleural and pericardial effusion in a patient with Behcet’s syndrome. Thorax. 1992;47(1):64–5. http://doi.org/10.1136/thx.47.1.64. 216. al Jaaly E, Baig K, Patni R, Anderson J, Haskard D. Surgical management of chylopericardium and chylothorax in a patient with Behçet’s disease. Clin Exp Rheumatol. 2011;29(4 SUPPL. 67). 217. Öz N, Sarper A, Erdogan A, Demircan A, Işin E. Video-assisted thoracic surgery for the management of pleural and pericardial effusion in Behcet’s syndrome. Tex Heart Inst J. 2000;27(3):304–6. 218. Zhang L, Zu N, Lin B, Wang G. Chylothorax and chylopericardium in Behçet’s diseases: Case report and literature review. Clin Rheumatol. 2013;32(7):1107–11. http://doi.org/10.1007/ s10067-013-2248-9. 219. Choi JY, Kim SH, Kwok SK, et al. A 30-year-old female Behçet’s disease patient with recurrent pleural and pericardial effusion and elevated adenosine deaminase levels: Case report. J Thorac Dis. 2016;8(7):E547–51. http://doi.org/10.21037/jtd.2016.05.88. 220. Tunaci A, Berkmen YM, Gokmen E. Thoracic involvement in Behcet’s disease: Pathologic, clinical, and imaging features. Am J Roentgenol. 1995;164(1):51–6. http://doi.org/10.2214/ ajr.164.1.7998568. 221. Gülyüz ÖC, Arslan S. An unusual complication of Behcet disease: Spontaneous bilateral pneumothorax. Am J Emerg Med. 2016;34(7):1320.e1–e2. http://doi.org/10.1016/j.ajem.2015.11.049. 222. Tuzun H, Seyahi E, Guzelant G, et al. Surgical treatment of pulmonary complications in Behçet’s syndrome. Semin Thorac Cardiovasc Surg. 2018;30(3):369–78. http://doi.org/10.1053/j. semtcvs.2018.07.008. 223. Tanaka H, Anno T, Takenouchi H, et al. IgG4-related lung disease with multifocal pulmonary consolidations near the pleura: A case report. Medicine (United States). 2022;101(34):E30285. http://doi.org/10.1097/MD.0000000000030285. 224. Inoue D, Yoshida K, Yoneda N, et al. IgG4-related disease: Dataset of 235 consecutive patients. Medicine. 2015;94(15). http://doi.org/10.1097/MD.0000000000000680. 225. Wallace ZS, Deshpande V, Mattoo H, et al. IgG4-related disease: Clinical and laboratory features in one hundred twenty-five patients. Arthritis Rheumatol. 2015;67(9):2466–75. http://doi. org/10.1002/ART.39205. 86

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226. Fernández-Codina A, Martínez-Valle F, Pinilla B, et al. IgG4-related disease: Results from a multicenter Spanish registry. Medicine. 2015;94(32). http://doi.org/10.1097/ MD.0000000000001275. 227. Fei Y, Shi J, Lin W, et al. Intrathoracic involvements of immunoglobulin G4-related sclerosing disease. Medicine. 2015;94(50). http://doi.org/10.1097/MD.0000000000002150. 228. Muller R, Habert P, Ebbo M, et al. Thoracic involvement and imaging patterns in IgG4related disease. Eur Respir Rev. 2021;30(162). http://doi.org/10.1183/16000617.0078-2021. 229. Zen Y, Nakanuma Y. IgG4-related disease: A cross-sectional study of 114 cases. Am J Surg Pathol. 2010;34(12):1812–19. http://doi.org/10.1097/PAS.0B013E3181F7266B. 230. Ryu JH, Sekiguchi H, Yi ES. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. Eur Respir J. 2012;39(1):180–6. http://doi.org/10.1183/09031936.00025211. 231. Sakata K, Kikuchi J, Emoto K, et al. Refractory IgG4-related pleural disease with chylothorax: A case report and literature review. Int Med. 2021;60(13):2135–43. http://doi.org/10.2169/ internalmedicine.6313-20. 232. Kasashima S, Kawashima A, Ozaki S, et al. Clinicopathological features of immunoglobulin G4-related pleural lesions and diagnostic utility of pleural effusion cytology. Cytopathology. 2019;30(3):285–94. http://doi.org/10.1111/cyt.12641. 233. Shimada H, Kato Y, Okuda M, et al. Pleuritis associated with immunoglobulin G4-related disease under normal thoracoscopic findings: A case report. J Med Case Rep. 2021;15(1). http:// doi.org/10.1186/s13256-021-02718-4. 234. Nagayasu A, Kubo S, Nakano K, et al. IgG4-related pleuritis with elevated adenosine deaminase in pleural effusion. Int Med. 2018;57(15):2251–7. http://doi.org/10.2169/ internalmedicine.0387-17. 235. Ishida M, Hodohara K, Furuya A, et al. Concomitant occurrence of IgG4-related pleuritis and periaortitis: A case report with review of the literature. Int J Clin Exp Pathol. 2014;7(2):808–14. 236. Damas F, Ghysen K, Gester F, et al. IgG4-related pleural disease in a patient with a history of unknown origin acute pancreatitis: A case report and review of the literature. Acta Clin Belg Int J Clin Labor Med. 2019;74(6):465–8. http://doi.org/10.1080/17843286.2018.1564173. 237. Tello-Sánchez M, Rodríguez-Duque MS, Loidi-López C, Martín-Arroyo J, González-Gay MÁ, Fernández-Ayala Novo M. Pleural and pericardial effusion as the only manifestation of IgG4-related disease. Arch Bronconeumol. 2020;56(9):597–9. http://doi.org/10.1016/j. arbres.2020.04.013. 238. Choi JH, Sim JK, Oh JY, et al. A case of IgG4-related disease presenting as massive pleural effusion and thrombophlebitis. Tuberc Respir Dis (Seoul). 2014;76(4):179–83. http://doi. org/10.4046/trd.2014.76.4.179. 239. Fan J, Feng R, Hou X, et al. IgG4-related disease can present as recurrent spontaneous hemothorax: A case report. BMC Pulm Med. 2019;19(1). http://doi.org/10.1186/ s12890-019-0785-y. 240. Murata Y, Aoe K, Mimura-Kimura Y, et al. Association of immunoglobulin G4 and free light chain with idiopathic pleural effusion. Clin Exp Immunol. 2017;190(1):133–42. http://doi. org/10.1111/cei.12999. 241. Choi IH, Jang SH, Lee S, Han J, Kim TS, Chung MP. A case report of IgG4-related disease clinically mimicking pleural mesothelioma. Tuberc Respir Dis (Seoul). 2014;76(1):42–5. http:// doi.org/10.4046/trd.2014.76.1.42. 242. Okamoto S, Tsuboi H, Sato R, et al. IgG4-related pleural disease with aortitis and submandibular glands involvement successfully treated with corticosteroid: Case-based review. Rheumatol Int. 2020;40(10):1725–32. http://doi.org/10.1007/s00296-020-04555-y. 243. Yasokawa N, Shirai R, Tanaka H, Kurose K, Oga T, Oka M. Thoracoscopic findings in IgG4related pleuritis. Int Med. 2020;59(2):257–60. http://doi.org/10.2169/internalmedicine.3031-19. 244. Mizushina Y, Shiihara J, Nomura M, et al. Immunoglobulin G4-related pleuritis complicated with minimal change disease. Int Med. 2022;61(5):723–8. http://doi.org/10.2169/ internalmedicine.7010-20. 245. Kim DH, Koh KH, Oh HS, et al. A case of immunoglobulin g4-related disease presenting as a pleural mass. Tuberc Respir Dis (Seoul). 2014;76(1):38–41. http://doi.org/10.4046/trd.2014.76.1.38. 246. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366(6):539–51. http:// doi.org/10.1056/NEJMRA1104650. 247. Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet. 2015;385(9976):1460–71. http://doi.org/10.1016/S0140-6736(14)60720-0. 87

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248. Ishida A, Furuya N, Nishisaka T, Mineshita M, Miyazawa T. IgG4-related pleural disease presenting as a massive bilateral effusion. J Bronchol Interv Pulmonol. 2014;21(3):237–41. http:// doi.org/10.1097/LBR.0000000000000082. 249. Umehara H, Okazaki K, Kawa S, et al. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. Mod Rheumatol. 2021;31(3):529–33. http://doi.org/10.1080/14397595.2020.1 859710. 250. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21–30. http://doi.org/10.1007/ s10165-011-0571-z. 251. Ricoy J, Suarez-Antelo J, Antunez J, et al. Pleuroparenchymal fibroelastosis: Clinical, radiological and histopathological features. Respir Med. 2022;191:1–7. http://doi.org/10.1016/j. rmed.2021.106437. 252. Kono M, Nakamura Y, Enomoto Y, et al. Pneumothorax in patients with idiopathic pleuroparenchymal fibroelastosis: Incidence, clinical features, and risk factors. Respiration. 2021;100(1):19–26. http://doi:10.1159/000511965.

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6 Approach to the Patient with Obstructive Airways Disease

6  Approach to the Patient with Obstructive Airways Disease Tessy K. Paul and Adam Q. Carlson List of Abbreviations A1AT Alpha-1 antitrypsin AAV ANCA-associated vasculitis ABPA Allergic bronchopulmonary aspergillosis ANA Antinuclear antibodies ANCA Antineutrophil cytoplasmic antibody BO Bronchiolitis BOOP Bronchiolitis obliterans with organizing pneumonia CCP Anti-cyclic citrullinated peptide CFTR Cystic fibrosis transmembrane conductance regulator COPD Chronic obstructive pulmonary disease csDMARD Conventional synthetic disease-modifying anti-rheumatic drug DLCO Diffusion capacity for carbon monoxide EGPA Eosinophilic granulomatosis with polyangiitis FB Follicular bronchiolitis Forced expiratory volume in 1 second FEV1 FVC Forced vital capacity GERD gastroesophageal reflux disease GPA Granulomatosis with polyangiitis HRCT High-resolution computed tomography ILD Interstitial lung disease LTS Laryngotracheal stenosis MALT Mucosa-associated lymphoid tissues MMEF25–75 Maximal mid-expiratory flow rates MPA Microscopic polyangiitis MPO Myeloperoxidase MRSA Methicillin-resistant Staphylococcus aureus NTM Nontuberculous mycobacteria PFT Pulmonary function test PR3 Proteinase 3 RA Rheumatoid arthritis RF Rheumatoid factor RPC Relapsing polychondritis RV Residual volume SARD Systemic autoimmune rheumatic disease SLB Surgical lung biopsy SLE Systemic lupus erythematosus SS Sjögren’s syndrome SSc Systemic sclerosis TLC Total lung capacity TNF Tumor necrosis factor 6.1 PATIENT EVALUATION The key components of evaluation for patients with systemic autoimmune rheumatic diseases (SARDs) and airway involvement include symptom history, an assessment of comorbid conditions, pulmonary function tests, and chest imaging. In some cases, additional invasive testing such as laryngoscopy, bronchoscopy, and surgical lung biopsy may be warranted. An overview of airway involvement in SARDs is depicted in Figure 6.1. 6.2 UPPER AIRWAYS DISEASE Upper airway obstruction in individuals with SARDs arises primarily as a result of intrinsic narrowing of the airway lumen. Though external airway compression has been reported in conditions such as sarcoidosis due to bulky lymphadenopathy, this type of obstruction is otherwise rare in patients with rheumatic conditions. Intrinsic narrowing of the central airways, often termed DOI: 10.1201/9781003361374-789

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Figure 6.1  Airway involvement in systemic autoimmune rheumatic diseases (SARDs).

Table 6.1: Rheumatic Etiologies of Laryngotracheal Stenosis Level of Upper Airway Involvement Larynx

Glottis Subglottis/trachea

Bronchi (extension from subglottic disease)

Rheumatic Disease Rheumatoid arthritis (cricoarytenoid involvement) Sarcoidosis IgG4-related disease Rheumatoid arthritis (rheumatoid nodules) Granulomatosis with polyangiitis Relapsing polychondritis Sarcoidosis IgG4-related disease Crohn’s disease Cutaneous blistering disease Granulomatosis with polyangiitis Relapsing polychondritis

laryngotracheal stenosis (LTS), encompasses a broad collection of both inflammatory and noninflammatory conditions. Epidemiologically, LTS is most often seen following local airway tissue injury due to mechanical, chemical, or thermal insults. Prolonged intubation has long been known to precipitate LTS as a result of pressure-induced tissue ischemia (2). LTS associated with systemic inflammatory and autoimmune conditions is thought to be the consequence of a primary inflammatory process arising within a component of the airway (3). “Idiopathic subglottic stenosis” is a unique form of LTS that occurs in the absence of any injury or systemic disease and affects predominately white women (4). This discussion focuses on LTS related to inflammatory and autoimmune conditions. The level of airway involvement provides a convenient framework for categorizing inflammatory or autoimmune causes of LTS (Table 6.1). Rheumatoid arthritis (RA) can affect the cricoarytenoid joints and may result in nodulosis of the vocal folds, resulting in relatively mild obstructive symptoms (5, 6). Sarcoidosis and IgG4-related disease can cause both supra- and infraglottic obstruction, though laryngeal disease seems to predominate in both conditions (7–9). Crohn’s disease and autoimmune cutaneous blistering diseases are rare causes of subglottic or tracheal stenosis. The majority of LTS related to autoimmune disease is due to granulomatosis with polyangiitis (GPA) and relapsing polychondritis (RPC). Both conditions preferentially affect the subglottic area and trachea with involvement that can extend into the bronchi. However, there are important features that help distinguish these two diseases based on the pattern of airway involvement. GPA more often leads to short-segment (10mL over 24 hours and clinical deterioration • Empiric antibiotics based on prior microbiology • Multidisciplinary approach with massive hemoptysis with pulmonology, interventional radiology, and thoracic surgery teams • First line: Bronchial artery embolization • Consider tranexamic acid • Surgical resection • Consider long-term antibiotics if ≥3 exacerbations/year • P. aeruginosa colonized patients • First: Inhaled colistin; alternate, inhaled gentamycin • Alternate/additive: macrolide (azithromycin or erythromycin) • Non-P. aeruginosa colonized patients • First: macrolide (azithromycin or erythromycin) • Alternate: inhaled gentamycin, doxycycline • Ensure NTM infections are ruled out prior to macrolide use with at least one respiratory culture • Use macrolides with caution in patients with hearing difficulties (Continued)

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Table 6.4: (Continued) Progressive/refractory disease

• Consider surgical lung resection in patients with localized disease who are not well controlled despite optimal medical management • Consider lung transplant referral in patients 7.5 mg/day or equivalent, the FRAX risk estimate should be increased by 15% for major osteoporotic fracture (1.15 multiplier) and by 20% for hip fracture (1.2 multiplier) (40). For patients with low fracture risk, calcium, vitamin D, and lifestyle modifications are recommended. For moderate, high, or very high fracture risk, it is recommended to add pharmacologic therapy with a parathyroid hormone (PTH) analog agent, teriparatide, as first-line therapy. Oral bisphosphonates are recommended in preference to no therapy if a patient is not a candidate for or does not wish to take a PTH analog. Intravenous bisphosphonate therapy or denosumab is recommended if an oral bisphosphonate is not an option. FRAX was not developed for use in patients less than 40 years of age, and premenopausal women comprise a patient population warranting special consideration regarding treatment during childbearing years, so adding osteoporosis medications for patients 40 years of age or younger should be assessed individually (40). 7.5 FLIGHT TRAVEL Flight travel for patients with lung disease carries increased risk, and the major airlines report that approximately 10% of in-flight medical emergencies are attributable to respiratory conditions (41). In flight, most planes are pressurized to about 10,000 feet, which would be equivalent to breathing 15–18% FiO2 (fraction of inspired oxygen) at sea level. An average healthy person breathing 15% oxygen at a high altitude would not demonstrate a drop in their oxygen saturation (SpO2). However, for patients with some degree of hypoxemia at sea level, a further decrease in the partial pressure of alveolar oxygen (PAO2) puts the patient on the steeper portion of the oxyhemoglobin dissociation curve, and this contributes to more prominent oxygen desaturation (42). A general approach to patients with underlying chronic lung disease: ■

If patients require oxygen supplementation of greater than 4 L/minute at rest, commercial air travel is not advised.

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■

If sea level resting SpO2 is higher than 95%, it is usually safe to travel without further testing.

■

If the patient is symptomatic with a sea level resting SpO2 below 95%, further testing should be considered with either a 6-minute walk test (6MWT) or a high-altitude simulation test (HSAT) to assess the need for in-flight supplemental oxygen.

Patients with advanced lung disease may not be able to increase minute ventilation sufficiently to compensate for hypoxia (43). Studies regarding flight travel in patients with ILD are limited. One retrospective analysis of patients with ILD concluded that a diffusion capacity of the lungs for carbon monoxide (DLCO) greater than 50% (predicted) and a PaO2 greater than 70.6 mmHg at sea level were independent predictors for passing a HSAT (44). Further studies (6MWT or HSAT) should be considered in patients with sea level resting hypoxia (SpO2 < 95%), DLCO less than or equal to 50%, or PaO2 less than or equal to 70.6 mmHg. Furthermore, for patients with bullous or cystic lung lesions, there is a concern for pneumothorax, especially for those who have experienced a prior spontaneous pneumothorax. As defined by Boyle’s law, as the atmospheric pressure falls during flight, gas within body cavities expands, thus increasing the potential risk for pneumothorax (45). However, for patients, the incidence of pneumothorax during air travel is relatively low if there is no prior history of pneumothorax (46). 7.6 PREGNANCY PREVENTION During pregnancy, there is a significant increase in oxygen demand due to ~20% increased oxygen consumption, and minute ventilation increases by ~40–50% (47). Not only may patients not be able to meet required oxygen demands during pregnancy, but also there is a concern for rapid fluid shifts following delivery, which puts patients with ILD at high risk for complications, especially those with PH (48, 49). The data regarding safety of pregnancy in patients with SARD-associated ILD are limited given the heterogeneity of data and sample sizes (50–54). The largest and most recent retrospective study with 86 pregnancies in patients with ILD had a 32% complication rate in the total cohort and a 100% complication rate in those with very severe lung disease (DLCO < 40% or FVC < 40%) (55). The ACR guidelines offer recommendations for reproductive health in rheumatic disease, but specific guidelines for patients with pulmonary complications are not addressed (56). The 2021 Thoracic society of Australia and New Zealand position statement reviews the safety of immunosuppressive medications during pregnancy (57). Given a paucity of data, guidelines are largely based on expert opinion. Careful management with a multidisciplinary approach involving a pulmonologist, rheumatologist, and obstetrician is recommended. Pulmonary hypertension among pregnant women carries a high mortality risk for both mother and fetus, with data suggesting a maternal mortality rate ranging from 30% to 56% (58). With recent advances in maternal–fetal medicine and PH management with newer medications, the guidelines have changed from complete avoidance of pregnancy to shared decision-making. The current European Society of Cardiology (ESC)/European Respiratory Society (ERS) 2022 guidelines support shared decision-making and recommend a multidisciplinary approach (59). Importantly, there are specific recommendations for some medications during pregnancy, including the discontinuation of endothelin receptor antagonists, riocigual, and selexipag due to potential teratogenicity. 7.7 OXYGEN SUPPLEMENTATION Oxygen supplementation for ILD and PH is not well studied. However, long-term oxygen supplementation is recommended with resting hypoxia (SpO2 < 88% for ILD or < 90% for PH) (60), but the data are primarily extrapolated from studies in patients with chronic obstructive pulmonary disease (COPD) (61, 62). There are conflicting data regarding ambulatory oxygen supplementation for exertional hypoxia for patients with ILD and/or PH. A recent study showed that oxygen supplementation in patients with stable COPD with mild resting hypoxia and exertional hypoxia did not show longer time to death or first hospitalization (63). However, patients with advanced ILD and/or PH have a more rapid and severe decline of oxygen saturation during exertion, so it may not be appropriate to extrapolate this finding to these patients (64). Some observational studies report improved exercise capacity and reduced exertional dyspnea with oxygen supplementation for in-laboratory tests (65, 66). A randomized prospective trial with ILD patients concluded that 2 weeks’ worth of ambulatory oxygen supplementation for patients with exertional hypoxia seemed to be associated with improved health-related QoL and reduced symptoms (67). However, the long-term clinical 111

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outcomes of oxygen supplementation for exertional hypoxia is still unknown, and further studies are warranted. 7.8 LUNG TRANSPLANTATION ILD is the most common indication for lung transplantation, surpassing COPD since 2007, with 40.5% of lung transplantations performed for ILD in 2017 (68). The median survival following lung transplantation is 5.2 years for IPF and 6.7 years for other forms of ILD for patients who underwent this procedure between 1992 and 2017 (68). In addition, a single-center study performed on patients with IPF showed a 75% reduction in the risk of death with lung transplantations (69). Determining the optimal timing for lung transplantation remains challenging. International guidelines recommend that lung transplantation be considered in patients with chronic lung disease and with a predicted high risk of death within 2 years (70, 71). A discussion of lung transplantation is encouraged at the time of diagnosis, and detailed evaluation for transplantation should occur promptly at the first sign of deterioration (60). IPF can have a rapidly progressive course and poor prognosis with a median survival of 3–5 years (72), although more than 20% of patients with IPF exhibit a less aggressive disease course (73), making it more difficult to guide precise timing for lung transplantation. Several criteria have been used to define disease progression: a decline in FVC by ≥5–10% or DLCO ≥10–15%, a drop in 6-minute walk distance of 50 meters, or worsening dyspnea and QoL scores (74–78). An absolute 1-year decline of FVC by ≥10% or 5–9% with a drop of DLCO ≥15% in systemic sclerosis-associated ILD (79) and an FVC decline of ≥10% (80) are associated with increased mortality. Considerations around the timing of referral for lung transplantation evaluation, particularly as they relate to factors associated with worsened clinical outcomes, are depicted in Table 7.2 (70, 81–89). PH (mPAP > 25 mmHg) has been reported in patients with IPF, with greater prevalence in advanced (30–50%) and end-stage (>60%) disease (90). The prevalence of PH in sarcoidosis is about 6–20%, and long-term survival is poor in sarcoidosis-associated PH (91–93). Current ESC/ERS guidelines in 2022 recommend to refer eligible patients with lung disease with concomitant PH for lung transplantation evaluation (94). Despite limited data regarding SARD-ILD, the International Society for Heart and Lung Transplantation (ISHLT) considers these patients to have poorer outcomes and recommends collaboration of the pulmonary specialist with an interdisciplinary team involving rheumatologists, gastroenterologists, and nephrologists for screening and managing extrapulmonary systemic disease (70). Carefully selected patients with SARD-ILD have similar outcomes in survival or allograft dysfunction compared to those undergoing transplantation for other indications (95–97). For patients with idiopathic inflammatory myopathies, a comprehensive cancer screening is required (70, 98).

Table 7.2: Criteria for Referral and Listing for ILD Referral recommended for transplantation evaluation

Transplantation listing recommended

• • • • • • • • • • • • • • • •

Histopathological usual interstitial pneumonia (UIP) Probable or definite UIP on radiograph FVC < 80% or DLCO < 40% Decline in PFT over 2 years Decline FVC ≥10% or Decline DLCO ≥15% or Decline FVC ≥5% with symptomatic or radiographic progression Any resting/exertional oxygen requirement Progression of inflammatory ILD despite medical therapy Hospitalization for a respiratory decline, pneumothorax, or acute exacerbation Desaturation < 88% on 6MWT or >50 m decline in 6MWD over 6 months PAH on RHC Absolute decline in PFT over the past 6 months despite treatment: Decline FVC >10% or Decline DLCO >10% or Decline FVC >5% with radiographic progression

Source: Adapted from Kapnadak et al. (81)

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7.9 PALLIATIVE CARE Palliative care focuses on symptom management rather than disease treatment. Patients with ILD and/or PH suffering from chronic respiratory symptoms, including breathlessness, have significantly impaired QoL. Early palliative care involvement in lung cancer has demonstrated substantial benefits, including improved survival (99). A study performed in patients with chronic dyspnea, of which 18% of the study population were patients with ILD, showed that palliative care improved QoL and even had a survival benefit (100). The safety of low-dose benzodiazepines and opioids in patients with ILD confirmed that this pharmacologic intervention for symptoms increased neither admission rate nor mortality (101). Often palliative care is erroneously viewed as a synonym for end-of-life care, which can further delay the implementation of palliative measures. Patients favor “supportive care” rather than palliative care (102). A careful explanation to patients by using appropriate language is essential. The practical and early implementation of palliative care in patients with pulmonary manifestations of SARDs benefits from an interdisciplinary approach incorporating religious and cultural differences (103, 104). 7.10 CONCLUSION In this chapter, we summarized current guidelines and evidence for the general care of patients with SARDs and pulmonary manifestations. Given constantly evolving therapies, general care, including preventative measures, is an essential and impactful part of patient care. Shared decision-making and an interdisciplinary approach are the key to managing the complexity of patients who have lung disease associated with SARDs. REFERENCES 1. Wallaert B, Monge E, Le Rouzic O, Wémeau-Stervinou L, Salleron J, Grosbois JM. Physical activity in daily life of patients with fibrotic idiopathic interstitial pneumonia. Chest. 2013;144(5):1652–8. 2. Vainshelboim B, Kramer MR, Izhakian S, Lima RM, Oliveira J. Physical activity and exertional desaturation are associated with mortality in idiopathic pulmonary fibrosis. J Clin Med. 2016;5(8). 3. Nishiyama O, Yamazaki R, Sano H, Iwanaga T, Higashimoto Y, Kume H, et al. Fat-free mass index predicts survival in patients with idiopathic pulmonary fibrosis. Respirology. 2017;22(3):480–5. 4. Dowman L, Hill CJ, Holland AE. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev. 2014(10):Cd006322. 5. Perez-Bogerd S, Wuyts W, Barbier V, Demeyer H, Van Muylem A, Janssens W, et al. Short and long-term effects of pulmonary rehabilitation in interstitial lung diseases: A randomised controlled trial. Respir Res. 2018;19(1):182. 6. Bye PT, Anderson SD, Woolcock AJ, Young IH, Alison JA. Bicycle endurance performance of patients with interstitial lung disease breathing air and oxygen. Am Rev Respir Dis. 1982;126(6):1005–12. 7. Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, et al. Interstitial lung disease guideline: The British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008;63(Suppl 5):v1–58. 8. Darvishian M, van den Heuvel ER, Bissielo A, Castilla J, Cohen C, Englund H, et al. Effectiveness of seasonal influenza vaccination in community-dwelling elderly people: An individual participant data meta-analysis of test-negative design case-control studies. Lancet Respir Med. 2017;5(3):200–11. 9. Park JK, Lee YJ, Shin K, Ha YJ, Lee EY, Song YW, et al. Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: A randomised clinical trial. Ann Rheum Dis. 2018;77(6):898–904. 10. Britton A, Embi PJ, Levy ME, Gaglani M, DeSilva MB, Dixon BE, et al. Effectiveness of COVID-19 mRNA vaccines against COVID-19-associated hospitalizations among immunocompromised adults during SARS-CoV-2 omicron predominance—VISION network, 10 States, December 2021-August 2022. MMWR Morb Mortal Wkly Rep. 2022;71(42):1335–42. 11. Tenforde MW, Patel MM, Gaglani M, Ginde AA, Douin DJ, Talbot HK, et al. Effectiveness of a third dose of Pfizer-BioNTech and moderna vaccines in preventing COVID-19 hospitalization among immunocompetent and immunocompromised adults—United States, August– December 2021. MMWR Morb Mortal Wkly Rep. 2022;71(4):118–24. 113

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79. Goh NS, Hoyles RK, Denton CP, Hansell DM, Renzoni EA, Maher TM, et al. Short-term pulmonary function trends are predictive of mortality in interstitial lung disease associated with systemic sclerosis. Arthritis Rheumatol. 2017;69(8):1670–8. 80. Solomon JJ, Chung JH, Cosgrove GP, Demoruelle MK, Fernandez-Perez ER, Fischer A, et al. Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2016;47(2):588–96. 81. Kapnadak SG, Raghu G. Lung transplantation for interstitial lung disease. Eur Respir Rev. 2021;30(161):210017. 82. Nasser M, Larrieu S, Si-Mohamed S, Ahmad K, Boussel L, Brevet M, et al. Progressive fibrosing interstitial lung disease: A clinical cohort (the PROGRESS study). Eur Respir J. 2021;57(2). 83. Raghu G, Ley B, Brown KK, Cottin V, Gibson KF, Kaner RJ, et al. Risk factors for disease progression in idiopathic pulmonary fibrosis. Thorax. 2020;75(1):78–80. 84. Snyder L, Neely ML, Hellkamp AS, O’Brien E, de Andrade J, Conoscenti CS, et al. Predictors of death or lung transplant after a diagnosis of idiopathic pulmonary fibrosis: Insights from the IPF-PRO registry. Respir Res. 2019;20(1):105. 85. Hayes D, Jr., Black SM, Tobias JD, Kirkby S, Mansour HM, Whitson BA. Influence of pulmonary hypertension on patients with idiopathic pulmonary fibrosis awaiting lung transplantation. Ann Thorac Surg. 2016;101(1):246–52. 86. Collard HR, King TE, Jr., Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2003;168(5):538–42. 87. Ratwani AP, Ahmad KI, Barnett SD, Nathan SD, Brown AW. Connective tissue diseaseassociated interstitial lung disease and outcomes after hospitalization: A cohort study. Respir Med. 2019;154:1–5. 88. Kirkil G, Lower EE, Baughman RP. Predictors of mortality in pulmonary sarcoidosis. Chest. 2018;153(1):105–13. 89. du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, et al. Six-minutewalk test in idiopathic pulmonary fibrosis: Test validation and minimal clinically important difference. Am J Respir Crit Care Med. 2011;183(9):1231–7. 90. Nathan SD, Barbera JA, Gaine SP, Harari S, Martinez FJ, Olschewski H, et al. Pulmonary hypertension in chronic lung disease and hypoxia. Eur Respir J. 2019;53(1). 91. Shlobin OA, Kouranos V, Barnett SD, Alhamad EH, Culver DA, Barney J, et al. Physiological predictors of survival in patients with sarcoidosis-associated pulmonary hypertension: Results from an international registry. Eur Respir J. 2020;55(5). 92. Bandyopadhyay D, Humbert M. An update on sarcoidosis-associated pulmonary hypertension. Curr Opin Pulm Med. 2020;26(5):582–90. 93. Savale L, Huitema M, Shlobin O, Kouranos V, Nathan SD, Nunes H, et al. WASOG statement on the diagnosis and management of sarcoidosis-associated pulmonary hypertension. Eur Respir Rev. 2022;31(163). 94. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, et al. 2022 ESC/ ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: Developed by the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG). Eur Heart J. 2022;43(38):3618–731. 95. Courtwright AM, El-Chemaly S, Dellaripa PF, Goldberg HJ. Survival and outcomes after lung transplantation for non-scleroderma connective tissue-related interstitial lung disease. J Heart Lung Transplant. 2017;36(7):763–9. 96. Takagishi T, Ostrowski R, Alex C, Rychlik K, Pelletiere K, Tehrani R. Survival and extrapulmonary course of connective tissue disease after lung transplantation. J Clin Rheumatol. 2012;18(6):283–9. 97. Park JE, Kim SY, Song JH, Kim YS, Chang J, Lee JG, et al. Comparison of short-term outcomes for connective tissue disease-related interstitial lung disease and idiopathic pulmonary fibrosis after lung transplantation. J Thorac Dis. 2018;10(3):1538–47. 98. Ameye H, Ruttens D, Benveniste O, Verleden GM, Wuyts WA. Is lung transplantation a valuable therapeutic option for patients with pulmonary polymyositis? Experiences from the Leuven transplant cohort. Transplant Proc. 2014;46(9):3147–53. 99. Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733–42. 117

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100. Higginson IJ, Bausewein C, Reilly CC, Gao W, Gysels M, Dzingina M, et al. An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: A randomised controlled trial. Lancet Respir Med. 2014;2(12):979–87. 101. Bajwah S, Davies JM, Tanash H, Currow DC, Oluyase Adejoke O, Ekström M. Safety of benzodiazepines and opioids in interstitial lung disease: A national prospective study. Eur Respir J. 2018;52(6):1801278. 102. Maciasz RM, Arnold RM, Chu E, Park SY, White DB, Vater LB, et al. Does it matter what you call it? A randomized trial of language used to describe palliative care services. Support Care Cancer. 2013;21(12):3411–19. 103. Kreuter M, Bendstrup E, Russell AM, Bajwah S, Lindell K, Adir Y, et al. Palliative care in interstitial lung disease: Living well. Lancet Respir Med. 2017;5(12):968–80. 104. Lindell K, Raghu G. Palliative care for patients with pulmonary fibrosis: Symptom relief is essential. Eur Respir J. 2018;52(6):1802086.

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APPROACH TO PULMONARY MANIFESTATIONS OF SPECIFIC SYSTEMIC AUTOIMMUNE RHEUMATIC DISEASES

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8  Pulmonary Manifestations of Rheumatoid Arthritis Robert K. Arao, Robert W. Hallowell, and Jeffrey A. Sparks List of Abbreviations ACPA Anti-citrullinated protein antibodies BAL Bronchoalveolar lavage CT Computed tomography DMARD Disease-modifying antirheumatic drug DLCO Diffusion capacity of the lungs for carbon monoxide FDG-PET Fluorodeoxyglucose positron emission tomography FVC Forced vital capacity HRCT High-resolution computed tomography ILD Interstitial lung disease IPF Idiopathic pulmonary fibrosis NSAID Nonsteroidal anti-inflammatory drug NSIP Nonspecific interstitial pneumonia PFT Pulmonary function test RA Rheumatoid arthritis RA-ILD Rheumatoid arthritis-associated interstitial lung disease RF Rheumatoid factor SARD Systemic autoimmune rheumatic disease TNF Tumor necrosis factor UIP Usual interstitial pneumonia 8.1 OVERVIEW OF RHEUMATOID ARTHRITIS Rheumatoid arthritis (RA) is an autoimmune disease that affects nearly 1% of the population, characterized by inflammatory polyarthritis (1). While RA typically affects the wrists, elbows, and small joints in the hands and feet in a symmetric fashion, nearly any joint can be affected. Longstanding RA may cause bone erosions that lead to deformities and disability. The diagnosis of RA is clinical and relies on the identification of synovitis through physical examination or imaging, chronicity, and laboratory markers such as autoantibodies and inflammatory markers (1). Rheumatoid factor (RF) and anti-cyclic citrullinated protein antibodies (ACPA) are not diagnostic by themselves and in some people with RA may be negative (1). Patients with RA are at increased risk for comorbid conditions such as cardiovascular disease, osteoporosis, cancer, and infections due to elevated systemic inflammation, autoimmunity, and adverse effects of medications (1). While most outcomes of RA have improved with expanded treatment options, the mortality of patients with RA and lung disease, such as interstitial lung disease (ILD), remains high (2). In this chapter, we will detail the most common pulmonary manifestations of RA, which include interstitial lung disease (ILD), airways disease and bronchiectasis, pleural disease, and pulmonary nodules. 8.2 INTERSTITIAL LUNG DISEASE 8.2.1 Epidemiology ILD is the most common pulmonary complication of RA (3, 4), with reported cumulative incidence rates ranging from 2% to 15%, depending on the duration of follow-up (5–8). ILD can occur prior to or following the development of joint manifestations (7, 9), and in one study, interstitial changes were detected on computed tomography (CT) of the chest with asymptomatic presentation in nearly half of patients (6, 10). RA-ILD seems to be more common in men (7, 9, 11), and additional risk factors for the development of ILD include older age at RA onset, RF or ACPA positivity and higher antibody titers, smoking, and RA disease severity (3, 5–7, 9, 10, 12–15). While the severity of RA has generally decreased in recent years with the advent of additional targeted therapies, the prevalence of RA-ILD seems to be rising (8). This may be due either to increased recognition or perhaps due to environmental factors such as inhalants or RA medications. A wide range of radiographic findings exist in patients with RA-ILD, with reticulation, groundglass opacities, and traction bronchiectasis being the most prominent features (16). Although a usual interstitial pneumonia (UIP) pattern is the radiographic and pathologic ILD subtype most frequently described (>55% of RA-ILD), nonspecific interstitial pneumonia (NSIP), organizing 120

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pneumonia, and overlapping patterns are also common (3, 4, 9, 17–21). Examples of UIP and NSIP in RA-ILD are shown in Figure 8.1. The presence of ILD is associated with significant morbidity and increased mortality in RA (5–7, 11, 22, 23), with worse outcomes and a greater propensity for disease progression in patients demonstrating more severe articular disease, findings consistent with a fibrotic or UIP pattern, older age, and higher RA disease activity scores (4, 9, 17, 20–22, 24–27).

Figure 8.1  Patterns of rheumatoid arthritis-associated interstitial lung disease on high-resolution chest computed tomography imaging. (A) Diffuse subpleural reticulation, traction bronchiectasis, and anterior upper lobe predominant honeycombing in a pattern suggestive of usual interstitial pneumonia (UIP). (B) Reticular opacities, perilobular thickening, and mild traction bronchiectasis in a pattern indeterminate for UIP. (C) Reticulations, ground-glass opacities, and evidence of subpleural sparing suggestive of a fibrotic nonspecific interstitial pneumonia (NSIP) pattern. 121

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8.2.2 Pathobiology The pathophysiology underlying the development of RA-ILD remains poorly understood, and the precise mechanism may vary depending on the individual subtype and the patient’s specific risk factors. One consistent observation has been the high prevalence of ACPA in patients with RA-ILD, with positivity rates ranging from 72% to 94% (3, 9, 14). Levels of ACPA are higher in patients with RA who have ILD compared to those without ILD (9, 28), and the presence of ACPA can predate the onset of RA by years (29). One hypothesis suggests that autoimmunity against citrullinated peptides begins in the synovium and subsequently shifts to the pulmonary tissue due to cross-reactivity with similar antigens found in the lungs (30, 31). Smoking is an established risk factor for the development of RA-ILD (12, 15), and there is evidence that smoking is associated with the upregulation of both peptidylarginine deiminase enzyme expression and levels of citrullinated proteins (32, 33). The idea of early lung injury as an inciting event for autoimmunity is supported by the fact that early interstitial changes are more common in patients with RA and positive ACPA than in those who are seronegative (34). The MUC5B promoter variant (rs35705950), which has been shown to be highly associated with the risk of developing idiopathic pulmonary fibrosis (IPF), is also associated with an increased risk of developing ILD in patients with RA, particularly the UIP pattern of disease that is characteristic of IPF (35, 36). Interestingly, a history of smoking has been associated with a UIP pattern of disease in RA-ILD (9), and smoking seems to potentiate the genetic risk of developing ILD in the presence of the MUC5B variant (37). Additionally, a genome-wide association study of RA-ILD in the Japanese population identified a variant in the RPA3 gene region—which is involved in regulation of telomere length—as a risk factor for developing RA-ILD (38, 39). Mutations in TERT, RTEL1, PARN, or SFTPC also seem to be more frequent in patients with RA-ILD when compared to controls, and this may also be related to telomere length (40). Patients with RA-ILD have shorter average telomere lengths than patients with other forms of systemic autoimmune rheumatic disease (SARD)-related ILD and lengths similar to those of patients with IPF (41). The many similarities of the UIP subtype of RA-ILD and IPF may explain high mortality of RA-ILD (42). It is hypothesized that the combination of an environmental trigger in a susceptible genetic host plus the loss of immune tolerance will lead to increased inflammation characterized by the production of chemokines, cytokines, and various interleukins. Tissue samples from patients with RA-ILD demonstrate elevated levels of IL-17RA in areas of fibrosis compared with normal lung tissue or IPF controls (43), and IL-17A and transforming growth factor-β1 are believed to play key roles in promoting myofibroblast differentiation and the subsequent deposition of extracellular matrix (31). 8.2.3 Evaluation Most often, patients with RA-ILD present with the insidious onset of dyspnea or a nonproductive cough. In hindsight, symptoms have often been present for months or years before being mentioned to a primary care provider or rheumatologist. The diagnosis may be further delayed by the fact that many patients attribute their decreased exercise capacity to aging or deconditioning (joint pain may limit the ability to exercise) (15, 44). Physical examination findings can be subtle and nonspecific. Bibasilar crackles are common but not always present, particularly early in the course of disease or in patients with an NSIP pattern of disease. Digital clubbing and signs of cor pulmonale, as signs of advanced lung disease, may develop. All patients with RA with respiratory symptoms warrant consideration for high-resolution computed tomography (HRCT) chest imaging and pulmonary function testing (PFT) as an initial evaluation to evaluate for the presence of ILD or other pulmonary manifestations of their disease. It is not uncommon for patients with RA and a history of smoking to develop emphysema, which can lead to “pseudonormal” spirometry (where patients may have normal FVC due to the concurrent pathophysiology of both diseases) in the setting of concurrent ILD and confound the interpretation of PFTs (44). However, patients with combined pulmonary fibrosis and emphysema often have a significant reduction in diffusion capacity of the lungs for carbon monoxide (DLCO). In addition, early in the course of RA-ILD, a reduction in forced vital capacity (FVC) or ambulatory desaturations may not be present. In such cases, the DLCO can be a much more sensitive marker for the presence of disease, highlighting the need to obtain comprehensive PFTs (i.e., lung volumes and DLCO in addition to spirometry) in patients with RA (15, 45). The role of bronchoalveolar lavage (BAL) in the diagnosis of ILD is questionable (46, 47) and should be reserved for cases 122

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where a superimposed infectious process is suspected as a potential cause of progressive symptoms or radiologic changes, particularly in patients receiving immunosuppressive therapies. Surgical lung biopsy is also rarely needed. Patients with RA and pulmonary manifestations should also be investigated for overlap with other SARDs, since inflammatory arthritis may be feature of many of these diseases. 8.2.4 Treatment To date, there are no large randomized controlled trials comparing different treatment modalities for patients with RA-ILD, nor does retrospective data suggest that one agent is more efficacious than another (14). In patients with mild and incidentally discovered interstitial changes, a conservative, watchful approach may be appropriate. In cases of more significant or progressive disease, there is some evidence that the use of immunosuppression, regardless of the radiologic pattern, is associated with improved or stabilized lung function (14, 24, 48). Although numerous case reports and case series have sought to implicate both conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) in the development or worsening of ILD in patients with RA, the data has been inconclusive (Table 8.1) (49).

Table 8.1: Pharmacologic Treatment Options for Rheumatoid ArthritisAssociated Interstitial Lung Disease Medication

Class/Mechanism of Action

RA-ILD Subtypes to Consider

Glucocorticoids

Glucocorticoids

OP and NSIP

Mycophenolate

Immunosuppressive

UIP and NSIP

Azathioprine

—

Janus kinase inhibitors Cyclophosphamide

Conventional synthetic DMARD Calcineurin inhibitor Biologic DMARD/ B-cell depletion Biologic DMARD/ T-cell co-stimulation inhibitor Biologic DMARD/ IL-6 receptor inhibitor Targeted synthetic DMARD Immunosuppressive

Nintedanib

Antifibrotic

UIP, fibrotic NSIP

Pirfenidone

Antifibrotic

UIP, fibrotic NSIP

Tacrolimus Rituximab Abatacept

Tocilizumab

—

Notes No trial data. Consider starting dose of prednisone 0.5 mg/kg/day, tapered to ≤10 mg daily after response (generally 4–12 weeks). Caution in UIP. No trial data. Efficacy is limited for inflammatory arthritis. No trial data. Caution in UIP.

—

No trial data. Reserved for refractory patients. No trial data. May have efficacy for both articular and lung involvement. No trial data.

—

No trial data.

—

No trial data.

—

No trial data. Reserved for fulminant or refractory patients. INBUILD trial included some patients with RA-ILD and showed slower decline of FVC than placebo. TRAIL1 trial composed of RA-ILD patients did not meet primary outcome, but subgroup with UIP had slower decline of FVC than placebo.

—

Abbreviations: DMARD: disease-modifying antirheumatic drug; FVC: forced vital capacity; IL: interleukin; RA-ILD: rheumatoid arthritis-associated interstitial lung disease; UIP: usual interstitial lung disease

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8.2.5 Glucocorticoids Glucocorticoids, with a tapering course, have traditionally been used as primary therapy for patients with a predominantly NSIP or organizing pneumonia pattern on CT chest imaging. However, data specific to the use of glucocorticoids is limited to small retrospective series. In these studies, glucocorticoids seem to be effective for improving or stabilizing lung function, though in many instances, the results are confounded by the fact that many patients have also received additional immunosuppressive agents (18, 50). We suggest a starting dose of prednisone 0.5 mg/kg per day, tapered to at least 10 mg per day generally 4–12 weeks after response. We suggest caution in patients with the UIP pattern based on the finding of worse outcomes in the group receiving glucocorticoids compared to the placebo group in the PANTHER-IPF trial (51). 8.2.6  Mycophenolate and Azathioprine Data on the utility of azathioprine and mycophenolate for RA-ILD treatment is limited to retrospective studies, often with only a fraction of the patients having RA as their specified SARD (52, 53). Matson et al. performed a retrospective analysis of 212 patients with RA-ILD treated with immunosuppression and found no significant difference in outcomes between those treated with mycophenolate, azathioprine, or rituximab. However, adverse events were more common in the azathioprine group (14). Also, the efficacy of mycophenolate for inflammatory arthritis is limited, so patients receiving mycophenolate for lung involvement may require concomitant immunosuppressive drugs. 8.2.7 Methotrexate Historically, there has been concern about the potential of methotrexate being associated with pulmonary toxicity, in part because numerous case reports and retrospective case series demonstrated an association between treatment with this agent and the development of ILD in patients with RA (31). However, larger studies in more recent years have failed to demonstrate any convincing evidence that methotrexate increases the risk of ILD in patients with RA. On the contrary, methotrexate is now associated with a reduced risk of ILD, longer time to ILD diagnosis, and improved survival (5, 48, 54, 55). However, acute pneumonitis (characterized by fever, cough, and infiltrates on chest X-ray) that is distinct from progressive RA-ILD can occur in patients treated with methotrexate, though the incidence appears to be on the order of 4% (56, 57). 8.2.8 Leflunomide Studies assessing the impact of leflunomide on pulmonary outcomes in patients with RA are limited. One prospective observational cohort study included 143 patients with RA-ILD, of whom 26 (18.2%) received leflunomide. Exposure to leflunomide was associated with an increased risk and shorter time to ILD progression (58). However, in a meta-analysis of eight studies involving 4579 patients, leflunomide was not associated with an increased risk of ILD and was possibly protective against noninfectious respiratory adverse events (59). There are case reports suggesting accelerated nodulosis and pulmonary artery hypertension in patients with RA treated with leflunomide (60, 61). 8.2.9 Sulfasalazine Pulmonary toxicity in the form of interstitial pneumonitis and eosinophilic pneumonia is a rare but well-accepted complication of sulfasalazine, though data is primarily limited to case reports. Most patients with suspected sulfasalazine-induced lung disease improve following the cessation of the drug, either with or without the addition of glucocorticoids (62). It is the authors’ practice to avoid the use of sulfasalazine whenever possible in patients with RA and known ILD. 8.2.10  Calcineurin Inhibitors Although calcineurin inhibitors have historically not been used as first-line therapy for the treatment of RA-ILD, case reports of cyclosporine being used to treat refractory RA-ILD do exist (63, 64). Yamano et al. reported 26 patients with ILD, 11 of whom had RA, who received treatment with a combination of tacrolimus and glucocorticoids. After 12 months, PFTs and dyspnea had significantly improved for the collective group, though the results of the individual patients were not reported (50). 8.2.11  TNF Inhibitors As with other medications, data regarding the safety of tumor necrosis factor (TNF) inhibitors in patients with RA-ILD has been mixed, and the British Society of Rheumatology continues to caution against their use in patients with significant lung disease. Of note, one study summarized 124

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122 cases of ILD potentially caused by biologic therapy between 1990 and 2010. The mean onset of pulmonary disease was 26 weeks after the initiation of therapy. Although most cases at least partially resolved following drug withdrawal, either with or without concurrent glucocorticoids, a lack of resolution and death occurred in 35% and 29% of patients, respectively (65). Conversely, in a large cohort study that included 8417 patients with autoimmune disease, the use of TNF inhibitors was not associated with an increased incidence of ILD compared to non-biologic DMARDs, including among 828 patients with RA (66). Finally, in the only prospective study to date involving 82 patients with RA, either with or without pre-existing ILD, the use of TNF inhibitors was not associated with an increased risk of ILD or worsening ILD scores and, interestingly, seemed to improve the extent of small airways disease (67). 8.2.12 Rituximab To date, no prospective studies evaluating the effects of rituximab on RA-ILD have been performed. In a 10-year study that included 44 patients with RA-ILD with available PFTs, improvement, stability, or decline in lung function was noted in 16%, 52%, and 32% of patients, respectively. The majority of patients who demonstrated ILD progression had severe disease prior to the onset of rituximab therapy (68). 8.2.13 Abatacept Although randomized or controlled studies assessing the utility of abatacept for the treatment of RA-ILD are lacking, the volume of observational data is growing. In a multicenter study including 63 patients with RA-ILD who received abatacept, roughly two-thirds experienced stability in their dyspnea and PFTs, and an improvement was seen in at least 20%. HRCT chest imaging was also stable or improved in most patients (69). Another multicenter study evaluating 44 patients with RA-ILD in Italy demonstrated stability or improvement in FVC, DLCO, and HRCT in 86.1%, 91.7%, and 81.4% of patients, respectively (70). Another observational study analyzed 263 patients with RA-ILD receiving at least one dose of abatacept with a median follow-up of 12 months. FVC and DLCO were stable or improved in 87.7% and 90.6% of patients, respectively. CT chest imaging was stable or improved in 76.6% of patients (71). 8.2.14 Tocilizumab While tocilizumab is FDA-approved for systemic sclerosis-associated ILD, there is only one small, uncontrolled observational study investigating tocilizumab for RA-ILD (n = 28) (72). After a mean follow-up of 30 months, the FVC was improved, stable, or worsened in 20%, 56%, and 24% of patients, respectively. HRCT chest imaging remained stable in 25/28 patients, suggesting some utility (72). 8.2.15  Janus Kinase Inhibitors Data regarding the use of Janus kinase inhibitors (JAKis) in patients with RA-ILD is limited. A recent observational study included 31 patients with RA-ILD who were treated with a JAKi. Using computer-aided methods to assess the extent of fibrosis on CT chest imaging, radiographic progression, stability, or improvement was reported in 16.1%, 64.5%, and 19.4% of the patients, respectively (46). 8.2.16 Cyclophosphamide In general, cyclophosphamide is typically avoided as a first-line therapy for the treatment of RA-ILD due to its unfavorable adverse effect profile and the availability of safer, better-tolerated immunosuppressants. In a retrospective study of 266 patients with RA-ILD, treatment with cyclophosphamide was associated with an improved prognosis, though this study was not designed to compare the use of cyclophosphamide with that of alternative therapies. Furthermore, PFT data was not included in the mortality analysis, so the baseline severity of disease in patients who received cyclophosphamide vs. those who did not remains unknown (73). 8.2.17  Antifibrotic Agents Regardless of therapy, many patients with RA-ILD develop a progressive fibrotic phenotype, with overt UIP being the most common ILD pattern (9, 17, 18). Given the phenotypic and genetic similarities between RA-related UIP and IPF (30, 35, 40), there is a growing interest in the use of antifibrotic agents for the treatment of RA-ILD. The INBUILD trial was a double-blind, placebocontrolled, phase 3 trial that demonstrated the ability of nintedanib to slow the decline of FVC in 125

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patients with non-IPF fibrosing lung disease (74). A subgroup, post-hoc analysis of the trial demonstrated a treatment benefit of nintedanib in the 25.6% of patients with autoimmune ILD, of which approximately half had RA (75). Pirfenidone, which has been shown to slow the decline of FVC in patients IPF, may also have an inhibitory effect on myofibroblast differentiation in the lungs of patients with RA-ILD (76). The recent TRAIL1 study was a randomized, double-blind, placebo-controlled, phase 2 trial to assess the efficacy of pirfenidone in patients with RA-ILD. After 123 patients were randomized, the study was terminated prematurely due to the COVID-19 pandemic and slow enrollment. There was no difference between the pirfenidone and placebo groups in the primary composite endpoint (decline in FVC% from baseline of 10% or more or death). However, patients in the pirfenidone group experienced a slower annual decline in absolute FVC, particularly those with UIP (77). 8.3 AIRWAYS DISEASE AND BRONCHIECTASIS 8.3.1 Epidemiology Airways disease in RA includes conditions that involve both the upper and lower airways. Upper airway manifestations are rare and typically occur in patients with severe or protracted disease (78). They include cricoarytenoid joint arthritis, vasculitis of the recurrent laryngeal or vagal nerve, and vocal cord rheumatoid nodules. Lower airway manifestations, including obstructive lung diseases such as bronchiectasis, reactive airways disease, and follicular and obliterative bronchiolitis, are the more common airways diseases seen in patients with RA and will be the focus of this section. Estimates of the incidence of lower airways disease in RA vary based on the patient population studied and criteria used to define specific airways diseases. Confounding factors such as the coexistence of RA-ILD, smoking status, and prior occupational exposure have added to the challenge of assessing the incidence of reactive airways disease attributable to RA. Across studies, patients have been included and excluded based on these factors which has added to variability of reported incidence (79, 80). Obstructive lung disease, defined by airflow limitation on PFT, has been shown to have an increased incidence in patients with RA compared to the general population (80, 81). The risk of developing obstructive lung disease in RA has been associated with male sex. Furthermore, the presence of obstructive lung disease in those with RA has been associated with increased mortality (82). Bronchiectasis, characterized by abnormal widening of the bronchi and bronchioles, is the most common airways manifestation in RA, affecting up to 20% of patients (83, 84). Bronchiectasis can both precede the clinical onset of RA, with some early studies showing bronchiectasis preceding RA onset by a mean of 16–28 years, as well as occur after the development of other clinical manifestations of RA (84, 85). Bronchiectasis in RA can be found both in symptomatic and asymptomatic patients (82, 85). The clinical significance of asymptomatic disease has not been widely studied; however, an increased risk of mortality in patients with concomitant bronchiectasis and RA compared to patients with RA alone has been demonstrated (86). Follicular and obliterative bronchiolitis are two rare airways diseases reported in patients with RA. Both diseases have been associated with a higher incidence in RA compared to that in patients with other SARDs (87). Follicular bronchiolitis, defined by hyperplasia of the bronchialassociated lymphoid tissue (BALT) and subsequent obstructive airways disease, has been characterized in patients with RA, often in their fifth decade of life, with the diagnosis of RA preceding their pulmonary manifestations (88). Obliterative bronchiolitis, characterized by the progressive narrowing of the bronchioles, is a severe airways disease that is most commonly seen in patients with RA who are female, have a high RF, and have longstanding untreated disease (89). Both types of bronchiolitis may present with cough and sputum production along with recurrent respiratory infections. This diagnosis may be made incidentally based on chest imaging performed for other reasons. Clinically, it may be difficult to distinguish these patients early in their disease course. High RF and ACPA as well as lower BMI have recently been associated with an increased risk for isolated bronchiolitis without ILD (90). Since bronchiectasis represents the most common RAassociated airways disease, the remainder of this section will focus on the pathobiology, evaluation, and treatment of bronchiectasis in patients with RA. 8.3.2 Pathobiology The mechanisms underlying the pathogenesis of bronchiectasis involve a combination of decreased host immune defense and recurrent airway inflammation leading to airway damage and dilation. The specific pathobiology of bronchiectasis in RA is not fully understood; however, 126

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various hypotheses exist that highlight contributions from genetic predisposition, autoimmune/ inflammatory insults, and recurrent infections. Several studies have demonstrated an association between patients with RA and symptomatic bronchiectasis with an increased incidence of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. Specifically, heterozygous expression of the delta F508 mutation has been seen with increased incidence in patients with RA and bronchiectasis and associated with increased pulmonary disease severity, suggesting that this genetic defect may be linked to the development of bronchiectasis in RA (91, 92). Autoimmunity and subsequent airway damage have been suggested as another potential cause of bronchiectasis in RA, similar to that which occurs in RA-ILD. This hypothesis stipulates that autoimmune-related inflammation can involve the airways and result in bronchiectasis both as a primary and secondary process related to traction after architectural distortion from other diseases such as ILD. One study demonstrated that healthy people with elevated ACPA and patients with ACPA-positive RA have an increased incidence of airway thickening and bronchiectasis on HRCT chest as compared to healthy controls without elevated ACPA, suggesting that autoimmune injury may play a role in developing bronchiectasis (93). Airway damage from chronic and recurrent pulmonary infections has also been proposed as a potential cause of RA-associated bronchiectasis. Both immune dysregulation in the setting of RA and the immunosuppressive effects of RA medications have been suggested as risk factors for recurrent infections, supported by data demonstrating an increased rate of pulmonary infections in patients with RA (94). 8.3.3 Evaluation While bronchiectasis in patients with RA can be clinically silent, an evaluation should be pursued in any patient who exhibits symptoms of sputum production, chronic cough, shortness of breath, or recurrent respiratory infections. An initial evaluation consists of both chest imaging with HRCT and PFTs (95). Screening for alternative causes of bronchiectasis unrelated to RA may also be pursued. There are currently no guidelines that support screening for bronchiectasis with imaging or PFTs in asymptomatic patients with RA. 8.3.4  Chest Imaging Radiologic evaluation for airways disease in RA is best pursued with HRCT chest imaging; however, a CXR is often obtained first. A CXR may demonstrate ring-like opacities or “tramtrack” lines corresponding to dilated, thickened airways. HRCT chest may demonstrate varicose, cylindrical, or tubular bronchiectasis. Findings suggestive of inflammation, including tree-in-bud nodules and bronchial wall thickening, may also be present. While the distribution of bronchiectasis in RA is variable, the disease often affects the lungs diffusely (87). Bronchiectasis can also be observed in association with pulmonary fibrosis, such as in RA-ILD, which is often a result of fibrotic tissue pulling on the bronchi, causing traction bronchiectasis rather than freestanding bronchiectasis as a primary disease process. 8.3.5  Pulmonary Function Tests PFTs, including spirometry, lung volumes, and gas exchange, are recommended for the diagnosis of bronchiectasis in symptomatic patients with RA. Spirometry may show an obstructive ventilatory defect with or without a positive bronchodilator response. The degree of obstruction in RA-associated bronchiectasis can be severe, with less reversibility than many other forms of bronchiectasis (83). A decrease in FVC in the absence of an obstructive ventilatory defect has also been associated with the presence of bronchial dilatation in some patients with RA (96). PFTs are additionally useful in guiding management strategies for symptomatic patients and for surveilling disease progression. 8.3.6 Treatment Specific guidelines for the treatment of RA-associated bronchiectasis are lacking. Treatment follows the same principles of managing symptomatic patients with other forms of non-cystic fibrosis bronchiectasis. The overarching goal of therapy is to reduce symptoms of cough, sputum production, and recurrent infections (95). For symptomatic patients, the mainstay of management is instituting an airway clearance regimen that may consist of chest physical therapy, airway clearance devices, and mucolytics, including hypertonic saline (particularly for patients with sicca syndrome). Patients with a reversible obstructive ventilatory defect may benefit from the initiation 127

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of a long-acting beta-2 agonist and/or inhaled corticosteroids (84). In patients with frequent exacerbations, prophylactic antibiotic therapy (including inhaled) may also be considered. Pulmonary rehab has been demonstrated to increase exercise tolerance and functional status in patients with bronchiectasis and should be offered similarly to patients with bronchiectasis and RA (97). The role of immunomodulatory drugs in the treatment of RA-associated bronchiectasis is unclear, and some studies have demonstrated an increased risk of infection in those receiving DMARDs and glucocorticoids (83). Thus, the choice of immunosuppressive therapy should weigh the risks of infection and benefits of treating articular disease. 8.4 PLEURAL DISEASE 8.4.1 Epidemiology RA can sometimes manifest as pleural and pericardial effusions. While this is thought to be a rare complication of RA, autopsy studies have found that nearly half of patients with RA may have some pleural abnormalities, so subclinical pleural disease is likely relatively common (98). Rarely, patients with RA may develop large, recurrent pleural effusions that require aggressive treatment and procedures. While robust research is lacking, male sex and high-titer RA-related autoantibodies seem to be risk factors for pleural disease in RA (99). 8.4.2 Pathobiology Several types of pleural disease of distinct etiologies may develop in those with RA. The most common type of pleural disease in RA is an exudative pleural effusion and may be related to chronic pleural inflammation, sometimes in relation to rheumatoid nodules that may affect the pleura and promote or disrupt pleural fluid production or clearance, respectively (100). Patients with RA may also develop chyliform effusions, perhaps in relation to the necrosis, rupture, and rarely subsequent cavitation of nodules in the pleura, chest wall, or lung parenchyma (100). Patients with RA are also at risk for empyema, other infections, asbestosis, and cancer that may manifest with pleural abnormalities. Finally, drug-induced pleural effusions may occur, particularly from TNF inhibitors as a form of drug-induced lupus (101). Rarely, patients with RA with chronic pleural disease and architectural destruction may develop a pneumothorax or bronchopleural fistulae. 8.4.3  Clinical Presentation Symptoms of pleural disease in those with RA are similar to those in the general population. Symptoms include dyspnea and chest tightness, which may be exacerbated by position and exertion. Some patients may require urgent treatment, particularly those with pericardial involvement, which may also include symptoms of palpitations and lightheadedness. 8.4.4 Evaluation Patients with RA with chest symptoms should have a comprehensive evaluation that includes CXR and often chest CT. Lung ultrasound may also be helpful to quantify the amount of pleural fluid and to assist in image-guided procedures. Patients with large effusions may require inpatient admission to coordinate urgent procedures and evaluate for other etiologies such as cancer and infections. Patients with more than mild effusions should undergo thoracentesis for pleural fluid analysis to evaluate etiologies that may guide the treatment plan. Typical exudative rheumatoid effusions generally have white cell count < 5000/mm3 (often lymphocytic, sometimes neutrophilic), pleural fluid glucose < 60 mg/dL, pH < 7.3, and high pleural fluid lactate dehydrogenase levels (99). On cytology, elongated multinucleated macrophages, known as “ragocytes,” may be identified (99). Pleural fluid studies may alternatively reveal infections, chylous effusions, or cancer or be transudative. A pleural biopsy should be considered for those with recurrent effusions to firmly determine the underlying diagnosis. 8.4.5 Treatment Due to the rarity of severe RA pleural effusions, there are only case reports to guide therapy. In patients with RA not already on treatment who present with mild pleural effusions, treating the underlying arthritis while monitoring for worsening of effusions may be sufficient. Methotrexate should be avoided in patients with pleural effusions since the drug may accumulate here and cause drug overdose (102). Patients on TNF inhibitors should be evaluated for drug-induced lupus as a cause of the effusion. Glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) may also be helpful to treat effusions. Some pleural effusions resolve spontaneously. 128

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Patients with symptoms or moderate effusions should undergo thoracentesis performed for therapeutic purposes. However, some patients may reaccumulate effusions. Some case reports suggest that rituximab, tocilizumab, or abatacept may be helpful to treat severe, recurrent pleural effusions (103, 104). However, procedures may be needed that include indwelling pleural drainage catheters, decortication, and pleurodesis (105). 8.5 PULMONARY NODULES 8.5.1 Epidemiology Pulmonary rheumatoid (necrobiotic) nodules are an uncommon manifestation of RA. Rheumatoid nodules involving the lung are often clinically silent and are discovered incidentally. They frequently require additional evaluation to rule out lung cancer. An understanding of the epidemiology of pulmonary rheumatoid nodules is limited and primarily based on data from case series. While subcutaneous rheumatoid nodules are more common, with an estimated incidence of 30%, the reported incidence of pulmonary rheumatoid nodules is highly variable and ranges from 0.4% to 32% depending on the mode of investigation (106, 107). Pulmonary nodules are frequently seen in patients with cutaneous nodules in an estimated 80% of cases. Limited data suggests that incidence is higher in patients who are male and have a positive RF (108). Cigarette smoking has also been associated with the presence of pulmonary rheumatoid nodules with a predilection for smokers who have a positive RF. The duration and amount of smoking do not appear to be associated with an increased risk of developing pulmonary rheumatoid nodules (109). Caplan syndrome is a rare complication of RA characterized by the rapid development of numerous pulmonary nodules, often in the lung periphery, sometimes also occurring with ILD. Also referred to as rheumatoid pneumoconiosis, it is often seen in patients with prior occupational exposure to inorganic dusts (coal, silica, asbestos) and a positive RF (110, 5). 8.5.2 Pathobiology The pathogenesis of rheumatoid nodules, both in the lung and in other tissues, is not fully understood. On histopathology, pulmonary rheumatoid nodules demonstrate central fibrinoid necrosis with palisading histiocytes, associated focal vasculitis and deposition of complement, fibrin, and immunoglobulins (107). It is hypothesized that tissue trauma results in immune complex deposition and a subsequent secondary inflammatory reaction, with the recruitment of macrophages and lymphocytes leading to a Th1-mediated granuloma characterized by necrosis and fibrin (111). The endothelial injury induced by smoking has been suggested as a possible mechanism for the formation of rheumatoid nodules in the lung (109). Nodules seen in Caplan syndrome (known as Caplan nodules) are similar to rheumatoid nodules in their histopathology but also demonstrate concentric rings of dust particles surrounding and within areas of central necrosis. An increased immune response to foreign material and subsequent granuloma formation are believed to drive the nodule formation in Caplan syndrome and perhaps other forms of pulmonary nodules in patients with RA (110). 8.5.3 Evaluation Pulmonary rheumatoid nodules are typically asymptomatic, and there are no specific guidelines to direct the evaluation and surveillance of these nodules. While rheumatoid nodules have distinct radiographic features that can help distinguish them from other pulmonary nodules, additional work-up is often pursued in patients who are at risk for lung malignancy and require further evaluation based on Fleischer Society guidelines (112). Notably, patients with RA have an increased risk of lung malignancy compared to the general population (113). Evaluation often consists of chest imaging with HRCT and may be followed with FDG-PET imaging and lung biopsy. 8.5.3.1  HRCT Imaging Rheumatoid nodules are often incidentally discovered in patients with RA who have undergone chest imaging for another clinical purpose. Features characteristic of rheumatoid nodules on HRCT are nodules that are generally round, lobulated, and localized to the lung periphery with an upper and mid-lung predominance. Nodules can range in size from a few millimeters to centimeters and can increase in size, resolve spontaneously, or remain stable over time on serial imaging (87). Distinguishing features that can help differentiate rheumatoid nodules from malignancy include a smooth border, multiplicity, calcification, cavitation, pleural contact, and subpleural rind of the soft tissue (114). Features of nodules on HRCT, however, can be nonspecific, and CT imaging alone may not be sufficient to distinguish rheumatoid nodules from lung malignancy. 129

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8.5.3.2 FDG-PET Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is sometimes used to help further evaluate pulmonary nodules in patients with RA who have radiographic features concerning for cancer. The use of FDG-PET to evaluate for lung malignancy has been well established as an accurate, non-invasive testing modality to evaluate pulmonary nodules with high sensitivity and moderate specificity for malignancy (115). Rheumatoid nodules typically have little to no uptake on FDG-PET, and when uptake is present, it is often less than for most lung malignancies (116). Associated FDG-avid lymph nodes are usually absent (114). Occasionally however, rheumatoid nodules can demonstrate high FDG uptake in the setting of active inflammation (117). The variability in appearance of rheumatoid nodules on FDG-PET adds to the challenge of differentiating benign nodules from malignancies. Case series have reported variable success in using FDGPET imaging to differentiate rheumatoid nodules from malignancies (118, 119). 8.5.4  Lung Biopsy Lung biopsy, either by needle, bronchoscopy, or VATS, is sometimes needed to evaluate pulmonary nodules in patients with RA who have features on CT or FDG-PET imaging that are suspicious for malignancy. There are case reports describing the use of lung biopsy to both successfully exonerate and identify malignancy in patients with RA (120, 121). 8.5.5 Treatment The treatment of pulmonary rheumatoid nodules is usually not warranted, as they infrequently cause symptoms, and the prognosis is generally excellent. Rarely, rheumatoid nodules can rupture or cavitate, causing pleural effusions, bronchopleural fistulas, pneumothorax, and/or infection, which may require additional management specific to the complication. Most pulmonary rheumatoid nodules are uncomplicated and may increase, remain stable, or spontaneously regress with biologic treatment for RA articular disease. There is limited data demonstrating the regression in number and size of rheumatoid nodules of some patients treated with rituximab or tocilizumab (122, 123). Paradoxical enlargement and an increase in nodules, referred to as accelerated nodulosis, have been characterized in some patients receiving treatment with methotrexate and leflunomide. The clinical significance of this phenomenon is unclear, and there are no published guidelines to direct the continuation or cessation of specific therapies in these patients (60, 124, 125). 8.6 CONCLUSION Pulmonary manifestations are common and potentially serious extra-articular manifestations of RA. Pulmonary features commonly seen in RA include ILD, airways disease and bronchiectasis, pleural disease, and nodules. These extra-articular manifestations can occur throughout the disease course of RA, sometimes presenting before patients have clinical articular involvement. Patients with RA and respiratory symptoms should warrant consideration for HRCT chest and PFTs. Research is ongoing to elucidate the risk factors, natural history, and potential treatments of pulmonary manifestations of RA. Currently, the screening, monitoring, and management of pulmonary manifestations of RA should be individualized related to severity and potential for progression. REFERENCES 1. Sparks JA. Rheumatoid arthritis. Ann Intern Med. 2019;170(1):ITC1–ITC16. 2. Farquhar HJ, Beckert N, Beckert L, Edwards AL, Matteson EL, Frampton C, et al. Survival of adults with rheumatoid arthritis associated interstitial lung disease—A systematic review and meta-analysis. Semin Arthritis Rheum. 2023;60:152187. 3. Duarte AC, Porter JC, Leandro MJ. The lung in a cohort of rheumatoid arthritis patientsan overview of different types of involvement and treatment. Rheumatology (Oxford). 2019;58(11):2031–8. 4. Yamakawa H, Sato S, Tsumiyama E, Nishizawa T, Kawabe R, Oba T, et al. Predictive factors of mortality in rheumatoid arthritis-associated interstitial lung disease analysed by modified HRCT classification of idiopathic pulmonary fibrosis according to the 2018 ATS/ERS/JRS/ ALAT criteria. J Thorac Dis. 2019;11(12):5247–57. 5. Koduri G, Norton S, Young A, Cox N, Davies P, Devlin J, et al. Interstitial lung disease has a poor prognosis in rheumatoid arthritis: Results from an inception cohort. Rheumatology (Oxford). 2010;49(8):1483–9. 130

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9  Pulmonary Manifestations of Sjögren’s Disease Hassan Baig, Nancy Carteron, Paul Dellaripa, and Augustine Lee List of Abbreviations ARDS Acute respiratory distress syndrome ACR American College of Rheumatology AZA Azathioprine BAL Bronchoalveolar lavage BALT Bronchus-associated lymphoid tissue CB Constrictive bronchiolitis CYC Cyclophosphamide DLCO Diffusion capacity for carbon monoxide ESSDAI EULAR Sjögren Syndrome Disease Activity Index EULAR European League Against Rheumatism FDG Fluorodeoxy glucose FB Follicular bronchiolitis FEV1 Forced expiratory volume in 1 second FVC Forced vital capacity HRCT High-resolution chest computed tomography ILD Interstitial lung disease LIP Lymphocytic interstitial pneumonia MMF Mycophenolate mofetil NYHA New York Heart Association NLH Nodular lymphoid hyperplasia NSIP Nonspecific interstitial pneumonia OP Organizing pneumonia PET Positron emission tomography PAH Pulmonary arterial hypertension PFT Pulmonary function test RTX Rituximab SGEC Salivary gland epithelial cell SjD Sjögren’s disease UIP Usual interstitial pneumonia 9.1 OVERVIEW OF SJÖGREN’S DISEASE 9.1.1 Epidemiology Sjögren’s disease (SjD) is a systemic autoimmune rheumatic disease most commonly involving the salivary and lacrimal glands, but it can also present with extraglandular manifestations (1). The disease can present by itself or be associated with other autoimmune conditions like rheumatoid arthritis, systemic lupus erythematous, inflammatory myopathy, or systemic sclerosis. This chapter will focus on SjD to minimize the overlap of clinical manifestations from associated causes of SjD. Regarding prevalence, SjD is second to rheumatoid arthritis among the most common rheumatic conditions in the United States (2). Most cases are seen in middle-aged white women and a small proportion of cases in men; in the latter, underdiagnosis is common. Female-to-male sex ratios are noted to range from 7:1 to 27:1 when adjusting for ethnicity. Ethnicity may also be associated with variable phenotypic expression, as certain symptoms, like sicca symptoms, have been noted less commonly among certain groups, including Asians (3). Unfortunately, prospective cohort studies of pulmonary complications of SjD to better understand incidence rates and natural history are lacking. 9.1.2 Pathogenesis Lymphocytic infiltration of the target organs, primarily the exocrine salivary and lacrimal glands, with subsequent organ dysfunction, has been the hallmark of SjD. The pathogenesis is thought to be a combination of a background genetic predisposition, which, when triggered by certain environmental antigens, leads to epithelial dysfunction and inflammation of the salivary glands, followed by a systemic dysregulated immune response. However, recent investigations suggest DOI: 10.1201/9781003361374-11137

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additional mechanisms, including the role of neurotransmitters and salivary gland innervation in driving organ dysfunction. In some cases, salivary gland biopsy has demonstrated absent lymphocytic infiltration, although patients may still demonstrate limited salivary flow (4–6). Certain genetic polymorphisms involved in the innate immune response, B-cell activation, and T-cell activation have been discovered via genomic analyses (7). Abnormal immune signaling pathways activated by unknown triggers (although some have postulated viruses such as cytomegalovirus, hepatitis C virus, and human immunodeficiency virus) may lead to a proinflammatory milieu with subsequent salivary gland epithelial cell (SGEC) dysfunction, which seems to be a key inciting factor for B-cell activation (8, 9). The SGECs can be caught in an apoptotic cascade promoting exposure to the several key autoantigens like SSA-52kD, SSA-60kD, and SSB-48kD among others, which are intracellular proteins mediating cell proliferation and interferon production (10). With subsequent B-cell activation and the proliferation of plasma cells, autoantibodies, anti-Ro/SSA, and anti-La/SSB, are formed. Anti-Ro/SSA has now been differentiated to represent two different autoantibodies, anti-SSA52 and anti-SSA60, corresponding to the respective autoantigens. The direct pathogenic role of these antibodies has not been confirmed, but murine studies have shown that anti-SSA52 can lead to SGEC dysfunction (11). Furthermore, patients with SjD and interstitial lung disease have a higher likelihood of having anti-SSA52 antibodies (12). T cells, especially CD4+ helper T cells, are also involved in the inflammatory process, including B-cell activation. As a result, prototypic lymphocytic infiltration with “germinal center-like structures” can be seen in all target organs (9). It is postulated that a similar epithelial cell dysfunction and inflammatory response in the respiratory tract may be responsible for the pulmonary manifestations of SjD. The increased lymphocyte stimulation may become monoclonal, increasing the lifetime risk of lymphomas and other lymphoproliferative disorders in patients with SjD. 9.1.3  Clinical Manifestations The hallmark symptoms of dry eyes and dry mouth can affect up to 90% of patients with SjD. Up to 25% can have extraglandular symptoms, and about 10–20% can have clinically relevant pulmonary involvement. However, if systematic testing is pursued with imaging and pulmonary function testing, lung involvement can be detected in up to 60% of patients, even when asymptomatic (13–15). Table 9.1 summarizes the various systemic manifestations. 9.1.4  Classification Criteria The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) in 2016 developed and validated classification criteria for SjD (1). Although the primary aim of the classification criteria was to facilitate a homogeneous approach to patient inclusion in clinical trials for investigations, these criteria can also assist clinicians toward establishing a diagnosis of SjD. The criteria assign a weighted score to five items, as shown in Table 9.2, with a total score of 4 or greater to meet criteria.

Table 9.1: Wide Spectrum of Systemic Manifestations of Sjögren’s Disease Manifestations of Sjögren’s Disease Organ involvement Constitutional Musculoskeletal Lymphoproliferative Hematologic Glands Pulmonary Neurologic Skin Renal

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Clinical features Fever, night sweats, weight loss Inflammatory arthritis, myositis Lymphadenopathy, splenomegaly, lymphoma Cytopenias, hypergammaglobulinemia, cryoglobulinemia, amyloidosis Salivary gland dysfunction, lacrimal gland dysfunction Airway, interstitial lung disease, lymphoproliferative disorders, pleuritis, pulmonary hypertension Axonal neuropathy, small fiber neuropathy, cerebral vasculitis, optic neuritis, lymphocytic meningitis, transverse myelitis Erythema multiforme, cutaneous vasculitis Proteinuria, glomerulonephritis, renal tubular acidosis

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Table 9.2: ACR/EULAR Classification Criteria for Sjögren’s Disease Clinical/Test Variables Anti-Ro/SSA antibody positive Labial salivary gland with focal lymphocytic sialadenitis and focus score ≥ 1 Ocular staining score ≥ 5 Schirmer testing with ≤ 5 mm wetting in 5 minutes Unstimulated whole saliva flow rate ≤ 0.1 mL/minute

Score 3 3 1 1 1

Note: A score of 4 or more is needed to fulfill classification criteria

These criteria are intended to be applied within the specific context of a patient with at least one symptom of dry eyes or dry mouth or suspicion of SjD due to characteristic systemic features. Other conditions in the differential diagnosis for SjD should be excluded as well, such as sarcoidosis, amyloidosis, graft-versus-host disease, IgG4-related disease, active hepatitis C infection, diffuse infiltrative lymphocytosis syndrome associated with HIV infection, or prior head and neck radiation treatment. Other adjunctive tests can provide diagnostic insight, for example, the scoring of hypoechoic regions via salivary gland ultrasonography can reliably correlate with glandular dysfunction (16). Disease activity is measured by a standardized clinical score, the EULAR Sjögren Syndrome Disease Activity Index (ESSDAI) (17), which includes organ-specific domains and rates the severity of involvement. Pulmonary manifestations are included in this as well. It is important to note that the ESSDAI does not encompass all possible manifestations; for example, pulmonary arterial hypertension and pleuritis are not included in the ESSDAI but can be associated with SjD (14). The Sjögren’s Foundation provides a training platform for mastering the ESSDAI as well as certification for clinical trial participation. 9.2 PULMONARY MANIFESTATIONS OF SJÖGREN’S DISEASE 9.2.1 Epidemiology Pulmonary involvement can be categorized as airways disease, interstitial lung disease (ILD), lymphoproliferative diseases, and other disorders. Complications of treatment, especially with drug reactions from immunosuppressive medications and secondary infections, should also be considered. When pulmonary function testing (PFT) or high-resolution chest computed tomography (HRCT) is performed, 24–65% of patients with SjD can be found to have pulmonary involvement but be asymptomatic from a respiratory standpoint (18, 19). In approximately 18% of cases, pulmonary involvement, specifically ILD, is the initial manifestation, with SjD being diagnosed concomitantly or subsequently (20). The incidence of clinically pertinent lung disease is at least 10% after the first year of diagnosis of SjD (21). Some risk factors for lung involvement, particularly of ILD, identified in populationbased studies include increasing age, disease duration, positive anti-SSA antibody, ANA or rheumatoid factor, and hypergammaglobulinemia (22, 23). Pulmonary involvement has been shown to reduce quality-of-life measures, and it also leads to reduced survival (21, 24). 9.2.2 Evaluation Several scenarios can be encountered when evaluating for pulmonary involvement in SjD: (1) a patient already diagnosed with SjD and no pulmonary symptoms, where subsequent screening for a pulmonary disorder may be appropriate; (2) a patient diagnosed with SjD who has pulmonary symptoms; (3) a patient with an apparent pulmonary disorder but no current diagnosis of SjD, where SjD should be considered in the differential diagnosis; and (4) a patient with diagnosed SjD and a known pulmonary manifestation with a new pulmonary event (e.g. background ILD with newly incident pulmonary lymphoma). Consensus guidelines have provided recommendations for screening and evaluation for pulmonary involvement (15). Given the relatively high prevalence, screening based on a history of respiratory symptoms, including cough and dyspnea, is recommend in all patients with SjD. If no respiratory symptoms are present at the time of diagnosis, a screening baseline two-view chest X-ray and a complete PFT (including spirometry, lung volumes, and diffusion capacity for carbon monoxide [DLCO]) can be considered. HRCT can be considered in this scenario if there is high suspicion for pulmonary disease. In patients with SjD and respiratory symptoms of chronic 139

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cough or dyspnea, complete PFTs and HRCT should be obtained, as chest imaging will be insensitive to several of the pulmonary complications of SjD. Echocardiogram to screen for pulmonary hypertension can be obtained in a patient with SjD and dyspnea when the symptoms are not fully explained by PFT and HRCT findings. In patients with a pulmonary disorder that raises suspicion for SjD but no current diagnosis of SjD, a search for SjD should be performed via clinical and serological evaluation. A questionnaire screening tool or detailed questioning for characteristic features in the patient’s history, such as sicca symptoms, arthralgia, myalgia, fatigue, and parotid gland swelling, can be helpful followed by application of the classification criteria to aid in diagnosis. A collaborative approach between pulmonary and rheumatology providers can further increase confidence in the diagnosis of SjD in the setting of pulmonary symptoms and/or findings. Follow up for patients with respiratory symptoms should include periodic clinical visits and monitoring of pulmonary function, which can be completed at 6- to 12-month intervals. 9.2.3  Pulmonary Symptoms Chronic cough is defined as cough lasting longer than 8 weeks in duration. A thorough evaluation is needed to eliminate common etiologies such as upper airway cough syndrome, asthma, eosinophilic bronchitis, gastroesophageal reflux disease, and medication adverse effects (15). Dyspnea could result from a single or combination of underlying pulmonary disorders. It is characterized by grading exertional limitation based on the New York Heart Association (NYHA) functional classification: NYHA Class I with no limitation in activity, Class 2 with slight limitation in ordinary physical activity, Class 3 with significant limitation in ordinary physical activity, and Class 4 with dyspnea at rest and with ordinary physical activity (17). 9.2.4  Pulmonary Function Testing Complete PFTs can identify early or even asymptomatic pulmonary involvement. Pre- and postbronchodilator spirometry can identify persistent airflow obstruction and/or bronchial hyperresponsiveness. A reduction in lung volume can help identify restrictive lung diseases such as ILD. Reduced DLCO, measuring the ability of oxygen exchange at the level of alveoli and the pulmonary capillary bed (25), can point toward either underlying ILD or pulmonary vascular disease. A variety of pulmonary function abnormalities have been observed, with a reduction in DLCO being the most common (26). Spirometry has suggested restriction (usually associated with ILD) and obstruction (bronchiolitis, bronchiectasis, asthma). As mentioned, asymptomatic patients may show underlying abnormalities when screening PFTs are performed (18). 9.2.5  Computed Tomography of the Chest An HRCT can demonstrate a variety of abnormalities, even in asymptomatic patients (19). As a general rule, the HRCT should include certain technical aspects, which allow for enhanced resolution and reduction in imaging artifacts as compared to a standard CT chest: inspiratory phase to limit the crowding of structures and artifacts; an expiratory phase to screen for small airways disease with air trapping; thin cuts of 1.5 millimeters or less, which allow for greater detail and better delineation of the small airways and for interstitial abnormalities; and prone imaging, which can help differentiate subpleural atelectasis from ILD (27). A variety of findings are observed, including reticulation, ground-glass opacities, bronchiectasis, honeycomb change, cysts, and nodules (26). HRCT remains an essential diagnostic tool for the ILDs. 9.2.6  Positron Emission Tomography Positron emission tomography (PET) is recommended when there is suspicion for a neoplasm, especially pulmonary lymphoma. Certain findings on imaging raising concern include persistent and/or enlarging nodules of eight millimeters or greater, a non-resolving consolidation, persistent and/or enlarging lymphadenopathy, and/or progressive cystic lesions (15). The degree of fluorodeoxy glucose (FDG)-avid metabolic activity can also provide valuable information; for example, an FDG uptake of greater than 4.7 in the parotid glands correlates with lymphoma, as does focal uptake in the lungs (28). 9.2.7 Bronchoscopy The cellularity of bronchoalveolar lavage (BAL) fluid in patients with SjD is usually lymphocytic predominant and may be associated with disease progression and mortality (29); however, these findings are not consistent among available studies. Given the uncertainty in their diagnostic 140

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value, it is recommended that BAL not be routinely performed but considered on a case-by-case basis such as to rule out superimposed infection or assess endobronchial lesions (15). Although a rare manifestation, diffuse alveolar hemorrhage has been reported and is primarily diagnosed by bronchoscopy with persistent blood return in lavage fluid (30). 9.2.8  Lung Biopsy Many pulmonary disorders can be diagnosed with the appropriate clinical context and HRCT findings, especially in the setting of ILD. Lung biopsy is not required to establish the diagnosis but can provide further clarity, especially if HRCT does not demonstrate a typical radiographic pattern or if there is concern for a superimposed neoplasm, lymphoproliferative disease, or amyloidosis (15). Although transbronchial-forceps biopsy can be performed via bronchoscopy, the diagnostic value for most fibrotic lung diseases remains low. Of note, bronchoscopic cryobiopsy techniques performed at some centers have the potential to increase the diagnostic yield (31). 9.2.9  Airway Disorders Airway involvement in patients with SjD can occur because of local exocrine gland dysfunction and/or lymphocytic cell infiltration. Airway involvement can account for up to 50% of cases of pulmonary involvement, depending on how involvement is defined (based on PFT and/or HRCT) (32, 33). A variety of disorders, including xerotrachea, reactive airways disease, and obstructive lung diseases like bronchiolitis and bronchiectasis, have been associated with SjD. 9.2.9.1 Xerotrachea Chronic cough affects up to 40–50% of patients with SjD and remains an important contributor to reduced quality of life (34, 15, 24). Cough can be secondary to a pulmonary disorder like airways disease or ILD. If PFTs and HRCT are normal and a careful search for other common causes of chronic cough is unrevealing, then xerotrachea (dry trachea) should be considered. Lymphocytic infiltration has been noted in bronchial walls, which may result in abnormal mucociliary clearance, inflammation, and airway desiccation (35, 36). Measures to improve airway hydration have been proposed but have limited evidence of benefit (15). Nebulized hypertonic saline can increase the intraluminal osmotic gradient in the airway lumen, thereby enhancing mucociliary clearance (37). It should be noted that nebulized saline can increase cough and should be preceded by bronchodilator use. Secretagogues like pilocarpine and cevimeline may also help improve airway hydration (15). 9.2.9.2  Reactive Airways Disease Bronchial hyperresponsiveness has been seen in 50–60% of patients with SjD (38, 39). It can manifest as chronic cough and may be associated with increased episodes or duration of bronchitis. Bronchial mucosal infiltration with T lymphocytes along with neutrophils and mast cells may be responsible for the bronchial hyperresponsiveness (40). Normal baseline spirometry with a positive methacholine challenge (administration of inhaled methacholine to assess for an exaggerated bronchoconstriction response as measured by a drop in forced expiratory volume in 1 second) establishes the diagnosis. Similar to asthma, inhaled corticosteroids and bronchodilators may be tried, although these are of unclear benefit in the context of SjD (41). 9.2.9.3 Bronchiolitis Bronchiolitis, inflammation of the small airways, can be present in isolation or in combination with other pulmonary disorders and has been noted in about 25% of patients with SjD (39). Histopathologically, several different subtypes of bronchiolitis have been observed, including constrictive bronchiolitis (CB), panbronchiolitis, and, most commonly, follicular bronchiolitis (FB) (42). In FB, lymphoid follicles adjacent to the bronchioles (bronchus-associated lymphoid tissue, BALT) are hyperplastic with prominent germinal centers (43). CB is primarily a submucosal fibrosing process of the bronchioles that leads to progressive and fixed obstruction of the airways (44). Dyspnea is a more common symptom than cough in patients with bronchiolitis. Pulmonary function testing can be normal. Alternatively, PFTs can demonstrate a restrictive pattern in FB and an obstructive pattern in CB (26, 45). If the PFTs are unrevealing, HRCT can demonstrate centrilobular micronodules/ground-glass opacities in FB, while patients with CB have mosaic attenuation and air trapping on expiratory views with some associated bronchiectasis (45, 46). As lymphocytic interstitial pneumonia (LIP) is on the spectrum of FB, cystic changes may also be present. 141

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Most cases of bronchiolitis remain stable based on PFT follow-up; however, some cases may progress to severe disease. In newly diagnosed and symptomatic patients, guideline recommendations suggest empiric treatment to assess for improvement with anti-inflammatory agents including systemic or inhaled corticosteroids or chronic macrolide therapy (15). Other immunosuppressive therapies such as rituximab, cyclophosphamide, mycophenolate mofetil, and azathioprine have been tried with variable success. Follow-up in symptomatic patients should occur regularly with serial PFTs. 9.2.9.4 Bronchiectasis Airway dilation of the bronchial tree, measured by comparing the airway to the adjacent pulmonary vessel, confirms the radiographic diagnosis of bronchiectasis (47). Noted in at least half of patients with SjD and pulmonary involvement, bronchiectasis can be seen in isolation or in conjunction with other airway disorders, like bronchiolitis, or it can be due to traction from adjacent fibrosis (26). Epithelial dysfunction may be responsible for isolated bronchiectasis (48). Presenting symptoms can include productive cough and/or recurrent episodes of bronchitis, yet some patients can remain asymptomatic. Affected patients have a significantly increased risk for respiratory tract infections, including pneumonia (48). Pulmonary function testing is not specific and can show obstruction, restriction, or both; a reduced DLCO is the most common abnormality. The diagnosis is confirmed by HRCT. For symptomatic patients, treatment focused on airway clearance is recommended and includes mucolytics, nebulized hypertonic saline, oscillatory positive expiratory pressure devices, and chest physiotherapy (15). 9.2.10  Interstitial Lung Disease Interstitial lung disease is another common pulmonary manifestation in patients with SjD and can be seen in combination with airway and lymphoproliferative disorders. The incidence of ILD has been noted to be 10% at 1 year from SjD diagnosis, and it increases to 20% by 5 years (21). Lymphocytic interstitial pneumonia (LIP) was the classical association; however, more recent data shows that nonspecific interstitial pneumonia (NSIP) is the most common type of ILD (45%), followed by usual interstitial pneumonia (UIP, 16%), LIP (15%), and organizing pneumonia (OP, 7%) (49). Typical symptoms include cough and shortness of breath. Patients can, however, be asymptomatic yet have PFT and/or HRCT abnormalities (50). When abnormal, PFTs can show a restrictive pattern on spirometry with reduced forced vital capacity (FVC) and a normal to increased forced expiratory volume in 1 second (FEV1)-to-FVC ratio (FEV1/FVC). Diffusion capacity can also be decreased. Assessment with exercise oximetry to determine oxygen requirements should also be conducted. In the appropriate clinical context, HRCT with inspiratory and expiratory views can provide the most information in determining the ILD subtype. Lung biopsy can be typically avoided if a diagnosis can be made using other diagnostic modalities (15). 9.2.10.1  Nonspecific Interstitial Pneumonia Nonspecific interstitial pneumonia (NSIP) is the most commonly encountered ILD in patients with SjD. Histopathologically, the alveolar interstitium is diffusely infiltrated by inflammatory cells with variable levels of associated fibrosis. Based on the degree of fibrosis, a predominant pattern of fibrotic or cellular NSIP can be seen. Although there is no single diagnostic feature on HRCT, the suspicion for NSIP can be increased when bilateral reticular and ground-glass opacities are seen predominantly in the lung bases with associated traction bronchiectasis. The subpleural regions can be spared in about 20% of cases. With characteristic imaging features, the diagnosis can most often be made without the need for lung biopsy. 9.2.10.2  Usual Interstitial Pneumonia The characteristic pathologic features for usual interstitial pneumonia (UIP) include dense interstitial fibrosis with architectural distortion and honeycomb cysts, subpleural and/or paraseptal distribution of fibrosis, patchy lung involvement, and fibroblast foci (subepithelial focal proliferation of fibroblasts). As the UIP pattern can be seen in many other diseases, including idiopathic pulmonary fibrosis, some additional features in SjD include more prominent mononuclear cell infiltration, lymphoid hyperplasia with germinal centers, and pleuritis (51). If a typical UIP pattern is seen on imaging, lung biopsy is not required for diagnosis. As compared to other ILD subtypes, UIP is associated with more progressive lung disease and a worse prognosis (52). 142

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9.2.10.3  Lymphocytic Interstitial Pneumonia Similar to follicular bronchiolitis, lymphocytic interstitial pneumonia (LIP) is characterized by lymphocytic infiltration, predominantly of the alveolar interstitium rather than around the bronchioles. The two entities may represent part of a spectrum of the same pathologic process and can coexist, as demonstrated on imaging and pathology (53). Histologic features include a dense alveolar septal infiltration by lymphocytes and plasma cells along with lymphoid follicles with germinal centers (53). HCRT findings include ground-glass opacities, centrilobular nodules, and reticulation. Thin-walled cysts are commonly seen and can be a dominant feature in LIP (54). Other disorders in the differential diagnosis for cystic lung diseases include emphysema, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, and Birt Hogg Dube syndrome. Based on imaging, NSIP and LIP can both have ground-glass opacities, but the distribution is different. Furthermore, NSIP lacks nodules and cysts. Shared histological features include lymphocytic interstitial inflammation, but this is less intense in NSIP as compared to LIP. When nodules and cysts are seen, a variety of lymphoproliferative disorders besides LIP need to be considered, including amyloidosis, light-chain deposition disease, MALT lymphoma, and focal nodular hyperplasia. With these considerations, PET imaging and lung biopsy may be warranted. 9.2.10.4  Organizing Pneumonia The histopathology of organizing pneumonia (OP) demonstrates patchy areas of loosely organizing connective tissue within the alveolar spaces (Masson bodies). There can be extension into the alveolar interstitium, but this is not a dominant feature. If the interstitium is prominently involved as well, then an NSIP/OP overlap syndrome should be considered (54). On HRCT, typical findings include patchy areas of consolidation and ground-glass opacities. The differential diagnosis is broad for persistent airspace consolidation, and ground-glass opacities, including pneumonia due to resistant or atypical infections, eosinophilic pneumonia, and malignancy, particularly MALT lymphomas, should be considered. In these cases, evaluation with bronchoscopy and BAL can help assess for infection. Lung biopsy may also be helpful, especially in the setting of persistent consolidation after appropriate treatment for OP and/or infection. 9.2.10.5 Treatment In a majority of patients with SjD, lung function can remain stable or improve with the exception being that of the patients with UIP, who will more commonly experience progressive disease and a higher mortality rate (55, 52, 56). There can sometimes be a sudden decline in lung function due to an acute ILD exacerbation, characterized by the acute or subacute worsening of lung infiltrates and worsening hypoxia, as seen in patients with acute respiratory distress syndrome (ARDS). Patients with ILD should be followed closely with serial PFTs every 3–6 months to assess for disease progression. Symptomatic patients with moderate to severe disease activity as defined by ESSDAI or those with progressive disease based on serial pulmonary function and/or imaging should be considered for treatment (15). Moderate pulmonary disease activity is characterized by exertional dyspnea (NYHA class II) or PFT abnormalities with the FVC 60–80% of predicted or DLCO 40–70% of predicted. Severe activity includes exertional dyspnea (NYHA class III, IV) or PFT abnormalities with the FVC less than 60% or DLCO less than 40%. Limited data is available to guide treatment, and clinical trials for most treatment options have not been performed. Based on consensus recommendations, when considering treatment, first-line therapy includes oral corticosteroids. Typically, after a treatment course of 6–12 weeks, reassessment of symptoms, PFTs, and imaging are conducted. There is limited data for efficacy, and a variable treatment response is noted in case series, including findings of improvement, stability, and even progression of disease (55, 57, 15). Among the ILD subtypes, OP has been typically the most steroid responsive (58). If there is a favorable response to treatment, then the corticosteroid dose should be weaned to the lowest efficacious dose. If there is a relapse or failure to wean and prolonged corticosteroid use is deemed necessary, then a steroid-sparing agent should be considered, and mycophenolate mofetil (MMF) or azathioprine (AZA) is recommended (57, 15). Efficacy data is derived from small case series in patients with SjD but also extrapolated from treatment series for a broader group of patients with autoimmune rheumatic disease-associated ILD (55, 59, 60). If there is continued disease progression with MMF or AZA, or if the medication is not tolerated, rituximab (RTX) or cyclophosphamide (CYC) can be considered (57, 15). An exception to consider is the patient with a UIP pattern of ILD, where AZA and oral prednisone should be avoided based on the prior PANTHER study, where there was a signal for harm in those receiving AZA in the setting of UIP from idiopathic pulmonary fibrosis (IPF) (61). Other options with limited efficacy evidence 143

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include abatacept and tacrolimus (62). For patients who continue to develop increasing lung fibrosis and PFT deterioration, antifibrotic treatment with nintedanib is of consideration (63). Ultimately, if disease stability cannot be achieved, lung transplantation evaluation may be warranted. 9.2.11  Lymphoproliferative Disorders This group of diseases encompasses polyclonal disorders (FB, LIP, focal lymphoid nodular hyperplasia) and oligoclonal or monoclonal disorders (amyloidosis, light-chain deposition disease, and MALT lymphoma) (64). While amyloidosis remains a rare entity, patients with SjD have a significantly increased risk for lymphoma development (65, 66). Given shared imaging features of nodules, consolidation, and/or cysts, interdisciplinary review and lung biopsy may be warranted to evaluate for malignancy. 9.2.11.1  Focal Nodular Lymphoid Hyperplasia Also termed pseudolymphoma, nodular lymphoid hyperplasia (NLH) occurs uncommonly in patients with SjD. Histopathologically, the proliferation of the BALT with germinal centers within the lymphoid follicles is noted. This is similar to lymphoma, and the distinction is made by immunohistochemical and molecular studies to determine the clonality of the lymphocytes. NLH is due to a polyclonal proliferation, while lymphoma results from monoclonal proliferation (67). Patients may be asymptomatic or have cough, but usually, HRCT shows nodules or areas of consolidation. The HRCT imaging findings are not specific; therefore, further evaluation with PET and biopsy may be required to assess for amyloidosis or lymphoma. 9.2.11.2  Pulmonary Lymphoma Patients with SjD have an increasing risk of developing lymphoma over time, affecting close to 20% of patients by 20 years after the initial diagnosis of SjD. The lymphoma subtypes include MALT lymphoma, the most common, followed by diffuse large B-cell lymphoma and follicular lymphoma. Risk factors include parotid enlargement, salivary gland focus score of 3 or greater, lymphadenopathy, vasculitis, palpable purpura, cryoglobulins, low complement C4 level, and lymphopenia (68, 69). Epithelial cell dysfunction leads to persistent B-cell stimulation via B-cell activating factor, which in turn results in monoclonal proliferation (70). Histologically, MALT lymphoma is similar to NLH, with the proliferation of B cells, but predominantly occurring in the marginal zones of the lymphoid follicles. Distinguishing features include tumor cells tracking along the bronchovascular bundle and alveolar interstitium, with invasion of the epithelium. Immunohistochemical and molecular studies are necessary to define the monoclonal nature of the tumor cells (46). Symptoms like fever, night sweats, and unexplained weight loss along with worsening dyspnea or cough can raise the suspicion for lymphoma. Imaging features include mediastinal adenopathy; lung nodules, especially if increasing in size; non-resolving consolidation, and occasionally cysts. PET scan can show increased focal metabolic activity in the areas of imaging abnormalities, which has been associated with lymphoma risk (28); however, a negative PET scan does not rule out lymphoma, as variable metabolic activity is noted (71). Biopsy is recommended, especially when encountering growing nodules, consolidation, or cystic disease (15). Surgical lung biopsy is usually necessary in this scenario, as CT-guided needle biopsy or bronchoscopic biopsy tend to be nondiagnostic because of limited tissue sampling (72). Most MALT lymphoma cases have an indolent course with a favorable 5-year survival near 90% (70). Decisions for lymphoma-directed treatment should be made in collaboration with oncology. 9.2.11.3 Amyloidosis Although an uncommon pulmonary manifestation, pulmonary amyloidosis can coexist with or mimic other pulmonary disorders seen in patients with SjD. Local lymphocyte and plasma cell proliferation is associated with increased light-chain production and the deposition of amyloid fibrils in the lungs (73). Microscopic examination reveals the background of lymphocyte and plasma cell infiltration, like in other lymphoproliferative disorders, along with prominent eosinophilic material representing amyloid deposition (73). Presenting symptoms can include cough. On imaging, scattered areas of nodules or consolidation can be seen. The nodules can demonstrate calcification and be distributed along the interlobular septae (46). Patients with cystic lung disease, when biopsied, have shown concomitant amyloidosis on histopathology (64). With an increasing size of nodules, consolidation, or air cysts, biopsy is typically required to rule out MALT lymphoma. Figure 9.1 demonstrates the spectrum of lymphoproliferative manifestations that can be seen in a single patient. No specific therapy has been studied in this scenario. 144

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Figure 9.1  (A) HRCT demonstrating cystic lung disease in a patient with Sjögren’s disease. (B) Lung histopathology demonstrating dense lymphocytic and plasma cell infiltration. (C) Positive CD79a staining consistent with monoclonal B-cell proliferation supporting the diagnosis of extranodal marginal zone B-cell lymphoma, MALT type, with plasmacytic differentiation. 145

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9.2.12  Pulmonary Arterial Hypertension Connective tissue disease-associated pulmonary arterial hypertension (PAH) has been commonly seen in systemic sclerosis and systemic lupus erythematosus but has also been increasingly recognized in SjD. Smaller case series have described varying frequencies, but a large multicenter cohort has shown a PAH prevalence of 16% in SjD patients. Risk factors for disease include the presence of anti-SSB antibodies, anti-U1RNP antibodies, later age of SjD onset, and keratoconjunctivitis sicca (74). Negative prognostic factors include lower cardiac index and higher pulmonary vascular resistance at disease onset. Five-year survival is close to 80%. Treatment involves pulmonary vasodilator therapy. The role of immunosuppressant therapy in lowering pulmonary pressures is unclear, as most of these patients usually receive combination PAH and immunosuppressive therapy. 9.3 CONCLUSION Pulmonary complications of SjD are prevalent, underrecognized, and associated with significant morbidity and mortality. Every compartment of the respiratory system can be affected by SjD, most prominently represented by the interstitial lung diseases and lymphoproliferative disorders. A high level of suspicion for possible pulmonary involvement is required for a patient affected by SjD, but SjD should also be considered in the differential diagnosis of a variety of respiratory manifestations that may be associated with SjD. Consensus guidelines are available to direct appropriate screening and monitoring, and the identification of optimal therapeutics will be promoted by the current robust pipeline of late-stage clinical trials. REFERENCES 1. Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American college of rheumatology/European league against rheumatism classification criteria for primary Sjogren’s syndrome: A consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol. 2017;69(1):35–45. 2. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheumatol. 2008;58(1):15–25. 3. Brito-Zeron P, Acar-Denizli N, Zeher M, Rasmussen A, Seror R, Theander E, et al. Influence of geolocation and ethnicity on the phenotypic expression of primary Sjogren’s syndrome at diagnosis in 8310 patients: A cross-sectional study from the Big Data Sjogren Project Consortium. Ann Rheum Dis. 2017;76(6):1042–50. 4. Sandhya P, Kurien BT, Danda D, Scofield RH. Update on pathogenesis of Sjogren’s syndrome. Curr Rheumatol Rev. 2017;13(1):5–22. 5. Sharma R, Chaudhari KS, Kurien BT, Grundahl K, Radfar L, Lewis DM, et al. Sjogren syndrome without focal lymphocytic infiltration of the salivary glands. J Rheumatol. 2020;47(3):394–9. 6. Jonsson R, Kroneld U, Backman K, Magnusson B, Tarkowski A. Progression of sialadenitis in Sjogren’s syndrome. Br J Rheumatol. 1993;32(7):578–81. 7. Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM, et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren’s syndrome. Nat Genet. 2013;45(11):1284–92. 8. Verstappen GM, Pringle S, Bootsma H, Kroese FGM. Epithelial-immune cell interplay in primary Sjogren syndrome salivary gland pathogenesis. Nat Rev Rheumatol. 2021;17(6):333–48. 9. Nocturne G, Mariette X. B cells in the pathogenesis of primary Sjogren syndrome. Nat Rev Rheumatol. 2018;14(3):133–45. 10. Kyriakidis NC, Kapsogeorgou EK, Tzioufas AG. A comprehensive review of autoantibodies in primary Sjogren’s syndrome: Clinical phenotypes and regulatory mechanisms. J Autoimmun. 2014;51:67–74. 11. Sroka M, Bagavant H, Biswas I, Ballard A, Deshmukh US. Immune response against the coiled coil domain of Sjogren’s syndrome associated autoantigen Ro52 induces salivary gland dysfunction. Clin Exp Rheumatol. 2018;36 Suppl 112(3):41–6. 12. Buvry C, Cassagnes L, Tekath M, Artigues M, Pereira B, Rieu V, et al. Anti-Ro52 antibodies are a risk factor for interstitial lung disease in primary Sjogren syndrome. Respir Med. 2020;163:105895.

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13. Shiboski CH, Baer AN, Shiboski SC, Lam M, Challacombe S, Lanfranchi HE, et al. Natural history and predictors of progression to Sjogren’s syndrome among participants of the Sjogren’s international collaborative clinical alliance registry. Arthritis Care Res (Hoboken). 2018;70(2):284–94. 14. Retamozo S, Acar-Denizli N, Rasmussen A, Horvath IF, Baldini C, Priori R, et al. Systemic manifestations of primary Sjogren’s syndrome out of the ESSDAI classification: Prevalence and clinical relevance in a large international, multi-ethnic cohort of patients. Clin Exp Rheumatol. 2019;37 Suppl 118(3):97–106. 15. Lee AS, Scofield RH, Hammitt KM, Gupta N, Thomas DE, Moua T, et al. Consensus guidelines for evaluation and management of pulmonary disease in Sjogren’s. Chest. 2021;159(2):683–98. 16. van Nimwegen JF, Mossel E, Delli K, van Ginkel MS, Stel AJ, Kroese FGM, et al. Incorporation of salivary gland ultrasonography into the American college of rheumatology/European league against rheumatism criteria for primary Sjogren’s syndrome. Arthritis Care Res (Hoboken). 2020;72(4):583–90. 17. Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E, et al. EULAR Sjogren’s syndrome disease activity index: Development of a consensus systemic disease activity index for primary Sjogren’s syndrome. Ann Rheum Dis. 2010;69(6):1103–9. 18. Kelly C, Gardiner P, Pal B, Griffiths I. Lung function in primary Sjogren’s syndrome: A cross sectional and longitudinal study. Thorax. 1991;46(3):180–3. 19. Uffmann M, Kiener HP, Bankier AA, Baldt MM, Zontsich T, Herold CJ. Lung manifestation in asymptomatic patients with primary Sjogren syndrome: Assessment with high resolution CT and pulmonary function tests. J Thorac Imaging. 2001;16(4):282–9. 20. Manfredi A, Sebastiani M, Cerri S, Cassone G, Bellini P, Casa GD, et al. Prevalence and characterization of non-sicca onset primary Sjogren syndrome with interstitial lung involvement. Clin Rheumatol. 2017;36(6):1261–8. 21. Nannini C, Jebakumar AJ, Crowson CS, Ryu JH, Matteson EL. Primary Sjogren’s syndrome 1976–2005 and associated interstitial lung disease: A population-based study of incidence and mortality. BMJ Open. 2013;3(11):e003569. 22. Wang Y, Hou Z, Qiu M, Ye Q. Risk factors for primary Sjogren syndrome-associated interstitial lung disease. J Thorac Dis. 2018;10(4):2108–17. 23. Gao H, Zhang XW, He J, Zhang J, An Y, Sun Y, et al. Prevalence, risk factors, and prognosis of interstitial lung disease in a large cohort of Chinese primary Sjogren syndrome patients: A case-control study. Medicine (Baltimore). 2018;97(24):e11003. 24. Palm O, Garen T, Berge Enger T, Jensen JL, Lund MB, Aalokken TM, et al. Clinical pulmonary involvement in primary Sjogren’s syndrome: Prevalence, quality of life and mortality— a retrospective study based on registry data. Rheumatology (Oxford). 2013;52(1):173–9. 25. Graham BL, Brusasco V, Burgos F, Cooper BG, Jensen R, Kendrick A, et al. 2017 ERS/ ATS standards for single-breath carbon monoxide uptake in the lung. Eur Respir J. 2017;49(1). 26. Kreider M, Highland K. Pulmonary involvement in Sjogren syndrome. Semin Respir Crit Care Med. 2014;35(2):255–64. 27. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44–e68. 28. Keraen J, Blanc E, Besson FL, Leguern V, Meyer C, Henry J, et al. Usefulness of (18) F-labeled fluorodeoxyglucose-positron emission tomography for the diagnosis of lymphoma in primary Sjogren’s syndrome. Arthritis Rheumatol. 2019;71(7):1147–57. 29. Dalavanga YA, Voulgari PV, Georgiadis AN, Leontaridi C, Katsenos S, Vassiliou M, et al. Lymphocytic alveolitis: A surprising index of poor prognosis in patients with primary Sjogren’s syndrome. Rheumatol Int. 2006;26(9):799–804. 30. Wang C, Simpkin C, Vielkind M, Galambos C, Lin C, Liptzin DR, et al. Childhoodonset Sjogren syndrome presenting as pulmonary hemorrhage. Pediatrics. 2021;148(2). 31. Maldonado F, Danoff SK, Wells AU, Colby TV, Ryu JH, Liberman M, et al. Transbronchial cryobiopsy for the diagnosis of interstitial lung diseases: CHEST guideline and expert panel report. Chest. 2020;157(4):1030–42.

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32. Kampolis CF, Fragkioudaki S, Mavragani CP, Zormpala A, Samakovli A, Moutsopoulos HM. Prevalence and spectrum of symptomatic pulmonary involvement in primary Sjogren’s syndrome. Clin Exp Rheumatol. 2018;36 Suppl 112(3):94–101. 33. Lohrmann C, Uhl M, Warnatz K, Ghanem N, Kotter E, Schaefer O, et al. High-resolution CT imaging of the lung for patients with primary Sjogren’s syndrome. Eur J Radiol. 2004;52(2):137–43. 34. Stojan G, Baer AN, Danoff SK. Pulmonary manifestations of Sjogren’s syndrome. Curr Allergy Asthma Rep. 2013;13(4):354–60. 35. Mathieu A, Cauli A, Pala R, Satta L, Nurchis P, Loi GL, et al. Tracheo-bronchial mucociliary clearance in patients with primary and secondary Sjogren’s syndrome. Scand J Rheumatol. 1995;24(5):300–4. 36. Tomashefski JF, Dail DH, Dail DH. Dail and Hammar’s Pulmonary Pathology. 3rd ed. New York: Springer; 2008. 37. Maiz Carro L, Martinez-Garcia MA. Nebulized hypertonic saline in noncystic fibrosis bronchiectasis: A comprehensive review. Ther Adv Respir Dis. 2019;13:1753466619866102. 38. La Corte R, Potena A, Bajocchi G, Fabbri L, Trotta F. Increased bronchial responsiveness in primary Sjogren’s syndrome. A sign of tracheobronchial involvement. Clin Exp Rheumatol. 1991;9(2):125–30. 39. Flament T, Bigot A, Chaigne B, Henique H, Diot E, Marchand-Adam S. Pulmonary manifestations of Sjogren’s syndrome. Eur Respir Rev. 2016;25(140):110–23. 40. Amin K, Ludviksdottir D, Janson C, Nettelbladt O, Gudbjornsson B, Valtysdottir S, et al. Inflammation and structural changes in the airways of patients with primary Sjogren’s syndrome. Respir Med. 2001;95(11):904–10. 41. Stalenheim G, Gudbjornsson B. Anti-inflammatory drugs do not alleviate bronchial hyperreactivity in Sjogren’s syndrome. Allergy. 1997;52(4):423–7. 42. Shi JH, Liu HR, Xu WB, Feng RE, Zhang ZH, Tian XL, et al. Pulmonary manifestations of Sjogren’s syndrome. Respiration. 2009;78(4):377–86. 43. Yousem SA, Colby TV, Carrington CB. Follicular bronchitis/bronchiolitis. Hum Pathol. 1985;16(7):700–6. 44. Visscher DW, Myers JL. Bronchiolitis: The pathologist’s perspective. Proc Am Thorac Soc. 2006;3(1):41–7. 45. Wight EC, Baqir M, Ryu JH. Constrictive bronchiolitis in patients with primary Sjogren syndrome. J Clin Rheumatol. 2019;25(2):74–7. 46. Egashira R, Kondo T, Hirai T, Kamochi N, Yakushiji M, Yamasaki F, et al. CT findings of thoracic manifestations of primary Sjogren syndrome: Radiologic-pathologic correlation. Radiographics. 2013;33(7):1933–49. 47. Milliron B, Henry TS, Veeraraghavan S, Little BP. Bronchiectasis: Mechanisms and imaging clues of associated common and uncommon diseases. Radiographics. 2015;35(4):1011–30. 48. Soto-Cardenas MJ, Perez-De-Lis M, Bove A, Navarro C, Brito-Zeron P, Diaz-Lagares C, et al. Bronchiectasis in primary Sjogren’s syndrome: Prevalence and clinical significance. Clin Exp Rheumatol. 2010;28(5):647–53. 49. Ramos-Casals M, Brito-Zeron P, Seror R, Bootsma H, Bowman SJ, Dorner T, et al. Characterization of systemic disease in primary Sjogren’s syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements. Rheumatology (Oxford). 2015;54(12):2230–8. 50. Taouli B, Brauner MW, Mourey I, Lemouchi D, Grenier PA. Thin-section chest CT findings of primary Sjogren’s syndrome: Correlation with pulmonary function. Eur Radiol. 2002;12(6):1504–11. 51. Enomoto Y, Takemura T, Hagiwara E, Iwasawa T, Okudela K, Yanagawa N, et al. Features of usual interstitial pneumonia in patients with primary Sjogrens syndrome compared with idiopathic pulmonary fibrosis. Respir Investig. 2014;52(4):227–35. 52. Zhang T, Yuan F, Xu L, Sun W, Liu L, Xue J. Characteristics of patients with primary Sjogren’s syndrome associated interstitial lung disease and relevant features of disease progression. Clin Rheumatol. 2020;39(5):1561–8. 53. American Thoracic S, European Respiratory S. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), 148

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and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002;165(2):277–304. 54. Travis WD, Costabel U, Hansell DM, King TE, Jr., Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European respiratory society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733–48. 55. Parambil JG, Myers JL, Lindell RM, Matteson EL, Ryu JH. Interstitial lung disease in primary Sjogren syndrome. Chest. 2006;130(5):1489–95. 56. Davidson BK, Kelly CA, Griffiths ID. Ten year follow up of pulmonary function in patients with primary Sjogren’s syndrome. Ann Rheum Dis. 2000;59(9):709–12. 57. Ramos-Casals M, Brito-Zeron P, Bombardieri S, Bootsma H, De Vita S, Dorner T, et al. EULAR recommendations for the management of Sjogren’s syndrome with topical and systemic therapies. Ann Rheum Dis. 2020;79(1):3–18. 58. Wang Y, Zhao S, Du G, Ma S, Lin Q, Lin J, et al. Acute fibrinous and organizing pneumonia as initial presentation of primary Sjogren’s syndrome: A case report and literature review. Clin Rheumatol. 2018;37(7):2001–5. 59. Oldham JM, Lee C, Valenzi E, Witt LJ, Adegunsoye A, Hsu S, et al. Azathioprine response in patients with fibrotic connective tissue disease-associated interstitial lung disease. Respir Med. 2016;121:117–22. 60. Amlani B, Elsayed G, Barvalia U, Kanne JP, Meyer KC, Sandbo N, et al. Treatment of primary Sjogren’s syndrome-related interstitial lung disease: A retrospective cohort study. Sarcoidosis Vasc Diffuse Lung Dis. 2020;37(2):136–47. 61. Idiopathic Pulmonary Fibrosis Clinical Research N, Raghu G, Anstrom KJ, King TE, Jr., Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968–77. 62. Thompson G, McLean-Tooke A, Wrobel J, Lavender M, Lucas M. Sjogren syndrome with associated lymphocytic interstitial pneumonia successfully treated with tacrolimus and abatacept as an alternative to rituximab. Chest. 2018;153(3):e41–3. 63. Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–27. 64. Baqir M, Kluka EM, Aubry MC, Hartman TE, Yi ES, Bauer PR, et al. Amyloid-associated cystic lung disease in primary Sjogren’s syndrome. Respir Med. 2013;107(4):616–21. 65. Kauppi M, Pukkala E, Isomaki H. Elevated incidence of hematologic malignancies in patients with Sjogren’s syndrome compared with patients with rheumatoid arthritis (Finland). Cancer Causes Control. 1997;8(2):201–4. 66. Theander E, Henriksson G, Ljungberg O, Mandl T, Manthorpe R, Jacobsson LT. Lymphoma and other malignancies in primary Sjogren’s syndrome: A cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65(6):796–803. 67. Song MK, Seol YM, Park YE, Kim YS, Lee MK, Lee CH, et al. Pulmonary nodular lymphoid hyperplasia associated with Sjogren’s syndrome. Korean J Intern Med. 2007;22(3):192–6. 68. Nishishinya MB, Pereda CA, Munoz-Fernandez S, Pego-Reigosa JM, Rua-Figueroa I, Andreu JL, et al. Identification of lymphoma predictors in patients with primary Sjogren’s syndrome: A systematic literature review and meta-analysis. Rheumatol Int. 2015;35(1):17–26. 69. Risselada AP, Kruize AA, Goldschmeding R, Lafeber FP, Bijlsma JW, van Roon JA. The prognostic value of routinely performed minor salivary gland assessments in primary Sjogren’s syndrome. Ann Rheum Dis. 2014;73(8):1537–40. 70. Routsias JG, Goules JD, Charalampakis G, Tzima S, Papageorgiou A, Voulgarelis M. Malignant lymphoma in primary Sjogren’s syndrome: An update on the pathogenesis and treatment. Semin Arthritis Rheum. 2013;43(2):178–86. 71. Albano D, Durmo R, Treglia G, Giubbini R, Bertagna F. (18)F-FDG PET/CT or PET role in MALT lymphoma: An open issue not yet solved-a critical review. Clin Lymphoma Myeloma Leuk. 2020;20(3):137–46. 72. Lat T, Sanchez JF, McGraw MK, Hodjat P, White HD, Boethel CD. Decision-making in diagnosis of bronchus-associated lymphoid tissue lymphoma. Proc (Bayl Univ Med Cent). 2021;34(4):451–5. 149

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73. Jeong YJ, Lee KS, Chung MP, Han J, Chung MJ, Kim KI, et al. Amyloidosis and lymphoproliferative disease in Sjogren syndrome: Thin-section computed tomography findings and histopathologic comparisons. J Comput Assist Tomogr. 2004;28(6):776–81. 74. Wang J, Li M, Wang Q, Zhang X, Qian J, Zhao J, et al. Pulmonary arterial hypertension associated with primary Sjogren’s syndrome: A multicentre cohort study from China. Eur Respir J. 2020;56(5).

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10  Pulmonary Manifestations of Systemic Lupus Erythematosus Megan M. Lockwood, Isabel C. Mira-Avendano, Selvin Jacob, Christopher Jenkins, and Rosalind Ramsey-Goldman List of Abbreviations ADMA Asymmetric dimethylarginine ALP Acute lupus pneumonitis ANA Antinuclear antibody aPL Antiphospholipid antibody APS Antiphospholipid syndrome ARDS Acute respiratory distress syndrome ASCVD Atherosclerotic cardiovascular disease BAL Bronchoalveolar lavage CAPS Catastrophic antiphospholipid syndrome CT Computed tomography CTEPH Chronic thromboembolic pulmonary hypertension CXR Chest radiography DAH Diffuse alveolar hemorrhage DLCO Diffusion capacity for carbon monoxide DMPA Medroxyprogesterone acetate DOAC Direct oral anticoagulant dsDNA Double-stranded deoxyribonucleic acid FEV1 Forced expiratory volume in 1 second FVC Forced vital capacity HCQ Hydroxychloroquine HRCT High-resolution computed tomography IgG Immunoglobulin G ILD Interstitial lung disease IUD Intrauterine device IV Intravenous IVIg Intravenous immunoglobulin Kg Kilogram LA Lupus anticoagulant LE Lupus erythematosus MEF Maximal expiratory flow rate mg Milligram mPAP Mean pulmonary artery pressure NO Nitric oxide PAH Pulmonary arterial hypertension PAP Pulmonary artery occlusion pressure PAPS Primary antiphospholipid syndrome PAWP Pulmonary artery wedge pressure PE Pulmonary embolism PFT Pulmonary function test PH Pulmonary hypertension PPI Proton pump inhibitor PVH Pulmonary venous hypertension RA Rheumatoid arthritis RBC Red blood cell SAPS Secondary antiphospholipid syndrome SARD Systemic autoimmune rheumatic disease SLE Systemic lupus erythematosus SLS Shrinking lung syndrome UV Ultraviolet VTE Venous thromboembolism

DOI: 10.1201/9781003361374-12151

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10.1 OVERVIEW Systemic lupus erythematosus (SLE) is a chronic, heterogenous autoimmune disease that primarily affects women of child-bearing age. It can affect nearly any organ in the body, ranging from mild cutaneous and musculoskeletal involvement to life-threatening renal or cardiopulmonary involvement. SLE is characterized by periods of flare and remission and risk for irreversible end organ damage. The pathogenesis of SLE is not fully understood. Both environmental factors and genetic susceptibility contribute to a lack of tolerance toward autoantibody production. These autoantibodies can then bind directly to tissues or form circulating immune complexes that deposit in tissues, leading to inflammation and organ damage (1–5). SLE has an estimated worldwide prevalence of 140 in 100,000, with an incidence of 1–10 per 100,000. In the United States, the estimated prevalence is 72.8 per 100,000 (6), disproportionately affecting minority populations, with up to 1 in 250 Black women affected, a risk two to three times higher than occurs in other groups (7–9), followed by Hispanics, Whites, and Asian/Pacific Islanders (6). Also, Black, and Hispanic women are diagnosed at a younger age and have more severe symptoms. Ninety percent of people living with SLE are female, though, of note, men with SLE often experience more severe disease manifestations. SLE is associated with a high mortality rate, particularly among young women of color. In an analysis of data from the Centers of Disease Control between 2000 and 2015, SLE ranked among the top 20 leading causes of death in females between 15 and 64 years of age. Among Black and Hispanic females, SLE ranked as the fifth leading cause of death at ages 15–24 years and sixth at ages 25–34 years, with the exclusion of three common external injury causes of death (10). Black and Hispanic women with SLE have mortality rates at least three times as high those of White women with SLE (11–15). Pulmonary involvement in patients with SLE can range from subclinical disease to potentially catastrophic manifestations, such as alveolar hemorrhage. Serositis, interstitial lung disease (ILD), alveolar hemorrhage, higher levels of disease activity, the presence of anti-RNP antibodies, and longer exposure to glucocorticoids are associated with shorter time to the development of pulmonary damage. The presence of malar rash, photosensitivity, and oral ulcers are associated with longer time to the development of pulmonary damage. The long-term use of hydroxychloroquine (HCQ), importantly, has also been associated with a reduced likelihood of pulmonary disease (16). In this chapter, we focus specifically on the pulmonary manifestations of SLE, including pleural disease, acute lupus pneumonitis, diffuse alveolar hemorrhage (DAH), ILD, airways disease, pulmonary arterial hypertension, antiphospholipid syndrome, shrinking lung syndrome, and acute reversible causes of hypoxemia. We also briefly review disease prevention, medication-related complications, vaccine-preventable illnesses, and toxic exposures. 10.2 PLEURAL DISEASE 10.2.1 Introduction Inflammation of the pleura in patients with SLE can range from mild symptoms of pleurisy to large pleural effusions. Pleural disease is one of the most common pulmonary manifestations in patients with SLE. Recurrent pleural pain is estimated to occur in up to 60% of patients, whereas pleural effusions are present in approximately one-third of patients (17, 18). 10.2.2 Pathobiology The pathogenesis of pleural involvement in patients with SLE is poorly understood. Autopsy studies demonstrate pleural involvement in over 90% of patients, suggesting significant subclinical involvement (19–21). The histopathology of involved pleura in patients with lupus characteristically demonstrates a nonspecific lymphocytic infiltrate with fibrosis and plasma cell infiltration, though granulomas have also been observed (19, 22). 10.2.3 Evaluation The diagnosis of pleuritis is often clinical, based on a careful history and physical examination. Patients will present with pleuritic chest pain, frequently associated with a pleural effusion. It is crucial that alternative etiologies of pleuritic chest pain and/or pleural effusions are considered, including infection, nephrotic syndrome, heart failure, pulmonary embolism (PE), and malignancy. Radiographically, pleural effusions are often bilateral. In persons with SLE, pleural fluid is typically exudative, with higher levels of glucose and lower levels of lactate dehydrogenase compared 152

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to those seen in patients with rheumatoid arthritis (RA) (23). Pleural fluid may contain antinuclear antibodies (ANAs), anti-double-stranded DNA antibodies (dsDNA), and lupus erythematosus (LE) cells. The presence of LE cells in the pleural fluid is a relatively specific finding, though this test is not routinely performed in commercial laboratories and thus requires manual examination (22, 24). This contrasts with the presence of ANAs in the pleural fluid, which is a nonspecific finding, similar to their presence in serum, and therefore, pleural fluid ANAs are not diagnostic of lupus pleuritis. For example, high-titer ANAs are frequently reported in malignant effusions (25, 26). However, in a patient with SLE and a pleural effusion, the high negative predictive value can be clinically useful, as the lack of ANA in the pleural fluid argues strongly against lupus pleuritis (27). Hypocomplementemia has more recently been suggested as a discriminating feature of lupus pleuritis, though this has not yet been examined prospectively in large cohorts (28). Pleural biopsies are not routinely performed unless needed to rule out alternative etiologies. 10.2.4 Treatment Symptoms from lupus pleuritis can often be treated with non-steroidal anti-inflammatory drugs (NSAIDs). For symptoms refractory to NSAIDs, glucocorticoids can be considered, though the optimal dose and duration of glucocorticoid therapy is not well defined. In general, we recommend the lowest possible dose for the shortest time period. Long-term HCQ use is associated with a decreased risk of pleuritis, either as an initial manifestation or with recurrence of disease (29). Azathioprine, mycophenolate, tocilizumab, rituximab, and cyclophosphamide use have been reported, though there is no high-level evidence regarding the most effective steroid-sparing agent (30–34). Invasive procedures such as chest tube placement or pleurodesis are rarely necessary (35, 36). 10.3 ACUTE LUPUS PNEUMONITIS 10.3.1 Epidemiology Acute lupus pneumonitis (ALP) is an uncommon pulmonary complication in patients with SLE, and it can be the initial manifestation (37), with an incidence of approximately 1–4%. Acute lupus pneumonitis is a life-threatening condition with a reported mortality rate as high as 50% despite treatment (38). As an infrequent disease manifestation, it is difficult to collect a substantial number of cases to better delineate treatment responses, and newer data relating to recent advanced therapeutic options is currently unavailable. 10.3.2 Pathobiology The histological findings in ALP are nonspecific and include inflammatory cell infiltration, edema, and hemorrhage, resulting in alveolar wall damage and necrosis. Additional pathologic characteristics include capillaritis, interstitial fibrosis, vasculitis, the presence of hematoxylin bodies, and pleural inflammation (37, 39). There are no pathognomonic histopathological features of ALP. The pathogenesis is driven by alveolar damage due to immune complex accumulation, supported by immunofluorescence studies demonstrating granular deposition of immunoglobulin G (IgG) and C3 along the alveolar walls, lung interstitium, and endothelial cells (19). 10.3.3 Evaluation The diagnosis of ALP is challenging, as similar clinical manifestations can be explained by other conditions such as infection, aspiration, cardiac dysfunction, uremia, and alveolar hemorrhage. It usually presents acutely with cough, dyspnea, hypoxia, and fever and typically occurs during an SLE exacerbation with multisystem involvement including nephritis and arthritis. In fact, experts question the existence of ALP in the absence of multisystem involvement (39). High titers of anti-dsDNA antibodies and anti-SSA antibodies (the latter in up to 82% of cases) are seen in patients with ALP when it is associated with multiorgan compromise (40, 41). Radiographic imaging may reveal unilateral or bilateral infiltrates with lung base predominance (42). Chest computed tomography (CT) often reveals ground-glass opacities and bilateral areas of patchy consolidation (43) (Figure 10.1). Bronchoalveolar lavage (BAL) is indicated to exclude alternative diagnoses such as infection and DAH (44); it is not useful for establishing a diagnosis of ALP. Transbronchial biopsies, similarly, are not warranted and are typically nondiagnostic (39). 10.3.4 Treatment Glucocorticoids are indicated for the acute management of ALP. If, at presentation, there is evidence of severe hypoxemic respiratory failure, the administration of IV pulse methylprednisolone 500 mg to 1 g daily for 3 days is recommended; otherwise, doses between 0.75 and 1 mg/kg/day 153

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Figure 10.1  Acute lupus pneumonitis. are used initially with a subsequent slow taper (39). Also, in cases of severe hypoxemic respiratory failure, IV pulse methylprednisolone followed by IV cyclophosphamide can be considered. Maintenance therapy is then indicated, with agents such as azathioprine (2 mg/kg/day), cyclophosphamide (oral dose of 1.5–2 mg/kg/day or IV 500 to 750 mg/m2 of body surface area, maximum 1200 mg per dose, with subsequent doses based upon response to therapy and nadir of white blood cell count, administered on average every 4 weeks for up to 6 months), or rituximab (1 gram on days 0 and 15, every 6 months) (45, 46). Distinguishing between infection and ALP can be challenging; thus it is important to consider empiric antimicrobial treatment after the collection of sputum or BAL fluid samples for culture if other clinical or radiographic findings support the possibility of infection. 10.4 DIFFUSE ALVEOLAR HEMORRHAGE 10.4.1 Epidemiology Diffuse alveolar hemorrhage is one of the most devastating complications of SLE, with an estimated mortality rate of 50%. The prevalence of DAH in patients with SLE can range from 0.6% to 5.4%, and it is responsible for 1.5–3.7% of all SLE-associated hospital admissions and 10–20% of mortality in patients with SLE (47, 48). It is more common in young women, with a female-to-male ratio of approximately 6:1 and a mean age of 27 years. In contrast to other pulmonary complications of SLE, DAH usually occurs early in the disease course, on average within 35 months of disease onset. There is an increased risk of DAH in patients with active lupus nephritis, and this association has been described in up to 80% of cases (49). 10.4.2 Pathobiology The pathophysiology of DAH is uncertain and is likely multifactorial. DAH likely results from the recruitment of macrophages and neutrophils in the lung, leading to infiltration outside of the capillaries prior to the development of clinical manifestations (47). Subsequently, there is neutrophilic infiltration of the alveolar septae, a loss of capillary structural integrity, and red blood cells in the interstitium and alveolar spaces (10, 50). Three histologic patterns have been described: bland hemorrhage, pulmonary capillaritis, and diffuse alveolar damage. Bland hemorrhage is the most common form of DAH. This form is associated with immune complex deposition and monocyte infiltration of the alveolar wall. The apoptosis of cells in the alveolar wall leads to the leakage of red blood cells (RBCs) into the alveolar space (48). Histologically, erythrocytes and fibrin are found within the alveolar spaces without signs of inflammation or destruction. In pulmonary capillaritis, there is immune complex deposition in the alveolar capillaries. This is followed by neutrophil infiltration and subsequent inflammation and necrosis of the alveolar and capillary walls with the leakage of RBCs into the alveolar space (10). Antiphospholipid antibodies have been described as potential initiating factors. Diffuse alveolar damage, a form of acute lung injury characterized by different stages, presents during its exudative phase with congestion of the alveolar capillaries, interstitial and alveolar edema, and intra-alveolar hemorrhage, along with the formation of hyaline membranes (50). 154

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10.4.3 Evaluation The clinical presentation of DAH includes a triad of hemoptysis, alveolar infiltrates, and acute anemia, although hemoptysis may be absent in approximately one-third of patients. Other symptoms are often nonspecific and may include fever, cough, dyspnea, and hypoxemia. Low hemoglobin levels could be seen before the development of hemoptysis, and in most cases, DAH is present along with other findings consistent with active lupus, including renal involvement. Respiratory distress with the need for mechanical ventilation may develop. Patients may also have thrombocytopenia and hypocomplementemia (48). The diffusion capacity (DLCO) may be elevated in the presence of alveolar hemorrhage, although typically patients are too ill to undergo pulmonary function testing (PFT). A DLCO increase by 30% or more over baseline or a DLCO of 130% predicted or higher suggests the presence of alveolar hemorrhage (40, 51). Chest radiography can show centrally distributed air-space opacities, and chest CT scan demonstrates focal asymmetric bilateral areas of consolidation or ground-glass opacities. However, these findings can also be present in other disorders such as ALP, infection, acute respiratory distress syndrome, pulmonary edema, and ILD (Figures 10.2, 10.3).

Figure 10.2  Diffuse alveolar hemorrhage (DAH).

Figure 10.3  Diffuse alveolar hemorrhage (DAH). (A) Axial chest CT image in the upper lobes demonstrating right greater than left centrilobular ground-glass opacities with subpleural sparing (black arrow) and interlobular septal thickening (white arrow). (B) Axial chest CT image from the same patient illustrating more dense areas of consolidation in the lower lobes. 155

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A diagnostic BAL is strongly recommended if clinically feasible. Sequential aliquots will be persistently or increasingly bloody. The presence of 20% or more hemosiderin-laden macrophages meets criteria for DAH; however, active bleeding needs to be present for 48–72 hours for this finding to appear. Samples must be analyzed for other etiologies, such as infection, which is the most common cause of lung disease in patients with SLE. Indeed, certain organisms, such as cytomegalovirus and legionella, can lead to bland alveolar hemorrhage (42, 48). Although unlikely needed, in the case of no clear diagnosis (more commonly following recurrent episodes), surgical lung biopsy can be considered, but this procedure should be avoided in the setting of acute hypoxemic respiratory failure due to its high risk. 10.4.4 Treatment Randomized controlled trials for the treatment of SLE-associated DAH are lacking. The initial and most used medication is methylprednisolone. Empirical studies have shown that survival is higher for those receiving methylprednisolone 4–8 grams given over the course of 4 to 8 days, instead of the conventional dose of pulse methylprednisolone of 3 grams over 3 days. Other medications can be added if no response is achieved following the high-dose glucocorticoid administration. A study that included 140 patients reported that glucocorticoids were used most frequently (98%), followed by cyclophosphamide (54%), plasma exchange (31%), azathioprine (7%), intravenous immunoglobulin (5%), mycophenolate mofetil (3%), rituximab (6%), and stem cell transplantation (2%) (48). Variability in treatment response with plasma exchange has been reported, which could be related to disease severity. It should be considered when other treatment modalities fail (37, 48). Empiric treatment for infection is recommended until it can be excluded. 10.5 ANTIPHOSPHOLIPID SYNDROME 10.5.1 Epidemiology Antiphospholipid syndrome (APS) is a systemic disorder characterized by arterial, venous, or small-vessel thromboembolic events, pregnancy morbidity, and persistent antiphospholipid antibodies (aPLs). APS commonly co-occurs with other autoimmune diseases, including SLE, RA, and systemic sclerosis, and is referred to as secondary APS (SAPS). Around one-third of patients with APS will also be diagnosed with SLE, and more than half of patients with SLE will test positive for aPLs (52, 53). The Sydney Classification Criteria are listed in Table 10.1. Beyond the thrombotic and obstetric manifestations included in the classification criteria, there are several non-criteria manifestations of APS, including valvular heart disease, renal dysfunction, livedo reticularis, cutaneous ulceration, hemolytic anemia, and chorea. Pulmonary manifestations of APS in patients with SLE can

Table 10.1: Sydney Classification Criteria of Antiphospholipid Syndrome At least one clinical criterion, and one laboratory criterion: Clinical Criteria 1. Vascular thrombosis: One or more episodes of definitive arterial, venous, or small-vessel thrombosis 2. Pregnancy morbidity: a. One or more unexplained fetal deaths of a morphologically normal fetus at or beyond the 10th week of gestation b. One or more premature births of a morphologically normal fetus at or before 34 weeks due to: i. Eclampsia ii. Severe pre-eclampsia iii. Placental insufficiency c. Three or more consecutive unexplained spontaneous abortions before 10 weeks Laboratory Criteria (repeat positivity of one of the following at least 12 weeks apart) 1. Lupus anticoagulant 2. Anticardiolipin IgG or IgM in medium–high titer (>40 IgG phospholipid units) 3. Anti-β2 glycoprotein-I IgG or IgM (>99th percentile) Source: Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. (ref 64)

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involve the vasculature or the parenchyma; the pleura is typically spared. Several studies have reported that the presence of aPLs in patients with SLE is associated with an increased risk of pulmonary embolism (PE) (54, 55). In contrast, the 10-year Euro-Phospholipid cohort study found similar rates of PE occurring in patients with APS with or without SLE (56). The APS-SH database, a patient registry and biobank of 252 patients with APS in Shanghai, China, found statistically significantly higher rates of PE in patients with primary APS (PAPS) compared to those with SLE and APS (57). Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) have been reported in patients with SLE with concomitant APS (58, 59). Interestingly, the presence of a lupus anticoagulant was a statistically significant risk factor for the development of PAH in patients with SLE, but anticardiolipin antibodies were not (58). There seems to be an additional association between APS and ILD, though it is unclear if there is a true pathophysiologic link or simply a co-occurrence given the paucity of reported cases (60). Data from the PRECISESADS study demonstrated aPL positivity as a risk factor for the development of pulmonary fibrosis in non-SLE connective tissue disease patients (53). Catastrophic APS (CAPS) is characterized by rapid-onset micro- and macrovascular thrombosis leading to life-threatening organ failure. As the name suggests, it is a devastating process, with mortality rates as high as 50%. The CAPS registry study showed that approximately 30% of patients with CAPS also had SLE, and this cohort had a higher mortality rate than that without SLE (61). The lungs are frequently affected by CAPS. Pulmonary manifestations include acute respiratory distress syndrome (ARDS), PE, and pulmonary hemorrhage. Renal failure, ischemic encephalopathy, myocardial ischemia, livedo reticularis or racemosa, and abdominal pain from intra-abdominal ischemia are also commonly reported. 10.5.2 Pathophysiology APS is a systemic autoimmune disorder that involves abnormal hemostasis with increased propensity for coagulation and reduced fibrinolysis. The pathophysiology of APS also involves activated cellular elements, including endothelial cells, monocytes, neutrophils, and platelets, in addition to complement activation, all of which play an important role in the development of inflammation, vasculopathy, thrombosis, and pregnancy complications (62–64). 10.5.3 Evaluation The spectrum of disease presentation varies widely, ranging from the presence of asymptomatic aPLs to the catastrophic multisystem organ failure that can occur in a small minority of patients with CAPS. We also now know that APS can occur as a primary condition or secondary to an autoimmune disease such as SLE. APS should always be considered in patients with thrombosis, especially those who are younger than age 50, have unprovoked or recurrent venous thromboembolism (VTE) or VTE at unusual sites, or recurrent, severe, or later-term pregnancy-related morbidity. To meet the classification criteria of APS, patients must fulfill both laboratory criteria and clinical criteria, as defined by the Sydney Classification Criteria (65) (Table 10.1). 10.5.4 Treatment The management of APS remains somewhat controversial and depends on whether the patient has thrombotic or obstetric clinical manifestations. The seminal APLASA (Anti-Phospholipid Antibody Acetyl-Salicylic Acid) trial showed that aspirin 81 mg daily did not provide primary prevention of acute thrombosis in patients with persistently elevated aPLs when compared to placebo (66). In contrast to the negative results from this study, several observational studies have demonstrated that certain antibody profiles confer a higher risk of thrombosis and might justify primary preventive measures. As a result, the European League Against Rheumatism (EULAR) guidelines for the management of APS in SLE recommend low-dose aspirin for patients with persistently positive LA, double positivity, or triple positivity (67). Women with aPL positivity should be on aspirin during pregnancy to reduce the risk of pre-eclampsia regardless of whether they have had a VTE event. If the patient does have obstetric APS, then they should also be on prophylactic heparin. Patients with thrombotic APS should be managed with warfarin after appropriate acute VTE therapy. The risk of recurrent thrombosis off anticoagulation is as high as 70%. Warfarin is the first-line treatment over direct oral anticoagulants (DOACs), as studies have suggested that stroke occurs more commonly in patients treated with DOACs compared to warfarin (68, 69). Hydroxychloroquine has been shown to reduce the incidence of thrombotic complications in patients with SLE and APS, but data is insufficient to suggest that it is useful in difficult-to-treat primary APS. 157

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As concomitant APS with SLE is a risk factor for developing DAH (70), the management of DAH in patients with SLE and APS begins with pulse-dose glucocorticoids (methylprednisolone 500–1000 mg daily for 3 to 5 days), with the continuation of high-dose glucocorticoids thereafter. Additional treatment strategies are less clear, though there is a consensus that immunosuppression is necessary. Because this is a relatively specific cohort of patients, much of the guidance comes from subgroup analyses or extrapolation from case series or case–control studies assessing SLE-associated DAH. Options that have shown benefits include cyclophosphamide, azathioprine, mycophenolate mofetil, and rituximab (71–73). Selection among these choices depends on side effect profile, acuity of patient illness, and clinician preference, as there is no head-to-head trial data; these medications can be given as single agents or used in a combination approach. In patients with DAH and acute or previous thrombosis, the decision regarding anticoagulation should be made on a case-by-case basis (74). It is also important to note the frequency of superimposed infection in patients with DAH and SAPS/SLE, warranting empiric antibiotic therapy based on local susceptibility patterns (75). Please refer to the Diffuse Alveolar Hemorrhage section of this chapter for further discussion. The management of CAPS has been relatively standardized to “triple therapy” with anticoagulation, glucocorticoids, and either plasma exchange or intravenous immunoglobulin (IVIg) (76). There is no survival difference between individuals who received IVIg or plasma exchange; thus, selection between these two treatments is often based on availability (76). In the subset of patients with CAPS, active SLE, and DAH, therapy should also include cyclophosphamide and/or rituximab (77). Additionally, the decision regarding anticoagulation, particularly in the setting of active pulmonary hemorrhage and thrombosis, must be individualized. Anticoagulation with heparin should be initiated once the clinician has judged that hemorrhage has stabilized, as triple therapy significantly decreases mortality when compared to any combination of dual therapy (76). Finally, eculizumab, a complement activation inhibitor targeting C5, can be considered for refractory disease (78). 10.6 CHRONIC INTERSTITIAL LUNG DISEASE 10.6.1 Epidemiology Chronic ILD occurs less commonly in patients with SLE than with other systemic autoimmune rheumatic diseases (SARDs). Findings of ILD on high-resolution computed tomography (HRCT) chest are seen in 30–40% of patients with SLE, with most of these patients being asymptomatic. Similarly, a reduction in DLCO and pulmonary restrictive physiology are seen in 27–56% and 8–80% respectively, of patients with SLE (without an established diagnosis of ILD) (42). However, clinically significant ILD is found in only approximately 3% to 8% of patients with SLE. Its prevalence increases with disease duration. It is more common in men over age 50 years and following a long-standing (>10 years) diagnosis of SLE (42, 44). 10.6.2 Histopathology The most common radiologic/histopathologic pattern is nonspecific interstitial pneumonia (NSIP) (46). Other reported patterns include lymphocytic interstitial pneumonia (LIP), more commonly in association with secondary Sjögren’s syndrome, and organizing pneumonia (OP), although its presence may be due to other comorbid conditions such as infection, drug toxicity, or other systemic disorders (42). 10.6.3 Evaluation Interstitial lung disease in SLE typically presents with a nonproductive cough, gradual worsening of dyspnea on exertion, and crackles on lung examination. Patients may also complain of pleuritic chest pain (40). Although usually insidious, SLE-ILD can be preceded by one or more episodes of acute pneumonitis. HRCT chest delineates the presence of ILD and helps determine the pattern. In the case of NSIP, lower lobe predominant ground glass opacities and subpleural reticulation will be present. If randomly located cystic lesions are seen, LIP leads the differential diagnosis. Areas of patchy consolidation on CT chest characterize OP (42, 44) (Figures 10.4, 10.5, 10.6). Surgical lung biopsy is typically not indicated for SLE-ILD. However, if performed, there is a predominance of neutrophils and lymphocytes throughout the interstitium (74). Bronchoscopy can be helpful to exclude other complications, such as comorbid conditions or infection, but is otherwise not indicated. 158

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Figure 10.4  Nonspecific interstitial pneumonia.

Figure 10.5  Lymphocytic interstitial pneumonia.

Figure 10.6  Organizing pneumonia. 10.6.4 Treatment There are no randomized controlled clinical trials for the treatment of chronic ILD due to SLE. Existing small studies have shown a clinical response and improvement in DLCO with oral glucocorticoid therapy. Other therapeutic options have been extrapolated from the treatment of systemic sclerosis and other SARDs complicated by ILD. In mild to moderate disease, glucocorticoids can be used for monotherapy; however, in severe or progressive disease, the addition of steroid-sparing 159

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agents such as azathioprine or mycophenolate mofetil is indicated. Rituximab is another option, its use is based on expert opinion (44, 79, 80). Collaborative care by a rheumatologist and pulmonologist with expertise in ILD is important. 10.7 AIRWAYS DISEASE 10.7.1 Epidemiology Airways disease in SLE has been described and is a rare disease manifestation. SLE can affect the upper and lower airways. Upper airway involvement can present as mucosal inflammation (28%), cricoarytenoiditis, and/or bilateral vocal cord paralysis (11%). Laryngeal involvement in patients with SLE has a prevalence of 0.3% to 30% (81). Lower airway involvement is seen in up to 6% of patients (42). An autopsy study reported bronchiolar dilation in 36% of patients with SLE (81). 10.7.2 Pathobiology The pathobiology leading to airway involvement in patients with SLE is poorly understood. It may be due to immune complex deposition, complement activation, and chronic peribronchovascular inflammation leading to fibrosis (81). 10.7.3 Evaluation The clinical presentation of airway involvement in SLE is nonspecific and is dependent on the location and degree of obstruction. It includes dyspnea, stridor, dry cough, hoarseness, and sore throat. There are no specific laboratory tests that correlate with the diagnosis of airways disease; therefore, this manifestation is supported by PFTs demonstrating an obstructive pattern on spirometry in up to two-thirds of patients, even in the presence of a normal CXR or chest CT (42, 81). Upper airway involvement is suggested by the flattening of either the inspiratory or expiratory limb (or both) of the flow volume loop that is obtained with spirometry. Small airways disease defined as a 25% maximal expiratory flow rate (MEF25) less than 60% was found in 17 (24%) patients in one small study; however, this did not differ significantly from the control group. A reduction in the FEV1/FVC ratio and maximal mid-expiratory flow rate were found in 5.7% to 24% of patients, compared to 70 age-matched controls without SLE (19). The surveillance of PFTs for 2 to 7 years revealed a progressive decline in values of small airway function independent of smoking (42). HRCT chest can reveal evidence of lower airway involvement, including bronchiectasis and bronchial wall thickening equally distributed over the upper, middle, and lower lung fields. Bronchiolitis obliterans has also been reported (81). 10.7.4 Treatment There are no randomized controlled studies for the treatment of airways disease associated with SLE. Initial treatment with glucocorticoids has been recommended. Supportive therapy with both inhaled short-acting and long-acting bronchodilators is indicated. Immunosuppressive agents can be used for progressive disease. The use of cyclophosphamide has been reported (44). 10.8 PULMONARY ARTERIAL HYPERTENSION 10.8.1  Definition and Classification Pulmonary hypertension (PH) refers to a pathophysiologic disorder characterized by an elevated mean pulmonary artery pressure (mPAP) at rest and rarely occurs in patients with SLE (82). It is defined by an mPAP of 20 mmHg or more as measured by right heart catheterization (RHC). Pulmonary arterial hypertension (PAH) is defined by mPAP > 20 mmHg when pulmonary artery occlusion pressure (PAP) < 15 mmHg and pulmonary vascular resistance (PVR) > 2 Wood units (WU). Pulmonary venous hypertension (PVH) corresponds to the elevation of the mPAP in the presence of left heart disease when the pulmonary arterial wedge pressure (PAWP) is ≥15 mmHg and PVR ≤ 2 WU. 10.8.2 Epidemiology The American REVEAL registry (The Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management) included 5.8% SLE patients. In patients with SLE, PAH develops more commonly within 5 years of disease onset, and most patients are women under the age of 40 years. The REVEAL study demonstrated 1-year survival in patients with PAH associated with SLE to be 94%, which is higher as compared to 82% to 88% among other SARDs (83, 84). 160

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10.8.3 Pathobiology The pathophysiology of PAH involves multiple pathways, with pulmonary artery endothelial cell dysfunction underlying many of the processes. Mechanisms include an impaired ability to produce nitric oxide (NO) and prostacyclin and the overexpression of vasoconstrictors, such as endothelin (85). In SLE, three different phenomena seem to be present. First is an increased risk for thrombotic arteriopathy associated with aPLs. Second is the observation of more consistent endothelial changes resulting in vascular remodeling and plexiform lesions. Third is an immune-mediated vasculopathy leading to pulmonary vasculitis, which could respond to immunosuppression (86). 10.8.4 Evaluation PAH is considered a rare complication of SLE with a prevalence of 60 years old, acute interstitial pneumonia (AIP), neutrophilic alveolitis on bronchoalveolar lavage (BAL), hypoxemia, initial forced vital capacity (FVC) ≤ 60%, elevated ferritin, C-reactive protein, Krebs von den Lungen 6 (KL-6) levels, MDA5 positivity, anti-Ro-52 positivity, and amyopathic DM (17, 18, 71, 72). Although the prognosis of ASyS-associated ILD is generally favorable, patients with PL-7 and PL-12 antibodies experience earlier and more severe ILD and a worse prognosis compared to those with Jo-1 antibody (73, 74). Black patients with IIM-ILD are also more likely to have severe ILD than White patients, while men with IIM-ILD have higher rates of mortality than women (73, 75). 176

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11.2.4 Evaluation We recommend that all patients with IIM undergo pulmonary function tests (PFTs) to establish a baseline and to evaluate for the presence of ILD. Obtaining a baseline chest high-resolution computed tomography (HRCT) scan should also be strongly considered in patients with a highrisk antibody profile (e.g., ASyS, MDA5, Ro-52) (76). As in systemic sclerosis (77), patients with radiographic IIM-ILD may have normal PFTs (69, 78). Additionally, annual monitoring for the development of ILD is recommended for patients with high-risk antibody profiles, as detailed earlier. However, extrapolating from studies in patients with systemic sclerosis, PFTs alone cannot reliably detect all cases of ILD. Establishing baseline PFT values is nonetheless important for monitoring disease course in any given patient with IIM. If there is a decline in PFTs over time (5% decline in FVC or 10% decline in diffusion capacity of the lungs for carbon monoxide [DLCO]) (79) or if new respiratory symptoms develop, a chest HRCT should be performed to evaluate for lung parenchymal changes. Further, a chest HRCT is important to obtain with the development of any respiratory symptoms or if the initial FVC or DLCO is less than 80% predicted. It is important to recognize that patients with IIM can also develop respiratory muscle weakness with the resulting impairment of pulmonary function, a complication that can be evaluated using a combination of upright/supine spirometry as well as the measurement of maximal inspiratory and expiratory pressures. The most common radiographic patterns include nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), and a combination thereof (80, 81). However, usual interstitial pneumonia (UIP) can also be seen (82). While patients with myositis-related UIP have a better outcome than patients with idiopathic pulmonary fibrosis (83), a recent study of ASyS patients found that a UIP pattern of ILD was associated with an increased risk of death (84). Pulmonary hypertension is a well-recognized complication of ILD and is associated with worsened survival (85, 86). Thus, an echocardiogram should be considered as a screening tool for pulmonary hypertension if any of the following are present: 1) physical exam findings concerning for pulmonary hypertension (e.g., loud P2, lower extremity edema, elevated jugular venous pressure), 2) respiratory symptoms out of proportion to ILD degree, 3) disproportionate decline in DLCO compared to FVC decline, 4) an enlarged pulmonary artery on chest CT scan, 5) a DLCO < 40% predicted (87, 88), or 6) elevated N-terminal pro-brain natriuretic peptide (NT-pro-BNP) or brain natriuretic peptide (BNP) (89). In general, there is a limited role for either bronchoscopy or lung biopsy in the evaluation of IIM-ILD, as BAL cannot reliably distinguish different histologic patterns or causes of ILD. Importantly, however, BAL may be useful when one cannot clinically or radiographically distinguish superimposed infection from an acute ILD exacerbation. While BAL is adequate for diagnosing most infections, transbronchial biopsies are superior to BAL alone for diagnosing invasive fungal and viral infections and should be considered in an immunocompromised host (90, 91). Surgical lung biopsies are typically avoided in IIM-ILD due to the potential morbidity and mortality of this procedure without much added benefit, particularly because immunosuppressive therapy is usually indicated regardless of histopathological subtype (92–94). 11.2.5 Treatment Data regarding efficacy of individual therapeutic agents in IIM-ILD are primarily derived from retrospective observational reports. Thus, management approaches discussed in this section reflect the authors’ recommendations (Figure 11.3). We monitor patients without treatment if they are asymptomatic, demonstrate 75% predicted and/or DLCO > 65% predicted. Glucocorticoids (GCs) are the cornerstone of therapy for IIM-ILD despite the lack of randomized controlled clinical trials. Initial GC regimens involve high-dose oral steroids (e.g., prednisone 1 mg/kg/day), but the dose may be lower if ILD is mild. Pulse-dose intravenous GC (methylprednisolone 1 gram intravenously once daily for 3–5 days) is usually administered in hospitalized patients who have rapidly progressive ILD or respiratory failure. Pulse dosing (prednisone ≥ 250 mg per day equivalent) is thought to work more quickly than lower-dose regimens, as the antiinflammatory effect through genomic targeting (i.e., effects on gene transcription due to nuclear location of the GC receptor) likely peaks at prednisone 40 mg daily, while additional anti-inflammatory benefits may be operative through non-genomic effects of GC at higher doses (95). Immunosuppressive therapy is frequently added to GC treatment for steroid-sparing purposes in the long-term management of IIM-ILD and as initial therapy in patients with significant or rapidly progressive ILD. A retrospective study comparing outcomes of patients who received 177

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Figure 11.3  Suggested treatment algorithm for patients with IIM-ILD. Created in Biorender.com. Abbreviations: IIM-ILD: idiopathic inflammatory myopathy associated interstitial lung disease, FVC: forced vital capacity, HRCT: high-resolution computerized tomography, GC: glucocorticoids, IV: intravenous, TAC: tacrolimus, IVIG: intravenous immune globulin, RTX: rituximab, AZA: azathioprine, MMF: mycophenolate mofetil, MTX: methotrexate

immunosuppressive therapy after failing to improve with GCs alone (step-up) versus those who received a combination of GCs and immunosuppressive drugs (upfront intensive) demonstrated a significant survival benefit in those who received upfront intensive therapy (96). Similarly, a retrospective study comparing early versus delayed treatment of IIM-ILD with cyclosporine showed a significantly lower mortality rate in patients who received early intervention (97). These studies suggest that early intensive therapy with a combination of GC’s and an immunosuppressive agent may have a survival benefit in patients with IIM-ILD. The immunosuppressive agent is selected based on the severity and course of ILD, comorbidities, and the presence of extrapulmonary manifestations such as arthritis and myositis. In patients with rapidly progressive ILD (i.e., worsening within 3 months of onset), we recommend high- or pulse-dose GC, combined with a rapidly acting agent (usually intravenous immune globulin) and an additional immunosuppressive agent. Options for immunosuppressive agents include rituximab (500–1000 mg intravenous every 6 months), cyclophosphamide (500–1000 mg or 300–800 mg/m2 body surface area intravenous every 2 to 4 weeks), and tacrolimus (0.0.075 mg/kg/day by mouth that can be titrated to achieve plasma trough levels of 5–20 ng/mL); however, there is no clear consensus regarding the use of these specific agents (98–101). Furthermore, with the COVID19 pandemic, additional safety concerns have been raised regarding the use of rituximab (102). In other patients with chronic slowly progressive disease (i.e., worsening over a period >3 months) or stable disease (i.e., stable disease over 3 months), mycophenolate mofetil (2000–3000 mg/day by mouth), azathioprine (2 mg/kg/day by mouth), or calcineurin inhibitors (tacrolimus or cyclosporine) can be used (103, 104). Prospective studies on immunosuppressive therapies are generally limited and predominantly include studies on calcineurin inhibitors. An open-label, single-arm, multicenter, 52-week clinical trial demonstrated improved survival in patients with IIM-ILD who received initial combination therapy with tacrolimus (0.075 mg/kg/day) and GC compared to historical controls treated with GC alone (105). Another open-label randomized controlled trial of tacrolimus versus cyclosporine showed a comparable progression-free survival in both arms, with significant improvements in FVC percent predicted at 52 weeks in both arms (106). In patients who demonstrate worsening despite initial therapy, we recommend either switching to a different agent not used in the initial regimen, (e.g., rituximab, cyclophosphamide, or intravenous immune globulin) or using combination therapy (such as azathioprine and tacrolimus; 178

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mycophenolate mofetil and tacrolimus; tacrolimus and rituximab). Beyond these agents, there is a growing number of case series showing the successful treatment of IIM-ILD, particularly MDA5associated ILD, with tofacitinib (107, 108). Currently ongoing clinical trials in IIM-ILD listed on the clinicaltrials.gov website are summarized in Table 11.1.

Table 11.1: Randomized Controlled Trials Enrolling Patients with IIM-ILD Listed on clinicaltrials.gov* NCT Number

Title

NCT03215927

Abatacept for the Treatment of Myositisassociated Interstitial Lung Disease Tolerability and Safety of Nintedanib in Myositis Associated Interstitial Lung Disease: A Pilot Study Clinical Study of MMF in Treatment of IIM-ILD and Its Effect on Peripheral Blood Treg Cells Rituximab Versus Cyclophosphamide in Connective Tissue Disease-ILD Cyclophosphamide and Azathioprine vs Tacrolimus in Antisynthetase Syndrome-related Interstitial Lung Disease Efficacy and Safety of Pirfenidone in Patients with Dermatomyositis Interstitial Lung Disease (Dm-ILD) Efficacy and Safety of Triple Therapy in Patients with Anti-MDA5 Antibody-positive Dermatomyositis Efficacy and Safety of Pirfenidone in CTD-ILD

NCT05335278

NCT05129410

NCT01862926

NCT03770663

NCT03857854

NCT05375435

NCT05505409

NCT04928586

Immunosuppressant Combined with Pirfenidone in CTD-ILD

Status

Interventions

Design Enrollment Locations

Completed Abatacept vs placebo Phase 2 20

USA

Recruiting Nintedanib

Openlabel pilot

25

Canada

Recruiting Mycophenolate mofetil

Open label

20

China

Completed Rituximab vs cyclophosphamide

Phase 2/3

104

United Kingdom

Recruiting Cyclophosphamide and azathioprine vs tacrolimus

Phase 3 76

France

Unknown status

Phase 3 152

China

Phase 4 120

China

Recruiting Pirfenidone, Phase 4 120 glucocorticoid, and immunosuppressant vs glucocorticoid and immunosuppressant Recruiting Pirfenidone and Phase 4 200 DMARDs vs DMARDs alone

China

Pirfenidone vs placebo

Recruiting Triple therapy vs dual therapy

China

*Note: Only randomized controlled trials with a posted update in the last 4 years have been included in the table. Accessioned on January 14, 2023 Abbreviations: ILD: interstitial lung disease; CTD-ILD: connective tissue disease-related interstitial lung disease; DMARD: disease-modifying anti-rheumatic drug

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Apart from these therapeutic considerations regarding the choice of immunosuppressive agents, there is no consensus on the duration of treatment for IIM-ILD. We typically monitor PFTs every 3 months for the first year and then every 3–6 months in subsequent years. We typically continue full-dose therapy for at least 2 years depending on the patient’s response and slowly taper immunosuppression thereafter. However, many patients require a much longer treatment duration, as flares can occur when seemingly stable patients, with years of well-controlled disease, are tapering their immunosuppressive regimens. Due to high mortality rates observed in patients with anti-MDA5 antibody who present with rapidly progressive ILD, a number of special considerations apply to the management of this disease subset. Paralleling findings from retrospective studies, a single-arm prospective trial of patients with newly diagnosed MDA5 (+) ILD demonstrated significantly higher survival rates in patients treated with the combination of high-dose GCs, tacrolimus, and intravenous cyclophosphamide (+/– plasma exchange, if worsening) compared to historical controls who received stepup therapy with glucocorticoids and the serial addition of an immunosuppressive agent (109). Of note, however, follow-up propensity scoring minimized some of the apparent treatment advantage in the combination therapy group (109). Furthermore, a recent retrospective study showed that patients treated with calcineurin inhibitors exhibited a significantly better survival rate than those treated with a combination of calcineurin inhibitors and intravenous cyclophosphamide (110). Given the conflicting results of the available studies, well-designed prospective trials are needed to better assess the efficacy of triple therapy (GC, tacrolimus, cyclophosphamide) versus other potential therapies. A number of recent reports have shown the potential benefit of plasma exchange in MDA5 (+) ILD patients refractory to triple therapy (111–113) and the survival benefit of intravenous immune globulin as an adjunct to first-line therapy (114). In one retrospective review of 10 patients with progressive lung disease despite triple therapy, the 1-year survival rate was significantly higher in six patients who received plasma exchange compared to four patients who did not (112). Small retrospective studies and case series also suggest a potential benefit of rituximab in these patients (115, 116). Based on these findings, we consider glucocorticoids, tacrolimus, and intravenous immune globulin in the initial management of patients with MDA5 (+) rapidly progressive ILD and may consider rituximab, intravenous cyclophosphamide, plasma exchange, or tofacitinib in some patients who do not respond to this initial therapy. While IIM patients with NSIP or OP patterns on HRCT tend to respond to GC and immunosuppressive therapies, there may be less response to such therapies in those with a UIP-like pattern of ILD. In these patients, antifibrotic agents—particularly nintedanib—should be considered (117). Although data regarding the combination of GCs and immunosuppressive agents with antifibrotics are currently limited, the potential use of these regimens remains an active area of investigation that is likely to yield new treatment paradigms in the near future. Lung transplantation can be considered for some patients with severe ILD. According to the 2021 International Society for Heart and Lung Transplant (ISHLT) guidelines, lung transplantation should be considered for individuals with a high (>50%) risk of death within 2 years from lung disease in the absence of transplant but, assuming adequate allograft function, whose overall health conveys a high (>80%) likelihood of 5-year survival post-transplant (118). The ISHLT recommends that outpatients with inflammatory ILDs such as IIM-ILD be referred to a lung transplant center if they experience a relative decline over 2 years (≥10% FVC or ≥15% decline in DLCO or ≥5% decline in FVC with radiographic or clinical deterioration), exhibit any oxygen requirement or functional limitation due to ILD, and fail to improve after a trial of medical therapy (118). Patients with acute hypoxic respiratory failure from rapidly progressive IIM-ILD may be considered for lung transplantation at some centers (119, 120). Notably, both muscle weakness and active skin disease are associated with an increased risk of death after lung transplantation; thus, extrapulmonary disease should be optimally controlled prior to transplantation (120). 11.3 CONCLUSION In summary, IIM-ILD is one of the leading causes of morbidity and mortality in patients with IIM. ILD may be asymptomatic and present after the onset of IIM in a significant proportion of patients, underscoring the importance of screening for ILD in patients with IIM. The tailored treatment of IIM-ILD is based on several factors that include disease severity, symptom status, radiographic pattern, trajectory of disease progression, and the presence of extrapulmonary manifestations. The quality of evidence for treatment suggestions is low, highlighting the need for randomized controlled trials in patients with IIM-ILD. 180

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83. Aggarwal R, McBurney C, Schneider F, Yousem SA, Gibson KF, Lindell K, et al. Myositisassociated usual interstitial pneumonia has a better survival than idiopathic pulmonary fibrosis. Rheumatology (Oxford). 2017;56(3):384–9. 84. Liu H, Xie S, Liang T, Ma L, Sun H, Dai H, et al. Prognostic factors of interstitial lung disease progression at sequential HRCT in anti-synthetase syndrome. Eur Radiol. 2019;29(10):5349–57. 85. Andersen CU, Mellemkjær S, Hilberg O, Nielsen-Kudsk JE, Simonsen U, Bendstrup E. Pulmonary hypertension in interstitial lung disease: Prevalence, prognosis and 6 min walk test. Respir Med. 2012;106(6):875–82. 86. Hervier B, Meyer A, Dieval C, Uzunhan Y, Devilliers H, Launay D, et al. Pulmonary hypertension in antisynthetase syndrome: Prevalence, aetiology and survival. Eur Respir J. 2013;42(5):1271. 87. Coghlan JG, Denton CP, Grünig E, Bonderman D, Distler O, Khanna D, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: The DETECT study. Ann Rheum Dis. 2014;73(7):1340–9. 88. King CS, Nathan SD. Pulmonary hypertension due to interstitial lung disease. Curr Opin Pulm Med. 2019;25(5). 89. Rahaghi FF, Kolaitis NA, Adegunsoye A, de Andrade JA, Flaherty KR, Lancaster LH, et al. Screening strategies for pulmonary hypertension in patients with interstitial lung disease: A multidisciplinary delphi study. Chest. 2022;162(1):145–55. 90. Cazzadori A, Di Perri G, Todeschini G, Luzzati R, Boschiero L, Perona G, et al. Transbronchial biopsy in the diagnosis of pulmonary infiltrates in immunocompromised patients. Chest. 1995;107(1):101–6. 91. Patel NR, Lee PS, Kim JH, Weinhouse GL, Koziel H. The influence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and allogeneic bone marrow transplant patients. Chest. 2005;127(4):1388–96. 92. Hariri LP, Roden AC, Chung JH, Danoff SK, Gomez Manjarres DC, Hartwig M, et al. The role of surgical lung biopsy in the diagnosis of fibrotic interstitial lung disease: Perspective from the pulmonary fibrosis foundation. Ann Am Thorac Soc. 2021;18(10):1601–9. 93. Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. In-hospital mortality after surgical lung biopsy for interstitial lung disease in the United States. 2000 to 2011. Am J Respir Crit Care Med. 2016;193(10):1161–7. 94. Sato T, Teramukai S, Kondo H, Watanabe A, Ebina M, Kishi K, et al. Impact and predictors of acute exacerbation of interstitial lung diseases after pulmonary resection for lung cancer. J Thorac Cardiovasc Surg. 2014;147(5):1604–11.e3. 95. Saygin D, Oddis CV. Glucocorticoids in myositis: Initiation, tapering, and discontinuation. Curr Rheumatol Rep. 2022;24(3):47–53. 96. Takada K, Kishi J, Miyasaka N. Step-up versus primary intensive approach to the treatment of interstitial pneumonia associated with dermatomyositis/polymyositis: A retrospective study. Mod Rheumatol. 2007;17(2):123–30. 97. Go DJ, Park JK, Kang EH, Kwon HM, Lee YJ, Song YW, et al. Survival benefit associated with early cyclosporine treatment for dermatomyositis-associated interstitial lung disease. Rheumatol Int. 2016;36(1):125–31. 98. Moreno-Torres V, Martin-Iglesias D, Vivero F, Gonzalez-Echavarri C, Garcia-Moyano M, Enghelmayer JI, et al. Intravenous cyclophosphamide improves functional outcomes in interstitial lung disease related to idiopathic inflammatory myopathies. Semin Arthritis Rheum. 2023;59:152164. 99. Oddis CV, Sciurba FC, Elmagd KA, Starzl TE. Tacrolimus in refractory polymyositis with interstitial lung disease. Lancet. 1999;353(9166):1762–3. 100. Yamasaki Y, Yamada H, Yamasaki M, Ohkubo M, Azuma K, Matsuoka S, et al. Intravenous cyclophosphamide therapy for progressive interstitial pneumonia in patients with polymyositis/dermatomyositis. Rheumatology (Oxford). 2007;46(1):124–30. 101. Doyle TJ, Dhillon N, Madan R, Cabral F, Fletcher EA, Koontz DC, et al. Rituximab in the treatment of interstitial lung disease associated with antisynthetase syndrome: A multicenter retrospective case review. J Rheumatol. 2018;45(6):841–50. 102. Singh N, Madhira V, Hu C, Olex AL, Bergquist T, Fitzgerald KC, et al. Rituximab is associated with worse COVID-19 outcomes in patients with rheumatoid arthritis: A retrospective, nationally sampled cohort study from the U.S. National COVID Cohort Collaborative (N3C). Semin Arthritis Rheum. 2023;58:152149. 185

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103. Morganroth PA, Kreider ME, Werth VP. Mycophenolate mofetil for interstitial lung disease in dermatomyositis. Arthritis Care Res (Hoboken). 2010;62(10):1496–501. 104. Huapaya JA, Silhan L, Pinal-Fernandez I, Casal-Dominguez M, Johnson C, Albayda J, et al. Long-term treatment with azathioprine and mycophenolate mofetil for myositis-related interstitial lung disease. Chest. 2019;156(5):896–906. 105. Takada K, Katada Y, Ito S, Hayashi T, Kishi J, Itoh K, et al. Impact of adding tacrolimus to initial treatment of interstitial pneumonitis in polymyositis/dermatomyositis: A single-arm clinical trial. Rheumatology (Oxford). 2020;59(5):1084–93. 106. Fujisawa T, Hozumi H, Kamiya Y, Kaida Y, Akamatsu T, Kusagaya H, et al. Prednisolone and tacrolimus versus prednisolone and cyclosporin A to treat polymyositis/dermatomyositisassociated ILD: A randomized, open-label trial. Respirology. 2021;26(4):370–7. 107. Kurasawa K, Arai S, Namiki Y, Tanaka A, Takamura Y, Owada T, et al. Tofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibodypositive dermatomyositis. Rheumatology (Oxford). 2018;57(12):2114–19. 108. Takanashi S, Kaneko Y, Takeuchi T. Tofacitinib in interstitial lung disease complicated with anti-MDA5 antibody-positive dermatomyositis: A literature review. Mod Rheumatol. 2022;32(1):231–7. 109. Tsuji H, Nakashima R, Hosono Y, Imura Y, Yagita M, Yoshifuji H, et al. Multicenter prospective study of the efficacy and safety of combined immunosuppressive therapy with high-dose glucocorticoid, tacrolimus, and cyclophosphamide in interstitial lung diseases accompanied by anti-melanoma differentiation-associated gene 5-positive dermatomyositis. Arthritis Rheumatol. 2020;72(3):488–98. 110. Gui XE. Treatment of interstitial lung disease in anti-MDA5-positive dermatomyositis: A retrospective study of 87 patients. 2022. Available from SSRN: https://ssrn.com/ abstract=4069705 or http://dx.doi.org/10.2139/ssrn.4069705 111. Saito T, Mizobuchi M, Miwa Y, Sugiyama M, Mima Y, Iida A, et al. Anti-MDA-5 antibodypositive clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease treated with therapeutic plasma exchange: A case series. J Clin Apher. 2021;36(1):196–205. 112. Abe Y, Kusaoi M, Tada K, Yamaji K, Tamura N. Successful treatment of anti-MDA5 antibodypositive refractory interstitial lung disease with plasma exchange therapy. Rheumatology (Oxford). 2020;59(4):767–71. 113. Shirakashi M, Nakashima R, Tsuji H, Tanizawa K, Handa T, Hosono Y, et al. Efficacy of plasma exchange in anti-MDA5-positive dermatomyositis with interstitial lung disease under combined immunosuppressive treatment. Rheumatology (Oxford). 2020;59(11):3284–92. 114. Wang LM, Yang QH, Zhang L, Liu SY, Zhang PP, Zhang X, et al. Intravenous immunoglobulin for interstitial lung diseases of anti-melanoma differentiation-associated gene 5-positive dermatomyositis. Rheumatology (Oxford). 2022;61(9):3704–10. 115. Ge Y, Li S, Tian X, He L, Lu X, Wang G. Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis responds to rituximab therapy. Clin Rheumatol. 2021;40(6):2311–17. 116. So H, Wong VTL, Lao VWN, Pang HT, Yip RML. Rituximab for refractory rapidly progressive interstitial lung disease related to anti-MDA5 antibody-positive amyopathic dermatomyositis. Clin Rheumatol. 2018;37(7):1983–9. 117. Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–27. 118. Leard LE, Holm AM, Valapour M, Glanville AR, Attawar S, Aversa M, et al. Consensus document for the selection of lung transplant candidates: An update from the international society for heart and lung transplantation. J Heart Lung Transplant. 2021;40(11):1349–79. 119. Trudzinski FC, Kaestner F, Schafers HJ, Fahndrich S, Seiler F, Bohmer P, et al. Outcome of patients with interstitial lung disease treated with extracorporeal membrane oxygenation for acute respiratory failure. Am J Respir Crit Care Med. 2016;193(5):527–33. 120. Riviere A, Picard C, Berastegui C, Mora VM, Bunel V, Godinas L, et al. Lung transplantation for interstitial lung disease in idiopathic inflammatory myositis: A cohort study. Am J Transplant. 2022;22(12):2990–3001.

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12 Pulmonary Manifestations of Systemic Sclerosis and Mixed Connective Tissue Disease Denise G. Sese, Katherine C. Silver, Kristin B. Highland, and Richard M. Silver List of Abbreviations 6MWD 6-minute walk distance ACA Anti-centromere antibody ACE Angiotensin-converting enzyme ACR American College of Rheumatology AE Adverse Event ASCT Autologous stem cell transplantation ASIG Australian Scleroderma Interest Group ATS American Thoracic Society BNP Brain natriuretic peptide CI Confidence interval CPFE Combined pulmonary fibrosis and emphysema CTD Connective tissue disease CTEPH Chronic thromboembolic pulmonary hypertension DB Double blind DcSSc Diffuse cutaneous systemic sclerosis DLCO Diffusion capacity for carbon monoxide ERA Endothelin receptor antagonist FC Functional class FDA Food and Drug Administration FEV1 Forced expiratory volume, 1 second FVC Forced vital capacity GERD Gastroesophageal reflux disease GRADE Grading of Recommendations, Assessment, Development and Evaluation H2-blocker Histamine-2 blocker HFpEF Heart failure with preserved ejection fraction HFrEF Heart failure with reduced ejection fraction HPAH Hereditary pulmonary arterial hypertension HR Hazard ratio HRCT High-resolution computed tomography IL-6 Interleukin-6 IL-13 Interleukin-13 ILD Interstitial lung disease IPF Idiopathic pulmonary fibrosis IPAH Idiopathic pulmonary arterial hypertension LcSSc Limited cutaneous systemic sclerosis LFT Liver function test MCTD Mixed connective tissue disease MMF Mycophenolate mofetil NSIP Nonspecific interstitial pneumonia NT-proBNP N-Terminal pro-B-type natriuretic peptide NVC Nailfold video capillaroscopy OL Open label PAH Pulmonary arterial hypertension PDE5i Phosphodiesterase type 5 inhibitor PFT Pulmonary function test PPI Proton pump inhibitor PVOD Pulmonary veno-occlusive disease PVR Pulmonary vascular resistance PVRi Pulmonary vascular resistance index qCT Quantitative computed tomography RA LS Right atrial longitudinal strain DOI: 10.1201/9781003361374-14187

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RAP RCT RP SARD SCL-70 SGC SLS SSc SVI TAPSE TGF-β TLC U1 snRNP UIP WHO FC WU

Right atrial pressure Randomized controlled trial Raynaud phenomenon Systemic autoimmune rheumatic disease Scleroderma-70 (topoisomerase) Soluble guanylate cyclase Scleroderma Lung Study Systemic sclerosis Stroke volume index Tricuspid annular plane systolic excursion Transforming growth factor-beta Total lung capacity U1 small nuclear ribonuclear particle Usual interstitial pneumonia World Health Organization functional class Wood units

12.1 INTRODUCTION Systemic sclerosis (SSc, scleroderma) is a rare systemic autoimmune rheumatic disease (SARD) characterized by autoimmunity, widespread endothelial cell injury, and fibrosis affecting the skin and internal organs. A rich vascular supply, abundant connective tissue, and contact with the external environment make the lung a frequent target in SSc. The importance of pulmonary disease in SSc was recognized as early as 1892, when Sir William Osler noted, in the first edition of The Principles and Practice of Medicine, that patients with scleroderma are “apt to succumb to pulmonary complaints or to nephritis” (1). Nearly 100 years later, angiotensin-converting enzyme (ACE) inhibitors were introduced and found successful for the management of scleroderma renal crisis; subsequently, pulmonary disease became the leading cause of death in patients with SSc, a trend that continues today. Mixed connective tissue disease (MCTD) is another rare systemic autoimmune rheumatic disease with overlapping clinical features of scleroderma, myositis, rash, arthritis, and serositis characterized by high levels of antibodies to the U1 small nuclear ribonucleoprotein particle (U1 snRNP). As in SSc, interstitial lung disease (ILD) and pulmonary hypertension (especially pulmonary arterial hypertension, PAH) frequently affect patients with MCTD. The high burden of morbidity and mortality together with the systemic disease expression of SSc and MCTD demand a multidisciplinary approach whereby the pulmonologist and rheumatologist collaborate, often seeking additional expert opinions from the thoracic radiologist, cardiologist, gastroenterologist, and others. Although all parts of the respiratory system (airways, parenchyma, pleura, chest wall, and vasculature) can be involved in patients with SSc or MCTD, this chapter will focus on the epidemiology, pathobiology, clinical presentation, evaluation, and management of interstitial lung disease and pulmonary arterial hypertension. 12.2 SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD) 12.2.1  Epidemiology of SSc-ILD The prevalence of SSc-ILD is quite high; however, the severity of disease is variable. Upwards of 80% of patients with SSc will have some interstitial abnormalities detected on high-resolution computed tomography (HRCT) of the chest (2). The percentage is even higher at autopsy, where 90% of cases show evidence of ILD (3). However, only 30–40% will develop clinically significant ILD, making it important to recognize those patients in this subgroup, given a 10-year mortality rate as high as 40% (2). Demographic features, clinical manifestations, and serologic markers may help to identify those patients at greatest risk of developing clinically significant SSc-ILD. Patients of African descent have a significantly higher frequency of radiographically evident pulmonary fibrosis when compared with other groups (4). Recently published data from two randomized controlled trials found patients of African descent with SSc-ILD to have similar morbidity and mortality outcomes compared with those of non-African descent (5). Clinical trial data, however, may not reflect real-world observations, and further investigation of this important demographic feature is warranted. Males have a greater prevalence and severity of SSc-ILD (2, 6). In a retrospective cohort study, Hussein and colleagues found that 41% of men with SSc had ILD compared to only 33% of women (7). Diffuse cutaneous SSc, defined as skin involvement proximal to the elbows and knees and often with 188

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truncal involvement, is another well-recognized risk factor for SSc-ILD (6). Several studies have shown that extent and degree of skin involvement, as determined by the modified Rodnan skin score, is significantly and independently associated with percent predicted forced vital capacity (FVC%) as well as with radiographically evident pulmonary fibrosis (4). Autoantibody status can also help identify those at the highest risk of developing clinically significant ILD. Several studies have demonstrated the presence of anti-topoisomerase antibodies (anti-Scl-70) may predict the development of SSc-ILD within the first 3 years of disease, whereas the presence of anticentromere antibodies (ACAs) is much less often associated with SSc-ILD (4, 6). 12.2.2  Pathobiology of SSc-ILD While the pathogenesis of SSc-ILD is not entirely understood, lung fibrosis in SSc is thought to be a multifaceted process resulting from the interaction of fibrosis, autoimmunity, and inflammation with vascular injury. It has been proposed that the inciting event is injury to the alveolar epithelium and/or endothelium (2). This leads to the activation of the immune system, resulting in fibroblast recruitment and activation as well as extracellular matrix overproduction, all of which ultimately culminates in the replacement of the normal lung parenchyma by fibrotic lung tissue (2, 8). Recurrent alveolar epithelial cell injury is believed to be central to the pathogenesis of SSc-ILD, leading to the recruitment, activation, and differentiation of fibroblasts to a myofibroblast phenotype that plays a major role in the process of fibrosis (2, 8). SSc-ILD fibroblasts are resistant to apoptosis in vitro, which may lead to the self-perpetuation of lung fibrosis (8). Anti-fibroblast antibodies, present in the serum of some patients with SSc, may promote fibroblast activation, adhesion, and the release of fibrogenic cytokines such as interleukin-6 (IL-6) (2). B-cells may also play a role by the production of autoantibodies as well as by producing transforming growth factor-β (TGF-β) and other profibrotic cytokines, e.g., IL-4, IL-6, and IL-13 (2). IL-6, produced by both fibroblasts and B-cells, is elevated in the serum of patients with SSc, particularly those with SSc-ILD, and may promote collagen synthesis by fibroblasts (9, 10). TGF-β, released by injured lung cells, promotes the survival of fibroblasts and the deposition of extracellular matrix while also attracting macrophages to the site of injury that then release more TGF-β in a positive feedback loop (2, 8). Immune- and inflammation-mediated injury to lung tissue also leads to the release of thrombin, a serine protease with notable profibrotic properties (8). 12.2.3  Evaluation of SSc-ILD Given the considerable morbidity and mortality associated with SSc-ILD, early detection is paramount. ILD may be the presenting feature of patients with SSc, MCTD, or other SARDs, so the pulmonologist must search for evidence of an underlying SARD and consult with the rheumatologist whenever such is suspected (11). The most common presenting symptom of patients with SSc-ILD is dyspnea on exertion, with other frequent nonspecific symptoms being a nonproductive cough and fatigue (12). Breathlessness may result from a multitude of potential SSc disease manifestations (Table 12.1), necessitating a multidisciplinary approach to diagnosis. Upon initial presentation to the rheumatologist, some patients may not complain of respiratory symptoms owing to a decreased activity level as a result of the extrapulmonary manifestations

Table 12.1: Dyspnea: A Multidisciplinary Approach to Diagnosis and Management • Interstitial lung disease (SSc-ILD) • Pulmonary arterial hypertension (SSc-PAH) • Heart failure (diastolic dysfunction) • Gastroesophageal reflux • Obstructive airways disease (pulmonary emphysema) • Nonparenchymal causes of restriction (taut skin and/or muscle weakness) • Serositis (pleural and/or pericardial) • Pleuroparenchymal fibroelastosis • Chronic thromboembolic disease • Pneumothorax • Combination of one or more of the prior

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of the disease, e.g., muscle, joint, and tendon inflammation; generalized pain; and fatigue (2). Conversely, upon presentation to the pulmonologist, some patients may not have overt findings of SSc or MCTD, and the clinician should look for more subtle features, e.g., Raynaud phenomenon, telangiectasias, digital pitted scars, puffy fingers, and proximal muscle weakness. Rarely, in patients with SARD-ILD, the physical examination of the lungs may be normal, especially in the early stages of ILD, so the clinician must be vigilant, screening all patients with SSc or MCTD for ILD at presentation and continuing to monitor frequently throughout the course of disease (12). Whenever a SARD such as SSc or MCTD is suspected, consultation between the pulmonologist and rheumatologist is strongly recommended. Pulmonary function tests (PFTs) play a pivotal role in screening for lung involvement (13). Because changes in pulmonary function can occur prior to onset of symptoms, all newly diagnosed patients with SSc or MCTD should have baseline PFTs. These should include spirometry and single breath diffusion capacity for carbon monoxide (DLCO). Patients with SSc-ILD demonstrate a restrictive PFT pattern with a decrease in both forced vital capacity (FVC) and forced expiratory volume (FEV1). The FEV1/FVC ratio is typically preserved or increased. DLCO is reduced due to the thickening of the interstitium by parenchymal lung inflammation and fibrosis and may be the first PFT abnormality in patients with ILD (14). Pulmonary vasculopathy may also lead to an additional reduction in DLCO. When the DLCO is reduced in the setting of normal spirometry, one must be concerned about possible pulmonary arterial hypertension (PAH) (vide infra). While a majority of patients with SSc will have some evidence of ILD, only about one-third are likely to develop clinically significant ILD (2). Therefore, it is important to monitor patients over time with serial PFTs. In patients with risk factors for severe ILD (e.g., male, African descent, presence of anti-Scl-70 antibody) (Table 12.2), we recommend follow-up testing every 3–6 months for the first 3–5 years following onset, since this is the time frame when lung function is most likely to be impacted. After this, spirometry and DLCO should be monitored at least annually with the consideration of more frequent testing in those having established ILD or worsening symptoms. While PFTs are certainly a crucial screening tool, they should not be relied on as the sole diagnostic test. In a study by the Canadian Scleroderma Research Group, combining physical examination and spirometry had low sensitivity, and as many as two-thirds of SSc-ILD cases would have been missed (15). These findings highlight the importance of imaging, namely HRCT chest, as a vital tool in the diagnosis of SSc-ILD. The advantages of HRCT include both earlier detection as well as more accurate quantification of disease extent when compared to chest radiography (14). The most common pattern seen in SSc-ILD is that of a nonspecific interstitial pneumonia (NSIP), accounting for more than 80% of cases and characterized by basilar predominant peripheral ground-glass opacities, often with subpleural sparing (Figure 12.1A). The next most common pattern is that of fibrotic NSIP, characterized additionally by reticulation and traction bronchiectasis, followed less often by a pattern of usual interstitial pneumonia (UIP) with its characteristic honeycombing (Figure 12.1B). Quantitative CT scanning (qCT) is under active investigation as an automated, reproducible, and quantifiable method to assess the nature and extent of lung disease and may prove to be a useful endpoint for clinical trials. Given the important role HRCT chest plays in identifying SSc-ILD, especially in those with early disease, scans should be obtained at baseline and repeated when/if new symptoms arise or if there is a significant decline in pulmonary function. Bronchoalveolar lavage is generally not recommended but can be useful if there is suspicion for an infectious process. Although histopathology is not often required for the diagnosis of SSc-ILD, if lung tissue is obtained, we recommend an interdisciplinary approach that includes a thoracic pathologist and radiologist together with the pulmonologist and rheumatologist.

Table 12.2: Risk Factors for Progressive SSc-ILD • Male sex • African descent • Presence of antibodies to topoisomerase I (Scl-70) • Older age • Extent of lung involvement on initial HRCT chest imaging • Reduced FVC and DLCO

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Figure 12.1  (A) Cellular NSIP pattern on HRCT chest scan of a 67-year old female with a 1-year history of SSc-ILD (anti-Scl-70+). (B) Fibrotic NSIP pattern on HRCT scan of a 62-year old female with a 5-year history of MCTD complicated by ILD. (Compliments of Dr. Pal Suranyi, Department of Radiology, Medical University of South Carolina.)

12.2.4  Management of SSc-ILD In recent years, considerable advances have been made in the treatment of SSc-ILD. Targeted biologic and antifibrotic therapies now supplement conventional immunosuppressive agents. Truly for the first time, patients and physicians have therapeutic options from which to choose. Due in part to the complexity and variability of the disease, the optimal therapeutic approach remains to be determined (16). Given a lack of comparative data among the current therapeutic options, management continues to rely heavily on expert opinion. Therefore, now more than ever, an interdisciplinary approach involving the rheumatologist and the pulmonologist is advisable to address important questions, e.g., which patient may require treatment and with which agent or agents. The first step is to determine if a patient requires treatment. While the prevalence of SSc-ILD may be as high as 80–90%, only about one-third of patients will develop clinically significant ILD; thus, not all patients will require treatment. Male sex, African descent, diffuse skin involvement, and the presence of antitopoisomerase antibodies (anti-Scl-70) (Table 12.2) are all believed to convey a risk for the progression of ILD (4, 6). Data from initial screening PFTs and HRCT chest imaging are also important determinants. Goh and colleagues devised a staging system whereby patients with extensive radiographic disease, defined as greater than 20% parenchymal involvement on HRCT chest, would require treatment, while those with less than 20% involvement could be managed with close monitoring (17). It can be difficult to quantify parenchymal involvement on conventional HRCT scans, and in those cases where extent of fibrosis on imaging is indeterminant, PFTs can be useful to determine which patient may benefit from treatment, e.g., recommended for those with an FVC below 70% predicted but not necessarily in all patients with an FVC greater than 70% predicted (17). Others have made the case for treating patients having subclinical ILD when risk factors for the progression of ILD are present (Table 12.2) (16). As more treatment options with better safety profiles become available, one might predict that even milder cases of SSc-ILD could be considered for treatment. Once it has been determined that a patient warrants treatment, the next step is to decide on a therapy. Scleroderma Lung Study 1 (SLS-1) was the first randomized controlled trial to demonstrate the efficacy of 1 year of daily oral cyclophosphamide treatment in improving lung function in patients with SSc-ILD (18). The improvement in lung function was not sustained after the completion of 1 year of treatment, however, and concerns for toxicity with the long-term use of cyclophosphamide then led to the design and conduct of SLS-2, comparing 12 months of daily oral 191

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cyclophosphamide followed by placebo to 24 months of mycophenolate mofetil (MMF) treatment (19). While neither medication showed superiority, safety and tolerance data favored MMF; hence, MMF is now a mainstay of treatment for SSc-ILD. Subsequently, the antifibrotic agent, nintedanib, and the biologic inhibitor of IL-6, tocilizumab, have joined the ranks of treatment options for SScILD, gaining US Food and Drug Administration (FDA) approval in 2019 and 2021, respectively. Nintedanib, a tyrosine kinase inhibitor, first gained FDA approval for the treatment of idiopathic pulmonary fibrosis (IPF). Nintedanib inhibits fibroblast proliferation, myofibroblast differentiation, and collagen release in vitro. The SENSCIS trial was designed to study the efficacy of nintedanib for patients with SSc-ILD (20). Patients in the SENSCIS trial had SSc-ILD (more than 10% involvement on HRCT) and were allowed to continue background therapy with stable doses of MMF or methotrexate. In the group receiving nintedanib, the annual rate of FVC decline was reduced by 44% compared to that in the group receiving placebo. For patients receiving background immunosuppressive therapy (most often MMF), the magnitude of the effect on FVC decline was less than in patients not on background immunosuppressive therapy. There was a numerically greater improvement in FVC decline when combination therapy was compared to nintedanib alone, which was greater than that for MMF alone and greater than for immunosuppressive therapy or nintedanib alone; however, these differences were not statistically significant, and the study was not powered to show differences in these groups. Based on these data, nintedanib became the first FDA-approved treatment for SSc-ILD. Using a different trial design, a later study (SLS-3) was envisioned to compare upfront combination therapy of an immunosuppressive drug (MMF) with an antifibrotic drug (pirfenidone). Challenges with recruitment led to the early termination of the SLS-3 trial, and there was insufficient statistical power to ascertain if upfront combination therapy would be superior to initial immunosuppressive therapy alone (21). With research showing a role for IL-6 in the pathogenesis of SSc-ILD, its inhibition with the biologic agent, tocilizumab, has been the focus of several studies. In the phase 2 faSScinate trial, a significant change in modified Rodnan skin score, the primary endpoint, was not achieved; however, evidence of less decline in FVC was noted in the participants with ILD (22). In the larger phase 3 focuSSced trial, which looked at patients with early and active SSc with elevated acutephase reactants, 8.6% of patients with SSc-ILD assigned to the tocilizumab arm had a 10% worsening in FVC compared to 24.5% of patients in the placebo group (p = 0.0016) (23). Tocilizumab became the first biologic medication to gain FDA approval for the treatment of SSc-ILD. Long-term follow-up is lacking, and we do not know if the improvement noted in short-term clinical trials will be sustained. Given the role of B lymphocytes in the pathogenesis of SSc, B-cell depletion with rituximab has been evaluated in small studies and has been used as rescue therapy in patients with progressive SSc-ILD. While initial observations were encouraging, a prospective study of patients in the European Scleroderma Trials and Research (EUSTAR) database showed no difference in decline in FVC or DLCO in those treated with rituximab (24). In the phase 2b RECITAL trial, rituximab was compared to intravenous cyclophosphamide in patients with various SARDs, including SSc-ILD (n = 37), over a 6-month treatment period (25). At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL [SD 329]) and in the rituximab group (97 mL [SD 234]). In an adjusted mixed-effects model, a difference of –40 mL (95% CI –153 to 74; p = 0.49) was seen at 24 weeks in favor of cyclophosphamide compared with rituximab. Although short-term treatment with rituximab did not show superiority to monthly intravenous cyclophosphamide, there were few adverse effects with rituximab (25), and rituximab should be considered for patients whose lung disease progresses despite conventional immunosuppressive and antifibrotic therapy. The EVER-ILD trial compared the efficacy of one course of rituximab (two infusions, 1000 mg each) with MMF (2 g daily) to one course of placebo and 6 months of MMF (2 g daily) treatment in patients with SARD-ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and NSIP pattern, most of whom had progressive disease with prior immunosuppressive therapies. At 6 months there was a small but statistically significant difference in FVC favoring the rituximab+MMF group (+1.60) when compared to the placebo+MMF group (-2.01) (between group difference, 3.60, [95% CI 0.41 to 6.80] p = 0.027), as well as in progression-free survival (p = 0.03) (26). At 12 months, however, there was no significant difference in FVC %predicted between the rituximab+MMF and the placebo+MMF groups (p = 0.072) (27). Although the positive effect on FVC evolution observed at 6 months was not maintained at 12 months, progression-free survival remained better (27).

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There have been three randomized controlled trials investigating immunoablation followed by autologous stem cell transplantation (ASCT) in patients with SSc—the ASSIST trial, the ASTIS trial, and the SCOT trial (28–30). While none of these trials was specifically focused on ILD, the transplant groups demonstrated stabilized or improved pulmonary function compared to control groups across all three studies. ASCT has emerged as a treatment option for patients with severe SSc and could be considered in selected patients with rapidly progressive SSc-ILD failing to respond to pharmacologic treatments. ASCT carries significant treatment-related morbidity and mortality and should be performed only in carefully screened patients at highly experienced centers. We await the results of studies employing allogeneic mesenchymal stem cells as therapy for SSc. Lung transplantation is another consideration for patients with SSc-ILD who have failed available treatments. Progressive decline in pulmonary function despite treatment with a combination of immunomodulatory and antifibrotic therapies should prompt referral for lung transplantation. In appropriately selected patients, outcomes following lung transplantation for patients with SScILD are similar to those for other fibrotic lung diseases. In addition to traditional immunosuppressive agents, targeted biologic agents, and anti-fibrotic drugs, patients with SSc-ILD should receive adjunctive therapies used for other types of chronic lung disease. These include supplemental oxygen when indicated, appropriate immunizations, and pulmonary rehabilitation. Given the association between gastroesophageal reflux disease (GERD) and SSc-ILD, the proper management of GERD should not be overlooked and should include pharmacologic agents such as proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2-blockers), as well as GERD precautions: elevating the head of the bed by six inches (or using a wedge pillow), eating small meals, avoiding foods that exacerbate GER symptoms, and avoiding recumbency after meals. These seemingly simple measures can have a significant impact by easing symptom burden and improving quality of life. Palliative care may be appropriate for some patients with SSc with end-stage ILD. While the arsenal of drugs to treat SSc-ILD is expanding, it remains in its relative infancy, with the “oldest” medicine having been used to treat this disease for less than 20 years, and with the two newest agents, nintedanib and tocilizumab, only recently gaining FDA approval. Almost all patients with clinically significant ILD should be initiated on treatment. Those with subclinical ILD should be monitored closely and treatment considered if they possess risk factors for progression (Table 12.2). Glucocorticoids should be avoided in patients with SSc-ILD due to the risk of precipitating scleroderma renal crisis. MMF is a reasonable first-line agent for most patients presenting with clinically significant SSc-ILD; however, for patients early in their disease course with elevated inflammatory markers and/or significant groundglass opacities on HRCT chest, then tocilizumab would be an acceptable alternative. Nintedanib is more suited to patients with predominantly fibrotic lung disease; it has been found to have no effect on extrapulmonary manifestations of SSc and is rarely used as a first-line single agent. In patients showing progression of disease on a single agent, consideration should be given to switching therapies, escalating to combination therapy with an immunomodulatory agent plus either an antifibrotic or biologic agent, or referring the patient for ASCT evaluation. With all these factors to consider, the importance of an interdisciplinary approach involving rheumatologists and pulmonologists in the management of patients cannot be overemphasized. The American Thoracic Society (ATS) convened an international guideline committee composed of experts in rheumatology, pulmonology, methodology, and personal experience with SSc-ILD to conduct a systematic review of published evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach and to provide evidence-based clinical practice guidelines for the treatment of patients with SSc-ILD (31). A summary of the treatment recommendations is provided in Figure 12.2. The American College of Rheumatology (ACR) and the American College of Chest Physicians (CHEST) similarly convened a committee to publish guidelines for the screening, monitoring, and treatment of patients with ILD and SARDs, including SSc (32). As is often the case when managing a rare disease, evidence-based treatment guidelines are often limited by studies with small numbers and low-quality data. One logical approach to treatment is shown in Figure 12.3. In the absence of more robust data, we strongly recommend a multidisciplinary discussion and shared decision-making.

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Figure 12.2  Treatment of systemic sclerosis-associated interstitial lung disease: Evidencebased recommendations. (Reprinted with permission of the American Thoracic Society. All rights reserved. Raghu G, Montesis S, Silver RM, et al. Amer J Resp Crit Care Med. 2024;209(2):137–152.)

Figure 12.3  A systematic approach to guide treatment decisions in patients with SSc-ILD. (Modified from Peralas A, et al. (2).)

12.3 SYSTEMIC SCLEROSIS-ASSOCIATED PULMONARY HYPERTENSION (SSc-PH) 12.3.1 Introduction Pulmonary hypertension (PH) is a progressive disease that leads to increased pulmonary vascular resistance, right ventricular failure, and death. It is defined by a mean pulmonary artery pressure (mPAP) greater than or equal to 20 mmHg (33). In SSc and MCTD, PH can be a consequence of pulmonary arteriopathy (group 1), left ventricular dysfunction (group 2), interstitial lung disease (group 3), or, rarely, chronic thromboembolic disease (group 4). These SSc phenotypes can co-exist and are summarized in Table 12.3. Regardless of the cause, the presence of PH in SSc or MCTD is 194

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Table 12.3: Phenotypes in SSc SSc Phenotype

Prevalence

SSc-PAH (I)

~ 5–19% (34, 35)

SSc PVOD (I’)

Up to 60% of patients with SSc-associated PH might have elements of PVOD

SSc-PH LHD (HFpEF and HFrEF) (II)

10–30% of cases (41)

SSc-PH lung disease (ILD and CPFE) (III)

25–50% More common in diffuse SSc (48–50)

SSc and CTEPH (IV)

SSc and multifactorial mechanisms (V)

Comments • True prevalence hard to establish as large registries use different definitions. • Mediastinal adenopathy, interlobular septal thickening, and centrilobular ground glass are radiologic features (36). • Greater hypoxemia and lower DLCO (37, 38). • Due to proliferation and fibrosis of intima in the intrapulmonary veins and venules causing hydrostatic pulmonary edema (39, 40). • Atherosclerosis is amplified by inflammation, leading to increased risk for coronary artery disease, with one study demonstrating myocardial necrosis on autopsy in 50% of patients with SSc (42). • Patients with SSc had greater risk of distinct cardiac disease compared to matched controls (mitral/aortic valve disease, atrial fibrillation, pericarditis) (43). • Reduced LV ejection fraction was found to be 5.4% in EULAR. • Prevalence of myocardial fibrosis is variable, ~40% in some studies on MRI and 12–80% on autopsy reports (44). • Poorer outcomes in patients with HFpEF and PH out of proportion to heart disease (45). • Physical stress-induced perfusion defects predict the occurrence of cardiac disease or death (46). • Cardiac Raynaud phenomenon is an independent factor associated with the development of LV systolic dysfunction and ventricular adverse remodeling (47). • Fibrosis leads to hypoxic pulmonary vasoconstriction and over time causes remodeling of the arterioles in addition to loss of the pulmonary vascular surface area, leading to PH. • Patients with CPFE and CTD may have no smoking history or minimal exposure. • Increased risk associated with antiphospholipid antibodies. • Greater incidence rates of DVT and VTE in a SSc populationbased study with a hazard ratio of 3.73 for pulmonary embolus (51). • Multifactorial mechanisms including myelodysplastic disease, sickle cell, etc. can concurrently occur in CTD.

Abbreviations: LHD: left-sided heart disease; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; PVOD: pulmonary veno-occlusive disease; CPFE: combined pulmonary fibrosis and emphysema; ILD: interstitial lung disease; CTEPH: chronic thromboembolic pulmonary hypertension; DVT: deep venous thrombosis; VTE: venous thromboembolism

a leading cause of morbidity and mortality. In 2022, the hemodynamic definition of precapillary PH (groups 1, 3, 4) was changed to include a pulmonary vascular resistance (PVR) ≥ 2 Wood units with a mPAP ≥ 20 mmHg and pulmonary artery occlusion pressure ≤ 15 mmHg (33) in recognition of the fact that with the progressive loss of microcirculation over time, even “mild PH” is considered significant, especially in those with SSc or MCTD. 12.3.2 Epidemiology The epidemiology of PH in SSc varies depending on the population and the diagnostic criteria used. It is estimated that the incidence of all forms of PH is 1.37/100 patient-years, with a similar incidence found in both pulmonary arterial hypertension (PAH) and PH as a consequence of 195

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Table 12.4: Risk Factors for Developing PAH in SSc Clinical features

Disease-specific risk factors

PFT

Biomarkers

Metabolic profiles

SSc-PAH

Comments

• Longer disease duration (10–15 years) • Diagnosed with SSc at a later age (>60, two-fold increase in PAH) • More severe in those of African ancestry (41, 63) • Limited skin disease • More severe Raynaud phenomenon, digital ischemia, and ulcerations • More telangiectasias • Decreased nailfold capillary density on NVC • Low DLCO< 55–60% predicted (64) in the absence of extensive ILD • Drop in diffusing capacity is the earliest PFT abnormality in PAH (42, 65) • DLCO does not correlate with FVC or degree of dyspnea (44) • FVC% pred/DLCO% pred > 1.6 (66–68) • Exercise-induced hypoxia on 6-minute walk test (38) • NT-proBNP > 395 pg/mL is 95% specific, 56% sensitive in detecting PAH (36) • Elevated ESR and IgG levels (63) • High uric acid • Hyponatremia

May be due to lead time bias where patients present at more advanced age and live longer (50).

18-fold increased risk of PAH with progressive loss of nailfold capillaries (34, 35).

FVC does not always correlate with severity of ILD. FVC/DLCO ratio predicts out-of-proportion decrease in DLCO. DLCO is the most sensitive marker of gas exchange.

Very high probability of SSc-PAH with >3-fold increase in mortality if there is a 10-fold increase in NT-proBNP while on therapy. Uric acid correlates positively with mean PA pressure, disease severity, and prognosis thought to be due to impairment of uric acid transport from occlusive vascular lesions in SSc-PAH (56, 69).

Abbreviations: LcSSc: limited cutaneous systemic sclerosis; DcSSc: diffuse cutaneous systemic sclerosis; NVC: nailfold video capillaroscopy; RP: Raynaud phenomenon; DLCO: diffusion capacity for carbon monoxide; FVC: forced vital capacity; TLC: total lung capacity

left-sided heart disease (52). The prevalence of PH has been reported to be 20–35% in patients with SSc using echocardiographic parameters (53, 55), and the prevalence of SSc-PAH confirmed by right heart catheterization (RHC) is estimated to be between 5% and 19% (34, 56–59). Up to 50% of patients with SSc-ILD have been reported to have PH (48–51, 60), and the presence and severity of PH-ILD may not correlate with the severity of the underlying ILD. Pulmonary veno-occlusive disease (PVOD) is a subtype of PAH that includes the obliteration of the pulmonary venules in addition to pulmonary arterioles. PVOD appears to be under-reported in SSc and is more likely to occur in patients with limited cutaneous SSc. Up to 60% of patients with SSc-PH may have imaging features of PVOD (40, 51, 61). PVOD should be considered in patients with SSc who respond poorly to PAH-specific therapy or who develop severe hypoxemia or rapid deterioration of functional capacity (40, 62). Clinical clues suggesting a high risk for the development of PAH are described in Table 12.4. PAH is more common in patients with limited cutaneous SSc, longstanding disease, and in those who are anticentromere positive (42, 43, 62). Important clinical features include additional vascular manifestations such as severe Raynaud phenomenon with digital ulcers, telangiectasias, and progressive nailfold capillary loss (35). A reduced DLCO, reduction in DLCO out of proportion to FVC (increased FVC%/DLCO% ratio), or declining DLCO (36) also should suggest the presence of PH and is associated with worsening gas exchange and poorer survival (37). Increases in NT-proBNP and/or serum uric acid are thought to be due to the prevalence of intrinsic cardiac abnormalities, vascular occlusions, and the unique response of myocytes demonstrating decreased contractile force and calcium sensitivity (41, 62). 196

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12.3.3 Screening Decades of studies in SSc-PAH demonstrate that even mild elevations on serial Doppler echocardiography examinations (PASP > 30 mmHg) (70) portend a worse prognosis without therapy (59, 70) due to the progressive nature of PAH. This is compounded by distinctive differences in the right ventricle and pulmonary artery coupling that occurs in SSc, which can lead to severe abnormalities in hemodynamics (71–74). In 2011, Humbert and colleagues demonstrated improvement in the long-term survival of patients with SSc using aggressive screening aimed at the early detection of PAH (34, 56). Subsequent interdisciplinary collaboration has led to the creation of a variety of screening protocols, leading to earlier diagnosis in those with the greatest risk of developing PAH (75). These include the ESC/ERS 2015 echocardiographic screening guidelines (76), DETECT (34, 69, 77, 78), ASIG (Australian Scleroderma Interest Group) (34, 77, 78), and DIBOSA (79–81) (Figure 12.4), each demonstrating similar operating characteristics, including NPV (negative predictive value), PPV (positive predictive value), sensitivity, and specificity. The ESC/ERS uses echocardiographic findings to inform the pre-test probability for PH (Figure 12.5) (33). The DETECT (34, 69) algorithm is a two-step algorithm that determines the need for an echocardiogram and, subsequently, RHC. The DETECT study PAH risk calculator is available online (www.detect-pah.com). The ASIG uses a combination of PFTs and NTproBNP, with the advantage of using fewer variables than DETECT (34, 77, 78, 82). The DIBOSA is a noninvasive score that includes three variables obtained during a 6-minute walk (DIstance, BOrg dyspnea index, oxygen SAturation at 6 minutes). It was validated in a cohort of more than 200 patients with SSc, where a score of 3 had a PPV of 86.58%, and a score of 0 had an NPV of 100% (79–81). The 6th World Symposium on Pulmonary Hypertension recommended annual screening for SSc and overlap syndrome patients who have an uncorrected DLCO < 80% predicted using the DETECT algorithm, the 2015 ESC/ERS recommendations for echocardiography, or FVC%/DLCO% ratio > 1.6, as long as there is only mild ILD and a >2-fold upper limit of normal NT-proBNP (34). The 2022 ESC/ERS guidelines further emphasize annual multimodal screening (33). They recommend following the DETECT algorithm in asymptomatic patients with more than 3 years disease duration, FVC ≥ 40%, and DLCO < 60%. Figure 12.5 summarizes the three most commonly used algorithms. Despite the availability of multiple screening algorithms, on average it takes 2 to 4 years from symptom onset for patients to receive the correct diagnosis of SSc-PAH (34).

Figure 12.4  Comparison of screening methods in SSc-PAH. 197

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Figure 12.5  Echocardiographic PH signs according to the ESC/ERS 2015 guidelines.

12.3.4 Diagnosis The multifactorial etiology of PH in SSc and MCTD makes accurate phenotyping challenging, so we emphasize referring patients to a pulmonary hypertension center of excellence for evaluation, including RHC, which remains the gold standard for confirming the diagnosis of PH. Patients should proceed to RHC if they screen “positive” or if they have persistent dyspnea of unclear etiology or as otherwise unexplained by known comorbidities. We emphasize lowering the threshold for performing RHC in patients with SSc or MCTD and recommend including provocative maneuvers such as exercise or fluid challenge (54, 83, 84). An exercise RHC is currently recommended in high-risk patients (Table 12.2) with persistent dyspnea who do not have typical echocardiographic features of early PAH. At least one-third of patients develop clinically relevant PAH within 1–3 years of catheterization when noted to have borderline elevations in mPAP (20–24 mmHg) during exercise testing (63, 85). Exercise RHC and/or fluid challenge are also valuable in unmasking left heart dysfunction. 12.3.5 Pathobiology SSc-PAH involves multiple pathogenetic mechanisms, including progressive vascular cell proliferation, endothelial cell dysfunction of the small and mid-sized vessels, and alterations in intercellular communication within the pulmonary arterial wall (62). Epigenetic mechanisms are thought to decrease the expression of the bone morphogenetic protein receptor type II gene, resulting in increased profibrotic signaling (86, 87). Structural and functional alterations in endothelial cells lead to vasoconstriction, thrombosis, and proliferative changes through the increased production of endothelin 1 (ET-1) and decreased production of nitric oxide (NO) and prostacyclin. ET-1 is a potent vasoconstrictor and promotes smooth muscle cell proliferation and vascular remodeling. The NO pathway plays a crucial role in maintaining vascular homeostasis and regulating pulmonary arterial tone. In patients with SSc-PAH, there is reduced expression and activity of endothelial nitric oxide synthase (eNOS) in the pulmonary vasculature and elevated levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS. Together, these result in the impaired production and bioavailability of NO, which contributes to further vasoconstriction and endothelial dysfunction (88, 89). Prostacyclin (PGI2), produced by the endothelium, is a potent vasodilator and inhibitor of platelet aggregation. Reduced prostacyclin synthase and prostacyclin expression have been observed in the pulmonary vasculature of patients with SSc-PAH, along with an upregulation in thromboxane A2 promoting vasoconstriction and platelet aggregation (90, 91). Abnormalities in the NO, endothelial, and prostacyclin pathways are targets for current FDAapproved therapies. 198

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12.3.6 Management Though landmark trials report poorer outcomes in CTD-PH compared to IPAH, specific eventdriven trials such as SERAPHIN (macitentan), GRIPHON (selexipag), and PATENT (riociguat) showed no difference in time to clinical worsening (79, 92, 93) (Table 12.5). In addition, subgroup analyses demonstrated that with upfront therapy, time to clinical worsening (death, atrial septostomy, lung transplantation, hospitalizations, clinical worsening of PAH) were similar in IPAH vs CTD-PH (94–96). The use of multidimensional risk tools allows for goal-directed therapy to optimize survival in patients with PAH (38, 129, 130). These multidimensional calculators incorporate patient characteristics, biomarkers, exercise capacity, functional class, hemodynamics, and right ventricular function. Owing to the heterogeneity of PH in SSc, clinicians must consider the context in those who remain at intermediate risk and consider more frequent hemodynamic assessment (128). REVEAL risk scores in SSc should be interpreted cautiously, as 1-year mortality risk may be overestimated in those with low 6MWD and high BNP (131). Escalating therapy to achieve a low-risk stratum is associated with better quality of life in addition to improved survival (127, 132). The 2022 ERS/ERS guidelines recommend initiating combination therapy with an endothelin receptor antagonist (ERA) together with a phosphodiesterase-5 inhibitor (PDE5i) in patients with PAH who are in a low or intermediate stratum on presentation and who have no other cardiopulmonary comorbidities (33). For those patients who present in a high-risk stratum, triple combination therapy should include the addition of a parenteral prostanoid. Some large academic centers have shown that >75% of their incident SSc patients are in a high-risk stratum on initial presentation, further emphasizing the need for early identification that could lead to improved outcomes (133). In patients with significant cardiopulmonary comorbidities, a finding not uncommon in SSc, monotherapy with an ERA or PDE5i is recommended with an individualized approach to the escalation of therapy (33). All patients should be reassessed frequently, and treatment should be escalated in an attempt to achieve low-risk status. For those patients who remain at high risk, a referral for lung transplantation should be considered. For patients with PH-ILD, inhaled trepostinil should be considered based on data from the INCREASE study (134). Unlike IPAH, calcium channel blockers are not recommended for PAH in CTD due to long-term efficacy in only 0.6% of patients (98, 135). The tolerance of vasodilator therapies is worse for patients with SSc, who may experience limiting side effects such as diarrhea, anemia, fatigue, body aches, and nausea that may already be features of their systemic disease. Palliative care referrals are thus important for supportive symptom control, and greater success is seen when practitioners and patients can minimize both the burden of therapy and psychosocial impact of the disease (136). The close management of fluid status and patient education are important for adherence and long-term treatment success. Though lacking data, oxygen therapy is recommended to maintain arterial blood oxygen ≥ 60 mmHg or saturation above 90%. Exercise is known to reduce inflammation and have positive effects on circulation and thus may improve aerobic capacity and quality of life (66, 137). Patients with SSc on therapy who received 3 weeks of inpatient exercise achieved significant increases in 6MWD. In the absence of cardiovascular indications such as thromboembolism, valvular heart disease, or atrial fibrillation, anticoagulation is not recommended for patients with SSc-PAH and has been associated with lower estimated survival rates. While the safety and efficacy of immunosuppression has been established for patients with SScILD (vide supra), many posit that there also may be benefit to immunosuppressive therapy for SScPAH patients. There is growing interest in the potential of B-cell depleting therapy (e.g., rituximab) in patients with SSc-PAH, as demonstrated by a proof-of-concept trial showing safety and a trend toward improvement of 6MWD at 24 weeks (138). 12.3.7 Survival In the new treatment era with the use of algorithmic screening such as DETECT and more aggressive upfront combination therapy, the median transplant-free survival for patients with SSc-PAH is reported to be 91%, 74%, and 60% at 1, 3, and 5 years, respectively (133). Unfortunately, outcomes in patients with PH as a consequence of ILD and concomitant cardiac disease, primarily heart failure with preserved ejection fraction (HFpEF), remain poor due to limited therapeutic options (67, 121, 122, 139). 199

Table 12.5: Clinical Trials in CTD-PAH Study Epoprostenol for SSc-PH 2001 (97)

Study Design RCT, OL

Duration (weeks) 12

N

SSc (CTD) %

111 100% SSc

Overall Outcome Increased 6MWD by 46 m, improved hemodynamics, improved dyspnea scores

SSc/CTD Outcome

Treprostinil INH

RCT, DB

12

470 19% (CTD 45: Improved 6MWD and SSc 25, SLE significantly decreased 17, MCTD 3) PVRi vs placebo Improved dyspnea scores

Compared to epoprostenol study in IPAH, there was no survival benefit in CTD (underpowered).

4. Improved NYHA FC and dyspnea scores

Trend toward improvement in RP for epoprostenol group.

12

235 Not given

12

67

Change in 6MWD

(TRIUMPH) NCT00147199 (100) Iloprost INH STEP-1 2006 (101)

1. Mean difference of 21 m favoring the treprostinil group (p = 0.28) 2. PVRi decrease (p = 0.05) 3. Dyspnea

RCT, DB

Comments

Epoprostenol IV starting at 2 ng/kg/minute titrated up to signs and 2. Median difference of 108 m symptoms + conventional therapy vs in epoprostenol group vs conventional therapy conventional therapy 3. Improved mPAP, PVR, RAP, alone CI, and mixed venous saturation

5. Trend toward improvement in Raynaud phenomenon

Treprostinil IV subgroup analysis of CTD patients 2004 (99)

Dose

1. Increase in 6MWD in epoprostenol from 270 m to 316 m (p < 0.001)

Patients had lower 6MWD baseline at 271 m—more moderate to severe SSc-PAH. Severity was defined hemodynamically.

Meta-analysis of the three RCTs of epoprostenol demonstrated an overall decrease in mortality by 70% (98). Treprostinil IV uptitrated Greatest improvement in to mean dose of 8.4 ng/ exercise capacity in treprostinil kg/minute vs group with highest dose conventional therapy + quartile. placebo

4. CI change (p = 0.007) fatigue rating (p = 0.014) 1. Improvement in 6MWD by Inhaled treprostinil + Safe and well tolerated. +21.6 m (p < 0.001) bosentan 125 mg daily or any prescribed dose of 2. No difference in time to clinical worsening between sildenafil, 20 mg TID treatment groups

45% (CTD 30) Iloprost group increase in No distinction between CTD 6MWD and delayed time to and other groups clinical worsening Iloprost increase in 6MWD (30 vs 4 meters, p = 0.051) Improved NYHA status by one class (34% vs. 6%, p = 0.002)

Ventavis/iloprost inhalation (dose, 5 µg) + bosentan background therapy vs placebo + background therapy

Combination therapy was well tolerated.

Delayed time to clinical worsening (p = 0.0219)

Sildenafil (PACES)

16

Improvement in mPAP and PVR (p < 0.001 for both) 267 16% (CTD 45: Increase of 28.8 m (95% CI, No distinction between CTD and other groups SSc-PAH 32) 13.9 to 43.8 meters)

2008 (102)

Greater change in mPAP by –3.8 mmHg Improved CO by 0.9 L/ minute

Tadalafil (PHIRST-1 (103) and PHIRST-2) (104)

RCT, DB

Longer time to clinical worsening 16 weeks, 206 27% (CTD 56) Tadalafil 40 mg resulted in then 52 weeks improved exercise capacity

2. Improved WHO FC seen in 10% of those patients with I/HPAH and 15% with CTD-PAH

2011

BREATHE-1

RCT, DB

16

2002 (105)

213 29% (CTD 47:SSc 16

EARLY 2008 (106) NCT00091715

1. Increase in 6MWD at the end of PHIRST maintained equally in CTD and PAH groups

RCT, DB

24

185 17.8% (CTD 33)

Sildenafil 20 mg TID titrated to 40 mg and 80 mg vs placebo + long-term epoprostenol background therapy

PHIRST-1: PO tadalafil (2.5, 10, 20, or 40 mg) or placebo PHIRST-2: PO tadalafil 40 mg

CTD-PAH patients were older, more likely female, had lower baseline exercise capacity, greater clinical worsening.

CTD-PAH patients had greater 50% of the patients were AEs and worse WHO FC. on background bosentan Patients on 20 mg of tadalafil that switched to 40 mg at PHIRST-2 experienced worsening walk distance. 1. IPAH: Improved walking 62.5 mg of bosentan BID More frequent LFT Improved 6MWD distance from baseline by 46 m for 4 weeks, then either abnormalities. 44 m mean difference 125 mg or 250 mg BID between placebo (21 m) and 2. CTD: Prevented deterioration in 6MWD by 3 for 12 weeks bosentan groups (67 m) (p < m in bosentan vs decline of 0.001) 40 m in placebo Improved Borg dyspnea Improved WHO FC PVR at rest, 6 months Change in 6MWD versus placebo

+19 m increase in 6MWD for CTD not significant but trended toward (p = 0.07)

PO bosentan + PO sildenafil

16% of patients had increased LFTs, mostly during the first 6 months. (Continued)

Table 12.5: (Continued) Study

Study Design

BREATHE-2 2004 (107)

Subgroup analysis of ARIES-E (extension) (108)

Duration (weeks) 16

RCT, DB

N

SSc (CTD) %

33

12 weeks, then OL extension up to 24 weeks

18% (CTD 5: SSc 1 unidentified CTD 124 100% CTD

Overall Outcome Improved hemodynamics defined by improved TPR

Improvement in 6MWD more common in the ambrisentan group

SSc/CTD Outcome

Dose

Trend toward greater TPR improvement in bosentan group (TPR –22.6 ± 6.2 vs –36.3 ± 4.3 in placebo group, p = 0.08) CTD-PAH 6MWD change at week 12 had long-term prognostic significance

PO bosentan vs placebo after 2 days of background epoprostenol ARIES-1: Ambrisentan 5 mg or 10 mg once daily

Long-term follow up at 1.2 and 3 years

ARIES 1 NCT00423748 ARIES 2

ARIES-2: Ambrisentan 2.5 mg or 5 mg once daily

Comments

Long-term ambrisentan therapy improved survival and decreased clinical worsening. No difference in the CTD and IPAH subgroup. Absolute 6MWD of 222 m is associated with improved survival.

NCT00578786

Event-Driven Trials: During this time, there was a shift in from looking at outcomes such as exercise capacity, hemodynamics, and serologies to composite end points and time to clinical worsening. PH clinical trials had longer durations, and patients had more long-term follow-up.

Study

Study Duration N Design (weeks) (total)

% Endpoint

SSc (CTD) %

Macitentan RCT, DB SERAPHIN2013 NCT00660179 (109)

24

742

Primary endpoint- 30% (224-CTD) worsening PH least in the 10 mg dose group (p = 0.001) 46% placebo 38% 3 mg dose 31% 10 mg dose

Riociguat RCT, DB PATENT-1 2013 NCT00810693 (110, 111)

12

443

25% (111-CTD: SSc 66, SLE 18, RA 11, MCTD 10, other 6)

Overall Outcome Those on macitentan experienced decreased time from initiation to first occurrence of composite end point— death, atrial septostomy, lung transplant, initiation of parenteral prostanoid, or worsening of PAH. HR 0.55; CI, 0.39 to 0.76; p < 0.001 in the 10 mg macitentan group

SSc/CTD Outcome

Dose PO macitentan on background therapy (PDE5i or oral/inhaled prostanoid) 3 mg daily vs 10 mg once daily

Comments

Worsening of PH was more common in those not treated with macitentan regardless of background baseline PH therapy. Headaches, nasopharyngitis, and anemia were more common in treatment groups; rate of discontinuation was similar between CTD and other PAH. Increase in mean 6MWD Increase mean 6MWD PO riociguat 2.5 mg total Improvements in walk by 30 m in the 2.5 mg by 18 ± 51 m in the 2.5 or max dose 1.5 mg three distance and FC were maximum dose group mg maximum dose times daily vs placebo maintained at 2 years in (p < 0.001) group for CTD the PATENT-2 OL extension. In CTD: Reduced the risk of PAH-related hospitalization by 50% vs placebo (HR 0.50; 97.5% CI, 0.34–0.75; p < 0.0001) and was similar to PAH from other causes Tolerability of drug consistent with the overall population

Riociguat OL 52 PATENT-2 extension 2015 NCT00863681 (111, 112)

396

Clinical worsening 24%(94-CTD) in 29% of CTD more frequent in the SSc subgroup

Treprostinil RCT, DB PO (FREEDOM EV) NCT01560624 (113)

12-week titration, then 60 weeks

690

AMBITION RCT, DB 2015 Tadalafil and ambrisentan NCT01178073 (94)

24

500

26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; p = 0.028) Oral treprostinil participants increased 6MWD 16 m Decrease NT-proBNP > dual oral group 67% dual oral therapy 50% monotherapy

PVR decreased by 223 dynes/second/cm–5 (p < 0.001) Dec NT pro BNP Dec WHO FC FC Safety and tolerability of Increased 6MWD by riociguat 51 m

25.8% (178-CTD) Time to clinical worsening was worse in placebo, lower risk profile achieved in treprostinil patients, more adverse events in the PO treprostinil group. NT-proBNP, multifaceted noninvasive risk assessment were better in the treprostinil group. 37.4% Decreased time to the (187 CTD: 118 first clinical failure event SSc, 17 SLE, 23 (PO monotherapy vs MCTD) dual therapy [combined or sequential]) HR vs the pooled monotherapy 0.50 (95% CI 0.35–0.72; p < 0.001) Greater improvement in 6MWD 48 m (p < 0.001) Greater dec in NT-proBNP mean change of 67% (p < 0.001)

No change in quality of life score.

PO riociguat 2.5 mg TID

Safety and tolerability established. 2-year survival rate of CTD was comparable to the IPAH population. 53% of CTD patients were on ERA therapy.

PO treprostinil vs placebo on top of baseline PH therapy Daily up-titration in 0.125 mg increments for the first 4 weeks and 0.25 mg daily titration thereafter to a maximum dose of 12 mg three times daily

Lower proportion of SSc-PAH with ≥15% decrease in 6MWD with dual therapy (114)

Monotherapy: Tadalafil 40 mg or ambrisentan 10 mg Dual therapy: Combination of tadalafil 40 mg and ambrisentan 10mg (114)

SSc-PAH patients on combination therapy had 56% lower risk of events than pooled monotherapy (HR, 0.43; 95% CI, 0.24–0.77) and was greater than IPAH/ HPAH at 49%. Adverse events occurred in 25% of CTD-PAH with combination therapy but was similar compared to IPAH/HPAH (114). (Continued)

Table 12.5: (Continued) Study

Study Duration N Design (weeks) (total)

Overall Outcome

SSc/CTD Outcome

Dose

Selexipag RCT, DB (GRIPHON) NCT01106014 (115)

>60 weeks 1156

41% reduced risk of 29% worsening PAH in (334 CTD: 170 the CTD-PAH SSc, 82 SLE, 82 Other)

Time to first clinical event—death or a complication related to PAH including 1. Disease progression or worsening of PAH that resulted in hospitalization 2. Initiation of parenteral prostanoid therapy or long-term oxygen therapy 3. The need for lung transplantation 4. Balloon atrial septostomy

Selexipag reduced the risk of composite morbidity/mortality events in patients with PAH-CTD by 41% (HR 0.59; 95% CI 0.41–0.85).

PO selexipag at 200 µg twice daily titrated up to the highest tolerated dose to 1600 µg

Inhaled RCT, DB Treprostinil (INCREASE) NCT02630316 (116)

16

Change in baseline 72% (22-CTD) 6MWD Mean difference between treprostinil group and placebo was 31.12 m (95% CI, 16.85 to 45.39; p < 0.001)

15% reduction in No mention of NT-proBNP levels from CTD-specific baseline outcomes Greater clinical worsening in the placebo group 33% vs inhaled treprostinil group 22% (p = 0.04)

326

% Endpoint

SSc (CTD) %

Comments

CTD subgroup was older with a greater proportion of females and shorter time since diagnosis compared to rest of GRIPHON. Trial with largest CTD subgroup. Treatment was well tolerated despite background therapy. No difference in all-cause death between treatment groups. Results were similar for CTD and non-CTD PAH groups. Inhaled treprostinil Group 3 PH population. through ultrasonic, Post-hoc analysis in the pulsed-delivery higher treprostinil group nebulizer in up to 12 revealed clinical benefit breaths (total, 72 μg) four at doses of >9 breaths in times daily those with PVR > 5 WU (117).

Abbreviations: CTD: connective tissue disease; SSc: systemic sclerosis; PVR: pulmonary vascular resistance; PVRi: pulmonary vascular resistance index; 6MWD: 6-minute walk distance; LFT: liver function tests; PDE5i: phosphodiesterase type 5 inhibitor; ERA: endothelin receptor antagonists; SGC: soluble guanylate cyclase stimulator; RCT: randomized controlled trial; OL: open label; DB: double blind; FC: functional class; HR: hazard ratio; CI: confidence interval; RP: Raynaud phenomenon; IPAH: idiopathic pulmonary arterial hypertension; HPAH: hereditary pulmonary arterial hypertension; WU: Wood units; AE: adverse event

12 Pulmonary Manifestations of SSc and MCTD

Table 12.6: Predictors of Poor Outcomes in SSc/MCTD-PAH Clinical factors (50, 118)

PFT

• Male sex (119) • Shorter time from SSc diagnosis to PAH • Diffuse cutaneous systemic sclerosis • ILD • Renal crisis (103) • Age at onset > 55–60 • Renal dysfunction • WHO FC IV symptoms • DLCO < 32–39 % (45) • Significant reduction in walk test (121) • Heart rate recovery of 2 years) course and more frequently require systemic therapy (117). Referral to dermatology is important to exclude other causes of skin granulomatous diseases, such as infections or granuloma annulare (114). 14.4.5.4 Treatment For sarcoidosis-specific lesions, topical glucocorticoids can be used in more localized disease. Intralesional glucocorticoids can also be used in refractory cases (114). Hydroxychloroquine and methotrexate have each been shown to be effective in small case series studies (118, 119), and a small randomized controlled trial demonstrated efficacy of adalimumab (120). In lupus pernio, TNFα inhibitors should be considered early due to their higher efficacy compared to other agents (121). More recently, tofacitinib (a Janus kinase inhibitor) was shown to help a patient with cutaneous sarcoidosis (indurated papules and plaques, annular lesions, and alopecia) refractory to multiple medications, including adalimumab (47). Since then, it has become a potential fourth-line agent for patients with sarcoidosis. Erythema nodosum is generally self-limited, with a median time to resolution of approximately 2 months, although treatment with a short course of systemic glucocorticoids or nonsteroidal antiinflammation medications can help accelerate the recovery (113). 14.4.6  Other Organ Manifestations 14.4.6.1 Epidemiology Virtually any organ can be affected in patients with sarcoidosis. We will limit further discussion to include hepatic sarcoidosis, affecting approximately 10% of patients; renal sarcoidosis; and hypercalcemia, the latter two each affecting about 5% of patients with sarcoidosis (88, 122). We will also briefly discuss sarcoidosis of the upper respiratory tract (SURT), which may involve the nose, sinuses, larynx, oral cavity, or ear and can affect up to 5% of sarcoidosis patients. 14.4.6.2 Evaluation Recommended baseline and follow-up tests in sarcoidosis are shown in Table 14.3. A recent guideline on the diagnosis of sarcoidosis made a strong recommendation for obtaining serum calcium to screen for hypercalcemia in patients with sarcoidosis (122). In patients with hypercalcemia, 1,25-(OH)2 vitamin D and parathyroid hormone (PTH) should be measured, as this can demonstrate a non-PTH-dependent process due to granuloma production of 1,25-(OH)2 vitamin D (123). Serum alkaline phosphatase and creatinine measurements are also recommended by these guidelines to screen for liver and kidney involvement, respectively (122). Granulomas in the liver are extremely common but not always clinically significant. Therefore, patients with an elevated alkaline phosphatase do not necessarily need to be treated. Referral to hepatology is needed to decide which patients have clinically significant disease (e.g. portal hypertension, cirrhosis) that require treatment. Liver or kidney biopsy could be obtained to confirm granulomatous inflammation, especially if a tissue diagnosis is still needed to confirm a diagnosis of sarcoidosis or if organ function is not improving with immunosuppression. In the kidney, granulomatous interstitial nephritis is the most common histopathological pattern, followed by interstitial nephritis without granulomas (124). As always, it is important to exclude other causes of granulomatous inflammation, such as primary biliary cholangitis or drug-induced liver injury in patients with suspected hepatic sarcoidosis (125). 245

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Table 14.3: Baseline Tests Recommended in Sarcoidosis Baseline tests Pulmonary function tests (spirometry and DLCO) Chest X-ray High-resolution CT scan of the chest ECG Ophthalmology evaluation Complete blood cell count Serum calcium Serum creatinine Serum alkaline phosphatase 25 OH-vitamin D 1,25 (OH)2-vitamin D Abbreviations: DLCO: diffusion lung capacity of carbon monoxide; CT: computed tomography; ECG: electrocardiogram Source: (122)

SURT should be suspected in patients with sarcoidosis and chronic upper airway symptoms such as nasal congestion, epistaxis, and hoarseness. In these patients, referral to an otolaryngologist is important to look for the classic appearance of submucosal nodules or laryngeal involvement. A biopsy is frequently necessary to confirm the diagnosis. 14.4.6.3 Treatment In patients with hypercalcemia, the discontinuation of calcium and vitamin D supplementation can resolve the hypercalcemia and is therefore recommended. Even in patients without hypercalcemia, vitamin D supplementation must be used with caution since it can exacerbate sarcoidosis. If immunosuppression is needed, glucocorticoids should be the first-line agent, with hydroxychloroquine being commonly used as a steroid-sparing agent. In refractory cases, other immunosuppressive agents, including TNFα inhibitors, could be used (123). Case reports have shown the efficacy of bisphosphonates and ketoconazole (126, 127). In renal sarcoidosis, improvement in renal function within the first month of immunosuppression is a good predictor of long-term response (124). In hepatic sarcoidosis, oral budesonide is a good alternative to prednisone due to its high levels achieved in the liver with few systemic side effects (128). In patients with SURT, despite some patients responding well to intranasal corticosteroids (in sinonasal involvement) or local intralesional corticosteroid (in laryngeal involvement), most patients require systemic therapy. Those patients usually require a high dose of oral glucocorticoids to control the disease; therefore, one should consider alternative immunosuppressive agents early. 14.4.7  Other Important Symptoms 14.4.7.1 Epidemiology Some symptoms in patients with sarcoidosis are not directly related to a specific organ involvement but can still significantly affect a patient’s quality of life. A multicenter European study demonstrated that patients with sarcoidosis commonly suffer from fatigue (90%), pain (67%), concentration difficulties (54%), or memory problems (41%) (129). 14.4.7.2 Evaluation Patients experiencing these symptoms, such as pain, should be evaluated for organ-specific manifestations such as SFN. In patients with suspected SFN, skin biopsy to quantify the number of small fibers and/or quantitative sudomotor axon reflex test (QSART) can confirm the diagnosis (130). In patients with fatigue, alternative causes should be evaluated, such as depression, anemia, hypothyroidism, and obstructive sleep apnea. Obstructive sleep apnea is common in patients with sarcoidosis, and fatigue can improve with continuous positive airway pressure therapy (131). If no alternative cause is identified, the patient most likely has sarcoidosis-associated fatigue (SAF). 246

14 Sarcoidosis

14.4.7.3 Treatment In patients with SAF, a few small randomized controlled trials have shown the efficacy of stimulants such as armodafinil or dexmethylphenidate (132, 133). However, non-pharmacological approaches such as anti-inflammatory diets, exercise programs, and mindfulness training have been recently explored in small studies and could be helpful in patients with SAF (134–136). 14.5 FUTURE DIRECTIONS The future of sarcoidosis clinical care lies in the discovery of therapeutics with greater efficacy and fewer side effects than currently available options. Neuropilin 2 is an exciting new pathway that has been explored in a recent phase 2 randomized controlled trial. Efzofitimod, a new immunomodulator that binds to neuropilin 2, was associated with improved outcomes in patients with pulmonary sarcoidosis (137). Nicotine, known to be protective against sarcoidosis based on epidemiologic studies, has also recently been shown to significantly improve forced vital capacity in 50 consecutive patients with pulmonary sarcoidosis in a randomized controlled pilot trial (138). 14.6 CONCLUSIONS Sarcoidosis is a multisystem disease that can cause significant morbidity in patients, therefore affecting their quality of life. Severe manifestations, such as fibrotic pulmonary sarcoidosis, pulmonary hypertension, and cardiac sarcoidosis, can impact survival. Treatment is available and can benefit many patients, but physicians must be aware of potential significant adverse effects, especially with glucocorticoids. Research exploring granuloma models and new therapeutic pathways can change the future of this condition, hopefully discovering new ways to help patients. REFERENCES 1. Baughman RP. Pulmonary sarcoidosis. Clin Chest Med. 2004;25(3):521–30. 2. Ma Y, Gal A, Koss MN. The pathology of pulmonary sarcoidosis: Update. Semin Diagn Pathol. 2007;24(3):150–61. 3. Ramstein J, Broos CE, Simpson LJ, et al. IFN-γ-producing T-helper 17.1 cells are increased in sarcoidosis and are more prevalent than T-helper type 1 cells. Am J Respir Crit Care Med. 2016;193(11):1281–91. 4. Broos CE, Hendriks RW, Kool M. T-cell immunology in sarcoidosis: Disruption of a delicate balance between helper and regulatory T-cells. Curr Opin Pulm Med. 2016;22(5):476–83. 5. Sakthivel P, Bruder D. Mechanism of granuloma formation in sarcoidosis. Curr Opin Hematol. 2017;24(1):59–65. 6. Sones M, Israel HL, Krain R, et al. Kveim test in sarcoidosis and tuberculosis. J Invest Dermatol. 1955;24(3):353–64. 7. Siltzbach LE. The Kveim test in sarcoidosis. A study of 750 patients. JAMA. 1961;178:476–82. 8. Eberhardt C, Thillai M, Parker R, et al. Proteomic analysis of Kveim reagent identifies targets of cellular immunity in sarcoidosis. PLoS ONE. 2017;12(1):e0170285. 9. Chen ES, Moller DR. Etiologies of Sarcoidosis. Clin Rev Allergy Immunol. 2015;49(1):6–18. 10. Cai H rong, Cao M, Meng F qing, et al. Pulmonary sarcoid-like granulomatosis induced by aluminum dust: Report of a case and literature review. Chin Med J (Engl). 2007;120(17):1556–60. 11. Jordan HT, Stellman SD, Prezant D, et al. Sarcoidosis diagnosed after September 11, 2001, among adults exposed to the World Trade Center disaster. J Occup Environ Med. 2011;53(9):966–74. 12. Werfel U, Schneider J, Rödelsperger K, et al. Sarcoid granulomatosis after zirconium exposure with multiple organ involvement. Eur Respir J. 1998;12(3):750. 13. Celada LJ, Hawkins C, Drake WP. The etiologic role of infectious antigens in sarcoidosis pathogenesis. Clin Chest Med. 2015;36(4):561–8. 14. Fang C, Huang H, Xu Z. Immunological evidence for the role of mycobacteria in sarcoidosis: A meta-analysis. PLoS ONE. 2016;11(8):e0154716. 15. Rotsinger JE, Celada LJ, Polosukhin VV, et al. Molecular analysis of sarcoidosis granulomas reveals antimicrobial targets. Am J Respir Cell Mol Biol. 2016;55(1):128–34. 16. Planck A, Eklund A, Grunewald J, et al. No serological evidence of Rickettsia helvetica infection in Scandinavian sarcoidosis patients. Eur Respir J. 2004;24(5):811–13. 247

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68. Milman N, Graudal N, Loft A, et al. Effect of the TNF-α inhibitor adalimumab in patients with recalcitrant sarcoidosis: A prospective observational study using FDG-PET. Clin Respir J. 2012;6(4):238–47. 69. Taimeh Z, Hertz MI, Shumway S, et al. Lung transplantation for pulmonary sarcoidosis. Twenty-five years of experience in the USA. Thorax. 2016;71(4):378–9. 70. Carré P, Rouquette I, Durand D, et al. Recurrence of sarcoidosis in a human lung allograft. Transplant Proc. 1995;27(2):1686. 71. Kazerooni EA, Jackson C, Cascade PN. Sarcoidosis: Recurrence of primary disease in transplanted lungs. Radiology. 1994;192(2):461–4. 72. Nessrine A, Zahra AF, Taoufik H. Musculoskeletal involvement in sarcoidosis. J Bras Pneumol. 2014;40(September 2013):175–82. 73. Bourdin A, Romagnoli M, Gamez AS, et al. Careful consideration of the bleeding caused by transbronchial lung cryobiopsies. Eur Respir J. 2020;55:1902415. 74. Judson MA, Boan AD, Lackland DT. The clinical course of sarcoidosis: Presentation, diagnosis, and treatment in a large white and black cohort in the United States. Sarcoidosis Vasc Diffuse Lung Dis. Published online 2012:119–27. 75. Morimoto T, Azuma A, Abe S, et al. Epidemiology of sarcoidosis in Japan. Eur Respir J. 2008;31(2):372–9. 76. Ungprasert P, Crowson CS, Matteson EL. Clinical characteristics of sarcoid arthropathy: A population-based study. 2016;68(5):695–9. 77. Grunewald J, Eklund A. Lofgren’s syndrome. Am J Respir Crit Care Med. 1994;8. 78. Jabs DA, Arnett FC. Familial granulomatous synovitis, uveitis, and cranial neuropathies. Am J Med. 1985;78:801–4. 79. Blau EB. Familial granulomatous arthritis, iritis, and rash. J Ped. 1985;107:689–93. 80. Caso F, Galozzi P, Costa L, et al. Autoinflammatory granulomatous diseases: From Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn’s disease. RMD Open. Published online 2015:1–7. 81. Khan NA, Donatelli CV, Tonelli AR, et al. Toxicity risk from glucocorticoids in sarcoidosis patients. Respir Med. 2017;132:9–14. 82. Smedslund G, Kotar AM, Uhlig T. Sarcoidosis with musculoskeletal manifestations: Systematic review of nonpharmacological and pharmacological treatments. Rheumatol Int. 2022;42(12):2109–24. 83. Marmor MF, Kellner U, Lai TYY, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123(6):1386–94. 84. Birnie DH. Cardiac Sarcoidosis.pdf. J Am Coll Cardiol. Published online 2016. 85. Nagai T, Kohsaka S, Okuda S, et al. Incidence and prognostic significance of myocardial late gadolinium enhancement in patients with sarcoidosis without cardiac manifestation. Chest. 2014;146(4):1064–72. 86. Vignaux O, Dhote R, Duboc D, et al. Detection of myocardial involvement in patients with and cine magnetic resonance imaging: Initial results of a prospective study. 2002;26(5):762–7. 87. Kouranos V, Tzelepis GE, Rapti A, et al. Complementary role of CMR to conventional screening in the diagnosis and prognosis of cardiac sarcoidosis. JACC Cardiovasc Imaging. 2017;12:1437–47. 88. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164:1885–9. 89. Ungprasert P, Carmona EM, Utz JP, et al. Epidemiology of sarcoidosis 1946–2013: A population-based study. Mayo Clin Proc. 2016;91(2):183–8. 90. Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J. 2021;58:2004079. 91. Rossman MD, Thompson B, Frederick M, et al. HLA and environmental interactions in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. Published online 2008:125–32. 92. Beijer E, Kraaijvanger R. Simultaneous testing of immunological sensitization to multiple antigens in sarcoidosis reveals an association with inorganic antigens specifically related to a fibrotic phenotype. Clin Exp Immunol. Published online 2020:115–24. 93. Silverman KJ, Hutchins GM, Bulkley BH. Cardiac sarcoid: A clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation. 1978;58:1204–11. 94. Ribeiro Neto ML, Jellis CL, Joyce E, et al. Update in cardiac sarcoidosis. Ann Am Thorac Soc. 2019;16:1341–50. 250

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95. Sadek MM, Yung D, Birnie DH, Beanlands RS, et al. Corticosteroid therapy for cardiac sarcoidosis: A systematic review. Can J Cardiol. 2013;29(9):1034–41. 96. Judson MA, Baughman RP, Costabel U, et al. Efficacy of infliximab in extrapulmonary sarcoidosis: Results from a randomised trial. Eur Respir J. 2008;31(6):1189–96. 97. Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm. 2014;11(7):1305–24. 98. Zajicek JP, Scolding NJ, Foster O, et al. Central nervous system sarcoidosis—diagnosis and management. QJM. 1999;92(2):103–17. 99. Schupp JC, Freitag-wolf S, Bargagli E, et al. Phenotypes of organ involvement in sarcoidosis. Eur Respir J. 2018;51:1–11. 100. Manz HJ. Pathobiology of neurosarcoidosis and clinicopathologic correlation. Can J Neurol Sci. 1983;10:50–5. 101. Stern BJ, Royal W 3rd, Gelfand JM, et al. Definition and consensus diagnostic criteria for neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus Group. JAMA Neurol. 2018;75:1546–53. 102. Dirk H, Felicitas P, Hayrettin R. Soluble CSF interleukin 2 receptor as indicator of neurosarcoidosis. J Neurol. Published online 2010:1855–63. 103. Ungprasert P, Sukpornchairak P, Moss BP, et al. Neurosarcoidosis: An update on diagnosis and therapy. Expert Rev Neurother. 2022;22(8):695–706. 104. Tavee JO, D M, Karwa K, Ahmed, Z, et al. Sarcoidosis-associated small fi ber neuropathy in a large cohort: Clinical aspects and response to IVIG and anti-TNF alpha treatment. Respir Med. 2017;126:135–8. 105. Baughman RP, Lower EE, Ph D, Kaufman AH. Ocular sarcoidosis. Semin Respir Crit Care Med. 2010;1(212):452–62. 106. Evans M, Sharma O, Labree L, et al. Differences in clinical findings between caucasians and African Americans with biopsy-proven sarcoidosis. Ophthalmology. Published online 2007:325–34. 107. Spagnolo P, Sato H, Marshall SE, et al. Association between heat shock protein 70/hom genetic polymorphisms and uveitis in patients with sarcoidosis. Invest Ophthalmol Vis Sci. 2007;48(7):1–7. 108. Mochizuki M, Smith JR, Takase H, Kaburaki T. Revised criteria of international workshop on ocular sarcoidosis (IWOS) for the diagnosis of ocular sarcoidosis . 2019;6:1418–22. 109. Sève P, Jamilloux Y, Tilikete C, et al. Ocular Sarcoidosis. Semin Respir Crit Care Med. 2020;1(212). 110. Baughman RP, Lower EE, Ingledue R, et al. Management of ocular sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. Published online 2012:26–33. 111. Jaffe GJ, Dick AD, Brézin AP, Nguyen QD, Thorne JE, Kestelyn P, Barisani-Asenbauer T, Franco P, Heiligenhaus A, Scales D, Chu DS, Camez A, Kwatra NV, Song AP, Kron M, Tari S, Suhler EB. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016;375:932–43. 112. Seve P, Biard L, Fraison JB, et al. Infliximab versus adalimumab in the treatment of refractory inflammatory uveitis a multicenter study from the French uveitis network. Arthritis Rheumatol. 2016;68(6):1522–30. 113. Ungprasert P, Wetter DA, Crowson CS, et al. Epidemiology of cutaneous sarcoidosis, 1976–2013: A population-based study from Olmsted County, Minnesota. J Eur Acad Dermatol Venereol. 2016:1799–804. 114. Wanat KA, Rosenbach M. Cutaneous Sarcoidosis. Clin Chest Med. 2017;36(4):685–702. 115. Marcoval J, Man J, Gallego I, et al. Foreign bodies in granulomatous cutaneous lesions of patients with systemic sarcoidosis. Arch Dermatol. 2023;137. 116. Judson MA, Costabel U, Drent M, et al. The WASOG sarcoidosis organ assessment instrument: An update of a previous clinical tool. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31(1):19–27. 117. Rubio M, Marcoval J, Man J. Specific cutaneous lesions in patients with systemic sarcoidosis: Relationship to severity and chronicity of disease. Clin Exp Dermatol. Published online 2011:739–44. 118. Jones E, Callen JP. Hydroxychloroquine is effective therapy for control of cutaneous sarcoidal granulomas. J Am Acad Dermatol. 1990;23(3):487–9. 119. Veien N, Brodthagen H. Cutaneous sarcoidosis treated with methotrexate. Br J Dermatol. 1977;97(213). 251

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120. Pariser RJ, Mph JP, Hirano S, et al. A double-blind, randomized, placebo-controlled trial of adalimumab in the treatment of cutaneous sarcoidosis. J Am Dermatol. 2019;68(5):765–73. 121. Stagaki E, Mountford WK, Lacklmul DT. The treatment of lupus pernio. Chest. 2008;135(2):468–76. 122. Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis an official American thoracic society clinical practice guideline. Ann Am Thorac Soc. 2020;201(8). 123. Baughman RP, Janovcik J, Ray M, et al. Calcium and vitamin D metabolism in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2013;(11):113–20. 124. Presentation H, Patients O, Mahe M, et al. Renal sarcoidosis. Medicine. 2009;88(2):98–106. 125. McCluggage W, Sloan J. Hepatic granulomas in Northern Ireland: A thirteen-year review. Histopathology. 1994;25(3):219–28. 126. Gibbs CJ, Peacock M. Hypercalcemia due to sarcoidosis corrects with bisphosphonate treatment. Postgrad Med J. 1986;62:937–8. 127. Conron M, Beyno, C. Ketoconazole for the treatment of refractory hypercalcemic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17:277–80. 128. Modaresi-Esfeh J, Culver D, Plesec T, et al. Clinical presentation and protocol for management of hepatic sarcoidosis. Expert Rev Gastroenterol Hepatol. 2015;9(3):349–58. 129. Voortman M, Hendriks CMR, Bonella MDPEF, et al. The burden of sarcoidosis symptoms from a patient perspective. Lung. 2019;197(2):155–61. 130. Parambil JG, Tavee JO, Zhou L, et al. Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. Respir Med. 2011;105(1):101–5. 131. Mari P, Pasciuto G, Siciliano M, et al. Obstructive sleep apnea in sarcoidosis and impact of cpap treatment on fatigue. Sarcoidosis Vasc Diffuse Lung Dis. 2020;37(March):0–2. 132. Lower EE, Harman S, Baughman RP. Dexmethylphenidate hydrochloride for the treatment of sarcoidosis-associated fatigue. Chest. 2008;133(5):1189–95. 133. Lower EE, Malhotra A, Surdulescu V, et al. Armodafinil for sarcoidosis-associated fatigue: A double-blind, placebo-controlled, crossover trial. J Pain Symptom Manage. 2019;45(2):159–69. 134. Saketkoo LA, Feasibility, utility and symptom impact of modified mindfulness training in sarcoidosis. ERJ Open Res. 2018;4:0–2. 135. Schönenberger KA, Schüpfer A catherine, Gloy VL, et al. Effect of anti-inflammatory diets on pain in rheumatoid arthritis: A systematic review and meta-analysis. Nutrients. 2021;13. 136. Kullberg S, Rivera NV, Eriksson MJ, et al. High-intensity resistance training in newly diagnosed sarcoidosis – An exploratory study of effects on lung function, muscle strength, fatigue, dyspnea, health-related quality of life and lung immune cells. Eur Clin Respir J. 2020;7(1). 137. Culver DA, Aryal S, Barney J, et al. Efzofitimod for the treatment of pulmonary sarcoidosis. Chest. 2023;163(4):881–90. 138. Crouser ED, Smith RM, Culver DA, et al. A pilot randomized trial of transdermal nicotine for pulmonary sarcoidosis. Chest. 2021;160(4):1340–9.

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15  Pulmonary Manifestations of Axial Spondyloarthritis

15  Pulmonary Manifestations of Axial Spondyloarthritis Kiana Vakil-Gilani, Tomas Cordova, Daniel Seifer, and Atul Deodhar List of Abbreviations ACR American College of Rheumatology AERD Aspirin-exacerbated respiratory disease APC Antigen-presenting cell anti-TNF Anti-tumor necrosis factor ASAS An Assessment in SpondyloArthritis International Society AS Ankylosing spondylitis AxSpA Axial spondyloarthritis BAL Bronchoalveolar lavage bDMARD Biologic disease-modifying antirheumatic drug CB Constrictive bronchiolitis CPAP Continuous positive airway pressure COP Cryptogenic organizing pneumonia COPD Chronic obstructive pulmonary disease csDMARD Conventional synthetic disease-modifying antirheumatic drug CXR Chest X-ray DLCO Diffusion capacity of the lung for carbon monoxide DPLD Diffuse parenchymal lung disease EMM Extra-musculoskeletal manifestations EULAR European League Against Rheumatism FRV Functional residual volume FVC Forced vital capacity HRCT High-resolution computed tomography ILD Interstitial lung disease NK cell Natural killer cell nr-axSpA Non-radiographic axial spondyloarthritis NSAID Nonsteroidal anti-inflammatory drug NSIP Nonspecific interstitial pneumonitis NTM Nontuberculous mycobacteria OSA Obstructive sleep apnea PAP Positive airway pressure PFT Pulmonary function test PT Physical therapy PTX Pneumothorax RA Rheumatoid arthritis r-axSpA Radiographic axial spondyloarthritis RML Right middle lobe RV Residual volume SAA Spondylitis Association of America SARD Systemic autoimmune rheumatic disease SI Sacroiliac SPARTAN Spondyloarthritis Research and Treatment Network Th cell T helper cell TLC Total lung capacity UIP Usual interstitial pneumonitis VC Vital capacity 15.1 INTRODUCTION Axial spondyloarthritis (axSpA) is an immune-mediated inflammatory disease predominantly affecting the axial skeleton. Based on the degree of structural damage to the sacroiliac (SI) joints, axSpA is divided into radiographic axSpA (r-axSpA, also called ankylosing spondylitis [AS]) and non-radiographic axial SpA (nr-axSpA). The prevalence of axSpA in the United States is approximately 1%. The most common extra-musculoskeletal manifestations (EMMs) of axSpA include DOI: 10.1201/9781003361374-17253

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uveitis, psoriasis, and inflammatory bowel disease; however, the kidneys (e.g., IgA nephropathy, nephrotic syndrome), heart (e.g., aortic valvular insufficiency, conduction abnormalities), and lungs can be involved as well. In this chapter, we describe the known epidemiology, pathophysiology, presentation, and treatment of pulmonary involvement in axial spondyloarthritis. Almost all known manifestations of axSpA are limited to patients with AS, and very little is known about lung involvement in patients with nr-axSpA. Hence in this chapter, we use axSpA synonymously with AS. AxSpA can be associated with chest wall disease, pulmonary parenchymal abnormalities, obstructive sleep apnea (OSA), and pulmonary hypertension. 15.2 PARENCHYMAL LUNG DISEASE 15.2.1 Epidemiology Restrictive lung impairment, either as a consequence of chest wall disease or pleuroparenchymal disease, is the most common pulmonary manifestation in patients with axSpA. Multiple reports indicate a substantially higher likelihood of restrictive pulmonary impairment in patients with axSpA compared with normal controls, with patients with axSpA being 14 times more likely to be afflicted (1, 2). Historically, axSpA was once thought to predispose patients to chronic pulmonary infection—in particular with Mycobacterium tuberculosis—given the elevated prevalence of apical parenchymal fibrosis on chest X-ray (CXR); however, a series of prospective cohort studies starting in the 1990s consistently showed increased rates of biapical fibrosis on CXR or high-resolution computed tomography (HRCT) chest in patients with AS, even in the absence of chronic infection (3). In actuality, apical fibrosis appears to be a rare direct manifestation of axSpA, with prevalence estimates varying between 1.2% and 6.9%. There appears to be a direct relationship between the duration of overall disease and the presence of parenchymal scarring (4). The estimated prevalence of interstitial lung disease (ILD) in axSpA varies widely (13.8–65%) and depends upon the methodology used for reporting (5). Much of what is known about associations between axSpA and distinct types of diffuse parenchymal lung disease (DPLD) is limited to case reports. Usual interstitial pneumonitis (UIP), nonspecific interstitial pneumonitis (NSIP), and cryptogenic organizing pneumonia (COP) are the most commonly reported patterns of ILD. Other commonly described pulmonary parenchymal findings include emphysema (9.1–45.0%), interstitial septal thickening (24.0–33.0%), and pulmonary nodules (25.0–40.0%) (6–9). Although this wide range of parenchymal abnormalities is reported in the literature, reports from our quaternary referral center’s pulmonology/rheumatology clinic fit within the lower end of reported ranges. This may be related to our location at a quaternary referral center within an urban area of the United States, which makes late-presentation and untreated cases less common. Diffuse cystic lung disease and small airway pathologies (e.g., constrictive bronchiolitis [CB] and progressive bronchiectasis) as sequelae of ILD have also been reported to occur rarely in patients with axSpA (10–14). When rare cystic or fibrotic parenchymal damage is present, patients are at increased risk of pneumothorax (PTX); however, without these rare complications spontaneous PTX has not been shown to occur more frequently in patients with axSpA compared to the general population (15). Unfortunately, it is often difficult to definitively rule out other possible comorbid sources of parenchymal lung damage once damage is noted, which further confuses attempts to understand the incidence and prevalence of specific abnormalities attributable to axSpA. There is limited evidence of a possible increased prevalence of pulmonary hypertension in patients with axSpA. A study of 28 patients with axSpA compared to healthy control subjects showed a significantly higher pulmonary artery systolic pressure (22.8 vs 12.6 mmHg) and a higher peak pulmonary vascular resistance (1.3 vs 0.6 WU) (16). The clinical significance of these differences is unknown given that the PVR is in the normal range. 15.2.2 Pathophysiology Lung biopsy samples from patients with axSpA with parenchymal lung disease are scarce. Available transbronchial biopsies, transcutaneous needle biopsies, and rare surgical lobectomy specimens show increased numbers of chronic inflammatory cells and prominent interstitial fibrosis with collagen deposition and hyaline degeneration. Focal lymphocytic infiltrates were seen in some cases and—in severe cases—cystic cavities were seen within fibrotic areas of the lung (17, 18). Thus far, no evidence of vasculitis on histopathology has been reported (18, 19). Following apical thoracotomy, one gross specimen examination in a patient with axSpA and persistent hemoptysis showed a fibrotic lung with cystic cavities lined by coarse granular tissue. Microscopic examination 254

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demonstrated inflammatory changes in bronchi and bronchioles ranging from simple infiltration by plasma cells and lymphocytes to the destruction of the epithelial lining and wall structures by palisaded epithelioid cells and multinucleated giant cells that were organized into epithelioid granulomas with a central zone (11). This is in contrast to other work reporting no evidence of granulomas (18, 19), strongly suggesting that granuloma formation is incidental in areas of severe parenchymal damage; this matches with reports of many other end-stage pathways of fibrotic lung scarring. Bronchoalveolar lavage (BAL) results are available from a few studies. Two small trials reported scant convincing evidence of a correlation between axSpA-related parenchymal lung damage and BAL abnormalities: normal BAL findings were seen in 87% of patients, and those with abnormalities had confounding comorbidities such as active cigarette smoking (18, 20, 21). In contrast, another study evaluating 34 patients with spondyloarthritis (16 patients with AS, four patients with reactive arthritis, two patients with psoriatic arthritis with axial involvement, and 12 patients with undifferentiated spondyloarthropathy with HLA-B27 positivity) reported that lymphocytic alveolitis with CD8+ cell predominance was found in early disease, while neutrophilic alveolitis was demonstrated in advanced disease (22). In our opinion, BAL has very little general diagnostic utility in axSpA but may be highly valuable in particular situations (e.g., when considering infectious complications or presence of malignancy). Regarding the pathophysiological development of apical fibrosis, there are many hypotheses but few convincing answers. Some groups have theorized that impaired ventilation in the upper lobes due to reduced chest expansion, rigidity of the thoracic spine, and kyphosis might lead to recurrent aspiration, resulting in pneumonitis and finally fibrosis after repeated injury (17, 18, 23). While this is a possibility, experience with patients with other systemic autoimmune rheumatic diseases (SARDs) and parenchymal lung damage such as systemic sclerosis suggest that an apical-only pattern of damage from aspiration events is unlikely. Alterations in apical mechanical stress from thoracic spine rigidity and chronically impaired cough due to changes in respiratory mechanics have also been proposed as theoretical causes of apical fibrosis (4). We find this slightly more compelling given the known relatively poor lymphatic drainage of the upper lobes, making them particularly vulnerable to indolent infection. Similarly, poor ventilation of the right middle lobe (RML) and left-lung analog of the lingula are theorized to contribute to nontuberculous mycobacteria (NTM) colonization of those areas. Overall, the evidence for this remains circumstantial at best. 15.2.3 Evaluation The availability of HRCT chest has allowed for detailed assessment of the lung parenchyma (17). HRCT chest-based assessment shows that parenchymal abnormalities in patients with axSpA may occur early (less than 5 years from onset of AS symptoms) and before the patient becomes symptomatic (4, 17). A prospective evaluation of 55 asymptomatic patients with axSpA found 52.7% to have pleuroparenchymal pulmonary abnormalities on HRCT chest, while only 34.5% were found to have a restrictive impairment on pulmonary function tests (PFTs). Although 43% were current or former tobacco cigarette smokers, the occurrence of HRCT chest abnormalities was not significantly different between smokers and nonsmokers (5, 6, 8, 9). Importantly, only two patients had abnormalities on CXR, highlighting the indispensable role of HRCT chest in the early identification of parenchymal lung disease (19). Although many patients may be asymptomatic, other common presentations include dyspnea, cough, hemoptysis, and stigmata of secondary chronic infection (e.g., fever, chest pain, malaise, anorexia, night sweats) (24). In addition to the parenchymal lung disease discussed earlier, nonspecific pulmonary changes such as ground-glass opacities on imaging, parenchymal micronodules, parenchymal bands, bronchial wall thickening, and blebs are also reported sporadically in patients with axSpA, particularly in early disease (4, 6, 17, 25). Most of these changes have not been categorized as ILD (8). Pleural thickening and pleural calcification may also occur (26). One study also found small airways disease, including mosaic perfusion, centrilobular nodules, and bronchiolectasis, on inspiratory HRCT chest images and air trapping on expiratory HRCT (25). Two small studies found increased coronal and sagittal tracheal diameter in association with proximal bronchiectasis. Rare cases of bronchiolitis obliterans, tracheobronchomegaly, cor pulmonale, pleural effusions, and PTX have also been reported in patients with AS (6, 27). One cross-sectional report of 26 patients found that although the overall majority of parenchymal changes were found in lung bases, actual fibrosis was more common in the apices. The generalizability of this distributional tendency is limited by study size, however, especially given 255

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that apical parenchymal scarring is by far the most well-known pattern of parenchymal damage (27). In this study, UIP was the most common pattern of non-apical lung disease and included subpleural band-like opacities, thickened interlobular septae, parenchymal bands, and stacked cysts referred to as “honeycomb cysts.” Apical lung fibrosis, when present, showed advanced cicatrization, cavitation, architectural distortion, and traction bronchiectasis. Apical parenchymal lung scarring in patients with axSpA has unique features, and some suggest that apical fibrosis and bronchiectasis are the only types of parenchymal involvement to become more prevalent with increased disease duration (5). That said, advances in recent decades make us wary of such a definitive statement given the relatively poor sensitivity of CXR and unclear causative association of axSpA with other parenchymal damage patterns (e.g., UIP, NSIP). Increased access to HRCT chest, with its higher sensitivity and specificity for slight damage when compared with CXR, has changed the diagnosis and tracking of apical fibrosis (4, 6, 17, 28). Apical fibrosis can be unilateral or bilateral and appears as linear or patchy opacities on imaging. With progression, this scarred damage eventually takes on cystic characteristics. While most patients are identified while asymptomatic, there are patients who present late and demonstrate severe presentations such as life-threatening hemoptysis. This is seen in patients whose scarred lungs and cystic parenchymal changes lead to the rupture of pulmonary capillaries or erosion into larger vasculature. This situation requires urgent evaluation at a center capable of intravascular embolization or other aggressive surgical intervention(s) and highlights the importance of screening for parenchymal lung disease early in the disease course (29). Apical fibrosis and bronchiectasis are irreversible. On the contrary, ground glass opacities seen on lung imaging more often reflect an inflammatory state, i.e., alveolitis, that may be reversible with treatment (18). Apical cavities, whether associated with fibrosis or not, may become chronically colonized with bacteria, fungi, or mycobacteria (4, 17, 19, 24). These infectious complications may be fatal through direct action, sepsis, or via secondary damage such as massive hemoptysis (10). In clinical practice, it is important to differentiate apical fibrosis from active secondary bacterial or fungal pulmonary infection, especially when articular or extra-articular disease management with immunomodulatory agents is ongoing or being considered. Spontaneous PTX is rarely reported, and it is worth noting that all cases reported by Momeni and colleagues were found in those patients with axSpA who were smokers and had CXR evidence of apical lung parenchymal fibrosis (4). Additionally, the mean disease duration of axSpA before PTX was 13 years; thus, it is not an early finding and may be associated with comorbid conditions such as tobacco use. 15.3 CHEST WALL DISEASE Ankylosis of the spinal facets, costovertebral, and costochondral joints leads to decreased spinal mobility and chest expansion. Early inflammation in these joints may cause significant pain, though by the time decreased mobility from ankylosis occurs, acute inflammation and pain are typically minimal (29). 15.3.1 Epidemiology As mentioned under the “Pleuroparenchymal Disease” section, restrictive lung impairment, whether from pleuroparenchymal pathology or chest wall disease, is the most common pulmonary manifestation in patients with axSpA. 15.3.2 Pathophysiology Advanced axSpA is associated with a loss of movement in the spine, facet joints, rib cage, and sacroiliac joints as a result of new bone formation (e.g., syndesmophytes causing vertebral bridging) as well as ankylosis of the costovertebral and costosternal joints. Interestingly, inflammation of the insertion sites for tendons and ligaments onto bones (enthesitis) is one of the driving factors behind the pathogenesis of axSpA skeletal damage. This stands in distinction from conditions involving autoantibodies or direct T-cell-mediated autoimmunity, in which the targets themselves are passive victims rather than active stimuli furthering damage. In conjunction with genetic predispositions such as HLA-B27 and gut microbial dysbiosis in susceptible individuals, enthesitis causes a cascade of immune cell activation involving antigen-presenting cells (APCs), CD8+ T cells, and KIR3DL2+ natural killer (NK) cells that results in mesenchymal stem cell proliferation and differentiation to osteoblasts and the upregulated production of inflammatory cytokines (e.g., IL-17, IL-22, IL-23, TNF-α, IFN-γ). Prostaglandin release secondary to trauma at the entheseal structures leads 256

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transcortical blood vessels to dilate, and a neutrophilic inflammatory process ultimately leads to osteoproliferation. Figure 15.1 depicts the pathophysiology of lung involvement in axSpA Vertebral fusion of the thoracic spine causes a reduction in lung expansion and decreased vital capacity via extraparenchymal restrictive impairment (Figures 15.2–15.4). Vital capacity (VC) is decreased in proportion to skeletal disease severity but only up to a certain point. This is because the skeletal surroundings of the lung cause restriction by impairing lung expansion above tidal volume limits (i.e., lowering inspiratory capacity [IC]) rather than by increasing lung compression. In other words, both functional residual volume (FRV) and residual volume (RV) typically remain

Figure 15.1  Pathophysiology of pulmonary involvement in axial spondyloarthritis.

Figure 15.2  Joint fusion in AxSpA causing extraparenchymal restrictive impairment through limitation on inhalation. 257

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Figure 15.3  Case of severe AS at T6–7 with T11 burst fracture.

unaffected or even increase with extraparenchymal restriction in patients with axSpA. A loss of lumbar lordosis and exaggerated thoracic kyphosis from both axSpA and vertebral compression fractures from osteoporosis also contribute to altered chest wall mechanics. Both the diaphragm and the accessory muscles of breathing have difficulty moving the lung against this increased resistance. Oftentimes this results in an unusual breathing pattern, with the diaphragm excursion going even further into the abdomen and resulting in visible abdominal protrusion with inspiration. Chest wall expansion may also be limited by pain (17, 18, 29). This pathophysiology highlights the importance of both early articular and extra-articular disease control to prevent such irreversible changes, as well as focused exercises to maintain chest expansion. Although expiratory muscle performance is not directly impaired, the chest wall rigidity will also resist compression below FRV, which will thus notably impair forced vital capacity (FVC) disproportionately compared to total lung capacity (TLC). When the parenchyma remains unaffected, the gas diffusion capacity of the lung (DLCO) remains largely unaffected (18, 29). 258

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Figure 15.4  Bamboo spine. Acute 3-column fracture of the T11 vertebral body in the setting of ankylosing spondylitis. Age-indeterminate compression fracture deformities of the T12–L2 vertebrae. Chronic compression fracture deformities of the C6, C7, T6, and L5 vertebrae.

Assessing the literature, it seems that restrictive impairment in people with axSpA is significantly more often due to chest wall extraparenchymal restriction than to parenchymal damage. This contributes to the difficulty in evaluating the impact of restrictive impairments on patients with axSpA since the pathologic mechanisms, physiologic adaptations, and prognosis are significantly different between the two possibilities. This may also explain why multiple studies have failed to show a reliable link between restrictive impairment, functional impairment, and disease activity. 15.4 OBSTRUCTIVE LUNG IMPAIRMENT 15.4.1 Epidemiology A mix of cross-sectional and prospective studies has found an increased incidence of obstructive airways disease among patients with axSpA, with an aggregate 1.45-fold increased risk. Multivariate analysis in one population-based cross-sectional study found axSpA to be associated with chronic obstructive pulmonary disease (COPD) independent of smoking status, which is crucial given the indelible causative association of tobacco smoke inhalation and COPD (30, 31). 15.4.2 Pathophysiology Whether or not the pathways of immune upregulation in axSpA predispose patients to develop irreversible obstructive airway impairments is unknown; however, there is limited research that has found an association between axSpA and reversible obstructive lung impairment (e.g., asthma or similar) (32). Over the last decade, our understanding of allergic airway response and its contributions to asthma subtype development has advanced considerably. Immune response in the airways of patients with asthma is primarily driven by CD4+ T helper (Th) cells with distinct phenotypes being recognized as Th2 or non-Th2 predominant; in the latter, Th1 and Th17 cells predominate in airway tissue, though it is worth also knowing that these phenotypes may actually 259

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shift depending on disease stage, treatment, and environmental factors (33). Given the inflammatory state perpetuated by axSpA and existing knowledge that chronic bronchitis is more likely to develop in states of upregulated immune activation, it is reasonable to hypothesize a link between axSpA and obstructive airways disease. Additional work is needed to better define the primary source of obstructive pulmonary impairments in patients with axSpA. 15.4.3 Evaluation Chronic obstructive pulmonary disease is detected by PFTs, with the condition defined as an obstructive impairment that does not reverse with inhaled bronchodilator administration. Clinical manifestations of COPD in those with axSpA are not expected to differ from those of the general population. Early mild COPD may be entirely asymptomatic and only recognized on PFTs, while later disease is frequently associated with dyspnea, cough, increased sputum production, wheezing, bronchospasm, and hypoxemia (30, 31). 15.5 OBSTRUCTIVE SLEEP APNEA 15.5.1 Epidemiology OSA occurs more frequently in patients with axSpA, with an estimated prevalence of 12–22% compared with 2–7% in the general population (17). Similarly, a nationwide cohort study in Taiwan demonstrated a hazard ratio of 2.86 for OSA in patients with axSpA (28). 15.5.2 Pathophysiology The causative link between axSpA and OSA is unclear, but multiple theories exist, including oropharyngeal airway compression by cervical bridging syndesmophytes, central respiratory depression caused by subluxation of the cervical spine leading to slight compression of the respiratory center in the medulla, and anterior thoracic bone cage changes leading to changes in breathing mechanics that lower a patient’s ability to compensate for minor existing unrelated upper airway instability. Interestingly, studies have not found an association between OSA and structural spinal changes in axSpA linked to extraparenchymal restrictive lung impairment. Many suggest that OSA and AS may share common inflammatory pathways— such as intermittent hypoxia in OSA activating NF-kB, which promotes cytokine production. Patients with OSA also have higher serum TNF levels than unaffected individuals, and these levels are reported to decrease after continuous positive airway pressure (CPAP) use. Lastly, patients with OSA have a higher risk of developing autoimmune disease more broadly, suggesting a bidirectional link due to chronically stressed disease states characterized by varying degrees and types of inflammation (17, 19). 15.5.3 Evaluation OSA is characterized by upper airway collapse and repeated episodes of apnea and hypopnea during sleep and diagnosed using polysomnography. OSA has been associated with comorbidities such as hypertension, cardiovascular disease, and fatigue, as well as with increased mortality (17). OSA presentation in a patient with axSpA is not expected to differ from that in the general population; however, if decreased chest mobility is present, extra consideration may need to be given to management with positive airway pressure (PAP) devices. 15.6 MANAGEMENT 15.6.1  Clinical Assessment Physical examination in every patient with axial spondyloarthritis should include pulmonary auscultation, chest expansion measurements, and evaluation of the fingers for clubbing. Ideally, PFTs (spirometry, lung volumes via plethysmography, and DLCO) should be obtained to assess for restrictive lung impairment and obtain a functional baseline from which to track patients longitudinally. That said, given the relatively low overall incidence of pulmonary complications, screening every axSpA patient with baseline PFTs and HRCT chest has a low return on health system investment. PFTs and HRCT are reasonable to consider at baseline in those patients with pulmonary risk factors (e.g., active smokers, existing dyspnea, advanced axSpA at the time of initial contact). If any pulmonary symptoms or higher pre-test likelihood of pulmonary damage become otherwise clinically apparent, PFTs and HRCT chest are indicated, and CXR is not an acceptable substitute. Those with excessive fatigue and daytime sleepiness despite low disease activity should be screened for OSA with polysomnography and treated with noninvasive ventilation if indicated (18). The consideration of 260

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immunomodulatory treatment warrants screening for Mycobacterium tuberculosis and hepatitis B at a minimum due to the risk of reactivation and poor outcomes. If there is suspicion for chronic infection due to fungal or nontuberculous mycobacterial pathogens, we recommend pursuing this as warranted (e.g., serologic testing, sputum culture, HRCT examination, bronchoscopy evaluation) prior to the initiation of immunomodulation. 15.7 TREATMENT Neither the American College of Rheumatology (ACR)/Spondylitis Association of America (SAA)/Spondyloarthritis Research and Treatment Network (SPARTAN) nor the Assessment in SpondyloArthritis International Society (ASAS)/European League Against Rheumatism (EULAR) treatment guidelines in patients with axSpA specifically address treatment in patients with AS and pleuropulmonary abnormalities. At this time, we do not know whether the early and appropriate treatment of AS with the existing modalities discussed herein decreases the risk of developing pleuropulmonary disease (18). Smoking cessation is strongly recommended due to direct evidence linking tobacco smoking with nearly each of the possible pulmonary manifestations in those with axSpA. Smoking is also linked to new bone formation in axSpA; as such, it should be strongly discouraged for a multitude of reasons. At this time, it is uncertain whether the early and appropriate treatment of axSpA with nonsteroidal anti-inflammatory drugs (NSAIDs) and biologic disease-modifying antirheumatic drugs (bDMARDs) decreases the risk of developing pleuropulmonary disease in these patients (18). Similarly, no reports exist thus far regarding OSA risk in axSpA after treatment with bDMARDs. 15.8 PHYSICAL THERAPY AND MOBILITY Physical therapy (PT) is the initial treatment for the musculoskeletal manifestations of axSpA, and a referral to a specialized chest physical therapist can be very helpful in patients with chest wall involvement (34). Yoga has shown promise in those with axSpA as a modality to decrease pain, increase mobility, and preserve lung function (35). Intervention prior to skeletal damage is more likely to prevent the loss of function in contrast with intervention after joint fusion. Large-scale reviews have found mixed evidence regarding additional types of exercise, and at this point, the most that may be said is that a sensible approach to aerobic exercise and resistance training is unlikely to harm patients (36). 15.9 POSITIVE AIRWAY PRESSURE (PAP) THERAPY The treatment of OSA in patients with a moderate or worse apnea–hypopnea index will help improve fatigue, lower daytime sleepiness, and decrease cardiovascular morbidities. 15.10 PNEUMOTHORAX MANAGEMENT Given that evidence suggests PTX in axSpA is most likely secondary to apical parenchymal lung damage, in patients without evidence of parenchymal damage, we believe PTX is unlikely to be a concern. In those patients with parenchymal damage, particularly if progressed to cystic scarring, some discussion with patients is likely warranted regarding increased risk associated with certain activities such as scuba diving, alpine hiking above an 8000-foot elevation, and skydiving. Commercial airline flight cabins are pressurized to approximately 5000 to 6000 feet, so for patients who have not already suffered an initial PTX, we believe this is unlikely to be a significant contributing factor. In step with the suggested management of other predisposing lung conditions, we suggest that prophylactic pleurodesis be considered after the first PTX in patients with axSpA due to a high risk of recurrence (4, 15, 19). 15.11 NONSTEROIDAL ANTI-INFLAMMATORY DRUGS NSAIDs commonly used as the initial pharmacologic treatment of pain in patients with axSpA have neither positive nor deleterious direct effects on lung function. Secondarily controlling pain may provide support for ongoing mobility, which may stave off progressive disability; however, this class of therapy may potentially induce or trigger aspirin-exacerbated respiratory disease (AERD). 15.12 CONVENTIONAL SYNTHETIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) have no role in the management of axial manifestations of axSpA, though these drugs (e.g., sulfasalazine, methotrexate, leflunomide) are useful for the peripheral joint manifestations. The effect of these drugs on lung involvement in axSpA has not been studied, though certain drugs such as methotrexate and 261

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leflunomide have known lung toxicities. Methotrexate-associated lung damage (more standard drug hypersensitivity vs direct alveolar toxicity from the drug) is widely reported, and thus MTX should be used more cautiously in patients with axSpA with existing parenchymal damage. 15.13 BIOLOGIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS The effect of tumor necrosis factor-alpha inhibitors (TNFis) on pulmonary abnormalities in patients with AS has not been carefully studied, and research on the effect of TNFis on patients with rheumatoid arthritis (RA) and ILD is conflicting. We are therefore unable to extrapolate these results for those with AS (19). Theoretically, bDMARD therapy should protect the lungs by decreasing inflammatory cytokines, but drug toxicity affecting the lungs may also occur. Examples of drug-induced damage include but are not limited to granulomatous inflammation targeted at the drug of choice (may be acute, subacute, or chronic; commonly termed “drug hypersensitivity”), lung damage defined by organization on pathology (“organizing pneumonia”), sarcoid-like granulomatous inflammation induced by bDMARDs, and a drug-induced patterndefined parenchymal lung damage (NSIP pattern is the most common initial presentation; may progress to UIP pattern if damage progresses). Most of the data underlying these lists is small and supplemented significantly with data on the use of these treatments in other autoimmune conditions like rheumatoid arthritis (19). That said, anti-TNF agents are associated with a reduction in spinal radiographic progression in patients with axSpA (37, 38). In one study, the odds of radiographic progression were about halved over a 2-year interval after initiation of a TNFi agent (39). This was mediated through TNF inhibition, leading to a decrease in inflammation levels as tracked by serum markers, followed in turn by a decrease in exam-monitored disease activity (39). Similar results have been recently found for secukinumab, a direct-binding inhibitor of IL-17 (40). Based on these results, TNFi drugs and IL17 inhibitor use are expected to help preserve pulmonary function by preventing new bone formation, chest wall fusion, and syndesmophyte formation; however, there are no prospective cohort studies of these agents or their direct effects on the prevention of parenchymal lung damage or apical fibrosis. Another note of caution is that administration of TNFi drugs is associated with an increased risk of reactivation of latent TB; as such, measures to screen for latent TB prior to the initiation of this class of medications are of great importance (19). 15.14 RESEARCH AGENDA There are many gaps in our understanding of axSpA-associated pulmonary disease. Epidemiologic studies are the most numerous in the field, but these are generally small and heterogeneous in design. Much of our pathophysiologic understanding of axSpA-associated pulmonary disease is theoretical, and therefore, effective treatment options in preventing or slowing pulmonary disease are poorly understood. Although the incidence of various pulmonary manifestations of axSpA has been frequently described, there is significant variation in the estimated prevalence of these functional and pulmonary parenchymal abnormalities. Larger studies and standardized classification are needed to better understand the true incidence of axSpA-associated pulmonary disease. Additionally, the clinical importance of these findings, especially over time, remains unclear. Longitudinal studies evaluating CT chest and PFT changes in axSpA-associated pulmonary disease are needed to better distinguish how pulmonary abnormalities change over time and how these changes affect functional status. The breadth and variety of pulmonary involvement are likely the salient features here, with certain manifestations such as parenchymal scarring likely warranting elevated concern and management than more self-limiting features such as nonspecific pulmonary nodules. The pathophysiologic processes that lead to axial disease in those with axSpA are reasonably well described, but this is not true of most pulmonary manifestations. The best understood pulmonary manifestation is extraparenchymal restriction from bony changes, a mechanical result of axSpA. Past that, though, speculation far outweighs evidence. In particular, we believe investigation is warranted into the mechanism of parenchymal scarring in axSpA given the progressive nature and life-limiting potential of this complication. In distinction, to avoid confusing different disease processes, further definitional subdividing and correlational work regarding axSpA-associated obstructive lung impairment is necessary before the pathophysiology of this manifestation can be elucidated. Overall, it seems likely that further investigation into the multisystem effects of systemic inflammatory cytokines (TNF, NF-kB, IFN-g, IL-17, IL-22, IL-23) will yield broad dividends in this area. 262

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The therapeutic efficacy of bDMARDs in the management of axSpA has been demonstrated, but their impact on the pulmonary manifestations of axSpA remains unknown. Much of the research in axSpA-associated pulmonary disease is limited to observational and retrospective data on epidemiologic or pathophysiologic descriptions rather than the effects of treatment. In fact, more is known about the potential adverse effects of therapy that may affect the lungs (e.g., mycobacterial reactivation, opportunistic pathogen infection) than is known about potential benefits. Controlled therapeutic trials are needed to better understand the effect of DMARD use on the development and progression of pulmonary axSpA and, in particular, the increased morbidity and mortality associated with parenchymal damage. REFERENCES 1. Brambila-Tapia AJL, Rocha-Muñoz AD, Gonzalez-Lopez L, Vázquez-Del-Mercado M, SalazarPáramo M, Dávalos-Rodríguez IP, et al. Pulmonary function in ankylosing spondylitis: Association with clinical variables. Rheumatol Int. 2013;33(9):2351–8. 2. Berdal G, Halvorsen S, van der Heijde D, Mowe M, Dagfinrud H. Restrictive pulmonary function is more prevalent in patients with ankylosing spondylitis than in matched population controls and is associated with impaired spinal mobility: A comparative study. Arthritis Res Ther. 2012;14(1):R19. 3. Casserly IP, Fenlon HM, Breatnach E, Sant SM. Lung findings on high-resolution computed tomography in idiopathic ankylosing spondylitis—correlation with clinical findings, pulmonary function testing and plain radiography. Br J Rheumatol. 1997;36(6):677–82. 4. Momeni M, Taylor N, Tehrani M. Cardiopulmonary manifestations of ankylosing spondylitis. Int J Rheumatol. 2011;2011:728471. 5. El Maghraoui A, Chaouir S, Abid A, Bezza A, Tabache F, Achemlal L, et al. Lung findings on thoracic high-resolution computed tomography in patients with ankylosing spondylitis. Correlations with disease duration, clinical findings and pulmonary function testing. Clin Rheumatol. 2004 Apr;23(2):123–8. 6. Şenocak Ö, Manisalı M, Özaksoy D, Sevinç C, Akalın E. Lung parenchyma changes in ankylosing spondylitis: Demonstration with high resolution CT and correlation with disease duration. Eur J Radiol. 2003;45(2):117–22. 7. Kiris A, Ozgocmen S, Kocakoc E, Ardicoglu O, Ogur E. Lung findings on high resolution CT in early ankylosing spondylitis. Eur J Radiol. 2003;47(1):71–6. 8. El Maghraoui A, Dehhaoui M. Prevalence and characteristics of lung involvement on high resolution computed tomography in patients with ankylosing spondylitis: A systematic review. Pulm Med. 2012;2012:965956. 9. Turetschek K, Ebner W, Fleischmann D, Wunderbaldinger P, Erlacher L, Zontsich T, et al. Early pulmonary involvement in ankylosing spondylitis: Assessment with thin-section CT. Clin Radiol. 2000;55(8):632–6. 10. Strobel ES, Fritschka E. Case report and review of the literature. Fatal pulmonary complication in ankylosing spondylitis. Clin Rheumatol. 1997;16(6):617–22. 11. Rohatgi PK, Turrisi BC. Bronchocentric granulomatosis and ankylosing spondylitis. Thorax. 1984;39(4):317–18. 12. Findik S, Erkan L, Gokcay S, Yildiz L, Uzun O, Guven Atici A. Usual interstitial pneumonia as an initial manifestation of ankylosing spondylitis. Respir Med Extra. 2007;3(1):48–51. 13. Daoud A, Rath P, Lim JM, Haque U. Migratory pulmonary infiltrates in a patient with ankylosing spondylitis. Chest [Internet]. 2021. Available from: https://journal.chestnet.org/article/ S0012-3692(21)02567-8/abstract. 14. Marquette D, Diot E, de Muret A, Blechet C, Favelle O, Sonneville A, et al. Chronic bronchiolitis in ankylosing spondylitis. Sarcoidosis Vasc Diffuse Lung Dis. 2013;30(3):231–6. 15. Lee CC, Lee SH, Chang IJ, Lu TC, Yuan A, Chang TA, et al. Spontaneous pneumothorax associated with ankylosing spondylitis. Rheumatology. 2005;44(12):1538–41. 16. Morvai-Illes B, Burcsar SZ, Monoki M, Varga A, Kovacs L, Balog A, et al. Assessment of the right ventricular-pulmonary circulation unit during stress in ankylosing spondylitis and psoriatic arthritis patients. Eur Heart J. 2022;43(Supplement_2):ehac544.088. 17. Mercieca C, van der Horst-Bruinsma IE, Borg AA. Pulmonary, renal and neurological comorbidities in patients with ankylosing spondylitis; implications for clinical practice. Curr Rheumatol Rep. 2014;16(8):434. 18. El Maghraoui A. Extra-articular manifestations of ankylosing spondylitis: Prevalence, characteristics and therapeutic implications. Eur J Intern Med. 2011;22(6):554–60. 263

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16  Pulmonary Manifestations of IgG4-Related Disease Guy Katz, Amita Sharma, Yin P. Hung, and John H. Stone List of Abbreviations ACR American College of Rheumatology ADA Adenosine deaminase ANCA Anti-neutrophil cytoplasmic antibody COVID Coronavirus disease CT Computed tomography CTL Cytotoxic T-lymphocyte DLCO Diffusion capacity of the lungs for carbon monoxide EULAR European Alliance of Associations for Rheumatology FDA Food and Drug Administration FDG F-18 fluorodeoxyglucose HLA Human leukocyte antigen HPF High-powered field HR Hazard ratio ICD International Classification of Diseases IgG4-RD IgG4-related disease ILD Interstitial lung disease LDH Lactate dehydrogenase mAb Monoclonal antibody OR Odds ratio PET Positron emission tomography PFT Pulmonary function test PSC Primary sclerosing cholangitis RPF Retroperitoneal fibrosis US United States 16.1 INTRODUCTION AND HISTORY OF IGG4-RELATED DISEASE IgG4-related disease (IgG4-RD) was first recognized as a distinct disease entity in the early 2000s (1). The known history of the disease, however, extends back to the 1800s. In 1892, Dr. Johannes Freiherr von Mikulicz-Radecki described a case of a 42-year-old man with massive, symmetric, painless enlargement of the lacrimal, parotid, and submandibular glands. The histopathologic evaluation of a submandibular gland demonstrated a dense inflammatory infiltrate (2). Over the following decades, there was debate over whether this presentation, termed Mikulicz disease, represented a phenotype of Sjögren syndrome, glandular involvement caused potentially by a variety of other systemic disease processes (e.g., malignancy, tuberculosis), or a distinct clinical entity (3, 4). In 1948, Dr. John K. Ormond described two cases of anuria resulting from bilateral extrinsic compression of the ureters from abnormal soft tissue infiltrating the retroperitoneum, consisting of fibrosis and an inflammatory infiltrate (5). This clinical presentation, later termed Ormond disease, is now known more commonly as retroperitoneal fibrosis. Both Mikulicz disease and Ormond disease are now recognized to be part of the IgG4-RD spectrum. More than a century after the first description of Mikulicz syndrome, and over half a century after the recognition of Ormond disease, researchers in Japan observed that serum IgG4 concentrations were elevated in many patients with “sclerosing pancreatitis” (6). Moreover, these high serum IgG4 concentrations served to differentiate this inflammatory pancreatic condition from other hepatobiliary disorders. Shortly thereafter, other investigators reported that patients with sclerosing pancreatitis frequently demonstrated inflammation concurrently in a variety of other organs, including the bile ducts, liver, retroperitoneum, salivary glands, lymph nodes, and lungs (1, 7). A striking feature of the inflammation in all these organs was that the inflammatory lesions were similar, regardless of the organ or body region affected. Lymphoplasmacytic infiltrates with an increased proportion of IgG4+ plasma cells were present at all sites of disease, accompanied by varying degrees of fibrosis marked by a storiform pattern (1). In 2003, researchers concluded that the sum of these inflammatory manifestations represented a unified autoimmune condition, which was termed “IgG4-related autoimmune disease” (1). DOI: 10.1201/9781003361374-18265

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Over the following decade, it became increasingly clear that numerous diseases previously thought to represent distinct entities—including the presentations described by Mikulicz and Ormond—as well as type I autoimmune pancreatitis, Riedel thyroiditis, fibrosing mediastinitis, sclerosing mesenteritis, and others, were united by this single diagnosis, now termed IgG4-RD (1, 7–16). 16.2 EPIDEMIOLOGY 16.2.1  Incidence, Prevalence, and Demographics Owing to its relatively recent discovery, its frequently indolent nature, the absence of a unique International Classification of Diseases (ICD)-10 code, and other factors, high-quality data on the global epidemiology of IgG4-RD are lacking. The yearly incidence of IgG4-RD in Japan was estimated in 2009 to be 0.28–1.08 per 100,000 people using nationwide surveys of medical centers (17). In the United States (US), the estimated annual incidence using a claims database to identify patients with IgG4-RD based on specific diagnosis codes was 1.20 per 100,000 (18). Analyses of a large US insurance claims database suggest that the mean age of patients is approximately 56.5 years (18). The incidence of IgG4-RD increased during the study period from 0.78 to 1.39 per 100,000 person-years in 2015 and 2019, respectively, with an average annual incidence rate of IgG4-RD during that period of 1.20 per 100,000 person-years. This estimate is likely conservative, however, because the calculated incidence of IgG4-RD nearly doubled over the 4-year period of the study. This fact is likely explained best by expanding awareness of this disease in the medical community. The point prevalence in 2019 was 5.3 per 100,000 persons. The mortality rate was approximately two and a half times higher in IgG4-RD patients compared to matched controls, with an adjusted hazard ratio (HR) of 2.5 (95% CI 1.8–3.6). These data suggest that the incidence and prevalence of IgG4-RD are similar to those of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and systemic sclerosis (19, 20). Other studies have suggested that IgG4-RD is diagnosed most commonly in patients’ sixth and seventh decades of life (21, 22). However, individuals of any age can be affected by this disease, and patients with classic manifestations of IgG4-RD have been reported in the pediatric population (23). Most studies and case series have described a male predilection for the disease overall, as well as in specific organs involved, such as the kidneys, retroperitoneum, pancreas, and large blood vessels (21, 22, 24–29). The disease’s reported male predilection appears to extend to disease manifestations in the chest (30, 31). The frequency of pulmonary involvement in IgG4-RD is estimated to be 13–35% (21, 22, 30, 31). The demographics and disease characteristics of patients with and without pulmonary involvement of IgG4-RD are similar, though patients with thoracic involvement may tend to have a higher number of extrathoracic organs involved (30, 31). 16.2.2  Environmental Risk Factors Cigarette smoking is the only well-established environmental exposure shown to increase the odds of developing IgG4-RD, but this association seems to be driven largely by the strong association of retroperitoneal fibrosis with smoking rather than a strong association of other disease manifestations with that risk factor (32). Reports from small cohorts have suggested that patients with IgG4-RD may be more likely to have held jobs resulting in various occupational exposures to airborne and other substances, but these findings have not been replicated, to date, in larger cohorts (33). 16.2.3  Association with Malignancy Although there is no evidence to suggest that IgG4-RD itself is a premalignant condition, there are data that indicate that certain patients with IgG4-RD, particularly those who are diagnosed at older ages, may be more likely to have had a malignancy prior to diagnosis, with an adjusted odds ratio (OR) of 3.1 (34). Similarly, patients with IgG4-RD may have an increased incidence of malignancy after IgG4-RD diagnosis (35). In particular, a systematic review and meta-analysis identified an increased incidence of pancreatic cancer and lymphoma in patients with IgG4-RD compared to the general population (35). The increased risk of pancreatic cancer may reflect the fact that chronic pancreatitis is a known risk factor for the development of pancreatic cancer (36). Some of the associations with environmental exposures and malignancy are weak or require further investigation. Nevertheless, they suggest a potential role for chronic antigenic exposure in the development of the disease. 266

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16.3 PATHOPHYSIOLOGY 16.3.1  Etiopathogenesis and Genetic Risk Since its discovery two decades ago, great advances have been made with respect to the immunopathogenesis and cellular mechanisms of tissue damage in IgG4-RD, and these remain areas of active research. IgG4-RD is a chronic, multisystem disease that is highly responsive to immunosuppression, and several autoantigens have been identified that are associated with the disease (37–39). Overall, these disease features suggest that IgG4-RD is an autoimmune disease rather than a malignant or premalignant condition. Small studies of Asian patients with certain manifestations of IgG4-RD have identified human leukocyte antigen (HLA) and non-HLA genes that confer risk for developing IgG4-RD (40). Large-scale genome-wide association studies with sufficient numbers of patients to address questions in a more definitive manner, however, have not been conducted. At this time, the specific immunologic events that trigger the onset of IgG4-RD are not well understood. 16.3.2  Mechanisms of Tissue Injury Patients with active IgG4-RD exhibit expansions of B cells, plasmablasts, T follicular helper cells, T follicular regulatory cells, and cytotoxic T cells (37, 41–46). The cellular composition of tissue infiltrates observed in the disease is similarly diverse, containing B cells, CD4+ cytotoxic T lymphocytes (CTLs), plasma cells, and eosinophils (46, 47). As suggested by the frequent presence of hypergammaglobulinemia in patients with IgG4-RD, cells of the B-cell lineage are central to the disease pathophysiology. Patients with IgG4-RD have expansions of plasmablasts and CD20+ B cells that correlate with disease activity (41, 41, 48). In addition, treatment with rituximab, a monoclonal antibody directed against CD20 that leads to B-cell depletion, is highly effective in controlling disease activity (49–51). CTLs are also expanded in patients with active disease, and rituximab not only leads to reductions in B cells and plasmablasts but also to declines in the concentrations of circulating CTLs (41, 42, 46, 52). Therefore, it is thought that IgG4-RD pathophysiology involves antigen presentation by B cells to CTLs as well as interactions between B cells and other CD4+ T cells (53). In addition to cellular mechanisms, it has been increasingly recognized that complement activation may contribute to tissue injury in IgG4-RD. Hypocomplementemia is common in patients with IgG4-RD, and its presence correlates with serum IgG4 concentrations and the extent of disease, suggesting the consumption of complement proteins during active disease (54, 55). Studies have demonstrated high levels of circulating immune complexes and C5a, an inflammatory mediator that is produced via activation of the complement cascade, in patients with IgG4-RD (56, 57). In addition, complement deposition has been observed on histology in kidneys and pancreata affected by IgG4-RD (25, 58–61). Taken together, these findings suggest that complement activation may be responsible for some of the organ damage observed in the disease. 16.3.3  The Role of IgG4 In normal human physiology, IgG4 comprises a small minority (about 5%) of the total quantity of IgG. The IgG4 antibody subclass has been regarded in the past as being immunologically inert, although this reputation may not be entirely deserved (62, 63). Elevated serum concentrations of IgG4 and tissue deposition of IgG4+ plasma cells are classic features of IgG4-RD. Indeed, these observations, combined with the commonalities of pathology findings across all affected organs, played a large role in identifying that IgG4-RD is in fact a single unified disease. Nevertheless, it has never been shown that IgG4 is directly responsible for tissue injury or inflammation in the disease; rather, it is possible that IgG4 may serve to counteract the inflammatory process that is central to IgG4-RD (37). 16.4 OVERVIEW OF IGG4-RD 16.4.1  Clinical Presentation IgG4-RD is a disease with protean manifestations, capable of affecting nearly any anatomic location and ranging from mild or asymptomatic to life- or organ-threatening disease. The disease leads to its clinical manifestations by causing inflammation, tumor-forming lesions, and fibrosis in the organs involved. During active disease, the inflammation of organs presents clinically as organ dysfunction or organomegaly. Mass-forming lesions are frequently identified incidentally, but masses in certain anatomic locations may lead to symptoms through a mass effect. The specific symptoms experienced by each individual patient with IgG4-RD depend on the sites of involvement. 267

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Most patients with IgG4-RD have multisystem disease, but single-organ disease can occur, particularly with more fibrotic manifestations of the disease (see “Disease Subtypes” later). In most cases, the disease is chronic and relapsing–remitting. The involvement of multiple organs simultaneously is frequently apparent at baseline evaluation, but the disease can also unfold in a metachronous manner, i.e., with new sites becoming involved during long-term follow-up (21). IgG4-RD generally has an indolent course, but this often constitutes a disadvantage for patients, who may have symptoms for months or years—and the development of ongoing damage on a subclinical basis—before coming for medical attention. In fact, despite possessing a substantial disease burden, many patients are relatively asymptomatic at the time their disease is discovered incidentally on the basis of radiologic findings. This is particularly true with respect to pulmonary involvement, where asymptomatic pulmonary nodules, masses, and bronchial wall thickening are common (64, 65). This characteristically slow tempo of the disease, however, should not be equated with a benign course. Prolonged periods of subclinical inflammation experienced by patients with IgG4-RD, combined with the disease’s tendency to evolve to highly fibrotic states, leads patients to develop a great burden of irreversible damage in affected organs, both at baseline and during follow-up (22). It is for this reason that the prompt recognition and treatment of the disease are critical. 16.4.2 Histopathology Histopathologic examination is crucial in most patients suspected of having IgG4-RD. Biopsy of an affected tissue is generally required to confirm the diagnosis and to differentiate IgG4-RD from its many mimickers (Table 16.1). Three major histopathologic findings can be seen in any organ affected by the disease (Figure 16.1) (47): 1. Dense lymphoplasmacytic infiltrate composed of plasma cells, T cells, occasional B cells, and scattered eosinophils as well as the formation of germinal centers 2. Fibrosis, typically in a storiform pattern characterized by whorled areas of fibrosis resembling spokes of a pinwheel 3. Phlebitis—inflammatory infiltrate within the walls and lumens of small veins—which may be obliterative (i.e., leading to obliteration of the venous lumen) These histopathologic features are common among all organs involved by IgG4-RD, though it is important to note that all three features are not necessarily observed simultaneously in a single patient or biopsy specimen. When the diagnosis of IgG4-RD is suspected either because of clinical findings or on the basis of histopathologic features, IgG4 immunostaining of available biopsy tissues should be performed. A high ratio (>40%) of IgG4+/IgG+ plasma cells and high number of IgG4+ plasma cells per highpowered field (HPF) are suggestive of the diagnosis (Figure 16.1). The cutoff for the number of IgG4+ plasma cells/HPF varies between organs. Distinct pathologic features characteristic of IgG4-related lung disease are often not observed at other sites of disease. Focal small aggregates of neutrophils can be present in the inflammatory infiltrate in lung disease, though this feature is not entirely specific for IgG4-RD and may be seen in ANCA-associated vasculitis or other mimickers (Table 16.1). Neutrophilic infiltrate in other sites of involvement is unusual and strongly suggests an alternative diagnosis (47). In addition, nonnecrotizing obliterative arteritis is commonly seen in pulmonary IgG4-RD (Figure 16.2) (as well as pancreatic disease), but this finding is unusual in other organs. Other histopathologic findings that are atypical in IgG4-RD include prominent necrosis, granulomatous inflammation, prominent neutrophilic inflammation, and the presence of multinucleated giant cells. The presence of any of these findings, even in the context of histopathology that is otherwise suggestive of IgG4-RD, strongly raises concern for alternative diagnoses such as granulomatosis with polyangiitis. Other histopathologic and clinical features that suggest alternative diagnoses are discussed later in this chapter (see “Approach to Diagnosis”). Histopathology is essential in the workup of most patients with IgG4-RD but should be considered as only one element of the assessment required to establish a firm diagnosis. None of the histopathologic features described earlier is specific to IgG4-RD. Rather, they can be seen in a variety of other conditions ranging from other autoimmune diseases to malignancies and infections. Therefore, histopathology must be interpreted in the context of clinical, serological, and radiological data. 268

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Figure 16.1  Histopathology of pulmonary involvement by IgG4-RD. (A) At low magnification, pulmonary IgG4-RD can display nodular fibroinflammatory scarring with conspicuous lymphoid aggregates. (B) At high magnification, there is dense lymphoplasmacytic infiltrate with scattered eosinophils in a collagenous stromal background. (C) Obliterative phlebitis can be subtle but can be nicely highlighted by a Verhoeff–Van Gieson elastin stain (inset). (D) Storiform fibrosis, as characterized by a whorl-like arrangement of the fibrosis, is characteristic. (E–F) Immunohistochemical stains for IgG (E) and IgG4 (F) demonstrate marked increase in the number of IgG4+ plasma cells, with IgG4 > 100/hpf and an IgG4:IgG ratio of >40%.

Table 16.1: Selected IgG4-RD Mimickers and “Exclusion Criteria” from the 2019 IgG4-RD Classification Criteria that Prompt Consideration Mimicker Autoantibody-associated systemic autoimmune rheumatic disease ANCA-associated vasculitis

Sarcoidosis

Suggestive Features Leukopenia and thrombocytopenia Specific autoantibodies, including Ro (SS-A), La (SS-B), dsDNA, U1-RNP, myositis-specific antibodies, and anti-CCP antibodies Fever Rapid progression Granulomatous inflammation Necrotizing vasculitis Glomerulonephritis Antibodies against proteinase 3 (PR3) or myeloperoxidase (MPO) Hypereosinophilia Lack of response to glucocorticoid monotherapy Fever Granulomatous inflammation (Continued )

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Table 16.1:  (Continued) Mimicker Lymphoma

Multicentric Castleman disease

Erdheim–Chester disease

Rosai–Dorfman disease Inflammatory myofibroblastic tumor

Suggestive Features Fever Leukopenia and thrombocytopenia Histopathologic features suggestive of malignancy Fever Rapid progression Lack of response to glucocorticoid monotherapy Lack of response to glucocorticoid monotherapy Long bone sclerotic lesions Lipid-laden histiocytes or granulomatous inflammation Mutations in BRAF or other associated genes S100-positive macrophages exhibiting emperipolesis Driver mutations of ALK, ROS1, NTRK gene family, or other associated genes

Abbreviations: dsDNA: double-stranded DNA; RNP: ribonucleoprotein; CCP: cyclic citrullinated peptide; ANCA: anti-neutrophil cytoplasmic antibody; PR3: proteinase-3; MPO: myeloperoxidase Source: (66)

Figure 16.2  Unique histopathologic feature in IgG4-related lung disease: obliterative arteritis. Obliterative arteritis is characterized by arterial infiltration by a lymphoplasmacytic infiltrate, with fibrosis and lumen obliteration (arrow); the latter is highlighted by an elastic stain at a deeper level (inset).

16.4.3 Biomarkers There are various laboratory markers that can aid in the diagnosis and long-term monitoring of IgG4-RD. The most useful of these is the serum IgG4 concentration, which is elevated in 50–90% of patients with IgG4-RD (21, 22, 67, 68). When elevated at baseline, serum IgG4 concentration inevitably declines as disease activity improves following treatment. Subsequent rises in serum IgG4 concentrations, particularly if continuous and sustained over longitudinal follow-up, reliably predict ongoing disease activity, even if subclinical, and risk of a clinical disease relapse (49, 69, 70). Nevertheless, it is important to recognize that elevated serum IgG4 concentrations are not specific to IgG4-RD. IgG4 elevations can occur in many other conditions, including other autoimmune diseases, malignancies, and infections (67, 71). Similarly, there is a significant subset of 270

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patients with IgG4-RD that never have serum IgG4 elevations or have concentrations that are only mildly elevated. This is particularly true of patients with fibrotic disease manifestations, such as retroperitoneal fibrosis (see “Disease Subtypes” later). Serum IgG4 concentrations must therefore be interpreted in the broader clinical context, as is also true for pathology findings. Although serum IgG4 concentration is the most useful serum biomarker for most patients, several others may also be helpful in the management of patients with IgG4-RD. In addition to IgG4, other immunoglobulins, namely, IgG1 and IgE, are frequently elevated in patients with IgG4-RD (22, 72–74). A mild to moderate degree of peripheral blood eosinophilia is frequently observed (22, 72, 73, 75), but profound eosinophilia is not typical of the disease (66). Low concentrations of complement components C3 or C4 are seen in 20–38% of patients with IgG4-RD and are associated with more active disease (22, 54, 55). Hypocomplementemia is especially common, and often profound, in patients with tubulointerstitial nephritis, the most common renal manifestation of IgG4-RD (25, 76). 16.4.4  Disease Subtypes IgG4-RD can be considered to have two phenotypes characterized by different clinical, serological, and histopathological patterns of involvement (77). These two subtypes, proliferative and fibrotic, were described based on clinical observation and reflect the distinct manners in which IgG4-RD often presents. The two patterns are not mutually exclusive, and patients generally fall somewhere on the continuum between either end marked by these two subtypes. The “proliferative” subtype is characterized by multiorgan involvement and a high degree of serologic activity (i.e., elevated serum IgG4, IgG1, and IgE; eosinophilia; and hypocomplementemia). Patients with the proliferative subtype of IgG4-RD often have involvement of anatomic locations associated with more intense inflammatory infiltrates, including the glands of the head and neck, pancreas, bile ducts, kidneys, paranasal sinuses, large blood vessels, and lymph nodes. Atopy is common in patients with proliferative IgG4-RD, and histopathology reveals prominent lymphoplasmacytic infiltration and germinal centers. Due to its largely inflammatory nature, the proliferative subtype tends to display a good response to immunosuppressive treatment. Pulmonary involvement in IgG4-RD most commonly occurs in the context of the proliferative subtype of IgG4-RD. In contrast, the “fibrotic” subtype of IgG4-RD more commonly manifests as single-organ involvement with less prominent serologic activity or atopy. The histopathology of organs affected by the fibrotic subtype features storiform fibrosis and obliterative phlebitis with a less prominent lymphoplasmacytic infiltrate. Predominant sites of involvement in the fibrotic subtype include the retroperitoneum, meninges, mesentery, and thyroid. Due to the inherently fibrotic nature, a less robust treatment response to immunomodulatory therapies is common. Within the thorax, fibrosing mediastinitis is a prototypical manifestation of this subtype of IgG4-RD. 16.5 EXTRATHORACIC CLINICAL MANIFESTATIONS 16.5.1 Constitutional Despite its chronic, inflammatory, and systemic nature, constitutional symptoms are not typically a prominent feature of IgG4-RD. Fever is rare in IgG4-RD; it was determined to be an exclusion criterion in the 2019 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) IgG4-RD Classification Criteria (66). Weight loss is common, and often profound, when IgG4-RD leads to exocrine pancreatic insufficiency. In the absence of pancreatic involvement by IgG4-RD, however, patients with the disease do not present with a “wasting” illness or substantial unintentional weight loss. When constitutional symptoms other than fatigue are a central feature of a clinical presentation, IgG4-RD mimickers should be considered (Table 16.1). 16.5.2 Atopy Many patients with IgG4-RD, particularly those with the proliferative subtype and those with head and neck involvement, have a history of atopy (72, 73, 78, 79). Historically, it was thought that an allergic process may underlie the pathophysiology of IgG4-RD given the known association between the disease and biomarkers such as peripheral blood eosinophilia and serum IgE. However, many non-atopic patients with IgG4-RD have eosinophilia and elevated IgE levels, suggesting that these biomarkers are inherent to the disease itself and not necessarily to associated atopy (73). In addition, a recent case–control study revealed that atopy may not be more common in patients with IgG4-RD compared to control subjects, raising the question of whether the association is true. Whether it is part of the disease process or not, atopy does not typically improve with treatment of IgG4-RD, and vice versa. 271

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16.5.3  Select Manifestations IgG4-RD is capable of involving virtually any anatomic site in the human body, but there are certain manifestations that are especially common or well described in the disease. The major extrathoracic manifestations of IgG4-RD are summarized in Table 16.2. Some of the cardinal manifestations are described in detail as follows: ■

Glandular enlargement: Mikulicz syndrome—symmetric and painless enlargement of the lacrimal, parotid, and submandibular glands—is one of the most common presentations of the disease. Sicca symptoms are typically less severe than those seen in Sjögren syndrome, but the degree of glandular enlargement is typically far greater in IgG4-RD. The involvement of all three sets of glands (i.e., Mikulicz syndrome) is quite suggestive of IgG4-RD, but some patients may have involvement of only one or two sets of glands.

■

Type 1 autoimmune pancreatitis: Pancreatic involvement in IgG4-RD can present as typical acute pancreatitis, characterized by abdominal pain and intolerance of oral intake. When this occurs, the pancreatitis tends to improve with glucocorticoids. Radiologically, the pancreas appears diffusely enlarged with a loss of its normal lobulations, termed “sausage pancreas” (80, 81). However, only a minority of patients with pancreatic involvement of IgG4-RD present with symptoms of acute pancreatitis. Rather, many patients present only with signs of irreversible damage: either new-onset, often insulin-dependent diabetes secondary to endocrine pancreatic insufficiency or weight loss, vitamin deficiencies, or steatorrhea secondary to exocrine pancreatic insufficiency. Radiologically, pancreata with endocrine or exocrine insufficiency often appear small and atrophic rather than enlarged.

■

Sclerosing cholangitis: IgG4-RD often involves the bile ducts, and this frequently occurs together with type I autoimmune pancreatitis. IgG4-related sclerosing cholangitis most closely resembles primary sclerosing cholangitis (PSC) in that it presents clinically with pruritus and jaundice secondary to cholestasis and, on imaging, with intra- and extrahepatic biliary ductal dilatation. However, unlike PSC, the biliary lesions of IgG4-RD are much more likely to improve with immunosuppression (82, 83).

■

Tubulointerstitial nephritis: Another frequently asymptomatic manifestation of the disease, tubulointerstitial nephritis, is the most common renal manifestation of IgG4-RD. Early in the disease course, this presents as mild, non-nephrotic-range proteinuria and appears on imaging as numerous cortical hypodensities that are most often present bilaterally. If not treated in the early asymptomatic phase, this can progress to chronic kidney disease, though end-stage kidney disease is fortunately rare.

■

Retroperitoneal fibrosis: Retroperitoneal fibrosis (RPF) refers to a fibroinflammatory process in the retroperitoneal space. RPF can occur as an idiopathic disease process or in association with IgG4-RD. However, as the most common manifestation of the fibrotic subtype of IgG4-RD, IgG4related RPF as determined by histopathologic analysis may still occur in isolation without other disease manifestations and a normal serologic evaluation. When associated with IgG4-RD, RPF most often presents on imaging as soft tissue proliferation that surrounds the infrarenal anterolateral abdominal aorta (often termed “peri-aortitis”) and extends to the iliac arteries. Patients may present with abdominal or back pain, but more often, symptoms result from local compression of the retroperitoneal structures. The anatomic distribution of RPF places the ureters at particularly high risk of injury. Medial displacement of the ureters may be observed in mild cases, but ureteral obstruction and resulting hydronephrosis is a common complication.

Table 16.2: Common Extrathoracic Manifestations of IgG4-RD Site of Involvement Hypertrophic pachymeningitis Hypophysitis Dacryoadenitis

Comments • May cause headache, hydrocephalus, cranial nerve palsies • Diffuse nodular pachymeningeal thickening • Often associated with hypertrophic pachymeningitis • Hypopituitarism • Typically bilateral, symmetric, painless lacrimal gland enlargement • Dry eye may or may not be present (Continued )

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Table 16.2:  (Continued) Site of Involvement Orbital inflammation

Sialadenitis

Sinusitis Riedel thyroiditis

Large-vessel vasculitis

Retroperitoneal fibrosis/peri-aortitis

Type 1 autoimmune pancreatitis

Sclerosing cholangitis Sclerosing mesenteritis Tubulointerstitial nephritis Membranous nephropathy Prostatitis

Comments • • • •

Extraocular muscle enlargement or contrast enhancement Orbital pseudotumor Presents with proptosis, diplopia, retro-ocular pain, vision loss Typically bilateral, symmetric painless enlargement of the parotid and/or submandibular glands • Dry mouth may or may not be present • Presents with facial pain, epistaxis, nasal discharge, or crusting • Can lead to bony destruction • Diffuse, firm enlargement of the thyroid gland • Can cause extrinsic compression of local structures • Patients may be hypo-, hyper-, or euthyroid • Thoracic or abdominal aorta, arch vessels, carotid arteries, iliac arteries, intra-abdominal vasculature • May lead to aneurysms or dissection • Soft tissue anterolateral to the infrarenal abdominal aorta extending to the iliac arteries • Frequently leads to ureteral compromise • May or may not present clinically with acute pancreatitis • Frequently presents as a pancreatic mass • Endocrine or exocrine pancreatic insufficiency common • Pancreas may appear enlarged with loss of lobulations (“sausage pancreas”) • Intra- and extrahepatic biliary ductal dilatation • Cholestasis • Mesenteric mass or soft tissue frequently encasing the mesenteric vasculature • Non-nephrotic proteinuria • Renal cortical hypodensities on computed tomography • Nephrotic syndrome • Glucocorticoid-responsive prostate enlargement • Presents with lower urinary tract symptoms

16.6 THORACIC MANIFESTATIONS IgG4-RD commonly involves the lungs and may also include the pleura, mediastinum, heart, and pericardium. Many patients can be diagnosed as having IgG4-RD based on evaluations of intrathoracic findings, emphasizing that not only rheumatologists but also pulmonologists, thoracic surgeons, and cardiologists should be aware of these manifestations. The various thoracic manifestations of IgG4-RD can occur in isolation, or they can occur together with other thoracic or extrathoracic manifestations of the disease. The pleuropulmonary manifestations of IgG4-RD are often asymptomatic or may cause symptoms such as dyspnea or cough, but fortunately, these manifestations are rarely severe or life-threatening. In contrast, other thoracic manifestations, such as aortitis and coronary arteritis, have the potential to cause severe consequences such as aortic dissection and myocardial infarction, respectively. 16.6.1  Airway Involvement Peribronchovascular thickening most commonly manifests as bronchial wall thickening and can be found incidentally (Figure 16.3) (84, 85). This finding may also be seen in asthma and may present similarly (85). Rarely, airway involvement in IgG4-RD can cause symptomatic tracheobronchial stenosis (86–88). Longstanding airway involvement in IgG4-RD can also lead to tracheal remodeling, which may appear on computed tomography (CT) as a “saber sheath” trachea (Figure 16.3) (89). Airway involvement in IgG4-RD tends to improve both clinically and on imaging with immunosuppressive treatment except in the event that irreversible airway modeling has occurred (e.g., saber sheath trachea). 273

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Figure 16.3  46-year-old woman with IgG4-RD involving the airways. (A) The trachea has a saber sheath configuration, a finding reported in COPD (arrow). (B) There is airway wall thickening involving the segmental airways in the right middle and lower lobes (arrows). 16.6.2  Parenchymal Lung Disease Parenchymal lung disease in IgG4-RD can broadly be categorized into two patterns of disease, which may overlap within individual patients: 1) nodules or masses and 2) nonfibrotic interstitial lung disease (ILD). 16.6.2.1  Nodules and Masses In one series, over 50% of patients with IgG4-RD had lung nodules detected radiologically (90). It is unclear how many of the patients’ nodules were due to IgG4-RD as opposed to other causes, as biopsies were not obtained in all patients; nevertheless, lung nodules are quite common in the disease (Figures 16.4 and 16.5). Lung nodules in IgG4-RD can be single or multiple, solid or ground glass, and small (≤1 cm in diameter) or large (>1 cm in diameter) (30, 31, 65, 90–93). There is no zonal distribution of the nodules that is especially typical of IgG4-RD, and any lung zone can be involved (90). However, nodules are often subpleural, perifissural, or peri-bronchiolar in distribution. Secondary characteristics such as irregular borders, lobulation, spiculation, air bronchograms, and calcification can occur (Figure 16.4) (90). In addition to nodules, larger masses also frequently occur, as is typical of the disease in other sites of involvement (64, 90–92). Nodules and masses in patients with IgG4-RD can grow with time and exhibit F-18 fluorodeoxyglucose (FDG) avidity on positron emission tomography (PET) scan (Figure 16.5C); as a result, they are frequently mistaken for malignancy (91). Indeed, it is common for patients with lung involvement due to IgG4-RD to receive the diagnosis after a biopsy or resection is done to evaluate for suspected malignancy (94). 274

16  Pulmonary Manifestations of IgG4-Related Disease

Figure 16.4  42-year-old man with IgG4-RD involving the lungs. Multiple lung nodules are centered along the airways and fissures (white arrows). There are air bronchograms within several nodules (black arrowheads).

Figure 16.5  58-year-old woman with IgG4-RD involving the lungs, pleura, and lymph nodes. (A) Multiple lung nodules and masses are centered along the airways and fissures (arrows). (B) There is hilar and mediastinal lymphadenopathy (solid arrows) and left pleural thickening (dotted arrows). (C) The FDG-PET scan demonstrates avidity in all these regions. 275

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Masses and nodules in IgG4-RD are most often asymptomatic, but since they frequently occur together with other manifestations of the disease, patients may have symptoms attributable to other areas of IgG4-RD involvement. For larger lesions, patients may also have symptoms due to local invasion or airway obstruction (91, 94). It is important to recognize that lung nodules and masses in the setting of known IgG4-RD may still be due to other conditions, including malignancy, so clinicians should perform routine surveillance imaging as is done for lung nodules outside the context of IgG4-RD. Nevertheless, when confronted with nodular lesions, if there is other evidence to suggest a diagnosis of IgG4-RD, a reduction in the size of the lesions following treatment with immunosuppressive agents can provide evidence that favors a primary inflammatory process rather than malignancy. 16.6.2.2  Interstitial Lung Disease Thickening of the peribronchovascular bundles and interlobular septa is a common feature of thoracic IgG4-RD (Figure 16.6) (65, 89). This may result in dyspnea and/or cough. While this pattern of involvement is not entirely specific for IgG4-RD, it is sufficiently typical of the disease that it is an inclusion criterion in the 2019 ACR/EULAR Classification Criteria for IgG4-RD (66). Various other radiologic patterns of ILD can occur in IgG4-RD (30, 31, 65, 95). Ground glass opacities and focal consolidative opacities resembling organizing pneumonia are most typical (Figure 16.6). Interlobular septal thickening is often seen (Figure 16.6). Features of pulmonary fibrosis, including traction bronchiectasis and honeycombing, are rare but have been described. Patients may present clinically with dyspnea, cough, hemoptysis, or chest pain; however, many patients are asymptomatic and are noted incidentally to have pulmonary parenchymal involvement. Pulmonary function tests (PFTs) are most often normal in patients with pulmonary IgG4-RD, although some patients may have an isolated reduction in the diffusion capacity of the lungs for carbon monoxide (DLCO) (65, 96–99). In response to immunosuppressive treatment, most cases of ILD from IgG4-RD exhibit partial improvement or complete resolution. In the rare cases of more fibrotic disease, treatment may halt progression without significant radiologic improvement. 16.6.3  Pleural Involvement Pleural thickening is a common feature of thoracic IgG4-RD (Figures 16.5 and 16.7). This can be focal or diffuse and unilateral or bilateral (95). The combination of parenchymal and pleural involvement can be especially suggestive of IgG4-RD, but this can also be seen with

Figure 16.6  65-year-old man with IgG4-RD involving the lungs. There are ground-glass opacities in a peripheral and peribronchiolar distribution (solid arrows). There is smooth interlobular septal thickening (dotted arrow). 276

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autoantibody-associated systemic autoimmune rheumatic diseases (89). Pleural disease in IgG4RD typically occurs in the setting of other thoracic or extrathoracic manifestations of the disease (30). Occasionally, patients with pleural involvement may also have pleural effusions (95, 100). When present, pleural effusions may be unilateral or bilateral, without an apparent side predilection, and are generally exudative, exhibiting increased lymphocytes and elevated pleural fluid protein and lactate dehydrogenase (LDH) (100–104). Elevated levels of pleural fluid adenosine deaminase (ADA) can be observed in IgG4-related pleural effusions; however, this finding warrants evaluation for tuberculous effusion (100–102, 104). Rarely, chylous effusions may occur in IgG4-RD, though the mechanism leading to this is unclear, as lymphangiography in one such case demonstrated an intact thoracic duct (104, 105). Treatment with immunosuppression typically reduces the degree of pleural thickening and rate of re-accumulation of pleural effusions. 16.6.4  Lymph Node Involvement Lymphadenopathy is common in IgG4-RD and can be present in any location. Mediastinal and hilar lymphadenopathy is common, and it often accompanies other thoracic manifestations of the disease (Figures 16.5 and 16.8). Lymph nodes in IgG4-RD are typically FDG-avid on PET scan during active disease. While lymph nodes most often decrease in size with immunosuppression, they may remain persistently enlarged even with adequate control of the disease. 16.6.5  Cardiac and Mediastinal Involvement As is the case with the pleura, pericardial inflammation in patients with IgG4-RD can manifest as pericardial thickening or effusion. Pericardial inflammation may be associated with more diffuse mediastinal fibrosis (i.e., fibrosing mediastinitis), which can cause encasement of the great vessels and other mediastinal structures. Coronary artery involvement, manifesting as coronary artery wall thickening or post-contrast enhancement, peri-arterial soft tissue proliferation, aneurysmal dilatation, or stenosis, is a well-described feature of the disease (29, 106). Aortitis involving the ascending and/or descending thoracic aorta as well as the abdominal aorta commonly occurs (Figure 16.7) (28). 16.6.6  Paravertebral Involvement A particularly striking manifestation of IgG4-RD is inflammation adjacent to the thoracic vertebrae. Occasionally termed retromediastinal fibrosis, this appears radiologically as soft tissue masslike bands extending laterally across multiple thoracic vertebrae (89, 95, 107). This most commonly occurs on the right, but left-sided or bilateral disease may occur (Figure 16.8). While it can occasionally cause back pain, paravertebral involvement is usually an asymptomatic manifestation of IgG4-RD, but its presence provides strong evidence for the disease, as few other entities can cause this type of presentation.

Figure 16.7  70-year-old man with IgG4-RD involving the pleura and aorta in (A) cross-sectional and (B) coronal views. There is bilateral pleural thickening (arrows) and soft tissue surrounding the aortic arch and descending thoracic aorta (arrow). 277

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Figure 16.8  74-year-old woman with IgG4-RD involving the lymph nodes and left paravertebral space in (A) cross-sectional and (B) coronal views. There are left hilar lymph nodes (solid arrows). There is left paravertebral soft tissue at T5/T6 that surrounds the intercostal artery without obstruction or narrowing (dotted arrows). 16.7 APPROACH TO DIAGNOSIS IgG4-RD is a clinical diagnosis. No single organ manifestation, laboratory value, radiologic finding, or feature on histology is adequately specific to make a diagnosis of IgG4-RD. Rather, the diagnosis of IgG4-RD begins with the recognition of either clinical features or histopathology that are suggestive of the disease. This recognition should prompt an evaluation for other sites of involvement of the disease, which includes clinical examination; cross-sectional imaging of the chest, abdomen, and pelvis; and serologies such as serum IgG subclasses, IgE, C3 and C4 complement, and eosinophil count. Whenever feasible, histopathologic evaluation of an affected site should be performed, both to confirm the histopathology is compatible with IgG4-RD and to ensure there are no atypical features suggestive of IgG4-RD mimickers. Beyond histopathology, it is important to conduct a thorough evaluation for mimicking conditions, including lymphoma, histiocytic disorders, sarcoidosis, ANCA-associated vasculitis, and autoantibody-associated systemic autoimmune rheumatic diseases (including Sjögren syndrome, systemic lupus erythematosus, inflammatory myopathy, and extra-articular manifestations of rheumatoid arthritis) (Table 16.1). Certain clinical features, such as fever, rapid progression, and a lack of response to treatment with glucocorticoids, are atypical in IgG4-RD and suggest a mimicking condition. This approach to clinical diagnosis mirrors the 2019 ACR/EULAR Classification Criteria for IgG4-RD, which can serve as a guide for clinicians (66, 108). 16.8 TREATMENT Pharmacologic treatment is not always indicated in patients with IgG4-RD. As the disease is indolent and often asymptomatic, clinical monitoring is often sufficient to ensure the disease does not lead to clinically meaningful consequences. This is true for various forms of thoracic involvement, such as lung nodules, pleural thickening, and paravertebral inflammation. However, treatment is indicated in patients who are symptomatic and in patients who have involvement of sites that have the potential to have clinically significant sequelae even in the absence of symptoms. Examples of IgG4-RD manifestations that frequently require treatment in the asymptomatic setting to prevent complications include retroperitoneal fibrosis, autoimmune pancreatitis, tubulointerstitial nephritis, and large-vessel vasculitis. The presence of active areas of thoracic involvement without associated symptoms should prompt a thorough assessment with clinical examination, serologies, and imaging to evaluate for other areas of active disease that could warrant treatment. When treatment is indicated, the approach to IgG4-RD consists of 1) induction of remission, 2) disease monitoring, and in some cases, 3) remission maintenance. 278

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16.8.1 Remission Induction For remission induction, response to glucocorticoids is nearly universal; a lack of response most often suggests an alternative diagnosis or the presence of irreversible damage. A typical course of glucocorticoids for new or relapsing IgG4-RD is 0.5–1 mg/kg/day prednisone equivalent tapered over 3–6 months depending on the severity of disease. Relapse rates following treatment with glucocorticoid monotherapy are high, and patients with IgG4-RD are therefore at risk for signifcant glucocorticoid toxicity, particularly given that many have diabetes secondary to endocrine pancreatic insuffciency (109–111). The only agent that has been shown to effectively induce remission in IgG4-RD as monotherapy, in the absence of concomitant glucocorticoids, is the B-cell-depleting agent rituximab (49). A typical regimen of rituximab is two 1-gram infusions separated by 2 weeks. Another 1-gram infusion is often administered after 4–6 months in cases of severe disease or if there is evidence of ongoing disease activity at that time. Unlike glucocorticoids, rituximab frequently leads to a prolonged remission that can last months to years, although the duration of clinical response following a single course of rituximab in IgG4-RD varies substantially between patients (49, 50, 111–113). Because of its nearly universal effectiveness, lower toxicity, and ability to induce prolonged remission, rituximab—with or without glucocorticoids, depending on severity of disease—is the preferred frstline treatment for most patients with IgG4-RD. It is important to recognize that rituximab causes prolonged and irreversible B-cell depletion, which is associated with an increased risk for infection, including severe coronavirus disease (COVID)-19. Additionally, its use may be limited by cost and availability. In the US, because rituximab is not approved by the Food and Drug Administration (FDA) for the indication of IgG4-RD, coverage for rituximab is often denied by insurance companies. In other countries, rituximab use is often limited by less widespread availability of the drug. 16.8.2 Disease Monitoring Remission can be achieved in the vast majority of patients with IgG4-RD. Patients who achieve remission exhibit improvement in their clinical symptoms and radiologic fndings. In addition, serum IgG4 concentrations are helpful in defning remission if they are elevated prior to the initiation of treatment. Following treatment, serum IgG4 concentrations decline as disease activity improves, though it should be noted that some patients, particularly those in whom baseline IgG4 concentration is markedly elevated, may still have a persistent, mild elevation in serum IgG4 during remission. After achieving remission, markers of disease activity (e.g., serum IgG4, IgE, eosinophil count, C3 and C4 complement, and organ-specifc markers) should be monitored serially (typically every 3–6 months). Subsequent rises in serum IgG4 concentrations or other markers of disease activity should prompt thorough evaluation with history, physical, and imaging to assess disease status, as rises in serum IgG4 typically herald disease relapses. In patients with disease that is largely detectable on imaging, serial imaging every 6–12 months should be considered to allow for the early identifcation of disease relapses. 16.8.3 Remission Maintenance In patients with severe or organ-threatening disease at baseline or patients who exhibit frequent relapses requiring repeated re-initiation of treatment, long-term remission maintenance should be considered. Some centers continue low-dose glucocorticoids (prednisolone 5–10 mg daily or equivalent) for long-term remission maintenance. While this approach does somewhat decrease fare rates, it also exposes patients to potentially substantial glucocorticoid toxicity (109–111, 114). Conventional immunosuppressive agents such as azathioprine, cyclophosphamide, lefunomide, and mycophenolate mofetil may modestly reduce the risk of fares in patients with IgG4-RD (115–118). As is the case for the induction of remission, long-term treatment with rituximab is quite effective at maintaining remission, and relapse rates are lower in patients treated with long-term rituximab compared with glucocorticoids or conventional immunosuppressive medications (49–51, 111). However, the optimal dose, frequency, and duration of treatment with rituximab are not wellestablished. When remission maintenance is indicated, we typically use rituximab, 1 gram every 6 months, and gradually reduce the frequency of infusions to balance disease control with risk associated with immunosuppression. Clinical trials evaluating the effcacy of other agents in this disease are ongoing, including the SLAMF7 inhibitor elotuzumab (ClinicalTrials.gov Identifer NCT04918147), anti-CD19 monoclonal antibody (mAb) inebilizumab (NCT04540497), BTK inhibitors rilzabrutinib (NCT04520451) and zanubrutinib (NCT04602598), anti-CD-19/FCγRIIb mAb obexelimab (NCT05662241), JAK inhibitor tofacitinib (NCT05625581), and anti-BLyS mAb belimumab (NCT04660565). 279

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16.9 CONCLUSION IgG4-RD is a relapsing–remitting systemic autoimmune disease that manifests as destructive tissue inflammation and mass-forming lesions that can affect nearly every anatomic site in the body. Thoracic involvement is common and can present as lung nodules or masses, ILD, pleural or pericardial thickening or effusion, bronchovascular thickening, tracheobronchial stenosis, mediastinal fibrosis, coronary arteritis and periarteritis, paravertebral masses, and aortitis. The diagnosis of IgG4-RD involves synthesizing clinical, radiological, serologic, and histopathologic data. Treatment is indicated in symptomatic patients or in cases of organ-threatening disease. Glucocorticoids and rituximab are the treatments of choice in most patients. REFERENCES 1. Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38(10):982–4. 2. Mikulicz J. Ueber eine eigenartige symmetrische Erkrankung Der Thränen- und Mundspeicheldrüsen. Beitr Z Chir, Festschrift F th. Billroth. 1892;610–30. 3. Manger B, Schett G. Jan Mikulicz-Radecki (1850 –1905): Return of the surgeon. Ann Rheum Dis. 2021;80(1):8–10. 4. Penfold CN. Mikulicz syndrome. J Oral Maxillofac Surg. 1985;43(11):900–5. 5. Ormond JK. Bilateral ureteral obstruction due to envelopment and compression by an inflammatory retroperitoneal process. J Urol. 1948;59(6):1072–9. 6. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344(10):732–8. 7. Kamisawa T, Funata N, Hayashi Y, Tsuruta K, Okamoto A, Amemiya K, et al. Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut. 2003;52(5):683–7. 8. Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol. 2006;16(6):335–40. 9. Khosroshahi A, Carruthers MN, Stone JH, Shinagare S, Sainani N, Hasserjian RP, et al. Rethinking Ormond’s disease: “Idiopathic” retroperitoneal fibrosis in the era of IgG4-related disease. Medicine (Baltimore). 2013;92(2):82–91. 10. Koo BS, Koh YW, Hong S, Kim YJ, Kim YG, Lee CK, et al. Clinicopathologic characteristics of IgG4-related retroperitoneal fibrosis among patients initially diagnosed as having idiopathic retroperitoneal fibrosis. Mod Rheumatol. 2015;25(2):194–8. 11. Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel ’s thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res (Hoboken). 2010;62(9):1312–18. 12. Stan MN, Sonawane V, Sebo TJ, Thapa P, Bahn RS. Riedel ’s thyroiditis association with IgG4related disease. Clin Endocrinol (Oxf). 2017;86(3):425–30. 13. Takeshima K, Inaba H, Ariyasu H, Furukawa Y, Doi A, Nishi M, et al. Clinicopathological features of Riedel ’s thyroiditis associated with IgG4-related disease in Japan. Endocr J. 2015;62(8):725–31. 14. Peikert T, Shrestha B, Aubry MC, Colby TV, Ryu JH, Sekiguchi H, et al. Histopathologic overlap between fibrosing mediastinitis and IgG4-related disease. Int J Rheumatol. 2012;2012:207056. 15. Gorospe L, Ayala-Carbonero AM, Fernández-Méndez MÁ, Arrieta P, Muñoz-Molina GM, Cabañero-Sánchez A, et al. Idiopathic fibrosing mediastinitis: Spectrum of imaging findings with emphasis on its association with IgG4-related disease. Clin Imaging. 2015;39(6):993–9. 16. Chen TS, Montgomery EA. Are tumefactive lesions classified as sclerosing mesenteritis a subset of IgG4-related sclerosing disorders ? J Clin Pathol. 2008;61(10):1093–7. 17. Uchida K, Masamune A, Shimosegawa T, Okazaki K. Prevalence of IgG4-related disease in Japan based on nationwide survey in 2009. Int J Rheumatol. 2012;2012:358371. 18. Wallace ZS, Miles G, Smolkina E, Petruski-Ivleva N, Madziva D, Cook C, et al. Incidence, prevalence and mortality of IgG4-related disease in the USA: A claims-based analysis of commercially insured adults. Ann Rheum Dis. 2023;ard-2023–223950. 19. Panupattanapong S, Stwalley DL, White AJ, Olsen MA, French AR, Hartman ME. Epidemiology and outcomes of granulomatosis with polyangiitis in pediatric and working-age adult populations in the United States: Analysis of a large national claims database. Arthritis Rheumatol. 2018;70(12):2067–76. 20. Bergamasco A, Hartmann N, Wallace L, Verpillat P. Epidemiology of systemic sclerosis and systemic sclerosis-associated interstitial lung disease. Clin Epidemiol. 2019;11:257–73. 280

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69. Wallace ZS, Mattoo H, Mahajan VS, Kulikova M, Lu L, Deshpande V, et al. Predictors of disease relapse in IgG4-related disease following rituximab. Rheumatology (Oxford). 2016;55(6):1000–8. 70. Sasaki T, Akiyama M, Kaneko Y, Yasuoka H, Suzuki K, Yamaoka K, et al. Risk factors of relapse following glucocorticoid tapering in IgG4-related disease. Clin Exp Rheumatol. 2018;36 Suppl 112(3):186–9. 71. Zhao EJ, Carruthers MN, Li CH, Mattman A, Chen LYC. Conditions associated with polyclonal hypergammaglobulinemia in the IgG4-related disease era: A retrospective study from a hematology tertiary care center. Haematologica. 2020;105(3):e121–3. 72. Culver EL, Sadler R, Bateman AC, Makuch M, Cargill T, Ferry B, et al. Increases in IgE, eosinophils, and mast cells can be used in diagnosis and to predict relapse of IgG4-related disease. Clin Gastroenterol Hepatol. 2017;15(9):1444–52.e6. 73. Della Torre E, Mattoo H, Mahajan VS, Carruthers M, Pillai S, Stone JH. Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease. Allergy. 2014;69(2):269–72. 74. Zhou J, Peng Y, Peng L, Wu D, Li J, Jiang N, et al. Serum IgE in the clinical features and disease outcomes of IgG4-related disease: A large retrospective cohort study. Arthritis Res Ther. 2020;22(1):255. 75. Zhang X, Zhang P, Li J, He Y, Fei Y, Peng L, et al. Different clinical patterns of IgG4-RD patients with and without eosinophilia. Sci Rep. 2019;9(1):16483. 76. Kawano M, Saeki T, Nakashima H, Nishi S, Yamaguchi Y, Hisano S, et al. Proposal for diagnostic criteria for IgG4-related kidney disease. Clin Exp Nephrol. 2011;15(5):615–26. 77. Zhang W, Stone JH. Management of IgG4-related disease. Lancet Rheumatol. 2019;1(1): e55–65. 78. Saeki T, Kobayashi D, Ito T, Tamura M, Yoshikawa S, Yamazaki H. Comparison of clinical and laboratory features of patients with and without allergic conditions in IgG4-related disease: A single-center experience in Japan. Mod Rheumatol. 2018;28(5):845–8. 79. Della-Torre E, Germanò T, Ramirez GA, Dagna L, Yacoub MR. IgG4-related disease and allergen-specific immunotherapy. Ann Allergy Asthma Immunol. 2020;124(6):631–3. 80. Sandrasegaran K, Menias CO. Imaging in autoimmune pancreatitis and immunoglobulin G4-related disease of the abdomen. Gastroenterol Clin North Am. 2018;47(3):603–19. 81. Khandelwal A, Inoue D, Takahashi N. Autoimmune pancreatitis: An update. Abdom Radiol (NY). 2020;45(5):1359–70. 82. Tanaka A. IgG4-related sclerosing cholangitis and primary sclerosing cholangitis. Gut Liver. 2019;13(3):300–7. 83. Ali AH, Bi Y, Machicado JD, Garg S, Lennon RJ, Zhang L, et al. The long-term outcomes of patients with immunoglobulin G4-related sclerosing cholangitis: The Mayo Clinic experience. J Gastroenterol. 2020;55(11):1087–97. 84. Matsui S, Taki H, Shinoda K, Suzuki K, Hayashi R, Tobe K, et al. Respiratory involvement in IgG4-related Mikulicz’s disease. Mod Rheumatol. 2012;22(1):31–9. 85. Baqir M, Garrity JA, Vassallo R, Witzig TE, Ryu JH. Asthma and orbital immunoglobulin G4-related disease. Ann Allergy Asthma Immunol. 2016;116(4):313–16. 86. Nallani P, Guo W, Mayerhoff RM, Meysami A. An unusual presentation of immunoglobulin G4-related disease (IgG4-RD) causing subglottic stenosis. Cureus. 2022;14(6):e26250. 87. Yamashita H, Takahashi Y, Ishiura H, Kano T, Kaneko H, Mimori A. Hypertrophic pachymeningitis and tracheobronchial stenosis in IgG4-related disease: Case presentation and literature review. Intern Med. 2012;51(8):935–41. 88. Ito M, Yasuo M, Yamamoto H, Tsushima K, Tanabe T, Yokoyama T, et al. Central airway stenosis in a patient with autoimmune pancreatitis. Eur Respir J. 2009;33(3):680–3. 89. Wallace ZS, Perugino C, Matza M, Deshpande V, Sharma A, Stone JH. Immunoglobulin G4-related disease. Clin Chest Med. 2019;40(3):583–97. 90. Xie Y, Xiong A, Marion T, Liu Y. Lung nodules and IgG4 related disease: A single-center based experience. BMC Pulm Med. 2020;20(1):218. 91. Inoue D, Zen Y, Abo H, Gabata T, Demachi H, Kobayashi T, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology. 2009;251(1):260–70. 92. Zen Y, Inoue D, Kitao A, Onodera M, Abo H, Miyayama S, et al. IgG4-related lung and pleural disease: A clinicopathologic study of 21 cases. Am J Surg Pathol. 2009;33(12):1886–93. 93. Fujinaga Y, Kadoya M, Kawa S, Hamano H, Ueda K, Momose M, et al. Characteristic findings in images of extra-pancreatic lesions associated with autoimmune pancreatitis. Eur J Radiol. 2010;76(2):228–38. 283

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115. Lanzillotta M, Fernàndez-Codina A, Culver E, Ebbo M, Martinez-Valle F, Schleinitz N, et al. Emerging therapy options for IgG4-related disease. Expert Rev Clin Immunol. 2021;17(5):471–83. 116. Yunyun F, Yu P, Panpan Z, Xia Z, Linyi P, Jiaxin Z, et al. Efficacy and safety of low dose Mycophenolate mofetil treatment for immunoglobulin G4-related disease: A randomized clinical trial. Rheumatology (Oxford). 2019;58(1):52–60. 117. Yunyun F, Yu C, Panpan Z, Hua C, Di W, Lidan Z, et al. Efficacy of Cyclophosphamide treatment for immunoglobulin G4-related disease with addition of glucocorticoids. Sci Rep. 2017;7(1):6195. 118. Wang Y, Zhao Z, Gao D, Wang H, Liao S, Dong C, et al. Additive effect of leflunomide and glucocorticoids compared with glucocorticoids monotherapy in preventing relapse of IgG4related disease: A randomized clinical trial. Semin Arthritis Rheum. 2020;50(6):1513–20.

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17 Pulmonary Toxicities of Medications Used for Treating Patients with Rheumatic Diseases Emily Littlejohn and Kristine Keaton List of Abbreviations ACR American College of Rheumatology bDMARD Biologic disease-modifying antirheumatic drug BMD Bone mineral density BSR British Society for Rheumatology COPD Chronic obstructive pulmonary disease CTD-ILD Connective tissue disease-associated ILD csDMARD Conventional synthetic disease-modifying antirheumatic drug CT Computed tomography DMARD Disease-modifying antirheumatic drug DILD Drug-induced lung disease GC Glucocorticoid GIOP Glucocorticoid-induced osteoporosis GPA Granulomatosis with polyangiitis HRCT High-resolution computed tomography ILD Interstitial lung disease OP Osteoporosis PJP Pneumocystis jirovecii pneumonia RCT Randomized controlled trial RA Rheumatoid arthritis RA-ILD Rheumatoid arthritis-associated interstitial lung disease SARD Systemic autoimmune rheumatic disease SSc Systemic sclerosis TNF Tumor necrosis factor TNFi Tumor necrosis factor inhibitor 17.1 INTRODUCTION Rheumatologists and pulmonologists often collaborate in the treatment of patients with systemic autoimmune rheumatic diseases (SARDs) that have pulmonary manifestations. They also comanage the pulmonary toxicities associated with the use of disease-modifying antirheumatic drugs (DMARDs), biologic agents, and small-molecule drugs. The goal of this chapter is to review pulmonary toxicities associated with the use of immunosuppressive drugs, common culprits, and the data associated with their adverse effects, as well as measures to prevent or mitigate the risks of these effects. 17.2 OVERVIEW Infections are one of the most common drug-induced lung diseases (DILDs), as medications used to treat SARDs work by targeting and suppressing different pathways of the immune system. Common infections include Pneumocystis jirovecii pneumonia (PJP) and other types of atypical, viral, fungal, mycobacterial, or bacterial pneumonias. Immunosuppressive medications are often withheld while infections are being treated or while acute symptoms persist. Hypersensitivity reactions, including acute respiratory distress syndrome (ARDS), can be seen with infusions such as pegloticase, intravenous immune globulin (IVIG), rituximab, belimumab, or anifrolumab. Other DILDs include pneumonitis, eosinophilic pneumonia, organizing pneumonia, interstitial lung disease (ILD) (typically with long-standing use of these medications), granulomatous disease, lung nodules, pulmonary embolism, and alveolar hemorrhage. As the armamentarium of treatment options expands, there is a continued need for rheumatologists and pulmonologists to work collaboratively. In addition to the material included in this chapter, a helpful resource includes Pneumotox online, The Drug-Induced Respiratory Disease Website https://www.pneumotox.com/drug/index/, which is an archive of data by both disease presentation and medication.

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17.3 ADVERSE EFFECTS OF GLUCOCORTICOIDS AND MITIGATING THESE RISKS The side effects and adverse reactions from the use of glucocorticoids (GCs) are numerous. These include, but are not limited to, increased risk of infection, weight gain, osteoporosis (OP), glaucoma, cataracts, proximal muscle weakness, steroid-induced diabetes, hypertension, dyslipidemia, fluid retention, electrolyte disturbances, osteonecrosis, peptic ulcer disease, and mood disturbance. In patients with systemic sclerosis (SSc), there is also a heightened risk of scleroderma renal crisis, particularly of normotensive renal crisis, with higher doses of GCs, prednisone or its equivalent, ≥15 mg daily (1, 2). Common side effects of GCs include peptic ulcer disease and dyspepsia. Authors generally encourage all patients on medium- to high-dose GCs to be placed on proton pump inhibitors, although evidence to support their use for prophylaxis is lacking (3). Patients with risk factors for peptic ulcer disease such as older age; history of gastroduodenal ulcer, bleeding, or perforation; and concomitant use of medications that are known to increase the likelihood of upper gastrointestinal adverse events should be highly considered for proton pump inhibitor prophylaxis. Data has demonstrated a dose-dependent response across the different levels of exposure to prednisone. The risk of developing new organ damage more than doubled in patients exposed to a mean prior prednisone dose of ≥20 mg daily versus 2.5 mg daily for >3 months, and this assessment should be done as soon as possible; it is recommended within 6 months of the initiation of long-term GC treatment initiation. This assessment is extensive and should include the dose and duration of GC use; an evaluation for falls, fractures, frailty; and other risk factors for fracture (malnutrition, low body weight, hypogonadism, secondary hyperparathyroidism, thyroid disease, family history of hip fracture, history of alcohol use or smoking) (6). Physical measures to be incorporated include weight, height, muscle strength, and assessment for other clinical findings of undiagnosed fracture (6). For adults over 40 years of age, the initial absolute fracture risk should be estimated using the Fracture Risk Assessment Tool (FRAX) (7) with the adjustment for GC dose and BMD testing (if available, or without BMD if it is not available). The ACR GIOP Guidelines provide recommendations for the treatment of patients on GCs with calcium and vitamin D supplementation, as well as considerations for the initiation of osteoporosis therapy. These guidelines are summarized in Table 17.1 (6). Levels of risk (low to very high) are based on BMD, history of fracture, dose and duration of glucocorticoids, and 10-year risk of major OP fracture and hip fracture. Given the complex nature of this topic, a referral to a metabolic bone specialist is encouraged. 17.3.1  Other Considerations for Mitigating GC Risks It is important to consider PJP prophylaxis in patients taking prednisone doses of 20 mg daily or higher for more than 1 month (8). Data on this topic is evolving, with a lack of benefit found in some rheumatic diseases (9). PJP prophylaxis regimens vary and include trimethoprim–sulfamethoxazole one double-strength tablet daily, one single-strength tablet daily, or one doublestrength tablet three times per week (preferred). Dapsone 50 mg twice daily or 100 mg daily, aerosolized pentamidine 300 mg monthly, or atovaquone suspension 1500 mg orally once daily are alternative regimens. 17.4 MEDICATION-INDUCED PULMONARY TOXICITY 17.4.1 Methotrexate Methotrexate is one of the most commonly used DMARDs, and it is also one of the most frequently implicated causes of DILD among the DMARDs. Methotrexate is used at low doses, up to 25 mg weekly, for a variety of rheumatic diseases, as compared to the more frequent or higher doses used in oncology. Nonetheless, the prescribing information for methotrexate warns that methotrexateinduced lung disease, including acute or chronic interstitial pneumonitis, can occur at any time during therapy and has been reported at doses as low as 7.5 mg weekly (10).

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Table 17.1: Recommendations According to Age and GC Exposure Age/Exposure All adults taking prednisone at a dose of ≥2.5 mg/day for >3 months

Adults aged ≥40 years at low risk of fracture Adults aged ≥40 years at high or very high risk of major fracture. *Very high risk of fracture: • Prior OP fracture • T-score 30% or hip >4.5% • High-dose GC therapy (>30 mg daily for >30 days or cumulative GC dose >5 grams in a year) Adults 1 course high-dose GC therapy (>30 mg daily for >30 days or cumulative GC dose >5 grams in a year) All adults at moderate risk of major fracture All adults at low risk of fracture

Recommendation Optimize calcium intake (1000–1200 mg/day), vitamin D intake (600–800 IU/day), and lifestyle modifications (balanced diet, maintaining weight in the recommended range, smoking cessation, regular weight-bearing or resistance training exercise, limiting alcohol intake to