Advances in Integrative Dermatology 9781119476047, 1119476046

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Advances in Integrative Dermatology

Advances in Integrative Dermatology Edited by

Katlein França, MD, PhD Department of Dermatology & Cutaneous Surgery Department of Psychiatry & Behavioral Sciences Institute for Bioethics & Health Policy University of Miami Miller School of Medicine Miami, FL, USA

Torello Lotti, MD Centro Studi per la Ricerca Multidisciplinare e Rigenerativa Università degli Studi Guglielmo Marconi Rome, Italy

This edition first published 2019 © 2019 John Wiley & Sons Ltd All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Katlein França and Torello Lotti to be identified as the author(s) of the editorial material in this work has been asserted in accordance with law. Registered Office(s) John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office 9600 Garsington Road, Oxford, OX4 2DQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging‐in‐Publication Data Names: França, Katlein, editor. | Lotti, T. M. (Torello M.), 1953– editor. Title: Advances in integrative dermatology / edited by Katlein França, Torello Lotti. Description: Hoboken, NJ : Wiley-Blackwell, 2019. | Includes bibliographical references. | Identifiers: LCCN 2018044907 (print) | LCCN 2018045692 (ebook) |   ISBN 9781119476092 (Adobe PDF) | ISBN 9781119475880 (ePub) |   ISBN 9781119476047 (hardcover) Subjects: | MESH: Skin Diseases–therapy | Skin Diseases–complications |   Complementary Therapies–methods Classification: LCC RL74 (ebook) | LCC RL74 (print) | NLM WR 650 |   DDC 616.5–dc23 LC record available at https://lccn.loc.gov/2018044907 Cover Design: Wiley Cover Images: © subodhsathe/iStock.com,© kapulya/iStock.com, © CasarsaGuru/Getty Images, © Dawid Garwol/EyeEm/Getty Images Set in 10/12pt Warnock by SPi Global, Pondicherry, India 10 9 8 7 6 5 4 3 2 1

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Contents Acknowledgements  ix Foreword  xi List of Contributors  xiii 1 Advances in Integrative Dermatology: Modifying the Concepts from the Past to  Change the Future of Dermatology  1 Katlein França and Torello Lotti­ 2 Psycho‐Neuro‐Endocrine‐Immunology: A Psychobiological Concept  9 Torello Lotti and Katlein França 3 Psychoneurocutaneous Medicine  25 Mohammad Jafferany, Paul Pastolero, and Katlein França 4 Acne 33 Bárbara R. Ferreira, José C. Cardoso, José P. Reis, and Américo Figueiredo 5 Rosacea 57 Victor Gabriel Clatici and Cristiana Voicu 6 Seborrheic Dermatitis  71 David E. Castillo, Ilana Gunczler, Katlein França, and Jonette Keri 7 Autoimmune Skin Disorders  89 Francesca Satolli, Miriam Rovesti, and Claudio Feliciani 8 Vitiligo 103 Serena Gianfaldoni and Torello Lotti 9 The Combined Approach to Atopic Dermatitis  119 Christopher Bridgett, Peter Norén, and Richard Staughton 10 Psoriasis  131 Uwe Wollina

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Contents

11 Urticaria  145 Li-Ping Zhao and Xing‐Hua Gao 12 Lichen Planus and Lichenoid Disorders  163 Valeria Mateeva and Snejina Vassileva 13 Itch: An Integrative Approach  187 Radomir Reszke and Jacek C. Szepietowski 14 Infections of the Skin  231 Carmen Maria Salavastru, Adelina Maria Sendrea, Stefana Cretu, and George Sorin Tiplica 15 Nonmelanoma Skin Cancer  257 Anagha Bangalore Kumar, Yasser Al-Qubaisy, and Katlein França 1 ­ 6 Melanoma  271 Karls Raimonds 17 The Microbiome in Hair Disorders  289 Andy Goren, Maja Kovacevic , John McCoy , Mirna Situm, Zeljana Bolanca , Andrija Stanimirovic, Rachita Dhurat, Jill Chitalia , Aseem Sharma, and Torello Lotti 18 Integrative Treatment for Chronic Wounds  295 Evan Darwin, Alexandra R. Vaughn, and Hadar Lev‐Tov 19 Diet and Skin  321 Veronica Di Nardo, Farah Daaboul, Catherine E. Amey, and Victoria Barygina 20 Supplements and Skin  345 Veronica Di Nardo 21 Water and Dermatology  351 Belma Türsen 22 Sleep and Skin  361 Ladan Mostaghimi 23 Exercise and Skin  367 Veronica Di Nardo, Aurelio Conte, Francesca Finelli, and Torello Lotti 24 Skin and Pollution  379 Katerina Damevska, Suzana Nikolovska, Jana Kazandjieva, Bisera Kotevska Trifunova, and Georgeta Bocheva 25 Cosmeceuticals  393 Jaishree Sharad

Contents

26 Botulinum Toxin: Cosmetic and Noncosmetic Dermatological Uses  413 Jaishree Sharad 27 Ayurvedic Dermatology  457 Anagha Bangalore Kumar, Sushmitha Grama Srinivasan, and Raghavendra Rao 28 Acupuncture  467 Paolo Amori and Liguori Aldo 29 Moxibustion in Dermatology  477 Ümit Türsen and Begüm Ünlü 30 Cupping Treatment in Dermatology  483 Begüm Ünlü and Ümit Türsen 31 Biofeedback  487 Jacopo Lotti 32 Meditation, Hypnosis, and Psychotherapy for Skin Disorders  503 Philip D. Shenefelt 33 Dermatoethics and Dermatobioethics in Integrative Dermatology  513 Reginaldo de França, Aparecida Porto França, and Katlein França Index  521

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Acknowledgements “If I have seen further it is by standing on the shoulders of giants” (Isaac Newton) We sincerely thank all the authors of this book, whose efforts in writing chapters are highly appreciated. Without your contribution, the production of this book would not have been possible. We also would like to thank the Università degli Studi Guglielmo Marconi and the World Health Academy of Integrative Dermatology for supporting

the development of the field of Integrative Dermatology. We are also indebted to our families for their support during the entire time we were editing this book. We are also thankful to Wiley for providing the opportunity to bring this book to the readers. It has been a pleasure working with them in this inspiring project. Avanti! Katlein França, MD, PhD Torello Lotti, MD, MD (Hon)

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Foreword Integrative dermatology combines conventional treatments with the complementary use of botanicals, herbal medicines, and nutritional guidance, as well as mind–body interventions such as hypnosis, biofeedback therapy, and mindfulness. The question “Could modern dermatology be considered to have two distinct camps?” has been debated. These proposed camps may be ­conceived of thusly: on one side, a growing number of dermatologists armed with dietary advice, nutritional supplements, and psychodermatological interventions; on the

other side, dermatologists providing traditional therapies such as biologics, immunosuppressants, antihistamines, and steroids. We believe that, in the future, the training of dermatologists should take an integrative approach, combining conventional and ­complementary treatments. Thanks to this unique book, tomorrow’s dermatologists will have the medical knowledge and necessary skills to safely practice evidence-based integrative dermatology. Dr. Ümit Türsen

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List of Contributors Yasser Al-Qubaisy, MD

Christopher Bridgett, MD

Department of Dermatology and Dermatological Surgery, Prince Sultan Military Medical City, Riyadh, KSA

Imperial College, Chelsea & Westminster Hospital, London, UK

Liguori Aldo, MD

Department of Dermatology, Coimbra Hospital and University Centre Coimbra, Portugal

Department of Anatomic, Histologic, Forensic Medicine and Locomotor System Sciences, Faculty of Pharmacy and Medicine, Paracelso Institute, Sapienza University, Rome, Italy Catherine E. Amey, BS

José C. Cardoso, MD

David E. Castillo, MD

Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

Azienda Ospedaliera San Giovanni di Dio e Ruggi D’Aragona Salerno, Italy

Jill Chitalia, MD

Paolo Amori, MD

Victor Gabriel Clatici, MD

Centro Studi per la Ricerca Multidisciplinare e Rigenerativa, Università degli Studi Guglielmo Marconi, Rome, Italy Victoria Barygina, PhD

Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy Georgeta Bocheva, MD, PhD

Department of Pharmacology and Toxicology, Medical University, Sofia, Bulgaria Zeljana Bolanca, MD

Department of Dermatology and Venereology, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia

Department of Dermatology, LTM Medical College and Hospital Sion, Mumbai, India DermaLife – Medlife Group, Bucharest, Romania Aurelio Conte, BS

Azienda Ospedaliera San Giuseppe Moscati Avellino, Italy Stefana Cretu, MD

2nd Clinic of Dermatology, Colentina Clinical Hospital, Bucharest, Romania Farah Daaboul, PhD

Institute of Dermatological and Regenerative Sciences, Florence, Italy Katerina Damevska, MD, PhD

University Clinic of Dermatology, Ss Cyril and Methodius University, Skopje, Republic of Macedonia

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List of Contributors

Evan Darwin, BA

Serena Gianfaldoni, MD

Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

Department of Dermatology, Università degli Studi Guglielmo Marconi Rome, Italy

Reginaldo de França, Msc, PhDc

Andy Goren, MD

Universidad del Museo Social Argentino, Buenos Aires, Argentina Rachita Dhurat, MD

Department of Dermatology, LTM Medical College and Hospital Sion, Mumbai, India Veronica Di Nardo, PhD

Centro Studi per la Ricerca Multidisciplinare e Rigenerativa Università degli Studi Guglielmo Marconi Rome, Italy Claudio Feliciani, MD

Dermatology Unit, Deparment of Medicine and Surgery, University of Parma Parma, Italy Bárbara R. Ferreira, MD

Department of Dermatology and Venereology, Università degli Studi Guglielmo Marconi, Rome, Italy Ilana Gunczler, MD

Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA Xing-Hua Gao, MD

Department of Dermatology, The First Hospital of China Medical University Shenyang, China Mohammad Jafferany, MD

Department of Psychiatry, Central Michigan University, Mount Pleasant, MI, USA

Department of Dermatology, Coimbra Hospital and University Centre Coimbra, Portugal

Jana Kazandjieva, MD, PhD

Américo Figueiredo, MD, PhD

Jonette Keri, MD, PhD

Department of Dermatology, Coimbra Hospital and University Centre Coimbra, Portugal Francesca Finelli, BS

Azienda Ospedaliera San Giuseppe Moscati Avellino, Italy Aparecida Porto França, Msc, PhD, PostDoc

Instituto Universitário Italiano de Rosario Rosario, Argentina Katlein França, MD, PhD

Department of Dermatology & Cutaneous Surgery Department of Psychiatry & Behavioral Sciences Institute for Bioethics & Health Policy Miami, FL, USA Centro Studi per la Ricerca Multidisciplinare e Rigenerativa Univeristà degli Studi Guglielmo Marconi, Rome, Italy

Department of Dermatology, Medical University, Sofia, Bulgaria Dermatology Service, Miami VA Hospital and Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA Bisera Kotevska Trifunova, MD

Department of Dermatology, Tokuda Hospital, Sofia, Bulgaria Maja Kovacevic, MD

Department of Dermatology and Venereology, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia Anagha Bangalore Kumar, M.B.B.S

Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA Hadar Lev-Tov, MD

Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

List of Contributors

Jacopo Lotti, PhD

Radomir Reszke, MD

Department of Nuclear, Sub‐nuclear and Radiation Physics, Università degli Studi Guglielmo Marconi, Rome, Italy

Department of Dermatology, Venereology, and Allergology, Wroclaw Medical University, Wroclaw, Poland

Torello Lotti, MD

Miriam Rovesti, MD

Centro Studi per la Ricerca Multidisciplinare e Rigenerativa, Università degli Studi Guglielmo Marconi, Rome, Italy

Dermatology Unit, Deparment of Medicine and Surgery, University of Parma, Parma, Italy

Valeria Mateeva, MD

Carmen Maria Salavastru, MD, PhD

Department of Dermatology and Venereology, Military Medical Academy, Sofia, Bulgaria John McCoy, PhD

Applied Biology, Inc., Irvine, CA, USA Ladan Mostaghimi, MD

Wisconsin Psychocutaneous Clinic, Middleton, WI, USA Suzana Nikolovska, MD, PhD

University Clinic of Dermatology, Ss Cyril and Methodius University, Skopje, Republic of Macedonia Peter Norén, MD

Laserkliniken in Uppsala, Department of Medical Sciences, Uppsala University Uppsala, Sweden Paul Pastolero, MD

Department of Psychiatry, Central Michigan University, Mount Pleasant, MI, USA Karls Raimonds, MD

Department of Infectology and Dermatology Derma Clinic Riga, Dr. R.Karla klīnika Riga Stradins University, Riga, Latvia

Pediatric Dermatology Unit, Carol Davila University of Medicine and Pharmacy Bucharest, Romania Francesca Satolli, MD

Dermatology Unit, Deparment of Medicine and Surgery, University of Parma Parma, Italy Adelina Maria Sendrea, MD

2nd Clinic of Dermatology, Colentina Clinical Hospital Developmental and Research Unit, Bucharest, Romania Jaishree Sharad, MD

Skinfiniti Aesthetic Skin and Laser Clinic Mumbai, India Aseem Sharma, MD

Department of Dermatology, LTM Medical College and Hospital Sion Mumbai, India Philip D. Shenefelt, MD

Department of Dermatology and Cutaneous Surgery, College of Medicine, University of South Florida, Tampa, FL, USA Mirna Situm, MD , PhD

Health Care Global, Bangalore, India

Department of Dermatology and Venereology, University Hospital Center Sestre Milosrdnice Zagreb, Croatia

José P. Reis, MD

Sushmitha Grama Srinivasan, M.B.B.S

Department of Dermatology Coimbra Hospital and University Centre Coimbra, Portugal

Department of Radiology, Kempegowda Institute of Medical Sciences Bangalore, India

Raghavendra Rao, PhD

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List of Contributors

Andrija Stanimirovic, MD

Begüm Ünlü, MD

Department of Clinical Medicine, University of Applied Health Sciences, Zagreb, Croatia

Department of Dermatology, Mersin University, Mersin, Turkey

Richard Staughton, MD

Snejina Vassileva, MD, PhD

Imperial College, Chelsea & Westminster Hospital, London, UK Jacek C. Szepietowski, MD, PhD

Department of Dermatology, Venereology, and Allergology, Wroclaw Medical University, Wroclaw, Poland George Sorin Tiplica, MD, PhD

2nd Clinic of Dermatology, Colentina Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Department of Dermatology and Venereology, Medical University Sofia, Bulgaria Alexandra R. Vaughn, MD

Department of Dermatology, University of California – Davis, Sacramento, CA, USA Cristiana Voicu, MD

DermaLife – Medlife Group Bucharest, Romania Uwe Wollina, MD

Tursen Dermatology Clinic, Mersin, Turkey

Department of Dermatology and Allergology, Academic Teaching Hospital Dresden, Dresden, Germany

Ümit Türsen, MD

Li-Ping Zhao, MD

Belma Türsen, MD

Department of Dermatology, Mersin University, Mersin, Turkey

Department of Dermatology, General Hospital, Shenyang, China

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1 Advances in Integrative Dermatology: Modifying the Concepts from the Past to Change the Future of Dermatology Katlein França1,2 and Torello Lotti1 1

 Centro Studi per la Ricerca Multidisciplinare e Rigenerativa, Università degli Studi Guglielmo Marconi, Rome, Italy  Department of Dermatology & Cutaneous Surgery; Department of Psychiatry & Behavioral Sciences; Institute for Bioethics & Health Policy, University of Miami Miller School of Medicine, Miami, FL, USA

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“Every writer creates his own precursors. His work modifies our conception of the past, as it will modify the future.” Jorge Luis Borges

­Introduction Medical practices that reside outside the mainstream medical structures have existed for centuries. [1] The origins of medicine are deeply rooted in civilization’s cultural beliefs, experiences, and observations, and those practicing medicine believed that the body and the mind were not two separate entities. In the 1600s Rene Descartes, in an attempt to protect the body from spirits, separated the body from the mind. This was the beginning of evidence‐based medicine where the understanding of parts would lead to an understanding of the whole [2]. Subsequent developments such as antibiotics, other pharmaceuticals, anesthetics, and sterile surgical procedures gave a different perspective to medicine [3]. In particular, the discovery of antibiotics in 1928 boosted the pharmaceutical model we have today which emphasizes drugs as a primary means to treat disease. In Western civilizations, complementary and alternative medicines (CAMs) only began to re‐emerge after the 1960s with the awareness

that chronic diseases were replacing acute diseases as the predominant health problem, and that a reductionist pharmaceutical model alone could not be sufficient for the prevention or treatment of these chronic diseases [4]. Different concepts and terms were given to describe the Integrative Medicine field: holistic medicine, alternative or complementary medicine, and then complementary and alternative medicine(CAM) [5]. The authors of this chapter understand that Integrative Medicine encompasses the coordination of conventional medicine with complementary therapies. The same concept applies to the Integrative Dermatology field. The skin is the largest organ of the human body interacting with other organs and responding to psychological, endocrines, and nervous stimuli through the Psycho‐Neuro‐Endocrine‐ Immune system [6]. The integrative approach consists of a comprehensive evaluation of the physical, biological, psychological, social, and environmental overlapping aspects that affect the patient’s life, offering them conventional and complementary therapies with scientific basis. The integrative approach is based on the concept that every human being has a “diffuse brain” that commands a cross‐talk of messengers (cytokines, neuropeptides, hormones, grow factors, etc.) involved in the Psycho‐ Neuro‐Endocrine‐Immune system.

Advances in Integrative Dermatology, First Edition. Edited by Katlein França and Torello Lotti. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

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Advances in Integrative Dermatology

This book explores a new kind of dermatological healthcare. It is patient centered, and considers the physical, biological, psychological, social, and environmental aspects of the patient’s life. It is based on dermatological healthcare promotion and skin ­diseases prevention, and embraces evidencebased conventional and complementary therapies.

dermatology is used in place of conventional dermatology [7, 8] (Figures 1.1 and 1.2).

­Integrative Dermatology: Conventional and Complementary Dermatology

Greeting the patient is the first step to establish rapport between the healthcare provider and the patient. In general, a handshake seems to be the most appropriate way to start a consultation. However, religious and cultural aspects may interfere in this process, so the healthcare professional should remain sensitive to nonverbal cues that might indicate whether patients are open to this behavior. The physicians should introduce themselves using their first and last names and also call the patients by their first and last names, at least in the initial contact, following the national patient safety recommendations concerning patient iden­ tification. [9, 10] The physician should ask the reason for the visit. The interview should address the duration and location of the patient’s cutaneous diseases (if any), other diseases, family medical history, use of and allergy to medications, sun exposure, current and previous skincare regimens, daily habits including exercise and diet, and the patient’s emotional state [11]. More questions should be asked during the physical examination as needed.

Conventional Dermatology Also called allopathic dermatology, mainstream dermatology, orthodox dermatology, or Western dermatology, this healthcare model of dermatology is generally taught in traditional medical schools and dermatology specialization programs. It uses evidence‐ based knowledge and uses drugs, surgery, and minimally invasive procedures as a form of treatment. Complementary Dermatology Complementary dermatology refers to a group of diagnostic and therapeutic disciplines that are used together with conventional dermatology. Complementary dermatology is different from alternative dermatology. Whereas complementary dermatology is used together with conventional dermatology, alternative

CONVENTIONAL DERMATOLOGY

­ illars of the Integrative P Approach Physical Findings What does the patient present, and is visible to the physician?

COMPLEMENTARY DERMATOLOGY

INTEGRATIVE DERMATOLOGY

Figure 1.1  Integrative dermatology: combination of conventional dermatology and complementary dermatology.

­Pillars of the Integrative Approac

PHYSICAL

ENVIRONMENTAL

SOCIAL

BIOLOGICAL

PSYCHOLOGICAL

Dermatological health promotion and diseases prevention

Use of conventional and complementary therapies

Use the concept of the Psycho-Neuro-Endocrine-Immune System and correlates it with the physical health of the skin

Offer a personalized dermatological care

Promotes patients empowerment and autonomy

Explore the connection between Nature, Health and Beauty

Protect and promote patient's rights and ethics

Incorporate the concepts of quality of life and balanced life to dermatology

Figure 1.2  Pillars and principles of integrative dermatology by França and Lotti.

A complete skin examination is essential in the assessment of patients. All healthcare professionals should have a fundamental knowledge of the structures and functions of the skin in order to assess any changes to normal skin [12]. The ideal physical examination includes a systematic exam of the entire skin and its appendages. It is important to examine the skin for lesions that are directly related to the chief complaint as well as for incidental findings, especially for lesions that may be skin cancer [13].

A study published in the British Journal of Dermatology showed that in a nine‐month period, in a sample of 483 new patients, three patients (0.6%) had potentially lethal skin malignancies identified that would not have been diagnosed without a complete skin examination. Sixteen (3.3%) patients had basal cell carcinomas that would have been missed without a complete skin examination. This study confirms the traditional teaching that complete skin examination has the potential to reduce morbidity and mortality from cutaneous malignancy [14].

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Advances in Integrative Dermatology

Dermatological equipment should be available during the physical examination, including: magnifying lens, dermatoscope, Wood’s light, a microscope, and a camera to document the findings. França performed a study in Brazil with 307 patients and found that 57% of that sample considered that the use of devices (magnifying lens, dermatoscope) by the physician ­during the physical examination would be fundamental for the correct diagnosis of the disease. Although not always true, these patients may believe that the technology helps their physician to make their diagnosis [15]. This physical findings session emphasizes the need for a complete physical assessment to find the physical manifestations of the disease or complaint, and the findings that are visible to the physician. Biological Factors: The Psycho‐ Neuro‐Endocrine‐Immune System What is the identity of the patient?

Biological factors refer to anything that could affect the function and behavior of a living organism. These factors could be physiological, chemical, neurological, endocrinological, and immunological, or a genetic condition which causes a psychological effect. Bio­ logical factors are seen as the primary ­determinants of human behavior [16]. The psychobiological concept involving the Psycho‐Neuro‐Endocrine‐Immune System is  particularly useful for the study of der­ matological diseases. The Psycho‐Neuro‐ Endocrine‐Immunology (PNEI) is a scientific field of study that investigates the link between multidirectional communications among the nervous system, the endocrine system, and the immune system, and the correlations of this cross‐talk with physical health of the skin. The authors emphasize that this innovative medical approach represents a paradigm shift from a strictly biomedical view of health and disease taken as hermetically sealed compartments to a more interdisciplinary and integrative one [17].

Psychological Aspects: Psychodermatology and Quality of Life How does the patient think, feel, and behave?

Exploring the psychological aspects and emotional state of patients with skin disorders is one of the bases of the integrative approach. The skin is a visible organ and any disease affecting this important organ can cause psychological distress. On the other hand, psychological distress can also trigger certain dermatologic diseases [18]. This vicious cycle should be kept in mind when assisting a patient in the integrative dermatology clinic. Medical care can be significantly improved when the physician pays more attention to the psychological aspects of medical assessment and treatment [19]. A good doctor–patient relationship, as well as empathy, is fundamental for a successful conversation between the doctor and the patient and disease management. The patient’s background, previous traumas, current feelings, and coping strategies should be explored during the consultation [19]. Skin diseases can affect the psychological state and quality of life of patients, affecting the health in general and the progression of the disease, as well as the patient’s response to therapy [20]. Different dermatology‐specific measures are available such as the Dermatology Life Quality Index (DLQI), the Dermatology Quality of Life Scales (DQOLSs), the Dermatology Specific Quality of Life (DSQL), and Skindex. Other disease‐specific measures such as the Psoriasis Disability Index (PDI), the Psoriasis Life Stress Inventory (PLSI), and the Acne Disability Index (ADI) can be also useful in the clinical practice. There are instruments used for measuring QOL in the pediatric popu­lation such as the Children’s Dermatology Life Quality Index (CDLQI) and for measuring the impact of atopic dermatitis on the families of affected children (the Dermatitis Family Impact [DFI] questionnaire). New versions of the current measurements and development of new ones are in process [21]. Chen explains that the improvement of

­Pillars of the Integrative Approac

health‐related quality of life (HRQoL) is a major goal of dermatology. Important targets in clinical dermatology include the identification of how the skin condition affects lives, quantifying this burden, and using this information to improve patients’ lives on an individual basis [22]. Balance is often mentioned in personal development and well‐being circles. The concept and idea of a balanced life should be incorporated into the dermatology practice and discussed with patients. Bloom et  al. define the domains for a balanced life and the list includes: health, family, spirituality, learning, primary relationship, sexuality, play, creative expression, emotional well‐being, career, finances, friendship, home, and service [23].

Social Perspective: Social Interactions that Worsen or Improve Patient’s Lives How does the condition affect the patient’s social life? How can social interactions improve or worsen the patient’s condition?

In 1934, Dr. George Minot wrote “a considerable fraction of the successful care and treatment of patients and, undoubtedly, the prevention of much illness is to be identified with the proper consideration of sociologic factors. The case of every patient who consults a physician has a medical social aspect. This social component of medicine may vary widely in importance, but frequently it plays a major role in diagnosis, prognosis, and treatment and in the prevention of disease and unhappiness.” [24] There is a cycle where social behavior influences the disease, and the disease influences the social behavior [25]. More than a cosmetic problem, skin diseases can cause stigma and d ­ isfigurement that could lead to bullying and social isolation [26, 27]. Stigmatization is defined as having a discrediting mark that leads to social discrimination and alienation [28]. One of the most stigmatizing diseases affecting the skin is leprosy. For many centuries, this disease has been responsible for social segregation, depression, and anxiety.

Over the years with the advancement of ­treatments and education of patients and the community, this situation has improved. However, it still poses a challenge for many cultures [29]. Psoriasis, a chronic, autoimmune and inflammatory skin disorder, is another challenging disease that causes rejection and stigma. Despite the fact that is not a contagious disease, it has a serious impact on the patients’ lives and well‐being [30]. It is important for the dermatologist to ask the patient about their social relationships and how the disease is affecting their social life. A  questionnaire named The Sociotype Questionnaire (SOCQ) containing 16 items that evaluate the quality of relationships through the dimensions of family, friends, acquaintances, and study/work colleagues (including four questions for each dimension) was developed to explore both structural and dynamic aspects of social networking. The SOCQ is pending publication [31]. Skin disorders can affect not only the patient’s quality of life but also that of partners and other family members in very diverse ways. Basra and Finlay proposed the term “the greater patient” to determine the secondary impact of a patient’s skin disease on the patient’s family or partner. The ‘Greater Patient’ concept describes the immediate close social group affected by a person having skin disease [32]. The concept of “Social Medicine” emerged in the nineteenth century and aims to understand how social and economic conditions impact health, disease, and the practice of medicine, and to foster conditions in which this understanding can lead to a healthier society [33]. Social support is necessary for the optimal management of certain skin conditions. Education and involvement of family members in the management of disease, or support groups with the presence of other patients and healthcare professionals, can help the patient to cope with their own condition and help others suffering from a similar disease. This helps the patient’s empowerment process.

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Advances in Integrative Dermatology

Environmental Overview: The Ecology and the Skin How do the external and internal environments contribute to the development, exacerbation, or improvement of the skin condition?

Environment is defined as the circumstances, objects, or conditions by which one is surrounded [34]. The environment plays an important role in the skin’s health. Exposures to smoke, pollution, ultraviolet radiation, different temperatures, toxic chemicals, or ­ prolonged/repeated exposure to water are environmental stressors [35]. It is the level of exposure that determines if damage to the organism will result. Diseases such as contact dermatitis, halogen acne, chemical depigmentation, connective tissue diseases, and skin cancer, etc. have the influence of the environment in their etiology [29]. The effects of environmental stressors on the skin were described by França et  al. These authors defined the concept of “Environmental Psychodermatology” as a developing area that studies the interaction between environmental and psychological stressors and the skin [36]. On the other hand, the environment can contribute to the improvement of certain skin conditions. For example, some patients with psoriasis may improve during summertime due to the exposure to UV rays. As part of the integrative approach, it is important to explore and understand the environment surrounding the patient and how this can affect the skin. Another way of exploring the environmental perspective is considering the “internal environment.” The microbiota are an important part of the internal environment and

Table 1.1  Integrative dermatology healthcare model: key questions‐ by França and Lotti. Physical

What does the patient present and is visible to the physician?

Biological

What is the identity of the patient?

Psychological

How does the patient think, feel, and behave ?

Social

How does the condition affect the patient’s social life? How can social interactions improve or worsen the patient’s condition?

Environmental

How do the external and internal environments contribute to the development, exacerbation, or improvement of the skin condition?

understanding how these bacteria interact with the innate immune cells to generate immune tolerance, as well as how they interact with the brain through the gut‐brain connection, may open up opportunities for development of new therapeutic strategies in dermatology. [37, 38] (Table 1.1)

­Conclusion Integrative dermatology is an upcoming field of study that encompasses the coordination of conventional dermatology with evidencebased complementary therapies. The integrative dermatology approach considers the physical, biological, psychological, social, and environmental aspects of the patient’s life.

­References 1 Jonas, W.B., Eisenberg, D., Hufford, D., and

Crawford, C. (2013). The evolution of complementary and alternative medicine (CAM) in the USA over the last 20 years. Forsch. Komplementmed. 20 (1): 65–72. https://doi.org/10.1159/000348284.

2 Petri, R.P. Jr., Delgado, R.E., and McConnell, K.

(2015). Med. Acupuncture. 27 (5): 309–317. https://doi.org/10.1089/acu.2015.1120. 3 Sierpina, V. (2006). The history of complementary and integrative medicine. South. Med. J. 99 (8): 906–907.

­Reference

4 Riley, D.S., Anderson, R., Blair, J.C. et al.

(2016). The academy of integrative health and medicine and the evolution of integrative medicine practice, education, and fellowships. Integr. Med. 15 (1): 38–41. 5 Dattner, A. (2014). The history, research, education, and future of integrative dermatology. In: Integrative Dermatology (ed. R.A. Norman, P.D. Shenefelt and R.N. Rupani). Oxford, UK: Oxford University Press Retrieved 29 Sep. 2017, from http:// oxfordmedicine.com/view/10.1093/ med/9780199907922.001.0001/ med‐9780199907922‐chapter‐30. 6 Lotti, T., Hercogova, J., Wollina, U. et al. (2015). Treating skin diseases according to the low dose medicine principles. Data and hypotheses. J. Biol. Regul. Homeost. Agents. 29 (1 Suppl): 47–51. 7 Complementary Medicine: Available at: https://www.medicinenet.com/script/ main/art.asp?articlekey=31077. Accessed on 11.29.2017 8 França, K. and Lotti, T. (2017). Complementary medicine and the role of integrative dermatology for the treatment of atopic dermatitis. Dermatol. Ther. 30: e12469. https://doi.org/10.1111/dth.12469. 9 Laird, J.E., Tolentino, J.C., and Gray, C. (2013). Patient greeting preferences for themselves and their providers in a military family medicine clinic. Mil. Med. 178 (10): 1111–1114. https://doi.org/10.7205/ MILMED‐D‐12‐00360. 10 Makoul, G., Zick, A., and Green, M. (2007). An evidence‐based perspective on greetings in medical encounters. Arch. Intern. Med. 167 (11): 1172–1176. 11 McKay, M. (1990). An overview of the skin and appendages. In: Clinical Methods: The History, Physical, and Laboratory Examinations, 3e (ed. H.K. Walker, W.D. Hall and J.W. Hurst). Boston: Butterworths. 12 Bianchi, J. and Cameron, J. (2008). Assessment of skin integrity in the elderly 1. Br. J. Community Nurs. 13 (3): S26, S28, S30‐2. 13 Soutor, C. History and physical examination of the skin, hair, and nails. In: Clinical Dermatology (ed. C. Soutor and

14

15

16

17

18

19

20

21

22

23

M.K. Hordinsky). New York, NY: McGraw‐ Hill http://accessmedicine.mhmedical. com/content.aspx?bookid=2184§ion id=165458551. Moran, B., McDonald, I., Wall, D. et al. (2011). Complete skin examination is essential in the assessment of dermatology patients: findings from 483 patients. Br. J. Dermatol. 165 (5): 1124–1126. https://doi. org/10.1111/j.1365‐2133.2011.10483.x. França, K. A dermatologia e o relacionamento medico‐paciente: aspectos psicosociais e bioéticos. Ed Juruá, 2012 Brazil. Psychology dictionary: biological factor. Available at: https://psychologydictionary. org/biological‐factor Access on December 5th, 2018 França, K. and Lotti., T. (2017). Psycho‐ neuro‐endocrine‐immunology: a psychobiological concept. Adv. Exp. Med. Biol. 996: 123–134. https://doi.org/10.1007/ 978‐3‐319‐56017‐5_11. França, K., Castillo, D.E., Roccia, M.G. et al. (2017). Psychoneurocutaneous medicine: past, present and future. Wien. Med. Wochenschr. https://doi.org/10.1007/ s10354‐017‐0573‐3. Kroenke, K. (2002). Psychological medicine: Integrating psychological care into general medical practice. Br. Med. J. 324 (7353): 1536–1537. Taborda, M.L. et al. (2010). Evaluation of the quality of life and psychological distress of patients with different dermatoses in a dermatology referral center in southern Brazil. An. Bras. Dermatol. 85 (1): 52–56. Finlay, A.Y. (1998). Quality of life assessments in dermatology. Semin. Cutan. Med. Surg. 17 (4): 291–296. Chen, S.C. (2012). Health‐related quality of life in dermatology: introduction and overview. Dermatol. Clin. 30 (2): 205–208, xiii https://doi.org/10.1016/j. det.2011.12.001. Bloom, L. and Bloom, C. How to Rebalance and Out‐of‐balanced life. Available at: https://www.psychologytoday.com/blog/ stronger‐the‐broken‐places/201509/ how‐rebalance‐out‐balanced‐life

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24 Minot, G. (1934). Medical social aspects In

25

26

27

28

29

30

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practice. Arch. Intern. Med. (Chic). 54 (1): 1–10. https://doi.org/10.1001/archinte. 1934.00160130004001. Russell, W.M. and Russell, C. (1983). Evolutionary and social aspects of disease. Ecol. Dis. 2 (2): 95–106. Barankin, B. and DeKoven, J. (2002). Psychosocial effect of common skin diseases. Can. Family Phys. 48: 712–716. Roosta, N., Black, D.S., Peng, D., and Riley, L.W. (2010). Skin disease and stigma in emerging adulthood: impact on healthy development. J. Cutan. Med. Surg. 14 (6): 285–290. https://doi. org/10.2310/7750.2010.09053. Hrehorów, E., Salomon, J., Matusiak, L. et al. (2012). Patients with psoriasis feel stigmatized. Acta Derm. Venereol. 92 (1): 67–72. https:// doi.org/10.2340/00015555‐1193. Couto Dal Secco, R.G., França, K., Castillo, D. et al. (2017). Wien. Med. Wochenschr 167 (Suppl 1): 27. https://doi.org/10.1007/ s10354‐017‐0590‐2. Łakuta, P., Marcinkiewicz, K., Bergler‐ Czop, B., and Brzezińska‐Wcisło, L. (2017). How does stigma affect people with psoriasis? Adv. Dermatol. Allergol. Postȩpy Dermatologii i Alergologii. 34 (1): 36–41. https://doi.org/10.5114/pdia.2016.62286. Marron, S.E., Del Moral, R., Navarro, J. et al. (2018). The Sociotype in Dermatology. J. Eur. Acad. Dermatol. Venereol. 32 (5): e188–e190.

32 Basra, M.K.A. and Finlay, A.Y. (2007). The

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family impact of skin diseases: the Greater Patient concept. Br. J. Dermatol. 156: 929–937. https://doi. org/10.1111/j.1365‐2133.2007.07794.x. McKeown, T. and Lowe, C.R. (1966). An Introduction to Social Medicine. Oxford and Edinburgh: Blackwell Scientific Publications. Merriam‐Webster Dictionary Online: Access: https://www.merriam‐webster. com/dictionary/environment on November 16th, 2017. English, J.S., Dawe, R.S., and Ferguson, J. (2003). Environmental effects and skin disease. Br. Med. Bull. 68: 129–142. França, K., França, A., and França, R. (2016). Environmental psychodermatology: stress, environment and skin. In: Stress and Skin Disorders: Basic and Clinical Aspects (ed. K. França and M. Jafferany). London: Springer. Hu, Y., Wong, F.S., and Wen, L. (2017). Antibiotics, gut microbiota, environment in early life and type 1 diabetes. Pharmacol. Res. 119: 219–226. https://doi. org/10.1016/j.phrs.2017.01.034. França, K. and Lotti, T. (2017). The gut‐brain connection and the use of probiotics for the treatment of depression, anxiety and obsessive‐ compulsive disorders in dermatology. Dermatol. Ther. 30 (5): https://doi. org/10.1111/dth.12506.

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2 Psycho‐Neuro‐Endocrine‐Immunology: A Psychobiological Concept Torello Lotti1 and Katlein França1,2 1

 Centro Studi per la Ricerca Multidisciplinare e Rigenerativa , Università degli Studi Guglielmo Marconi, Rome, Italy Department of Dermatology & Cutaneous Surgery, Department of Psychiatry & Behavioral Sciences, Institute for Bioethics & Health Policy, University of Miami Miller School of Medicine, Miami, FL, USA 2 

In the field of experimental psychology applied to medicine, the second half of the 1980s is characterized by Dr. Rober Ader and his colleagues. They theorized and divulged the principles of Psycho‐Neuro‐Endocrine‐ Immunology (PNEI), the scientific field of study that investigates the link between bidirectional communications among the nervous system, the endocrine system, and the immune system, and the correlations of this cross‐talk with physical health. The sentence “For this is the great error of our day that the physicians separate the soul from the body” (Hippocrates, sixth century BCE) clearly represents the primum movens of Dr. Ader’s studies against the traditional scotomized medical view which is described, for example, by the assertion that the immune system is autonomous, with its self‐regulatory and functions separate and independent from the rest of the body. Dr. Ader’s initial research in the 1970s on the conditioning of the immune system by psychosocial factors become a cornerstone for studies that described the vast communications network among immune cells, hormones, and neurotransmitters; Ader’s early observations were also confirmed by Ader himself and other researchers at Harvard University during the 1980s.

Thanks to Dr. Ader’s work devoted to the postulation and the development of the new science of PNEI, these old views become less legitimate and, nowadays, the PNEI concepts guide the scientific community to a unified vision of the biological functions of the body [1–4]. The PNEI innovative medical approach represents a paradigm shift from a strictly biomedical view of health and disease taken as hermetically sealed compartments to a more interdisciplinary one. After years of ostracism and diffidence, mind–body interactions are now well recognized, deeply studied in the medical literature, and taught at most important medical schools. In 1983 Dr. Ader wrote: “Converging data from a variety of disciplines suggest that the immune system is integrated with other physiological systems and, like all such systems operating in the interests of homeostasis, is sensitive to regulation or modulation by the brain. Thus, the immune system stands as a potential mediator of a variety of psychophysiologic effects” [5]. The concept of cross‐talk between PNEI system components and the pivotal role of the immune ­system clearly appear in these sentences. years have passed since More than 30  Ader’s pioneering observations and the PNEI concept is now well established and accepted,

Advances in Integrative Dermatology, First Edition. Edited by Katlein França and Torello Lotti. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

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despite the initial resistances. An example of a modern, full, integrated medical approach to reduce job‐related distress symptoms (e.g. in healthcare workers) and adrenocortical activity is represented by Psycho‐Neuro‐ Endocrino‐Immunology‐based meditation (PNEIMED) an innovative approach that combines the teaching of philosophy and meditation practice with biomedical analysis from a systemic and integrative perspective [6]. Moreover, from the biochemical point of view, the advances in the fields of molecular biology and physiopathology identified hormones, neuropeptides, cytokines, and ­ growth factors as the signaling molecules involved in both physiological and pathological biological processes, are in clear accordance with the principles of PNEI

­ idirectional PNEI Cross‐talk B in Dermatology: The  Gut–Brain–Skin Axis The key element of PNEI approach is represented by the concept of bidirectional cross‐ talk [7] between the psychoneuroendocrine and immune systems (Figure 2.1). The psychoneuroendocrine system can influence the immune response and, therefore, HOMEOSTATIC CONTROL SYSTEMS

P N

CENTRAL NERVOUS SYSTEM & NEUROVEGETATIVE SYSTEMS

E

ENDOCRINE SYSTEM

I

IMMUNE SYSTEM

Figure 2.1  Schematic representation of homeostatic control systems within the PNEI network.

the capacity of the organism to react against diseases; conversely, the immune system can influence the neuroendocrine functions of the whole body. Such cross‐talk among systems is carefully trimmed by feedback loops that simultaneously act in order to maintain the homeostatic equilibrium. This complex interplay is mediated by a wide network of cytokines, hormones, growth factors, neuropeptides, and other intermediate molecules collectively named signaling (or messenger) molecules. These molecules are the “ABC”, the fundamental language of physiological cross‐talk which efficiently regulates cellular responses to both endogenous and exogenous stimuli. The state of health or disease of a whole body can be depicted by the fluctuations of signaling molecules circulating levels: if the fluctuations are outside the homeostatic range (upper or lower than the physiological limits) we consider this status as a pathologic one. Gut and skin roles and relations with other organs and tissues are paradigmatic examples of the PNEI logic. Gut and skin are crucial contact organs through which the mammalian body communicates with the environment. They share some important characteristics: they are richly vascularized and innervated, and they are also heavily colonized by specific microbial strains [8, 9]. Gut and skin can be considered as complex immune and neuroendocrine organs integrated into the whole immune–endocrine system and their ­correct functioning is crucial to guarantee the homeostasis and, consequently, the ­survival of the entire organism [10]. All the PNEI axes, such as the Gut–Brain Axis and the Gut–Skin Axis, are multi‐level networks; they are continuously physiologically modulated by the cellular signaling exchange driven by cytokines, neuropeptides, neurohormones, and other messenger molecules. In physiological conditions, this continuous cross‐talk maintains the PNEI homeostasis of the axes. Recently, the ­concept of Gut–Brain–Skin Axis has been discussed by Petra Arck and colleagues [11].

  Bidirectional PNEI Cross-Talk in Dermatology

In 2009 the researchers observed for the first time the connection between the well‐ known Gut–Brain Axis and Gut–Skin Axis and, through experimental data (in vivo mice model), described the effectiveness of a probiotic‐based treatment for the reduction of stress‐induced neurogenic skin inflammation and hair growth inhibition. These evidences are in line with the observations of John H. Stokes and Donald M. Pillsbury who first theorized the Gut– Brain–Skin unifying vision in 1930 [12] (a clear example of PNEI approach application ante litteram). Arck and colleagues validated the unifying model Gut–Brain–Skin Axis in order to highlight the idea that beneficial effects on skin homoeostasis and skin inflammation can be achieved by the consumption of the right kind of probiotics. The complexity of the Gut–Brain–Skin Axis induces a deep reflection on its regulation, with particular emphasis on the role of the signaling molecule involved in this network. The imbalance of the signaling molecule at skin level is linked with the majority of inflammation‐related and autoimmune skin diseases (Figure 2.2). The Gut–Brain–Skin Axis is a PNEI microcosm that acts as a homeostatic controller

not only of its own systems but of the whole organism. Both the intestinal mucosa and the skin have in fact nervous (are able to secrete neuropeptides and neurohormones), endocrine (are able to secrete hormones), and immune (are able to secrete cytokines) competence, and they are in intimate connection with other organs, systems and apparatuses. By virtue of these interactions it appears that the presence of a state of physiological inflammation represents a normal phenomenon both in the intestine and at skin level. The intestinal mucosa and skin are constantly exposed to a heavy antigenic charge, mainly represented by bacterial flora. The tolerance of the microbiota is the key physiological inflammation. These PNEI concepts also offer the opportunity and the tools to study the inflammatory phenomenon in all its complexity, and to identify the homeostatic mechanisms governing all stages of the inflammatory phenomenon, from its onset to its resolution. From a PNEI point of view, inflammation is such an essential physiological process, and it can be homeostatically controlled to trigger, develop, and stop. The healthy status of an organism coincides with the condition of

PROINFLAMMATORY TRIGGERS

INFLAMMATION

CNS/PNS ALTERATIONS E.G.: STRESS, DEPRESSION MOOD PROBLEMS

GUT (MICROBIOTA) ALTERATION E.G.: IBDs/LEAKY GUT SYNDROME

SKIN (MICROBIOTA) ALTERATION E.G.: ACNE, PSORIASIS VITILIGO

Figure 2.2  Schematic representation of the action of proinflammatory triggers on Gut‐Brain‐Skin‐Axis.

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homeostasis, in which the vital parameters (pH, temperature, glycemia, and oxygen’s partial pressure) are maintained within a precise and defined range, and whose deviation up or down is identified with the pathological state. Inflammation is fully embedded in the physiological functions of homeostatic control; there is thus a level of physiological inflammation that falls within the parameters of “normality”[13]. In the intestine, some physiologically controlled inflammation is necessary for immunological function, as regulatory immune cells are triggered by intestinal microbiota and food constituents in order to regulate pro‐inflammatory pathways and maintain the correct immunocompetence. Phlogogenic events such as epithelial barrier disruptions, sudden changes of microbiota composition, altered immune balance, and, finally, homeostatic balance disruption can however contribute to disease onset. Physiological inflammation is overcome by a low‐intensity chronic inflammatory condition called Low Grade Chronic Inflammation (LGCI) [14–16]. LGCI and quali/quantitative alterations of the microbiota may contribute to the onset of local diseases characterized by alterations in the permeability of the intestinal mucosa (IBD [Inflammatory Bowel Disease], IBS [Irritable Bowel Syndrome], gluten sensitivity, and leaky gut syndrome). Systemic diseases such as autistic spectrum disorders, the anxious‐depressive syndromes, Alzheimer’s disease, type II diabetes, obesity, psoriasis, rheumatoid arthritis, BPCO (Bronco‐Pulmonary‐Chronic‐Obstructive pulmonary disease) and RRI (Recurrent Respiratory Infections) are also linked with inflammatory conditions and PNEI homeostasis alterations. Interestingly, skin microbial changes and loss of physiological immunocompetence are also related to some local and systemic diseases such as acne vulgaris, vitiligo, and atopic dermatitis (AD) [9, 12, 17].

Alteration of PNEI Homeostasis, Inflammation, and Dermatologic Diseases Focusing the attention on skin compartment, it is important to remember that the skin’s defense system is composed of three main levels: the skin’s mechanical barrier, innate immunity, and acquired immunity [18, 19]. These levels play specific roles to react against external and internal inflammatory triggers. An example of the intercellular cross‐talk at the cutaneous level is the complex of signaling pathways that regulate the functional interactions between keratinocytes and melanocytes, fundamental for skin pigmentation. Keratinocytes produce growth factors and other signaling molecules which can drive melanocytes’ migration, differentiation, and melanin synthesis. Keratinocyte‐melanocyte cross‐talk represents a small PNEI network at the epidermal level: the psychoneuro component is guaranteed by the embryologic origin of melanocytes which derive from the same embryonic layer that originates some neuronal cell lines, the neural crest [20]. The intercellular cross‐talk between keratinocytes and melanocytes is homeostatically regulated by growth factors and cytokines of endocrine origin. The immune function is linked with and represented by the involvement of melanocytes in the anti‐oxidative stress protective mechanisms mediated by keratinocyte‐derived b‐FGF (basic‐Fibroblast Growth Factor) (Figure 2.3). These observations highlight the pivotal role of PNEI homeostatic mechanisms in the maintenance of healthy skin conditions. An alteration of skin structure (due to infection or mechanical/chemical injuries) and/or the loss of immune skin homeostasis contributes to the pathogenesis of inflammatory skin diseases that are characterized by the breakdown of the homeostatic cross‐talk. The role played by the immune system in the context of the PNEI network within the “skin system” is crucial for the maintenance of physiological inflammation.

Alteration of PNEI Homeostasis, Inflammation, and Dermatologic Diseases

b-FGF

Keratinocute

Keratinocytes-derived signaling molecules involved in melanocyte cell functions (Keratinocytes-melanocytes cross-talk)

SCF ET

FGF2R c-Kit

EDNBR MEK

MAPK

MEK Melanocyte

Raf-1

ERK 1/2

PKC

P

P STAT3 PAX3

RSK

CREB

MITF-M

TYR TYRP1 TYRP2

Cell growth Cell differentiation Melanin synthesis

Figure 2.3  Schematic representation of the keratinocytes‐melanocytes cross‐talk mediated by keratinocytes‐ derived signaling molecules (ET; SCF; b‐FGF).

The physiological inflammatory process is supported by a panel of Th1‐related cytokines which comprise IL‐1, TNF‐α, and IL‐6 that exert their role in a precise chronobiology. Within 72–96 hours after the proinflammatory stimulus, the response is managed by a sequence of cytokine activation and deactivation: IL‐1 and TNF‐α (primary inflammatory cytokines) induce the production of adhesive molecules, chemokines, growth factors, and lipid mediators such as prostaglandins and nitric oxide (NO). These mediators stimulate leukocyte recruitment at the site of inflammation by amplifying the innate immune mechanisms. Then, IL‐6 acts as ­secondary mediator, responsible for maintaining the inflammatory response, and stimulates the production of acute phase proteins in the liver. This chronobiology reflects the

temporal scan triggering mechanisms and maintenance of the acute inflammatory ­phenomenon, which is followed by the progressive decrease in the levels of IL‐1, TNF‐α, and IL‐6 and increased levels of IL‐10, the most important Th2 anti‐inflammatory cytokine, typical of the phase of inflammation resolution [21, 22]. In the presence of LGCI, the two phases of inflammation maintenance and resolution coexist. The inflammation is continuously enhanced without an effective restitutio ad integrum; the phases of sequential release of cytokines are altered, and IL‐1, TNF‐α, and IL‐6 levels are about three to four times higher than baseline. Contextually, we do not assist the up‐regulation of IL‐10 anti‐inflammatory. Inflammation persists over time, like a fire smoldering under the ashes.

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The persistence of an altered immune response to pro‐inflammatory triggers leads to the instauration of a chronic inflammatory process characterized by the absence of the typical signs and symptoms, the LGCI. A relevant number of dermatologic diseases include within their etiologic factors the presence of a shift of the immunological balance, which reflects an imbalance between the cytokines expressed by Th1/Th17 and  Treg/Th2 lymphocyte subpopulations [23, 24]. The so called “Th1/Th2 shift” paradigm is supported by the evidence that Th1 cytokine hyper‐production is strictly linked with inflammatory and autoimmune skin diseases such as psoriasis, vitiligo, and alopecia areata. An example of the complexity of the skin PNEI cross‐talk is given by the deep analysis of the inflammatory mechanism at skin level. In 1999, Caroline Robert and Thomas S. Kupper published on The New England of Medicine [25] an exhaustive review on immune imbalance related to inflammatory skin diseases. The authors highlighted the fundamental role of T cell‐mediated immune surveillance in both physiological and pathological skin conditions, pointing out the ­central role of a class of memory T cells characterized by the presence of the Cutaneous Lymphocyte Antigen (CLA) on their surface and responsible for skin‐homing T cell. CLA‐positive T cells are generated in the draining lymph nodes and recruited back to the skin during inflammation. The presence of LGCI is a potent trigger for CLA+ T cells and their continuous activation is linked with the inappropriate immune surveillance which characterizes, for example, psoriasis, allergic contact dermatitis, and AD. Also, in vitiligo, CLA+ T cells contribute to the massive death of melanocytes driving the skin‐­ homing (mainly near disappearing melanocytes) of CD8+ T cells at perilesional level. The increased in situ presence of a CLA+/ CD8+ T cells is responsible of the destruction of melanocytes, with consequent skin depigmentation [26].

LGCI is one of the most important e­ tiopathogenetic factors of the most dramatic dermatologic chronic inflammatory autoimmune diseases, and consequently a therapeutic target. At present, there are no classical therapeutic opportunities to treat LGCI because the chronic use of anti‐inflammatory active principles studied for the management of acute phenomena shows an unfavorable efficacy/ adverse effects balance; in particular, chronic nonsteroidal anti‐inflammatory drug (NSAID) use is connected to an increased incidence of chronic diseases such as heart failure and hypertension [27]. In the 1990s, anti‐cytokine therapy was proposed and tested for the treatment of inflammatory and autoimmune diseases mainly counteracting the expression of Th1 proinflammatory cytokines such IL‐1 and TNF‐α. Moreover, the therapeutic use of Th2 cytokines (e.g. IL‐10) and specific antibodies was applied for alopecia areata, psoriasis, and AD treatment. However, side effects due to high dosages normally used for these molecules have slowed down the development of possible new drugs [28]. The most important and ­limiting pitfalls connected with the use of high‐dosage cytokines and other signal molecules are: ●●

●●

the need for high doses of active molecules in order to reach the therapeutic goal the low compliance of systemic administration performed by injective routes.

An innovative approach to the treatment of LGCI based on new therapeutic tools and concepts is needed. Low‐Dose Medicine (LDM) fulfills these specifications.

L­ ow‐Dose Medicine (LDM): Theoretical, Physiological, and Biochemical Bases LDM is an innovative therapeutic approach based on the most advanced knowledge in molecular biology, PNEI, and research results in the field of low‐dose pharmacology.

­Low‐Dose Medicine (LDM): Theoretical, Physiological, and Biochemical Bases

LDM has deep roots within the fundamental PNEI principles based in the centrality of the human mind–body entity. Each patient is considered as a unique identity; this assumption guides the study of a specific therapeutic approach for a particular disease. The primary outcome of the LDM approach is the restoration and preservation of the homeostatic equilibrium; the oral administration of the appropriate biological signaling molecules, which are selected after identification of the altered PNEI networks, is the therapeutic tool that allows the patient to reach the expected outcome. The use of biological molecules to control and drive the intercellular cross‐talk in order to restore physiological homeostasis is the innovative core of LDM. The main characterizing points of the LDM approach are: ●● ●●

●●

oral administration of signaling molecules systemic and synergistic activity of the orally administered molecules accurate modulating action of specific signaling pathways exerted by the orally administered molecules.

The most representative aspect of LDM is the efficacy of orally administered low‐dose signaling molecules. From a biochemical point of view, cytokines, hormones, neuropeptides, and growth factors are oligo‐peptides and small proteic sequences. Oligo‐peptides and small fragments of proteins reach the intestinal tract and here exert their biological actions [29]. The proposed action mechanism for orally delivered signaling molecules involves the intestinal M cells which act as a carrier, signaling to T cells in Peyer’s patches lymph nodes [30]. The interaction between delivered signaling molecules and M cells is the key event that underlays the effectiveness of this administration route [31–33]. The critical issue of the oral administration route is the low bioavailability (within 1% and 2%) of signaling molecules and oligo‐ peptides in general [34]; to overcome this critical p ­ itfall an effective drug delivery system is needed.

The SKA (Sequential Kinetic Activation) technology, codified and standardized by GUNA S.p.a. Italy, allows the low doses of signaling molecules to be active even below the minimum dose classically considered as effective. SKA technology also permits low‐ dose molecules to be as effective as classic recombinant peptides administered at higher concentrations, overcoming the high dose‐ related adverse effects. The action mechanism of SKA low‐dose signaling molecules takes advantage of the activation of some units of cellular (or plasmatic) receptors in their low concentration. Low‐dose SKA signaling molecules are administered in agreement with their physiological working levels (between 10−6 [micromolar] for hormones [35] and 10−12 [picomolar] for other messenger molecules [36]) (Figure 2.4). A demonstration of the effectiveness of low doses of signaling molecules is made possible by referring to the effects demonstrable in accordance with Arndt‐Schultz experiments [37, 38]. W. H. Hauss observed and explained the effects of Arndt‐Schultz’s Law on “mesenchymal non‐specific reaction” [39]. Recently, the research of Edward J. Calabrese on the phenomenon called “hormesis,” which means “different behavior of the same substance at different doses,” [37, 40] further elucidated Arndt‐Schultz’s observations. Furthermore, the pharmacological importance of low doses is recognized by both regulatory bureaus and industries in the pharmacological field [41–43]. The biological response to low doses of signaling molecules is also linked with the characteristic of specific ligand/receptor binding. Receptors for both class‐I and class‐II helical signaling molecules [44, 45] undergo ligand‐induced receptor homo‐ or hetero‐ oligomerization laws [46], which can explain the dose‐dependent mixed agonist/antagonist activity of some cytokines and oligo‐ peptides [46, 47], a characteristic linked with low dose response [41]. The peculiar ligand/receptor interactions exerted by low‐dose SKA molecules induce

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TOXIC EFFECT

TOXIC CONCENTRATION mg/ml

SIDE EFFECTS

PHARMACOLOGICAL CONCENTRATIONS μg-ng/ml

Up to 10–3 M

THERAPEUTIC EFFICACY

MINIMAL EFFECTIVE PHARMACOLOGICAL DOSE 10–5 M 10–6 M WITHOUT SKA ACTIVATION: NO THERAPEUTIC EFFECTS

PHYSIOLOGICAL CONCENTRATIONS ng-pg-fg/ml

WITH SKA ACTIVATION: THERAPEUTIC EFFICACY WITHOUT SIDE EFFECTS

10–12 M MINIMAL EFFECTIVE PHYSIOLOGICAL DOSE

10–15 M

Figure 2.4  Biological concentration‐dependent effects of signaling molecules.

the activation and fine regulation of a great number of intercellular signaling pathways, contributing to the restoration and/or ­protection of the biological function of the entire PNEI network. Low‐dose SKA molecules can activate (or reactivate) the PNEI self‐tuning intra‐ and intercellular pathways, representing the innovative and highly effective tools of LDM as highlighted in a relevant number of in vitro/ex vivo, in vivo and clinical studies [48–64] (Table 2.1).

L­ ow‐Dose Medicine and Skin Diseases: Preclinical Studies As previously described, the skin diseases etiology is complex, and the alteration of both innate and adaptive immune responses occupies a relevant role in disease onset and maintenance. From a biological point of view, the importance of LGCI in both psoriasis onset and progression, and the efficacy of low‐dose SKA molecules in the reduction of its ­negative impact, were recently evaluated by V. Barygina and colleagues.

A panel of in vitro experiments were performed on fibroblasts obtained from lesional skin of psoriatic patients [54] evaluating the oxidative stress level as marker of an inflammatory condition. Extracellular Reactive Oxygen Species (ROS), over‐expressed by fibroblasts, exert a pro‐inflammatory action in psoriatic lesional skin; the effectiveness of low‐dose SKA interleukin‐4; 10, b‐FGF, and β‐Endorphin (IL‐4, IL‐10, b‐FGF, and b‐End – 10 fg ml−1) in the reduction of ROS production by lesional fibroblasts highlights one possible LDM medicine’s action mechanism against LGCI, a crucial etiologic component of psoriasis onset and progression. V. Barygina and colleagues also designed and performed a basic preclinical in vitro study [58] in order to evaluate the effects of low‐dose SKA IL‐4, IL‐10, b‐FGF, and β‐End (10 fg ml−1) in the modulation of intra‐ and extra‐cellular oxidative stress, and on the proliferation of human perilesional keratinocytes (PL) from the skin of vitiligo patients (in vitro study on cells obtained from lesion skin biopsies). Vitiligo, a highly psychologically disabling skin disorder characterized by a progressive depigmentation, is another

Table 2.1 List of the major published works in the field of Low‐Dose Medicine (2009–2018). Year

Authors

Journal

Study type

Title

2009 Gariboldi S. et al.

Pulmonary Pharmacology & Therapeutics

In vivo basic research

Low‐dose oral administration of cytokines for treatment of allergic asthma

2012 D’amico L. et al.

Journal of Cancer Therapy

Ex vivo basic research

Low dose of IL‐12 stimulates T cell response in cultures of PBMCs derived from non‐small cell lung cancer patients

2013 Cardani D. et al.

Gastroenterology Research

In vivo basic research

Oral administration of interleukin‐10 and anti‐IL‐1 antibody ameliorates experimental intestinal inflammation

2014 Radice E. et al. International Immunopharmacology Ex vivo basic research

Low‐doses of sequential‐kinetic‐activated interferon‐gamma enhance the ex vivo cytotoxicity of peripheral blood natural killer cells from patients with early‐stage colorectal cancer. A preliminary study

2014 Roberti ML. et al.

Journal of Biological Regulatory & Homeostatic Agents

Clinical trial

Immunomodulating treatment with low dose interleukin‐4, interleukin‐10 and interleukin‐11 in psoriasis vulgaris

2015 Luchetti P.

Minerva Medica Oftalmologica

Clinical trial

Increasing of visual function in patients with retinal atrophy treated with drugs of low‐dose medicine. Monocentric retrospective observational study

2015 Barygina V. et al.

Journal of Dermatological Science

In vitro basic research

Treatment with low‐dose cytokines reduces oxidative‐mediated injury in perilesional keratinocytes from vitiligo skin

2015 Lotti T. et al.

Journal of Biological Regulatory & Homeostatic Agents

Clinical trial

Vitiligo: successful combination treatment based on oral low‐dose cytokines and different topical treatments

2015 Radice E. et al. Translational Oncology

Ex vivo basic research

Enhancement of the immunostimulatory Functions of ex vivo‐generated dendritic cells from early‐stage colon cancer patients by consecutive exposure to low doses of sequential‐kinetic‐activated IL‐4 and IL‐12

2015 Lotti T. et al.

Der Hautarzt

Clinical trial

Successful combination treatment for psoriasis with phototherapy and low‐dose cytokines: a spontaneous, retrospective observational clinical study

2016 Barygina V. et al.

Journal of Dermatological Science

In vitro basic research

Low‐dose cytokines reduce oxidative stress in primary lesional fibroblasts obtained from psoriatic patients

Clinical trial (veterinary)

Clinical improvement in feline herpesvirus 1 infected cats by oral low dose of interleukin‐12 plus interferon‐gamma

2016

Fiorito F. et al. Comparative Immunology, Microbiology and Infectious Diseases

(Continued)

Table 2.1 (Continued) Year

Authors

Journal

Study type

Title

Bollettino di Ginecologia Endocrinologica Frontiers in Gynecological Endocrinology

Observational pilot study

Pharmacological and integrative treatment of stress‐induced hypothalamic amenorrhea

2017 Martin‐ Drug Design, Development and Martin S. et al. Therapy

Clinical trial

An open randomized active‐controlled clinical trial with low‐dose SKA cytokines versus DMARDs evaluating low disease activity maintenance in patients with rheumatoid arthritis

2017 Carello R. et al.

Italian Journal of Pediatrics

Clinical trial

Long‐term treatment with low‐dose medicine in chronic childhood eczema: a double‐blind two‐stage randomized control trial

2017 Castiglioni S. et al.

International Journal of Molecular Sciences

In vitro basic research

Femtograms of interferon‐γ suffice to modulate the behavior of jurkat cells: a new light in immunomodulation

2018 Mancini F. et al.

International Immunopharmacology In vitro basic research

2016 Genazzani A. et al.

Low‐dose SKA progesterone and interleukin‐10 modulate the inflammatory pathway in endometriotic cell lines

­Low‐Dose Medicine and Skin Diseases: Clinical Result

example of a dermatologic disease characterized by the presence of LGCI and related excessive oxidative stress. Obtained results showed that low‐dose SKA IL‐4, IL‐10, and b‐FGF are effective in significantly reducing the intra‐cellular oxidative stress rates. Furthermore, low‐dose SKA IL‐4 and b‐FGF are also able to reduce the extra‐cellular oxidative stress. Low‐dose SKA IL‐10, b‐FGF, and β‐End induce a significant increase of keratinocyte viability compared to untreated perilesional cells. IL‐4, IL‐10, β‐End, and b‐FGF show a positive effect on both redox mechanism effectiveness and cell viability without interfering with the keratinocyte’s cell cycle.

L­ ow‐Dose Medicine and Skin Diseases: Clinical Results In 2014, the first study conducted on a dermatologic disease (psoriasis vulgaris) in order to test the LDM approach of oral administration of low‐dose SKA activated cytokines was published. Roberti and colleagues designed and performed a multicenter double‐blind placebo‐ controlled clinical study [52] in order to test the efficacy of low‐dose SKA interleukin‐4, interleukin‐10, and interleukin‐11 (IL‐4, IL‐10, IL‐11 at the concentration of 10 fg ml−1) for the therapy of psoriasis vulgaris. The main outcomes chosen for the evaluation of the treatment with low‐dose SKA interleukins were ●●

●●

presence and extension of psoriatic plaques evaluated in agreement with PASI (Psoriasis Area Severity Index) scale. improvement of the quality of life parameters evaluated in agreement with DLQI (Dermatology Life Quality Index) rating scales.

The results of the study revealed the efficacy (and safety) of oral‐administered low‐ dose SKA interleukins in the reduction of both evaluated scores. The study also highlighted the long‐lasting efficacy of the ­proposed treatment, opening the way to for-

mulating a treatment protocol for psoriasis and other dermatologic chronic diseases characterized by an immune imbalance with the presence of a LGCI status. In 2015, another interesting study in the field of LDM applied to the treatment of psoriasis was published by Lotti and colleagues [57]. The results of a spontaneous retrospective observational clinical study were collected and evaluated. The clinical outcomes of the most up‐to‐date therapeutic approach for psoriasis treatment, based on UV‐A‐1 phototherapy combined with low‐dose SKA cytokine therapy, were evaluated. It was revealed that the combination of UV‐A‐1 phototherapy with laser plus low‐ dose SKA interleukin‐4 and interleukin‐10 and low‐dose SKA antibodies anti IL‐1α/β was more effective than UV‐A‐1 phototherapy alone and also equally safe. The combination of phototherapy and LDM represents an innovative strategy for the treatment of inflammatory skin diseases such as psoriasis vulgaris. Lotti and colleagues also performed a retrospective spontaneous clinical study comparing the effectiveness of current vitiligo treatments with LDM therapy [55]. In this study, some groups of patients treated in accordance with standard and experimental therapeutic protocols were evaluated; two groups, treated respectively with orally administered low‐dose SKA IL‐4, IL‐10, Anti‐IL‐1 antibodies, and low‐dose SKA b‐FGF were evaluated and compared with other groups of patients who received topical treatments with a cortisone cream (alone or in combined associations with both groups of low‐dose SKA molecules) and phototherapy (narrow‐band UV‐B radiation) alone or in combined associations with the low‐dose SKA molecules. Two groups of subjects treated with natural sunlight exposure and systemic oral intake of Gingko biloba extract were evaluated as control groups. An inclusion criterion applicable for all current vitiligo treatments is that the skin surface presenting vitiliginous lesion is not exceeding the 15% of the total skin surface. The study highlighted that the low‐dose SKA treatment effectively reduces the

19

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Psycho-Neuro-Endocrine-Immunology

­ epigmented skin areas and stops the spread d of the vitiliginous lesions, in particular when co‐administered with UV‐B phototherapy, with a significant reduction of the depigmented areas. The effectiveness of the association of low‐dose SKA treatments with the topical UV‐B treatment opens new scenarios for the combined use of phototherapy and LDM. In the pediatric field, Carello and colleagues [62] evaluated the efficacy of a low‐dose SKA cytokine treatment (IL‐12 and IFN‐γ at a concentration of 10 fg ml−1) in association with a low‐dose multicomponent medication (exerting connective drainage action) in a pediatric population presenting chronic AD. This randomized, controlled double‐blind two‐stage clinical study has been conducted to evaluate the effects of a long‐term treatment with LDM. The clinical trial included children with low‐medium grade AD in acute phase. The evaluation was based on the SCORAD [Scoring Atopic Dermatitis] index, which should not exceed a score of 40 (minimum score: 6) with a recurrence rate of ≥4 per year and with skin lesions occurring for at least six months after the enrollment. The primary outcome, the reduction in the severity of AD, was evaluated through the SCORAD index; the elongation of the “disease‐free interval” was assumed as a secondary outcome. Tolerability and compliance of the treatment and management of adverse events was also evaluated. The results showed that the LDM group had a final decrease in SCORAD score of 54%; this trend was maintained during the follow‐up period, with an improvement of the SCORAD index to 64%. In the same observation period, the treated group showed a significant reduction in the consumption of drugs for symptomatic control (antihistamines and topical corticosteroids). The study also showed an improve-

ment in the quality of life (reduction of both itching and night‐time disturbances) of ­subjects treated with the LDM protocol.

­Conclusion Many dermatologic diseases have a complex pathogenesis; the inflammatory phenomenon is one of the most important etiological components, and it is driven by the imbalance between Th1/Th17 and Th2/Treg responses and induces a profound alteration in immune response homeostasis. The consequent disruption of the PNEI equilibrium has not only local but also systemic negative outcomes that compromises the whole body’s health condition. An effective therapeutic action exerting a rebalancing action of the immune inflammatory response, not adequately managed with currently available therapies, is needed. Today, the LDM is one of the most promising approaches, allowing researchers to design innovative therapeutic strategies for the treatment of skin diseases based on the rebalance of the immune response. The availability of low‐dose SKA signaling molecules is the cardinal point of LDM. The effective and safe oral administration of low‐dose SKA signaling molecules represents the innovative core of the entire strategy for the treatment of dermatological diseases characterized by an immune imbalance and LGCI such as in psoriasis vulgaris, vitiligo, and AD. Preclinical and clinical results confirm the effectiveness of the LDM approach and give the physician the therapeutic tools and theoretic basis for a fine tuning of the immune system in order to restore its homeostatic equilibrium in accordance with PNEI principles.

­References 1 Commins, S.P., Borish, L., and Steinke, J.W.

(2010). Immunologic messenger molecules: cytokines, interferons, and chemokines. J. Allergy Clin. Immunol. 125 (2 suppl 2): S53–S72.

2 Bacchus, W., Aubel, D., and Fussenegger, M.

(2013). Biomedically relevant circuit‐design strategies in mammalian synthetic biology. Mol. Syst. Biol. 9: 691.

­Reference

3 Ader, R. and Cohen, N. (1993).

Psychoneuroimmunology: conditioning and stress. Annu. Rev. Psychol. 44: 53–85. 4 Ader, R., Cohen, N., and Felten, D. (1995). Psychoneuroimmunology: interactions between the nervous system and the immune system. Lancet 345 (8942): 99–103. 5 Ader, R. (1983). Developmental Psychoneuroimmunology. Dev. Psychobiol. 16 (4): 251–267. 6 Bottaccioli, F., Carosella, A., Cardone, R. et al. (2014). Brief training of psychoneuroendocrinoimmunology‐based meditation (PNEIMED) reduces stress symptom ratings and improves control on salivary cortisol secretion under basal and stimulated conditions. Explore (NY) 10 (3): 170–179. 7 Haroon, E., Raison, C.L., and Miller, A.H. (2012). Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 37 (1): 137–162. 8 Tojo, R., Suárez, A., Clemente, M.G., and de los Reyes‐Gavilán, C.G. (2014). Intestinal microbiota in health and disease: role of bifidobacteria in gut homeostasis. World J. Gastroenterol. 20 (41): 15163–15176. 9 Myles, I.A., Williams, K.W., Reckhow, J.D. et al. (2016). Transplantation of human skin microbiota in models of atopic dermatitis. JCI Insight 1 (10): e86955. 10 O’Neill, C.A., Monteleone, G., McLaughlin, J.T., and Paus, R. (2016). The gut‐skin axis in health and disease: a paradigm with therapeutic implications. Bioessays 38 (11): 1167–1176. 11 Arck, P., Handjiski, B., Hagen, E. et al. (2010). Is there a ‘gut‐brain‐skin axis’? Exp. Dermatol. 19 (5): 401–405. 12 Bowe, W.P. and Logan, A.C. (2011). Acne vulgaris, probiotics and the gut‐brain‐skin axis – back to the future? Gut Pathog. 3 (1): 1. 13 Kotas, M.E. and Medzhitov, R. (2015). Homeostasis, inflammation, and disease susceptibility. Cell 160 (5): 816–827. 14 Hueston, C.M. and Deak, T. (2014). The inflamed axis: the interaction between

15

16

17

18

19

20

21

22

23

24

25

stress, hormones, and the expression of inflammatory‐related genes within key structures comprising the hypothalamic‐ pituitaryadrenal axis. Physiol. Behav. 124: 77–91. Khan, M.J., Gerasimidis, K., Edwards, C.A., and Shaikh, M.G. (2016). Role of gut microbiota in the Aetiology of obesity: proposed mechanisms and review of the literature. J. Obes. 2016: 7353642. Mancuso, P. (2016). The role of adipokines in chronic inflammation. Immunotargets Ther. 5: 47–56. Ganju, P., Nagpal, S., Mohammed, M.H. et al. (2016). Microbial community profiling shows dysbiosis in the lesional skin of Vitiligo subjects. Sci. Rep. 6: 18761. Turvey, S.E. and Broide, D.H. (2010). Innate immunity. J. Allergy Clin. Immunol. 125 (2 Suppl 2): S24–S32. Dainichi, T., Hanakawa, S., and Kabashima, K. (2014). Classification of inflammatory skin diseases: a proposal based on the disorders of the three‐layered defense systems, barrier, innate immunity and acquired immunity. J. Dermatol. Sci. 76 (2): 81–89. Rawles, M.E. (1947). Origin of pigment cells from the neural crest in the mouseembryo. Physiol. Zool. 20: 248–266. Hussain, T., Tan, B., Yin, Y., and Blachier, F. (2016). Oxidative stress and inflammation: what polyphenols can do for us? Oxid. Med. Cell. Longev. 2016: 7432797. Trifunović, J., Miller, L., Debeljak, Ž., and Horvat, V. (2015). Pathologic patterns of interleukin 10 expression–a review. Biochem. Med. (Zagreb). 25 (1): 36–48. Deng, Y., Chang, C., and Lu, Q. (2016). The inflammatory response in psoriasis: a comprehensive review. Clin. Rev. Allergy Immunol. 50 (3): 377–389. Zhen, Y., Yao, L., Zhong, S. et al. (2016). Enhanced Th1 and Th17 responses in peripheral blood in active non‐segmental vitiligo. Arch. Dermatol. Res. 308 (10): 703–710. Robert, C. and Kupper, T.S. (1999). Inflammatory skin diseases, T cells, and immune surveillance. N. Engl. J. Med. 341 (24): 1817–1828.

21

22

Psycho-Neuro-Endocrine-Immunology

26 van den Wijngaard, R., Wankowicz‐

27

28

29

30

31

32

33

34

35

Kalinska, A., Le Poole, C. et al. (2000). Local immune response in skin of generalized vitiligo patients. Destruction of melanocytes is associated with the prominent presence of CLA+ T cells at the perilesional site. Lab. Invest. 80 (8): 1299–1309. Marcum, Z.A. and Hanlon, J.T. (2010). Recognizing the risks of chronic nonsteroidal anti‐inflammatory drug use in older adults. Ann. Longterm Care 18 (9): 24–27. Dinarello, C.A. (2003). Anti‐cytokine therapeutics and infections. Vaccine 21 (Suppl 2): S24–S34. Tessaro, I., Modina, S.C., Franciosi, F. et al. (2015). Effect of oral administration of low‐dose follicle stimulating hormone on hyperandrogenized mice as a model of polycystic ovary syndrome. J. Ovarian Res. 8 (1): 64. Yun, Y., Cho, Y.W., and Park, K. (2013). Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery. Adv. Drug Deliv. Rev. 65 (6): 822–832. Burnett, A.F., Biju, P.G., Lui, H., and Hauer‐Jensen, M. (2013). Oral interleukin 11 as a countermeasure to lethal total‐body irradiation in a murine model. Radiat. Res. 180 (6): 595–602. Hanson, M.L., Hixon, J.A., Li, W. et al. (2014). Delivery of IL‐27 recombinant bacteria attenuates immune colitis in mice. Gastroenterology 146 (1): 210–221. Forster, K., Goethel, A., Chan, C.W. et al. (2012). An oral CD3‐specific antibody suppresses T‐cell‐induced colitis and alters cytokine responses to T‐cell activation in mice. Gastroenterology 143 (5): 1298–1307. Renukuntla, J., Vadlapudi, A.D., Patel, A., and Boddu, S.H. (2013). Approaches for enhancing oral bioavailability of peptides and proteins. Int. J. Pharm. 447 (1–2): 75–93. Vandenberg, L.N., Colborn, T., Hayes, T.B. et al. (2012). Hormones and endocrine‐ disrupting chemicals: low‐dose effects and nonmonotonic dose responses. Endocr. Rev. 33 (3): 378–455.

36 Biancotto, A., Wank, A., Perl, S. et al.

37

38

39

40

41

42

43

44

45

46

47

48

(2013). Baseline levels and temporal stability of 27 multiplexed serum cytokine concentrations in healthy subjects. PLoS One 8 (12): e76091. Amendola, A., Cerioli, N.L., and Migliore, L. (2006). Ormesi: la rivoluzione dose‐ risposta. APAT 15–19. Stumpf, W.E. (2006). The dose makes the medicine. Drug Discovery Today 11 (11/12): 550–555. Hauss, W.H., Hulsing, G.J., and Gerlach, U. (1968). Die unspezifische Mesenchymreaktion Zur Pathogenese der reaktiven Mesenchymerkrankungen, 29–35. Stuttgart: Georg Thieme Verlag. Mattson, M.P. and Calabrese, E.J. (2010). Hormesis a Revolution in Biology, Toxicology and Medicine. New York Dordrecht Heidelberg London: Springer. ICH (1994). Guideline for Industry Dose‐Response Information to Support Drug Registration. European Medicines Agency November 1994, 378/95. ICH. Olson, H.M., Kadyszewski, E., and Beierschmitt, W. (2001). Hormesis – a pharmaceutical industry perspective. Crit. Rev. Toxicol. 31 (4–5): 659–661. Maynard, K.I. (2011). Hormesis pervasiveness and its potential implications for pharmaceutical research and development. Dose‐Response 9: 377–386. Krause, C.D. and Pestka, S. (2005). Evolution of the class 2 cytokines and receptors, and discovery of new friends and relatives. Pharmacol. Ther. 106 (3): 299–346. Huising, M.O., Kruiswijk, C.P., and Flik, G. (2006). Phylogeny and evolution of class‐I helical cytokines. J. Endocrinol. 189 (1): 1–25. Wells, J.A. (1996). Binding in the growth hormone receptor complex. Proc. Natl. Acad. Sci. U.S.A. 93 (1): 1–6. Scheller, J., Chalaris, A., Schmidt‐Arras, D., and Rose‐John, S. (2011). The pro‐ and anti‐inflammatory properties of the cytokine interleukin‐6. Biochim. Biophys. Acta. 1813 (5): 878–888. Gariboldi, S., Palazzo, M., Zanobbio, L. et al. (2009). Low dose oral administration

­Reference

49

50

51

52

53

54

55

56

of cytokines for treatment of allergic asthma. Pulm. Pharmacol. Ther. 22: 497–510. D’Amico, L., Ruffini, E., Ferracini, R., and Roato, I. (2012). Low dose of IL‐12 stimulates T cell response in cultures of PBMCs derived from non‐small cell lung cancer patients. J. Cancer Ther. 3: 337–342. Cardani, D., Dusio, G.F., Luchini, P. et al. (2013). Oral administration of interleukin‐10 and anti‐IL‐1 antibody ameliorates experimental intestinal inflammation. Gastroenterol. Res. 6: 124–133. Radice, E., Miranda, V., and Bellone, G. (2014). Low‐doses of sequential‐kinetic‐ activated interferon‐gamma enhance the ex vivo cytotoxicity of peripheral blood natural killer cells from patients with early‐stage colorectal cancer. A preliminary study. Int. Immunopharmacol. 19 (1): 66–73. Roberti, M.L., Ricottini, L., Capponi, A. et al. (2014). Immunomodulating treatment with low dose interleukin‐4, interleukin‐10 and interleukin‐11 in psoriasis vulgaris. J. Biol. Regul. Homeost. Agents 28 (1): 133–139. Luchetti, P. (2014). Increasing of visual function in patients with retinal atrophy treated with drugs of low dose medicine. Monocentric retrospective observational study. Minerva Medica Oftalmologica 56 (3–4): 53–61. Barygina, V., Becatti, M., Lotti, T., and Taddei, N. (2016). Low dose cytokines reduce oxidative stress in primary lesional fibroblasts obtained from psoriatic patients. J. Dermatol. Sci. 83 (3): 242–244. Lotti, T., Hercogova, J., Wollina, U. et al. (2015). Vitiligo: successful combination treatment based on oral low dose cytokines and different topical treatments. J. Biol. Regul. Homeost. Agents 29 (1 Suppl): 53–58. Radice, E., Bellone, G., and Miranda, V. (2015). Enhancement of the immunomodulatory functions of ex vivo‐generated dendritic cells from early‐ stage colon cancer patients by consecutive exposure to low doses of sequential kinetic

57

58

59

60

61

62

63

64

activated IL‐4 and IL‐12. A preliminary study. Transl. Oncol. 8: 327–338. Lotti, T. et al. (2015). Successful combination treatment for psoriasis with phototherapy and low dose cytokines. A spontaneous observational retrospective clinical study. Hautarzt 66 (11): 849–854. Barygina, V., Becatti, M., Lotti, T. et al. (2015). Treatment with low‐dose cytokines reduces oxidative‐mediated injury in perilesional keratinocytes from vitiligo skin. J. Dermatol. Sci. 79 (2): 163–170. Fiorito, F., Cantiello, A., Granato, G.E. et al. (2016). Clinical improvement in feline herpesvirus 1 infected cats by oral low dose of interleukin‐12 plus interferon‐gamma. Comp. Immunol. Microbiol. Infect. Dis. 48: 41–47. Genazzani, A.D., Despini, G., Chierchia, E. et al. (2016). Pharmacological and integrative treatment of stress‐induced hypothalamic amenorrhea. In: Frontiers in Gynecological Endocrinology ISGE Series (ed. A. Genazzani and B. Tarlatzis), 69–84. Cham: Springer https://doi.org/10.1007/978 ‐3‐319‐23865‐4_9. Martin‐Martin, L.S., Giovannangeli, F., Bizzi, E. et al. (2017). An open randomized active‐controlled clinical trial with low‐ dose SKA cytokines versus DMARDs evaluating low disease activity maintenance in patients with rheumatoid arthritis. Drug Des. Dev. Ther. 11: 985–994. Carello, R., Ricottini, L., Miranda, V., and Panei, P. (2017). Long‐term treatment with low‐dose medicine in chronic childhood eczema: a double‐blind two‐stage randomized control trial. Ital. J. Pediatr. 43 (1): 78. Castiglioni, S., Miranda, V., Cazzaniga, A., and Campanella, M. (2017). Femtograms of interferon‐γ suffice to modulate the behavior of jurkat cells: a new light in immunomodulation. Int. J. Mol. Sci. 18 (12): E2715. Mancini, F., Milardi, D., Carfagna, P., and Grande, G. (2018). Low‐dose SKA progesterone and interleukin‐10 modulate the inflammatory pathway in endometriotic cell lines. Int. Immunopharmacol. 55: 223–230.

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3 Psychoneurocutaneous Medicine Mohammad Jafferany1, Paul Pastolero1, and Katlein França2,3 1

 Department of Psychiatry, Central Michigan University, Mount Pleasant, MI, USA  Department of Dermatology & Cutaneous Surgery; Department of Psychiatry & Behavioral Sciences, Institute for Bioethics & Health Policy, University of Miami Miller School of Medicine, Miami, FL, USA 3  Centro Studi per la Ricerca Multidisciplinare e Rigenerativa, Università degli Studi Guglielmo Marconi, Rome, Italy 2

­Introduction The integumentary system and the nervous system share the same embryonic origin. They both derive from the ectoderm. The ectoderm is the germ layer that differentiates to form the brain, spine, and peripheral nerves of the nervous system, as well as the tooth enamel, epidermis, sweat glands, hair, and nails of the integumentary system [1]. These systems work closely together. The skin is the barrier that protects the internal organs from the external world. Conversely, the intrinsic conditions of the body can be transmitted to the external world through the skin after sensing and integrating envi­ ronmental cues [2]. It is through these inter­ actions between skin and mind that the study of psychoneurocutaneous medicine arises. Although a relatively young science, the ear­ liest mentions of psychoneurocutaneous med­ icine can be found in texts from thousands of years ago. In ancient Greece, Hippocrates (460–377  BCE) mentioned the relationship between the skin and the nervous system. He described people who tore out their hair in response to emotional stress. He also described the association of emotion with dermatologi­ cal manifestations, such as sweating when fearful. Aristotle (384–322  BCE) theorized

that the skin and mind were c­ omplementary and inseparable [3]. However, it was only in the last two centuries that this field has been studied in further depth. During the eight­ eenth century, the English physician Robert Willan (1757–1812) described a patient who believed that there were parasites causing skin damage, although no parasite could be found [3]. This is now known today as delusional parasitosis. Sir William James Erasmus Wilson (1809–1884) also described delusional parasi­ tosis [3]. He also described anxiety and depres­ sion associated with hyperhidrosis, further highlighting the interaction between mind and skin. Today, with the creation of associations and academic groups, along with the emerging of subspecialties dedicated exclusively to the study of the psychological impact of skin disor­ ders, psychoneurocutaneous medicine contin­ ues to evolve. A number of subspecialties have been deve­ loped today. Pediatric and Geriatric Psychodermatology are subspecialties that focus on the assessment, diagnosis, and com­ prehensive treatment of their respective patient populations [4, 5]. Trichopsycho­ dermatology is a subspecialty focused on understanding and treating the psychological pathologies related directly and indirectly to hair [6]. Psychodermato‐oncology focuses on

Advances in Integrative Dermatology, First Edition. Edited by Katlein França and Torello Lotti. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

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Psychoneurocutaneous Medicine

the psychological impact of skin cancer and the role of stress in the development of skin cancers [7]. Cosmetic Psychodermatology is a subspecialty developed to evaluate the psychological aspects of patients seeking ­ cosmetic procedures [8]. Tropical psychoder­ matology is a field that studies the psychoso­ cial and quality of life aspects of tropical skin diseases such as endemic pemphigus folia­ ceus and different infections caused by fungi, virus, ectoparasites, bacteria, and helminths [9]. Sports psychodermatology is a new emerging subspecialty. It focuses on the psy­ chological impact of skin diseases on athletes [10]. Environmental psychodermatology focuses on the interaction between stressors, skin, and the environment [11]. All of these subspecialties further highlight how far the field of psychodermatology has come. Psychoneurocutaneous Medicine is a rapidly growing field that encompasses numerous schools of medicine. It involves psychiatry, psy­ chology, neurology, and dermatology. It is an integrative science that studies the interaction between the mind, the nervous system, and the  integumentary system [12]. Psychiatry is involved in the study of mental processes and pathological illness. Psychology examines the mind and behavior. Neurology is involved with the nervous system and the diseases that affect it. Dermatology is the study of skin diseases. All these specialties combined provide an integra­ tive approach to the analysis and treatment of psychodermatological pathology. The treatment of psychoneurocutaneous disorders focuses on the management of depression and anxiety asso­ ciated with dermatological diseases, improving quality of life, managing social isolation, and improving the self‐esteem of patients. This chapter will discuss the characteristics, epidemi­ ology, diagnosis, and management of various psychoneurocutaneous disorders.

­Classification of Psychodermatological Diseases Psychodermatological diseases are divided into different classifications based on the presentation, origin, and system in which the

pathology is mainly involved [12]. The clas­ sifications are as follows: psychophysiologi­ cal disorders, psychiatric disorders with dermatological symptoms, dermatological ­ disorders with psychiatric symptoms, and miscellaneous [12]. Psychophysiological disorders are skin diseases that are precipitated or exacer­ bated by psychological stress [12]. Patients can determine a clear and chronological association between stress and precipita­ tion/exacerbation of the skin disease. Examples of psychophysiological disorders include acne, alopecia areata, atopic der­ matitis, psoriasis, psychogenic purpura, rosacea, seborrheic dermatitis, and urti­ caria (hives). Psychiatric disorders with dermatologi­ cal symptoms are defined as diseases of the  skin that are self‐inflicted [12]. These disorders are always associated with underlying psychopathology. They are also known as stereotypes of psychodermato­ logical diseases. Examples of psychiatric disorders with dermatological symptoms are body dysmorphic disorder, delusions of parasitosis, eating disorders, factitial dermatitis, neurotic excoriations, obses­ ­ sive compulsive disorders (OCDs), and trichotillomania. Dermatological disorders with psychiatric symptoms are defined as the emotional and psychological problems that are a result of having a skin disease [12]. The psychologi­ cal consequences begin to be more severe than the physical symptoms themselves. The psychological problems can include but are not limited to: depression, anxiety, and social withdrawal. Examples of dermatolog­ ical disorders with psychiatric symptoms are alopecia areata, albinism, chronic eczema, hemangiomas, ichthyosis, psoria­ sis, rhinophyma, and vitiligo. Several other disorders have been described and are grouped under miscella­ neous conditions. This includes the derma­ tological side effects of psychotropic medications; for example, psychogenic purpura syndrome and cutaneous sensory syndrome [12].

­Trichotillomania (Hair‐Pulling Disorder)

­Dermatitis Artefacta Dermatitis Artefacta is a form of factitious disorder. It is defined as self‐induced cutane­ ous lesions that the patient denies having induced. The lesions are typically bilateral and symmetrical in distribution. They have a propensity to be within easy reach of the dominant hand. Shapes can vary and may pre­ sent with sharp geometrical or angular bor­ ders. Depending on how the lesions are afflicted, they may also present as burns, scars, blisters, ulcers, or purpura. Inflammatory signs such as erythema and edema may be present as well. Various methods to self‐induce these cutaneous lesions include rubbing, scratching, cutting, picking, punching, sucking, biting, or by applying heat, caustics, or dyes. Some patients may even go as far as injecting substances, including feces and blood. The condition is more common in women than men, with prevalence rates ranging from 3 to 20 times more in women than in men [13]. Reported associated conditions include OCD, borderline personality disorder, depres­ sion, psychosis, and mental retardation [14, 15]. Complications of dermatitis artefacta include infection, scar formation, and even malignant transformation of lesions [16]. Management of dermatitis artefacta requires an integrative approach. First, patients should be approached in a supportive, non‐judgmen­ tal way. Confrontation with the patient should be avoided. Regular follow‐up should occur for supervision and support even if the lesions are no longer present [13]. A focus on appropriate coping skills, such as the teaching of relaxation techniques, has been shown to be useful [17, 18]. Pharmacological management of antianx­ iety medications such as selective serotonin reuptake inhibitors (SSRIs) and low‐dose atyp­ ical antipsychotics such as olanzapine have also shown to be effective [19].

­Delusions of Parasitosis Delusions of parasitosis is a psychiatric dis­ order that may present with dermatological symptoms. It is a somatic type delusion. As a

delusion, it is a fixed belief that is not amena­ ble to change in light of evidence that points to the contrary. In those with delusions of parasitosis, patients believe that organisms infest their bodies despite adequate medical evidence that indicates otherwise. Patients may present with small bits of excoriated skin, debris, insects or insect parts as evidence of the infection. Non‐dermatological patients may present their feces if they believe the parasitic infection involves their gastrointes­ tinal system. Management of delusions of parasitosis vary. The antipsychotic pimozide (1–10 mg d−1) has been shown to be effec­ tive [20–22]. Other options include ris­ peridone, trifluoperazine, haloperidol, and chlorpromazine. Nonpharma­cological management with electroconvulsive ther­ apy has also been reported to be beneficial [23–25].

­Trichotillomania (Hair‐Pulling Disorder) Trichotillomania (Hair‐Pulling Disorder) was defined in the past as a disorder of impulse control. Today it is defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM‐V) as an obses­ sive‐compulsive related disorder. It is char­ acterized by the recurrent pulling out of one’s hair. Patients feel an overwhelming sense of tension before hair pulling which is followed by relief and sometimes even grat­ ification after the hair pulling occurs. The location of the hair is not limited to one’s head and can be anywhere on the body, but the most common sites affected are the scalp, eyebrows, and eyelashes. The sites of hair‐pulling can change over time and may include axillary, pubic, and peri‐rectal hair regions. The hair pulling may cause clini­ cally significant distress and may affect social, occupational, and other important areas of functioning. There has been evidence to suggest that childhood trauma and emotional neglect

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may have a role in the development of this disorder [26]. The onset of the disorder ­typically occurs around puberty. Associated psychiatric conditions may include anxiety, depression, dementia, mental retardation, excoriation (skin‐picking) disorder, comor­ bid substance abuse, and eating disorders [15, 27, 28]. Management of trichotillomania is similar to those methods utilized for the management of OCD. Pharmacological management includes SSRI medications such as fluoxetine, paroxetine, and sertraline. Other medications used include clomipramine, lithium, bus­ pirone, and risperidone. Non‐pharmacological management methods such as cognitive‐ behavioral therapy, habit‐reversal therapy, and hypnotherapy have also been shown to be efficacious [29, 30].

­Obsessive‐Compulsive Disorder Obsessive‐compulsive disorder is defined in the DSM‐V as the presence of obsessions, compulsions, or both. Obsessions are des­ cribed as persistent and intrusive thoughts and urges that are difficult to suppress or ignore. They are often neutralized by a ste­ reotyped reaction known as a compulsion. Compulsions are repetitive behaviors or mental acts that are aimed at providing relief of the tension caused by the obsession. In the scope of psychoneurocutaneous medicine, OCD is a psychiatric disorder that may pre­ sent with dermatological symptoms. A com­ mon presentation of OCD is skin lesions as a result of scratching, picking, and other self‐ injurious behaviors. Dermatologically related compulsions include hair‐pulling of the scalp, eyebrows, and eyelashes, biting of the nails, lips, tongue, and cheek, and excessive hand washing. The prevalence of OCD in the United States is 1.2% of the population. Females are affected at a slightly higher rate than males

in adulthood, but younger males tend to be  more commonly affected than younger females. OCD in child and adolescent popu­ lations have been found to present most commonly as trichotillomania, onychotillo­ mania, and acne excoriée. Pharmacological management of OCD includes the use of SSRIs and clomipramine [30]. Behavioral modification and psychodynamic psycho­ therapy have also been reported to be effec­ tive in treating the disorder.

­Excoriation (Skin‐Picking) Disorder Excoriation disorder is a psychiatric condition with a dermatological presentation. Neurotic excoriations are self‐inflicted lesions caused by recurrent picking of one’s skin. They often present as weeping, crusted, or lichenified lesions. Often postinflammatory hypopig­ mentation or hyperpigmentation may be pre­ sent. Most common sites affected are the extensor aspects of the extremities, face, hands, scrotum, and perianal regions. The disease process typically starts with an urge; such as an itch or a desire to excoriate a benign skin lesion. This is followed by repeti­ tive scratching which in turn produces more lesions. The act of excoriation provides grati­ fication or pleasure to the patient. Patient demographics are similar in exco­ riation disorder and trichotillomania. They also share similar psychiatric comorbidities and personality traits. Excoriation disorder is more common in those with obsessive‐ compulsive personality and borderline personality disorders. Comorbid psychiatric disorders include OCD, anxiety disorders, mood disorders, body dysmorphic disorders, substance abuse disorders, and trichotillo­ mania [31–34]. The severity of the disorder can vary and has been reported to be a reflection of a patient’s underlying personal­ ity or current level of psychosocial stress. Complications of neurotic excoriations

­Conclusio

include infections such as epidural abscess formation. Management of excoriation disorder includes the use of SSRIs, doxepin, clomi­ pramine, naltrexone, benzodiazepines, and amitriptyline. Antipsychotics such as olanzapine and pimozide have also been shown to be effective. Nonpharmacological management methods such as habit‐reversal training and cognitive‐behavioral therapy have also been beneficial [35–38].

­Psychogenic Pruritus Psychogenic pruritus is a psychophysio­ logical disorder. It is characterized by the cyclical nature of stress precipitating pru­ ritus, and pruritus precipitating stress. Itch sensitivity is increased as a result of psy­ chological stress or comorbid psychiatric conditions. Stress causes the release of histamine, vas­ oactive neuropeptides, and inflammatory mediators causing an increased itch response. Furthermore, stress‐related hemodynamic changes such sweat response may contribute as well. This leads to an itch‐scratch‐itch cycle [39]. Psychogenic pruritus has been noted in patients with anxiety, depression, obsessional behavior, and substance abuse. The severity of psychological distress may correlate with pruritus severity [40]. Management includes habit‐reversal training and c­ ognitive‐behav­ ioral therapy. Antidepressants have also been shown to be beneficial [37].

­Management Guidelines Treatment should always start with a good doctor–patient relationship. Doctors and patient should foster a therapeutic alliance that develops empathy while increasing patient satisfaction and adherence to treat­ ment [41]. A multidisciplinary team

consisting of dermatologists, psychiatrists, psychologists, and social services provides a greater scope of care [42]. Realistic goals that should be discussed with the patient include reducing pruritus and scratching, improving sleep, and managing psychiatric symptoms such as anxiety, depression, and social embarrassment. Both pharmacologi­ cal and nonpharmacological treatments have been shown to be effective. Pharmacological treatments include anti­ depressants, anxiolytics, and antipsychotics to treat the various psychopathologies of depression, anxiety, psychosis, and obses­ sions and compulsions. Dermatological medications include antihistamines, corti­ costeroids, and topical medications to treat pruritus, scarring, and infections. Nonphar­ macological management through psycho­ therapy, behavioral therapy, hypnosis, stress management techniques, biofeedback, and guided imagery have also been shown to be beneficial.

­Conclusion Skin conditions have much more depth than just cosmetic disfigurement, as made evident in this chapter. To be adequately managed they require a fund of knowledge in embryol­ ogy, physiology, pathology, pharmacology, and psychology. Psychoneurocutaneous medicine is unique due to its integrative approach to both diagnosis and management of the patient. Dermatological, neurological, and psychiatric conditions must all be man­ aged for complete resolution of symptoms and improvement in the quality of life. With the increase in psychodermatologically focused research and medical associations, patients have access to more education and treatment options than ever before. There is still room to grow, and doctors and patients alike need to be made aware of this growing field of study to increase their scope of prac­ tice and help those who are in need.

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­References 1 Standring, S. (2015). Cell populations at the

2

3

4

5

6

7

8

9

start of organogenesis. In: Gray’s Anatomy The Anatomical Basis of Clinical Practice (ed. S. Standring, N. Anand, R. Birch, et al.), 193–199.e1. London: Elsevier. Salmon, J.K., Armstrong, C.A., and Ansel, J.C. (1994). The skin as an immune organ. West. J. Med. 160 (2): 146–152. França, K., Chacon, A., Ledon, J. et al. (2013). Pyschodermatology: a trip through history. An. Bras. Dermatol. 88 (5): 842–843. Feinberg, A.N., Shwayder, T.A., Tareen, R.S. et al. (2013). Perspectives on management of pediatric dermatologic disorders. In: Pediatric Psychodermatology: A Clinical Manual of Child and Adolescent Psychoneurocutaneous Disorders (ed. R.S. Tareen, D.E. Greydanus, M. Jafferany, et al.), 3–68. Berlin: DeGruyter. Jafferany, M. and França, K. (2015). The interface between geriatrics, psychiatry and dermatology. In: Geriatric Psychodermatology: Psychocutaneous Disorders in the Elderly (ed. M. Jafferany and K. França), 3–8. New York: Nova Science. França, K., Panchaprateep, R., and Tosti, A. (2015). Optimal Patient Management of Alopecia. Oxford: Gardner Healthcare Communications. França, K. and Nouri, K. (2015). Psychodermato‐oncology: skin cancers in the elderly. In: Geriatric Psychodermatology: Psychocutaneous Disorders in the Elderly (ed. M. Jafferany and K. França), 187–193. New York: Nova Science. Castillo, D., França, K., and Lotti, T. (2016). Psychological approach in cosmetic dermatology: clinical approach and procedures in cosmetic dermatology. In: Daily Routine in Cosmetic Dermatology (ed. M.C.A. Issa and B. Tamura), 1–15. Lupi, O., Madkan, V., and Tyring, S. (2006). Tropical dermatology: bacterial tropical diseases. J. Am. Acad. Dermatol. 54 (4): 559–578.

10 Freiman, A., Barankin, B., and Elpern, D.J.

11

12

13

14

15

16

17

18

19

20

21

22

(2004). Sports dermatology part 1: common dermatoses. Can. Med. Assoc. J. 171 (8): 851–853. França, K., França, A.P., and de França, R. (2017). Environmental psychodermatology: stress, environment and skin. In: Stress and Skin Disorders (ed. K. França and M. Jafferany), 47–51. Cham: Springer. Jafferany, M. and França, K. (2016). Psychodermatology: basics concepts. Acta Derm. Venereol. 96: 35–37. Koblenzer, C.S. (2000). Dermatitis artefacta. Clinical features and approaches to treatment. Am. J. Clin. Dermatol. 1: 47–55. Fabisch, W. (1980). Psychiatric aspects of dermatitis artefacta. Br. J. Dermatol. 102: 29–34. Spraker, M.K. (1983). Cutaneous artefactual disease: an appeal for help. Pediatr. Clin. North Am. 30: 659–668. Alcolado, J.C., Ray, K., Baxter, M. et al. (1993). Malignant change in dermatitis artefacta. Postgrad. Med. J. 69: 648–650. Koblenzer, C.S. (1992). Cutaneous manifestations of psychiatric disease that commonly present to the dermatologist: diagnosis and treatment. Int. J. Psychiatry Med. 22: 47–63. Sneddon, I. and Sneddon, J. (1975). Self‐inflicted injury: a follow‐up study of 43 patients. Br. Med. J. 3: 527–530. Garnis‐Jones, S., Collins, S., and Rosenthal, D. (2000). Treatment of self‐mutilation with olanzapine. J. Cutan. Med. Surg. 4: 161–163. Koo, J. and Lebwohl, A. (2001). Psychodermatology: the mind and skin connection. Am. Fam. Physician 64: 1873–1878. Damiani, J.T., Flowers, F.P., and Pierce, D.K. (1990). Pimozide in delusion of parasitosis. J. Am. Acad. Dermatol. 22: 312–313. Hamann, L. and Avnstorp, L. (1982). Delusions of infestation treated by pimozide: a double‐blind crossover clinical study. Acta Derma. Venereol. 62: 55–58.

­Reference

23 Koo, J. and Lee, C.S. (2001). Delusions of

24

25

26

27

28

29

30

31

32

parasitosis: a dermatologist’s guide to diagnosis and treatment. Am. J. Clin. Derm. 2: 285–290. DeLeon, O.A., Furmaga, K.M., Canterbury, A.L. et al. (1997). Risperidone in the treatment of delusion of infestations. Int. J. Psychiatry Med. 27: 403–409. Srinivasan, T.N., Suresh, T.R., Jayaram, V. et al. (1994). Nature and treatment of delusional parasitosis: a different experience in India. Int. J. Dermatol. 33: 851–855. Lochner, C., DuToit, P.L., Zungu‐Durwayi, N. et al. (2002). Childhood trauma in obsessive‐compulsive disorders, trichotillomania and controls. Depress. Anxiety 15: 66–68. Mittal, D., O’Jite, J., Kennedy, R. et al. (2001). Trichotillomania associated with dementia: a case report. Gen. Hosp. Psychiatry 23: 163–165. Schlosser, S., Black, D.W., Blum, N. et al. (1994). The dermography, phenomenology, and family history of 22 persons with compulsive hair pulling. Ann. Clin. Psychiatry 6: 147–162. Zalsman, G., Hermesh, H., and Sever, J. (2001). Hypnotherapy in adolescents with trichotillomania: three cases. Am. J. Clin. Hypn. 44: 63–68. Cohen, H.A., Barzilai, A., and Lahat, E. (1999). Hypotherapy: an effective treatment modality for trichotillomania. Acta Paediatr. 88: 407–410. Calicusu, C., Yucel, B., Polat, A. et al. (2002). Expression of anger and alexithymia in patients with psychogenic excoriation: a preliminary report. Int. J. Psychiatry Med. 32: 345–352. Gupta, M.A., Gupta, A.K., and Habermann, H.F. (1987). The self‐inflicted

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36

37

38

39

40

41

42

dermatoses: a critical review. Gen. Hosp. Psychiatry 9: 45–52. Fruensgaard, K. (1984). Neurotic excoriations. A controlled psychiatric examination. Acta Psychiatr. Scand. Suppl. 312: 1–52. Krupp, N.E. (1977). Self‐caused skin ulcers. Psychosomatics 18: 15–19. Ko, S.M. (1999). Underdiagnosed psychiatric syndrome, 2: pathologic skin picking. Ann. Acad. Med. Singapore 28: 557–559. Weintraub, E., Robinson, C., and Newmeyer, M. (2000). Catastrophic medical complication in psychogenic excoriation. South Med. J. 93: 1099–1101. Harris, B.A., Sherertz, E.F., and Flowers, F.P. (1987). Improvement of chronic neurotic excoriations with oral doxepin therapy. Int. J. Dermatol. 26: 541–543. Biondi, M., Arcangeli, T., and Petrucci, R.M. (2000). Paroxetine in a case of psychogenic pruritus and neurotic excoriation. Psychother. Psychosom. 69: 165–166. Koblenzer, C.S. (1999). Itching and the atopic skin. J. Allergy Clin. Immunol. 104 (3 pt 2): 109–113. Gupta, M.A., Gupta, A.K., Schork, N.J. et al. (1994). Depression modulates pruitus perception: a study of pruritus, atopic dermatitis, and chronic idiopathic urticaria. Psychosom. Med. 56: 36–40. França, K. and Mahmud, M. (2015). Doctor‐patient relationship in Geriatric Psychodermatology. In: Geriatric Psychoermatology: Psychocutaneous Disorders in the Elderly (ed. M. Jafferany and K. França), 9–13. New York, NY: Nova Science Publishers. Jafferany, M. (2011). When the mind and skin interacts. Psychiatric Times 28: 12. (available at www.psychiatrictimes.com).

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4 Acne Bárbara R. Ferreira, José C. Cardoso, José P. Reis, and Américo Figueiredo Department of Dermatology, Coimbra Hospital and University Centre, Coimbra, Portugal

­Introduction and Epidemiology Celsus was one of the most important Roman medical writers, known for his first‐century medical work, “De Medicine.” Celsus also first described a dermatosis characterized by lesions on the face of young people that, according to the description, may correspond to acne. He used terms like “varus” and “varius” in order to highlight the polymorphism of the lesions. Later, Aetius Amidenus, a physician in Constantinople, first used the word “acne,” in the sixth century, underlining that the lesions occurred on the face at the “acme” of life, pointing to “puberty” [1]. In the field of the history of dermatology, we have also suggested in a recent paper on a controversial disease in psychodermatology, “Morgellons disease,” that some past reports incorrectly identifying Morgellons could correspond to “comedones,” and then to acne, highlighting the impact of acne throughout time [2]. Acne is a very common inflammatory disor­ der of the pilosebaceous unit that belongs to the group of psychophysiological dermatoses due to its relationship with psychological stress and has multifactorial etiopathogenesis, deserving a holistic approach. In fact, a link has been suggested between acne, psychosocial issues, and several environmental factors, such as Western diet and pollution, which

has led to the emergence of a discussion on complementary treatments [3]. The global prevalence is 9.4%; acne is the eighth‐most prevalent disease worldwide [3] and one of the most common dermatoses [4]. Important epidemiological studies conducted in 2011 and 2012 reported that the prevalence may be different according to ethnic group (for instance, African American with 37% and Caucasian with 24% prevalence), although this may not be so significant, since environ­ mental factors may have a deep contribution too. Acne is most commonly observed between 16 and 20 years [5, 6] and boys have higher risk for the most severe forms. Acne seems to be more common in girls at the lower age groups and, at puberty, acne is more prevalent in boys [3]. Thereafter, in adults, women are more affected [3], with a prevalence of 12% [7]. Adolescents are thus by far the biggest group affected by this der­ matosis, with a prevalence ranging from 35% to 90% [8], which points to the need to pay particular attention to the psychosocial issues related to this age group, namely due to the physical changes that occur at that time and the deeper concerns of peer group integration and of self‐image, as well as the higher sensitivity to stigmatization and feel­ ings of shame [9]. Thus, this chapter intends to present an integrative approach to acne, taking into

Advances in Integrative Dermatology, First Edition. Edited by Katlein França and Torello Lotti. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.

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account the relationship between psychoso­ cial and environmental factors, the subtleties of the adolescent psychodermatology, and management according to the subtleties of each affected age group.

­ linical Features and C Classification Acne vulgaris is easily diagnosed by its clinical features. The dermatosis typically has a chronic evolution and distribution on the body areas where there is a higher quantity of pilosebaceous glands, particularly the face, chest, and back, as it is an inflammatory disease of the pilosebaceous unit. The first lesion of acne is a microcomedo, which is a microscopic lesion. Through the clinical evolution of the dermatosis, we may find non‐inflammatory or inflammatory lesions [4]. The former corresponds to comedonal acne, where opened and closed comedones, which are skin‐colored papules, with and without a clear follicular opening respectively, can be seen. The latter includes erythematous pap­ ules and pustules as well as nodules and cysts that can be filled with pus or serosanguinous content. In addition, patients may also pre­ sent secondary features, namely: erosions; excoriations, in the setting of acne excoriée; ulcers and crusts, in the context of acne fulminans; and scars, especially as a conse­ quence of the severe forms. As a complication, some patients may rarely exhibit a clinical variant of acne called solid facial edema, or Morbihan’s disease, that clinically presents with induration and erythema of the face, and whose etiopathogenesis may be linked to chronic inflammation together with genetic predisposition. Commonly, post‐inflammatory hyperpigmentation can also be secondarily observed [10]. Acne should then be classified according to the following points: type of cutaneous lesion observed, severity, age of onset, factors of worsening or of induction of the dermatosis and associated disorders or syndromes [4, 10].

Thereby, considering the type of cutaneous lesions (primary and/or secondary lesions), acne can be classified as comedonal, papulo­ pustular, nodular, nodulocystic, and conglo­ bate. The latter may be considered the ending part of the spectrum of nodulocystic acne, with a predominance of highly inflammatory lesions and sinus tracts. This form can be part of the follicular occlusion tetrad together with hidradenitis suppurativa, dissecting ­cellulitis of the scalp, and pilonidal cysts [4]. The male gender is much more affected and, despite the severity of the dermatosis, sys­ temic findings are not present [11]. According to the severity, acne can be classified as mild, moderate, or severe and this classification also takes into account the type and number of the cutaneous lesions described above. More precisely, both mild and moderate forms include comedonal and papulopustular lesions, but, in the former, comedones are the main lesions and nodules are not observed. The latter has comedones, papules, and pustules, and may have some nodules, but cysts and sinus tracts are not observed. In mild acne, there are fewer than 20 comedones and fewer than 10 papules or pustules on the face. In moderate acne (Figure  4.1), the number of comedones on the face may range from 10 to 40 as well as the number of papules and pustules. Nodules can be occasionally seen in moderate acne, but the number of these lesions on the face should not be higher than 10 [4]. Concerning

Figure 4.1  Moderate acne, with comedonal and papulopustular lesions.

­Clinical Features and Classificatio

Figure 4.2  Nodulocystic acne.

the severe forms, here we observe comedones, papules, pustules together with nodulocystic acne (Figure  4.2) or even acne with clinical criteria for acne conglobata. Acne fulminans, previously called “acne maligna” or “acute febrile ulcerative acne conglobate,” is the most severe form of acne, commonly affect­ ing boys in adolescence, in contrast with acne conglobate which typically occurs in early adulthood. Clinically, it is characterized by a sudden onset of severe cutaneous lesions in a patient who had mild to moder­ ate acne; there are painful and hemorrhagic nodules which can evolve into ulceration, commonly on the trunk and healing with significant scars [12, 13]. Acne fulminans can occur with or without systemic findings and abnormalities in laboratory parameters, such as fever, arthralgia, leukocytosis, and increased erythrocyte sedimentation rate and C‐reactive protein. Osteolytic lesions can be observed in its most severe presen­ tation. The etiopathogenesis is not fully understood. Testosterone therapy, intake of anabolic androgen steroids, and isotretinoin, especially when started with high doses, have been suggested as triggers interfering with the activity of Propionibacterium acnes (P. acnes) [13]. Acne fulminans should be classified as “acne fulminans without systemic symptoms,” “acne fulminans with systemic symptoms,” “isotretinoin‐induced acne fulminans with systemic symptoms,” and “isotretinoin‐induced acne fulminans without systemic symptoms,” the latter being the most common. Overall, acne fulminans is

more common in Caucasians and has genetic predisposition; a history of two years of evolu­ tion and macrocomedones are also typical [12]. Considering the age of onset, acne can be pediatric (neonatal, infantile, mid‐childhood, preadolescent), adolescent, or adult acne [14]. Adult acne is that observed in patients above the age of 25, both those who also had acne during puberty and those with late‐ onset acne [4]. Adolescent acne includes patients between the age of 12 and adult­ hood. Pediatric acne is used for patients from birth up to the age of 11: neonatal acne from birth to the fourth week of life; infantile acne from the first month of life up to the age of first year of life; mid‐childhood acne from the first to the sixth year of life; and preado­ lescent acne from the seventh year of life to the age of 11 years old. Neonatal acne is char­ acterized by an inflammatory component, with erythematous papules and pustules, and, rarely, comedones. Neonatal cephalic pustulosis is a more pustular form of the same disease, without comedones, according to some authors, although some discussion still exists whether they are different condi­ tions due to these subtleties on the clinical presentation [14]. The etiopathogenesis of neonatal acne is still being discussed and some authors have linked it to the stimula­ tion of the sebaceous glands by the maternal androgens, while neonatal cephalic pustulosis would be more closely related to the tran­ sient inflammatory response to Malassezia furfur or Malassezia sympodialis. Both neonatal acne and infantile acne are more common in boys and on the face, typically on the cheeks. In contrast with neonatal acne, in infantile acne comedones are prominent as well as nodules and cysts and its etiopatho­ genesis is explained by the physiological and transient increase in androgen levels (pro­ duction of testosterone and dehydroepian­ drosterone [DHEA]) [10, 14]. Preadolescent acne is the first cutaneous finding of pubertal maturation, typically with comedones on the frontal region, and the etiopathogenesis is explained by the increasing levels of adrenal androgens, namely DHEA [14].

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Acne

Furthermore, acne can also be classified in variants that take into account some factors which induce acneiform lesions or worsen the dermatosis. In this context, we can consider the following variants: contact acne, drug‐ induced acne, and acne excoriée. Contact acne is the result of persistent occlusion of the follicular opening, leading to development of comedones, and includes acne mechanica, acne cosmetica, and occupational acne. The first is the result of repetitive local trauma, such as by helmets and collars. Acne cosmet­ ica is the term used for acneiform lesions caused by certain cosmetics [10]. Occupa­ tional acne is caused by exposure to a wide range of substances in the workplace. For example, occupational exposure to some halo­ genated aromatic hydrocarbons is called “chloracne” and is considered one of the most sensitive markers of systemic poisoning by them. It is relevant to mention, furthermore, that chloracne can also occur as a result of non‐occupational exposure, namely through contaminated food, and represents an impor­ tant matter in public health since the chlorac­ negens are lipophilic and persist for years in the body fat. Clinically, patients may present both comedones and inflammatory lesions. The clinical picture is characteristic because, firstly, the lesions appear on the face and neck and, afterwards, they develop on the trunk, genitalia, and extremities, and tend to be chronic [15]. Interestingly, the first example provided in the literature of drug‐induced acne was that it is caused by iodides and chlo­ rinated hydrocarbons. From a clinical point of view, drug‐induced acne can be differentiated from acne vulgaris since the first can be observed not only on the face, neck, and chest, but also beyond the seborrheic areas [16]. Besides, more frequently, follicular erythema­ tous papules and pustules are predominant and comedones are not characteristic [10]. Drug‐induced acne seems to be more resist­ ant to conventional acne treatment. The drugs that have a recognized relationship with acneiform eruptions are the previously described halogens, corticosteroids, testoster­ one, anabolic steroids, isoniazid, lithium, and

Figure 4.3  Acne excoriée.

anticancer drugs such as epidermal growth factor receptor (EGFR) inhibitors, BRAF inhibitors and mitogen‐activated protein kinase (MAPK) inhibitors. Some studies have also highlighted an association between acnei­ form eruptions and other drugs, namely, cyclosporine A, azathioprine, tricyclic antide­ pressants, and tacrolimus [16]. Acne excoriée “des jeunes filles” (Figure 4.3) is an example of a skin‐picking disorder that typically affects young women, who scratch the papules, pustules, and comedones, and is within the obsessive‐compulsive spectrum [17]. Finally, acne should also be clinically ana­ lyzed as a cutaneous sign of systemic disease [18]. Some patients with acne may also have criteria for some syndromes, the following being the most traditionally described: syno­ vitis, acne, pustulosis, hyperostosis, osteitis or SAPHO Syndrome, involving synovitis, acne from mild to severe forms, pustulosis (the most common observed dermatosis), hyperostosis, and osteitis; pyogenic arthritis, pyoderma gan­ grenosum, and acne or PAPA syndrome, with pyogenic sterile arthritis, pyoderma gan­ grenosum and acne conglobata; pyoderma gangrenosum, severe acne, and hidradenitis suppurativa or PASH; and pyogenic arthritis, pyoderma gangrenosum, severe acne, and hidradenitis suppurativa or PAPASH [11, 19]. Although the etiopathogenesis is not fully understood, it is possible that SAPHO could be triggered by P. acnes, causing important cellular and humoral inflam­matory responses. PAPA has been linked to mutations in PSTPIP1 (proline‐serine–threonine‐phosphatase

­Clinical Features and Classificatio

interacting protein 1) gene, also called the gene of CD2‐binding protein 1 (CD2BP1), modify­ ing the activity of pyrin and causing neutro­ philic infiltration [19]. Mutations in PSTPIP1 were also described in some patients with PASH, but the genetic background seems to be wide and not fully clarified [20]. Furthermore, acne fulminans was occa­ sionally seen in the setting of Marfan syn­ drome and late‐onset congenital adrenal hyperplasia [12]. Congenital adrenal hyper­ plasia corresponds to the presence of a wide range of genetic disorders of the cortisol and/ or aldosterone enzymatic pathways, with the deficiency of 21‐hydroxilase being the most common. As a consequence, there is glucocor­ ticoid deficiency, mineralocorticoid deficiency, and higher levels of androgens, the latter explaining the early development of acne [18]. Acne can also be part of the seborrhea‐acne‐ hirsutism‐androgenetic alopecia syndrome (SAHA), the polycystic ovarian syndrome (PCOS), the hyperandrogenism‐insulin resist­ ance‐acanthosis nigricans (HAIR‐AN) syn­ drome, and the Apert syndrome. SAHA results from high circulating levels of androgens or higher sensitivity of the pilosebaceous unit to androgens in women. In PCOS there are clinical and biochemical signs of hyperandro­ genism, disorder of ovulation, and polycystic

ovaries, probably related to genes also linked with obesity. This condition should be sus­ pected in women with severe acne or acne with late onset or acne which is resistant to conven­ tional treatment. HAIR‐AN is considered a type of PCOS, where the insulin resistance leads to high levels of insulin. Insulin and insu­ lin‐like growth factor (IGF‐1) stimulate epider­ mal thickness through its binding to receptors on keratinocytes and fibroblasts. The activity of sebaceous glands is also increased by IGF‐1, stimulating the development of acne lesions. The high levels of insulin also interfere with steroidogenesis and increase the production of androgens that also contribute to epithelial thickness and a higher density of melanin, sub­ sequently explaining acanthosis nigricans [21]. Apert syndrome is a congenital and autosomal dominant disorder due to the mutation of the growth factor receptor 2 (FGFR2) and is defined by craniosynostosis, syndactyly, and abnormalities of the skin and other organs. Inflammatory acne in adolescence that is also observed beyond the seborrheic areas is the typical skin finding. There is also a mosaic cutaneous form of Apert syndrome observed along the lines of Blaschko, which is called Munro’s acne nevus [22]. Table 4.1 summarizes the clinical spectrum of acne and the factors to consider in its classification.

Table 4.1  Acne: spectrum of cutaneous lesions and classification. Acne: clinical features and classification

Primary cutaneous lesions (papules, pustules, nodules)

Comedonal acne; Inflammatory acne: papulopustular ± nodulocystic; acne conglobata

Severity (number and type of primary lesions)

Mild; moderate; severe.

Age of onset

Pediatric (neonatal, infantile, mid‐childhood, preadolescent) acne; adolescent acne; adult acne

Factors of worsening/induction

Contact acne; drug‐induced acne; acne excoriée

Associated disorders/syndromes

Examples: SAPHO, PAPA, PASH, PAPASH, Congenital adrenal hyperplasia, Apert syndrome

Secondary cutaneous lesions/ complications

Morbihan’s disease; Acne fulminans (inflammatory acne+ulcers and crusts); Acne scars; Acne excoriée

SAPHO syndrome: synovitis, acne, pustulosis, hyperostosis, osteitis; PAPA syndrome: pyogenic sterile arthritis, pyoderma gangrenosum and acne conglobata; PASH: pyoderma gangrenosum, acne and hidradenitis suppurativa; PAPASH: pyogenic arthritis, pyoderma gangrenosum, severe acne and hidradenitis suppurativa

37

38

Acne

­Perspective of Multifactorial Etiopathogenesis and Relevance of an Integrative Approach The etiopathogenesis of acne is centered in the pilosebaceous unit and involves four main mechanisms: high sebum synthesis by the sebaceous gland; the activity of P. acnes; disorder of the keratinization in the follicle, with hyperproliferation and a reduction in the shedding of intra‐follicular keratinocytes, leading to obstruction and, then, to the for­ mation of microcomedones (the first cuta­ neous lesion); and the role of inflammatory mediators, namely proteases, lipases, and chemotactic factors released by P. acnes, acti­ vating mediators of both innate and adaptive immunity [23]. Furthermore, androgens, stress‐related hormones, the endocannabi­ noid system, diet, lifestyle, and environmental factors together with genetics can also help to understand the development and evolution of this dermatosis. The Sebaceous Gland: Sebum Synthesis and Acne – An Overview The sebaceous glands are holocrine glands. They secrete through the disruption of the glandular cells to the upper part of hair follicles and contribute to the production of the cutaneous lipid film together with lipids of keratinocyte origin. The density of seba­ ceous glands is higher on the face, back, and chest and they are not observed on the palms, soles, and dorsal surface of feet. The face, particularly the T‐zone, is where they show the highest density. Besides these anatomic considerations, the activity of sebaceous glands may differ according to age and gen­ der [24]. This may explain why acne presents different prevalence in the male and female gender throughout life, as described above in the clinical features. The lipid composition of sebum differs from that of keratinocyte ori­ gin and includes 57% triglycerides and free fatty acids, 26% wax esters, 12% squalene, and 2% cholesterol, and in the pilosebaceous

unit it is made up of triglycerides, squalene, and wax esters [24, 25]. Knowledge of the physiology and pathophysiology of the seba­ ceous gland and lipid production is ­relevant to attain an integrated approach to the der­ matosis. For instance, patients with acne have higher cutaneous levels of squalene, which can also contribute to the development of comedones. Isotretinoin, a 13‐cis‐retinoid acid, and spironolactone, an antiandrogenic drug, have a sebostatic role, modulating these mechanisms [24]. Moreover, sebaceous glands are also modulated by sexual hormones and adrenal corticosteroids, a fact that is impor­ tant to integrating this dermatosis in the con­ text of associated disorders and syndromes. For instance, it was observed that sebaceous glands in acne show a high manifestation of activity of 11‐beta‐hydroxysteroid dehydroge­ nase (HSD) type I. This is important to under­ stand, at a biochemical level, the connection between acne and psychological stress, because this enzyme converts cortisone to cortisol and modulates lipid synthesis, and this was correlated with acne severity in some studies [24, 26–28]. Actually, a large number of studies showed that stress response‐related hormones, particularly corticotrophin releas­ ing hormone (CRH), adrenocorticotrophic hormone (ACTH) and melanocyte stimulat­ ing hormone (MSH) are expressed in seba­ ceous glands and modulate lipid synthesis in sebocytes [29, 30]. Dihydro­testosterone, testosterone, and a wide range of mediators and hormones, like CRH and IGF‐1, increase the activity of sebocytes, which, together with P. acnes, stimulate the release of inflammatory mediators in the perifollicular dermis, con­ tributing to the development of comedones and inflammatory lesions [23]. Propionibacterium acnes Propionibacterium acnes (P. acnes) is a rod‐ shaped gram‐positive that is commensal in the pilosebaceous unit [31]. However, some strains of P. acnes are pathogenic. It has been shown that patients with acne do not significantly differ from those without the

  Perspective of Multifactorial Etiopathogenesis

dermatosis in terms of the quantity of P. acnes; rather, the strains are different [32]. In a recent study, the phylotypes IA‐2, IB‐1, and IC were identified as being associated with acne, which could be of interest for further research on type‐specific therapies [33, 34]. Pathological strains may be more prone to secrete lipases that hydrolyze the triglycer­ ides of sebum, bind Toll‐like receptor (TLR) 2 and TLR4 on sebaceous glands, leading to an increase in antimicrobial peptides, such as granulysin and cathelicidin, and trigger an inflammatory mechanism with high levels of interleukin (IL)‐1, IL‐6, IL‐8, and tumor necrosis factor‐α (TNF‐α), and recruitment of neutrophils and macrophages, with rup­ ture of the follicle wall. This inflammatory mechanism is, then, enhanced by macro­ phages through higher production of IL‐8 and IL‐12 and also T‐helper 1 (Th1) response. Besides, P. acnes stimulates hyperkeratini­ zation through an increase in the levels of integrin and filaggrin [31]. P. acnes also secretes proteases and hyaluronidases that, together with lipases, enhance destruction through the stimulation of pro‐inflammatory mechanisms in the pilosebaceous unit, the activation of the classical and alternative complement pathways and recruitment of neutrophis [35]. Furthermore, other micro­ organisms, namely Streptococcus epidermidis, may interact with P. acnes in patients with acne and may also have a role in the etiopatho­ genesis of the dermatosis [32]. Disorder of Follicular Keratinization The disorder of follicular keratinization corresponds to hyperkeratinization, result­ ing from a proliferation of epithelial follicular cells with retention of keratinocytes that leads to a keratin plug placed in the follicular infundibulum and, then, to the formation of the precursor cutaneous lesion of acne, the microcomedo. Several mechanisms contribute to the etiopathogenesis of the microcomedo: hormones, particularly, the androgens, and the lipid content, strains, and activity of

P.  acnes and inflammatory mediators, such as IL‐1 and leukotriene B4, the latter leading to the recruitment of inflammatory cells through a peroxisome proliferator‐activated protein (PPAR), namely, PPAR‐α [31, 36]. Macrophages and CD4+ lymphocytes stim­ ulate the pilosebaceous vasculature, also contributing to the process of follicular hyperkeratinization, together with the higher local levels of squalene and matrix metallo‐ proteinases present in the sebum [36]. Innate and Adaptive Immunity The etiopathogenesis of acne involves both innate and adaptive immunity [37, 38]. The innate system involves the cutaneous barrier, disturbed through an imbalance of the lipid content, and the TLRs, particularly, the TLR2 and TLR4, with subsequent involvement of keratinocytes, neutrophils, macrophages, nat­ ural killer, and dendritic cells, like Langerhans cells, as well as the release of antimicrobial peptides and activation of matrix metallo‐ proteinases, the latter being correlated with the development of scars [31]. Pathological strains of P. acnes are important in the activa­ tion of these mechanisms [32, 38]. Langerhans cells will then present the antigens to CD4+ T cells and, later, an infiltrate of CD8+ cells also occurs, and these mechanisms involve adaptive immune response, particularly on the Th17 axis, also shared with psoriasis, involving the cytokines IL‐6, IL‐1ß, and tumor growth factor‐ß (TGF‐ß). Retinoids, zinc, and dihydroxyvitamin D3 have an effect on the Th17 pathway. Besides, isotretinoin down­ regulates TLR2, controlling the migration of monocytes and neutrophis [37]. SAPHO syn­ drome shows good response to anti‐IL‐1 [39]. Further research on acne and associated disorders and syndromes could be targeted to cytokines involved in this pathway. Androgens Androgens can be produced by gonadal, adrenal, and sebaceous glands [10]. DHEA, testosterone, and dihydrotestosterone (DHT)

39

40

Acne

regulate genes involved in the synthesis of the lipid content by the sebaceous glands [40]. The first is converted into testosterone by 3ß‐HSD and 17ß‐HSD and then into DHT by 5α‐reductase, the major androgen that interferes with the sebaceous gland [10]. In addition, androgens also stimulate come­ dogenesis [31]. Androgens interfere with sebaceous glands beginning in the neonatal period. The levels are higher during the first year of life and then decrease up to the adrenarche, when the levels of DHEA‐sulfate, of adrenal production, increase, correlating with the development of comedones. One‐ third of women with post‐adolescent acne have hyperandrogenia. Hyperandrogenia should be suspected in women with hirsutism and androgenetic alopecia and children who develop acne between the age of two up to seven years and have typically severe acne which is resistant to treatment [10]. As explained above, in the management, syn­ dromes that also present hyperandrogenism should be excluded, such as SAHA, PCOS, and congenital adrenal hyperplasia [21]. Endocannabinoids Endocannabinoids are endogenous lipid mediators that are also expressed in the skin and have a wide range of functions, especially in the pilosebaceous unit, controlling sebum production and having an anti‐inflammatory effect. This has raised interest in researching its usefulness for acne treatment [41]. CRH‐ACTH: Cortisol Axis, Psychological Stress, and Acne Psychological stress was reported to worsen acne in 50% of patients [42]. Psychological stress modulates immunity, sharing mecha­ nisms with several chronic dermatoses, considering that the skin has a peripheral hypothalamo‐pituitary‐adrenal (HPA) axis. Psychological stress induces the production of CRH in the paraventricular nucleus of

hypothalamus, leading to the secretion of ACTH and cortisol. However, corticosteroid receptors become insensitive to the persistent effects of cortisol and the effect of catechola­ mine on macrophages becomes preponder­ ant, stimulating the secretion of TNF‐α, IL‐1, and IL‐6. In the brain, these cytokines induce or exacerbate symptoms of depression, lead­ ing to the persistence of these mechanisms, both at a central and peripheral level [43, 44]. Sebaceous glands express receptors for neuroendocrine mediators related to stress, since they are involved in the peripheral HPA axis. They have receptors for CRH and other components of stress response, such as vasoactive intestinal polypeptide, neuropeptide Y, and calcitonin gene‐related peptide, which interfere with the synthesis of lipid content as well as the androgen metabolism by the sebaceous gland [45]. Furthermore, in the setting of HPA axis stimulation there is a local increase of sub­ stance P, which stimulates peptidases and lipid production, and then comedogenesis, by the sebaceous gland [44, 45]. Thereafter, there is proliferation of P. acnes and high inflammatory responses involving mast cells [46]. The sebaceous gland is also influenced by CRH in response to stress, increasing sebum production [36]. Besides, CRH also promotes the conversion of precursors of androgens into testosterone and psychologi­ cal stress also induces a slower wound heal­ ing process and repair of the active cutaneous lesions of acne [47]. Diet, Lifestyle Habits, and Environmental Factors A field of recent heated discussion in the etiopathogenesis of acne is its relationship with lifestyle and diet [3]. The absence of acne in native people in Papua New Guinea and in Paraguay raised interest to examine the link between acne vulgaris and the Western diet, particularly food with high glycemic load, leading to hyperinsulinaemia and high levels of IGF‐1 [36]. Randomized

  Perspective of Multifactorial Etiopathogenesis

controlled dietary intervention studies showed that there is a strong link between acne and diet. It  was documented that a lower glycemic diet was related to improve­ ment in acne, both for non‐inflammatory and inflammatory cutaneous lesions, with correlated reduction in inflammatory markers. Besides, omega‐3 fatty acids and γ‐linolenic acid were shown to improve inflammatory cutaneous lesions of acne after 10 weeks [35]. Melnik et  al. reported that there is overstimulation of mammalian target of rapamycin complex (mTORC) 1 in the pilosebaceous unit by Western diet through dairy‐origin essential amino acids. In addition, an insulinotropic Western diet  disturbs the activity of forkhead box transcription factor O1 (FoxO1). As a con­ sequence, mTORC1 is stimulated and enhances hyperkeratinization and hyper­ plasia and function of the sebaceous gland, so that acne vulgaris can be considered as part of the family of mTORC1‐driven diseases of civilization, as well as cancer [48]. Further­ more, patients with acne vulgaris exhibit lower levels of adiponectin which is also connected with a diet with high glycemic load, and this may facilitate the hyperactivity of mTORC1 [49]. The link with vitamin deficiency was also recently studied. Vitamin D deficiency was significantly more prevalent in patients with acne, as it was previously documented for obesity, a finding that needs further study. Vitamin D could modulate the expres­ sion of inflammatory cytokines, namely IL‐6 and IL‐8, and matrix metalloproteinases in the pilosebaceous unit. Moreover, it was observed that vitamin D inhibits P. acnes and the Th17 pathway [50]. A recent case‐control study came to ­reinforce the connection between acne and lifestyle, correlating adult acne in women and lifestyle. More precisely, it was found that women more than 25 years old, who were recently diagnosed with any level of acne severity, had a positive association with working as an office worker, higher levels of

psychological stress, and lower consumption of vegetables, fruits, and fish [51]. Two controversial topics are the relation­ ship between acne and chocolate consump­ tion, as well as acne and smoking, since some studies have argued that a connection with acne exists, even for unsweetened chocolate, while others did not prove that. Regarding chocolate, in 2017, the results from a multi­ center cross‐sectional population‐based online survey documented that, in the multivariate analysis, chocolate was independently linked with acne. But this could possibly be explained by the fact that chocolate combines sugar and milk, particularly skim milk, which are under­ lined as important mediators of diet in acne etiopathogenesis. They may potentiate each other and influence the evolution of the der­ matosis [52]. Alcohol consumption was also associated with acne in one study [53]. Moreover, environmental pollutants can contribute to acneiform lesions, particularly endocrine disruptors. Endocrine chemical disruptors are used in industry in a large number of products and exposure to them can lead to hormonal disturbances involving androgens, which may contribute to the etiopathogenesis of acne. For instance, ­ ultraviolet filters, such as octocrylene and benzophenone‐2, can act as androgen recep­ tor agonists in the pilosebaceous gland, and pesticides such as triadimenol can inhibit aromatase activity and lead to the accumula­ tion of androgens [54]. A type of induced acne, called chloracne, results from halogen­ ated aromatic hydrocarbons, such as dioxin. This is an endocrine disruptor found world­ wide and most exposure has been linked to  contaminated food. Dioxin (2, 3, 7, 8‐­tetrachlorodibenzo‐p‐dioxin) is the most potent inductor of chloracne. In turn, chlo­ racne is considered the most consistent form of manifestation of intoxication by dioxin [15, 55]. Dioxin can accumulate in the sebum and persist in activating the aryl hydrocar­ bon receptor (AhR), which is expressed in bipotential stem cells of the sebaceous gland, disturbing its homeostasis [55].

41

42

Acne

Genetics In a study with twins it was observed that 81% of the variance of the dermatosis was related to additive genetic effect. In 2017, a multicenter study with more than 10 000 people showed that 65% of respondents mentioned that one or both parents cur­ rently or previously had acne, which is in accordance with previous studies [52]. In the last decades, twin studies have documented a genetic influence in acne, pointing out some variants, for example, related to TNF‐α, TLR2, and TLR4 [56]. In 2014, in the genome‐ wide association study on severe teenage acne in European Americans, the chromo­ some 8q24 locus was associated with severe clinical presentation of acne, a region which was also associated with diverse cancers, such as breast and prostate cancer. Clinically, severe teenage acne brings a 17% higher risk for breast cancer and a 70% higher risk for prostate cancer. The gene MYC is a proto‐ oncogene close to the chromosome 8q24 region and regulates androgen responsive­ ness, which could explain the link between severe acne, prostate, and breast cancer [56]. Besides, as mentioned above, some phylo­ types of P. acnes have been linked to the development of acne vulgaris [33, 34]. Laron syndrome can be helpful to study the etiopathogenesis of acne and its relation­ ship with diet. It is a rare disease, recessively inherited with reports worldwide, that is related to mutation or deletion in the growth hormone (GH) receptor or post‐receptor pathways, causing deficiency in IGF‐1. These patients do not develop acne and seem to be protected from cancer [57, 58]. Although still in a normal range, adult women with acne have higher levels of androgens and this is explained by higher IGF‐1. Moreover, the link between acne and milk consumption can also be explained by IGF‐1. IGF‐1 can stimulate lipogenic enzymes in the sebaceous glands and also modulate the secretion of androgens, which may explain its relationship with the etio­ pathogenesis of acne [58].

Finally, acne can be part of the clinical spec­ trum of genetic disorders and syndromes, such as congenital adrenal hyperplasia, Apert syndrome, PAPA, and PASH (see Section 4.2).

­Psychopathology and Quality of Life Impairment: An Overview The assessment of comorbidities should be an important component in acne manage­ ment. As described in the previous sections, some disorders have been consistently mentioned as related to acne and should be remembered in the clinical examination. In recent years, some studies have suggested a link with other conditions. For instance, in 2014, a cross‐sectional questionnaire‐based study of 9417 children showed that the prevalence of severe acne was significantly higher between the age of 11 and 17 years and was associated with psychiatric comor­ bidities, together with sinopulmonary and upper gastrointestinal disorders. Although further studies are needed to clarify the rele­ vance of the latter comorbidities, the impact of psychiatric comorbidities in acne has been well described, even when not commonly regarded as so relevant in the clinical prac­ tice. Nevertheless, a wide spectrum of rele­ vant psychiatric disorders, with consequent psychosocial and quality of life impact, has been highlighted. For example, in this study, depression, anxiety, attention deficit disorder/ attention deficit hyperactivity disorder and insomnia were significantly associated with acne [59]. Though depression and anxiety are traditionally reported as the main comorbid­ ities of acne vulgaris, the relationship between acne vulgaris and attention deficit disorder/ attention deficit hyperactivity disorder was not confirmed by other studies [60]. Acne vulgaris is far more common in ado­ lescence, which is a period of intense physical and psychosocial modification. Adolescents have deep sensitivity to their appearance, as this is highly important for social integration.

  Psychopathology and Quality of Life Impairment

Acne interferes with self‐esteem and can lead to feelings of shame, stigmatization, and quality of life impairment [9, 61]. Because the development of identity occurs during ado­ lescence, from a psychoanalytic perspective, acne excoriée, which is typically observed in young females, could be interpreted in the context of a connection between the skin and ego, as suggested by the French psychoana­ lyst Didier Anzieu. Skin picking could then be interpreted as an attempt to remove something felt as dirtiness [62]. At a bio­ chemical level (see Section 4.3), psychologi­ cal stress may modulate the etiopathogenesis of acne and worsen the dermatosis. Thus, in patients with acne, we may have psychiatric comorbidities as a consequence of a chronic and disfiguring dermatosis, with impact on the body image and self‐esteem, such as depression and anxiety [63, 64], and these secondary psychiatric comorbidities can in turn worsen the dermatosis through modula­ tion of the CRH‐ACTH‐cortisol axis, both at a central and peripheral level [43, 44, 47, 65]. Besides this, there is psychopathology that is far more common in some patients with acne, such as the spectrum of obsessive‐­ compulsive disorder, with more expression in the context of acne excoriée [17]. This is an interesting example of the kind of psychoso­ cial impact of dermatosis in adolescence. Actually, during this period of life, acne has a strong impact on the self‐centered psyche of adolescents, also explaining the development of acne excoriée and other disorders on the obsessive‐compulsive spectrum, such as ­eating disorders [63]. Similarly to other psychophysiological dermatoses, namely psoriasis and vitiligo, ­ the psychosocial component of acne should take into account the gender, ethnic group, culture, family or peer group, and work or school. This is connected with the Erickson stages of development: for example, adoles­ cents have a psychosocial conflict centered in identity/confusion, connected with inte­ gration in peer groups [63]. Regarding gen­ der and race, female gender seems to have worse psychosocial impact and higher risk

for major depression and suicide [64]. Additionally, non‐Caucasian patients can be more sensitive, having more impact on social interaction [63]. Thus, several studies have argued that acne should be considered a psy­ chosomatic dermatosis and documented its psychosocial impact and associated second­ ary psychiatric disorders, particularly loneli­ ness, lower self‐esteem, anhedonia, social anxiety and social phobia, generalized anxi­ ety disorder, depression and, then, quality of life impact [65–67]. Even less severe forms are likely to induce secondary psychosocial issues and most studies have reported that, due to the multidimensional component of the dermatosis, there is not a direct correla­ tion between a higher severity of acne and stronger psychosocial impact [63, 66], although this was disputed by others, who mentioned that the higher the severity, the higher the psychosocial and quality of life impact [68]. In contrast with adolescents, women, and patients with acne between 20 and 24 years have impaired sexual relations [68], which can also be understood consider­ ing the Erickson Stage of Development, since young adults have a conflict centered in inti­ macy [63]. For all patients, symptoms of anxiety and depression seem to be the most prevalent comorbidities in patients with acne, corresponding to 55% of all psychiatric comorbidities [69]. Moreover, body dysmor­ phic disorder (BDD) is another prevalent comorbidity in patients with acne and the prevalence may range between 14% and 21%. The onset of BDD is usually during adolescence, similarly to most cases of acne vulgaris, and consists of a disarticulation between how the patients see their body and the physical anomaly of how others see it. This psychiatric comorbidity is strongly con­ nected with skin picking, obsessive‐compulsive disorder, depression, and anxiety, with per­ sistent seeking of medical treatment and stronger drugs for the overvalued or imagi­ nary anomaly but concomitant dissatisfac­ tion with the results [70]. Finally, it is important to highlight that dis­ cussion exists on the hypothetical existence

43

44

Acne

of secondary psychopathology due to isotretinoin (13‐cis‐retinoic acid), because there have been reports of mood disorders and suicide since the first use of the drug in 1982. In a recent study, using the French pharmacovigilance database, with 205 cases of psychiatric disorders or complications related to systemic treatments from 1984 to 2014, there were 179 reports of isotretinoin and this was the only oral treatment for acne that correlated with severe psychiatric adverse drug reactions. The study highlights that psychiatric symptoms observed in patients with acne during the treatment with this drug should be suspected to be drug reaction [71]. Isotretinoin may induce or worsen affective symptoms and disorders, including suicidal ideation [72]. The etiopath­ ogenic mechanisms behind this connection are not fully understood, but they may involve the dopaminergic, serotoninergic, and noradrenergic pathways, with a reduc­ tion in brain metabolism in the orbitofrontal cortex and dysregulation in corpus striatum and in the neurogenesis in the hippocampus [71, 72]. Furthermore, it seems to create increased expression of the retinoic acid‐ induced gene 1 (RAI‐1) in the dorsolateral prefrontal cortex, which is involved in the etiopathogenesis of bipolar disorder and major depression [72]. However, we should not forget that isotretinoin can improve secondary psychiatric symptoms, including

anxiety and depression symptoms, related to the impact on quality of life [71]. Although psychiatric symptoms are mostly related to the psychosocial and quality of life impact of the dermatosis, a psychological assessment and personal and familiar psychi­ atric history should be performed before treatment selection. Besides, other psychiatric comorbidities, like those on the obsessive‐ compulsive spectrum, have to be considered and evaluated, as they may also require addi­ tional treatment strategies.

­Assessment of Patients with Acne From the start, ideally, patients with acne should be globally assessed, which includes a clinical history, personal and family past medical history, medication, global physical examination, dermatological evaluation, psychological and quality of life assessment, and, eventually, information on diet and environmental factors. Occasionally, labo­ ratory tests may also be important. Actually, together with the biological mechanisms shared by all patients (see Section 4.3), acne is a dermatosis with multidimensional ­features, with subtleties in diverse domains that should be globally considered. Table 4.2 intends to compile an integrative approach for these patients.

Table 4.2  Acne assessment: an integrative approach. Acne: an integrative assessment Important topics from history

Demographic characteristics

Age; gender; ethnic group/race; education; occupation; family.

Examples to explain significance/relevance ●●

●● ●●

●●

●●

The classification (see Table 4.1) and management should consider the age group. Boys have a higher risk for the most severe forms of acne [3, 7]. Acne in adult women was correlated with office work and psychopathology [51]. Female patients with acne may have worse psychosocial impact, with higher risk for major depression and suicide [64]. Contact acne can occur due to occupational exposure [10, 15].

­Assessment of Patients with Acne

Table 4.2  (Continued) Acne: an integrative assessment Important topics from history

Examples to explain significance/relevance

Medical history

●●

To identify diseases which contra‐indicate some treatments; to exclude acne‐related syndromes and pregnancy.

●●

●●

Medication for other diseases

To exclude drug‐ induced acne.

Past and current medication for acne

To prescribe adequate treatment; to analyze patient behavior.

●●

●●

●●

Combined oral contraceptive is not indicated if: breast cancer, hypertension (systolic ≥160 mmHg + diastolic ≥100 mmHg), diabetes with end‐organ lesion or > 20 years; past or current episode of deep vein thrombosis/pulmonary embolism; major surgery with prolonged immobilization; past or current ischemic heart disease; valvular heart disease + complications; past cerebrovascular accident; migraine + neurologic symptoms at any age, or without aura if ≥35 years; active viral hepatitis; decompensated cirrhosis; liver neoplasia [7]. Infertility, polycystic ovaries, infrequent menses require additional evaluation [7]. Osteitis and synovitis: SAPHO syndrome [11, 19]. Examples of the most common suspicious drugs for drug‐induced acne are: corticosteroids, testosterone and anabolic steroids, isoniazid, lithium [16]. Isotretinoin‐induced is the most common form of acne fulminans [12]. Some patients can exhibit demotivation with several treatments, seeking for additional drugs when they have no lesions or far less severe disease disproportionate to their preoccupation, in which case body dysmorphic disorder should be excluded [70].

Cosmetics use

To exclude acne cosmetica and eliminate potentially implicated cosmetics [10].

Family history

To know about acne in parents.

Psychiatric history

To prescribe adequate treatment

●●

●●

●●

The link between acne and a family history of the dermatosis has been highlighted in several studies, stating a hereditary component [52]. Isotretinoin can induce or worsen mood disorders and increase the risk of suicide [71, 72]. Acne excoriée is linked with obsessive‐compulsive spectrum disorders [17].

Diet

High glycemic index diet and skim milk may influence acne pathogenesis [7, 35, 36, 48, 49].

Hobbies

To exclude acne mechanica (due to chronic friction by a musical instrument, such as a violin) [10]. Physical examination and complementary assessment

The following topics should be considered: Morphology of the lesions, namely primary or secondary cutaneous lesions (see Table 4.1), including the presence of scars, post‐inflammatory hyperpigmentation and more rare complications, such as Morbihan’s disease; ●● The severity and subtleties regarding the age of onset (comedones can be clinically absent in adult female acne) [73]; ●● Distribution of the lesions, typically on the “T‐zone” of the face in adolescents (forehead, nose, upper chin area) and “U‐zone” in female adults (cheeks, perioral, and lower chin area) [73], chest and back: a distribution beyond the seborrheic areas should evoke, for instance, chloracne or other differential diagnoses [10, 15]; ●●

(Continued)

45

46

Acne

Table 4.2  (Continued) Physical examination and complementary assessment ●●

●●

●●

●● ●●

●● ●● ●● ●●

Signs of hyperandrogenism: acne before puberty, early‐onset body odor, advanced growth and bone age, genital maturation, axillary or pubic hair in children; infrequent menses, androgenetic alopecia, hirsutism, infertility, clitoromegaly, polycystic ovaries, deep voice in women after puberty. In these cases, a hormone screening with free and total testosterone, androstenedione, dehydroepiandrosterone sulfate, luteinizing hormone, and follicle‐stimulating hormone should be performed. A referral to endocrinologist should be done for further management [7, 10]; Co‐existence of other dermatoses, such as pyoderma gangrenosum and hidradenitis suppurativa, to consider SAPHO, PAPA, PAPASH; Evolution: acne vulgaris is chronic; an abrupt flare of severe inflammatory lesions can represent acne fulminans; Co‐existence of systemic symptoms, such as fever, arthralgias, myalgias; The evaluation of acne fulminans requires: laboratory study (complete blood count, liver function, C‐ reactive protein, erythrocyte sedimentation rate) and radiography (in the setting of symptoms of bone/ joint involvement) [12, 13]. Differential diagnosis both for comedonal and inflammatory acne: For comedonal acne: e.g. eruptive vellus hair cysts (in the trunk), adnexal neoplasms, milia; For inflammatory lesions: e.g. rosacea, folliculitis, pseudofolliculitis barbae and follicular mucinosis. Microbiologic tests are not recommended except for patients who evoke a differential diagnosis with Gram‐negative folliculitis, namely monomorphic pustules, perioral and perinasal, commonly as a consequence of long use of tetracycline. Occasionally, Staphylococcus aureus can induce acneiform lesions of acute development, which may also benefit from microbiologic test [7]. Psychopathology

Purpose: the psychiatric diagnoses (DSM‐V) [74] that can be comorbidities of acne are anxiety disorders, depression disorders and obsessive‐compulsive and related disorders; less frequently, feeding and eating disorders, sexual dysfunctions. Assessment: the following topics can be assessed by a dermatologist trained in psychodermatology, in order to exclude important psychopathology that may be found in patients with acne: ●● Appearance (posture, clothes) and behavior (psychomotor activity, eye contact, compulsions); ●● Speech (volume, fluency, rhythm) and thought (form, content); ●● Mood, insight, perception, suicidal thoughts; ●● Cognitive domains. Psychiatric questionnaires can also be used to complement the evaluation, particularly the hospital anxiety and depression scale (HADS), the dimensional obsessive‐compulsive scale (DOCS), the skin picking scale (SPS), the cosmetic procedure screening questionnaire (COPS) and the body dysmorphic disorder questionnaire (BDDQ) [75]. Depending on the results, the patient may need special management by a psychodermatology multidisciplinary team [75]. Quality of life

Purpose: acne has deep impact on quality of life and its assessment can provide additional information on the impact of the dermatosis in diverse domains of daily life. Quality of life impairment is multifactorial and includes comorbid psychopathology, gender (females have higher quality of life impairment), culture and patient adherence to treatment. Assessment: Dermatologic‐specific questionnaires for clinical practice are: dermatology life quality index (DLQI), children’s dermatology life quality index (CDLQI) and Skindex‐29. The acne‐specific questionnaires useful in clinical practice are: Cardiff acne disability index (CADI) and acne‐specific quality of life questionnaire (Acne‐QoL) [76].

­Managemen

­Management Conventional Topical and Oral Treatment The conventional treatment of acne vulgaris includes topical and systemic treatments that are prescribed, taking into account the severity and variants of acne. In the first group, the available evidence highlights the following possibilities: benzoyl peroxide (BP), retinoids and retinoid‐like agents, topical antibiotics, salicylic/azelaic acids, and topical dapsone 5% gel [7]. Neonatal acne is an exception (see Section  4.2) as it benefits from treatment with topical imidazole [10]. In the second group, there is evidence for the use of systemic antibiotics, hormonal agents, and isotretinoin. BP is bactericide, reducing P. acnes, with no resistance documented, and it also has comedolytic properties. It is available as topi­ cal washes, creams, and gels, with concentra­ tion from 2.5% up to 10%. Occasionally, an irritant contact dermatitis can be observed [7, 10]. Topical retinoids consist of vitamin A derivatives which bind to retinoic acid recep­ tors expressed in sebocytes such as tretinoin 0.025–0.1% in cream or gel and adapalene 0.1–0.3% in cream [7, 41]. Tretinoin was the first topical treatment used for acne; it corresponds to all‐trans retinoic acid and binds to alpha, beta, and gamma receptors. Adapalene is a naftoic acid derivative, having similar properties, and binds to beta and gamma receptors [7, 10]. They are the main­ stay for acne treatment, resolving the pre­ cursor lesion, the microcomedone, and they also have comedolytic and anti‐inflammatory effects [77]. The main side effects are ­erythema, irritation, and dryness of the skin, but they tend to reduce with continuous application so, to improve tolerance and adherence, the patient can be taught to per­ form the treatment on alternate days during the first month and then every day. The use of a cosmetic in the morning is adequate, as it can normalize the irritation and dryness due to retinoids (both topic and oral retinoids) and BP, but patients should be advised to use

non‐comedogenic products to avoid acne cosmetica (see Section 4.2). Some cosmetic products can increase the clinical outcome [78]. Because topical retinoids can also induce photosensitivity and some formulations are photolabile, it is recommended to use them at night. They should not be used by preg­ nant women [7, 10]. Retinoids should be used for patients ≥12 years, and can be applied in combined formulations, namely clindamycin phosphate 1.2%/tretinoin 0.025% gel, except for the combination of BP 2.5%/adapalene 1% gel that is approved for children ≥9 years. Topical antibiotics are well tolerated, without particular local side effects, and include clindamycin 1% solution or gel and erythro­ mycin 2%, for example, in cream, gel, or lotion, which act as anti‐inflammatory agents. They are available in monotherapy, with higher potential for resistance, or combined with retinoids or BP, increasing efficacy and reducing antibiotic resistance [7, 10, 79]. Azelaic acid has comedolytic, bacteriostatic, and anti‐inflammatory effects and it also has benefits for patients with rosacea, being use­ ful in less precise clinical presentations and cases with overlapping features [80]. Besides, it is better tolerated than retinoids [7, 10]. Dapsone 5% gel has moderate anti‐inflam­ matory activity and has proven to be useful for adult female acne. Salycilic acid has moderate comedolytic effect [7]. Oral antibiotics should be used for moderate to severe acne together with a topical reti­ noid or BP for a maximum of three to four months. Doxycycline and minocycline, at a mean daily dose of 100 mg at night, are the most used oral antibiotics, but are contraindi­ cated in children ≤12 years and in pregnant women [10, 81]. Subantimicrobial doses of doxycycline (40 mg daily) can be effective in patients with moderate forms of acne as well. Their mechanism consists of the inhibition of the chemotaxis as well as the activation of metalloproteinases, with consequent anti‐ inflammatory properties  [7]. Macrolides, namely erythromycin and azithromycin, can also have some anti‐inflammatory effect, but should be reserved for patients who cannot

47

48

Acne

be treated with tetracycline derivatives [81]. Concerning adverse effects, they can induce gastrointestinal disorders and photosensi­ tivity, which is more frequent with doxycy­ cline; minocycline can more frequently induce hyperpigmentation and more severe adverse events, particularly drug reaction with eosinophilia and systemic symptoms (DRESS) and drug‐induced lupus, although they are rare. The most common adverse events with macrolides are gastrointestinal disorders. Oral antibiotics for acne should be avoided during pregnancy and breastfeeding. For severe cases, after the first trimester, erythromycin can be used at a dose of 250 mg twice daily (maximum of six weeks); the other options are amoxicillin 250 mg twice a day up to 500 mg three times a day and cephalexin 500 mg two times a day [7, 73, 81, 82]. Rarely, trimethoprim‐sulfamethoxazole could be used for acne, when patients cannot take the above mentioned oral antibiotics (as well as other systemic treatment options) or are treatment‐resistant, but it is not allowed during pregnancy [7]. Hormonal agents include estrogen‐­ containing combined oral contraceptives, spironolactone, flutamide, and oral corticos­ teroids. Estrogen‐containing combined oral contraceptives are useful due to the andro­ genic effect, reducing the androgen synthesis in the ovary and binding free circulating tes­ tosterone. Those which have been approved for acne are ethinyl estradiol/norgestimate, ethinyl estradiol/norethindrone acetate/­ferrous fumarate, ethinyl estradiol/drosperinone and ethinyl estradiol/drospirenone/levomefolate [7]. Their use has, however, several contra‐ indications (see Table 4.2) and should be used together with other treatments. Estrogen‐ containing combined oral contraceptives can be effective even for women with androgen levels within the normal range and for women with adult acne, with exacerbation of the der­ matosis before menses [10]. Spiro­nolactone is a synthetic 17‐lactone steroid that acts as a non‐selective mineralocorticoid receptor antagonist, having moderate affinity for ­ ff‐ androgen receptors. It has been used o

label for acne and there is significant evi­ dence that it is useful for adult‐onset acne in women at a dose of 200 mg d−1. The side effects are mainly dose‐related, typically irregular menses. The use of estrogen‐ containing combined oral contraceptives can reduce these side effects. Potassium monitor­ ing is not recommended except in the pres­ ence of risk factors for hyperkaliemia, such as renal or cardiovascular disease, and some concomitant treatments, such as angiotensin‐­ converting enzyme inhibitors [73]. Oral corti­ costeroids, namely prednisone, are useful at a dose of 0.5–1 mg  (kg/d)−1 with slow taper over months for the treatment of acne fulmi­ nans. Flutamide is a selective antagonist of androgen receptors that in doses ranging from 62.5 mg daily to 250 mg twice daily can show some improvement, but its use should be avoided since it is associated with a risk for severe hepatotoxicity [7, 10]. Isotretinoin is an isomer of retinoic acid approved for patients ≥12 years for the treat­ ment of severe acne, as well as for moderate acne with frequent relapses after stopping oral antibiotics (which is particularly fre­ quent in adult female acne), being useful for both comedonal and inflammatory lesions, and also having a benefit on scarring. It should be taken with food as it is lipophilic and it is recommended to start at a dose of 0.5 mg  (kg/d)−1, which can be increased according to tolerance, up to a maximum of 1 mg (kg/d)−1, with the target of a cumulative dose of 120–150 mg kg−1 [7]. Lower doses (0.25–0.4 mg (kg/d)−1) can be effectively used to reduce the side effects. At a clinical level, isotretinoin is associated with mucocuta­ neous dryness. Routine monitoring for liver function, serum triglycerides, and choles­ terol should be done at baseline and during the treatment until the response to treatment is achieved. Pregnancy is a major contra‐ indication and has to be avoided up to one month after the end of the treatment [7, 10, 79, 81]. Table 4.3 compiles the conventional acne treatments, including specificities for the treatment of pregnant women and acne fulminans [7, 10, 12, 24, 79–82].

­Managemen

Table 4.3  Acne: conventional treatment. Severity and special population

First‐line treatment

Second‐line treatment

Mild severity

Comedonal

Topical retinoid/retinoid‐like

Alternative topical retinoid or azelaic acid or topical dapsone

Papulopustular

Topical retinoid + antimicrobial

Alternative topical retinoid + antimicrobial agent or azelaic acid or topical dapsone

Moderate severity

Oral antibiotic + topical retinoid ± BP

Alternative oral antibiotic + topical retinoid±BP/azelaic acid or oral isotretinoin or, for women, add spironolactone or combined oral contraceptive

Severe forms

Acne conglobata

Oral isotretinoin (±low‐dose prednisone to prevent isotretinoin‐induced acne fluminans)

oral antibiotic + topical retinoid ± BP or, for women, consider spironolactone or combined oral contraceptive

Acne fulminans

Prednisone 0.5–1 mg (kg/d)−1 as monotherapy for at least 4 weeks for acne fulminans with systemic symptoms and 2 weeks if without systemic symptoms. Prednisone should be continued up to healing of the crusted lesions, when low dose isotretinoin (0.1 mg (kg/d)−1) can be started. An overlap between prednisone and isotretinoin should be maintained at least for 4 weeks and then isotretinoin can be increased and prednisone reduced gradually for 4–8 wk.

Mild to moderate

Topical azelaic acid

Severe

Amoxicillin, cephalexin or erythromycin ± low‐dose prednisone

Pregnant women and Breastfeeding

Physical Modalities As explained above, isotretinoin‐induced acne fulminans is related to the presence of macrocomedones. Thus, some authors rec­ ommend identifying these lesions before starting isotretinoin and treating them with cautery or hyfrecation [79]. Intralesional administration of triamcinolone acetonide can improve nodular acne lesions [7]. Salicylic and glycolic acid peels can lead to mild improvement in comedonal acne. The benefits of light devices and lasers have been demonstrated in the treatment of papulopustular and comedonal acne, but ­ with limited evidence to recommend them as routine. Photodynamic therapy, radiofre­ quency, intense pulsed light, pulsed dye laser, fractionated and non‐fractionated infrared lasers and potassium titanyl phosphate (KTP) laser are some examples, and the first seems

Topical antibiotic (erythromycin or clindamycin) ± BP

to have the most robust evidence [7, 10]. The management of acne scarring is also an important issue since facial scarring occurs in up to 95% of cases and several physical modalities have been discussed. It includes different types of resurfacing, namely chemi­ cal peels, lasers, and dermabrasion, as well as the use of injectable fillers and surgical methods, such as needling (collagen induction therapy), subcision, punch excision, or punch elevation. Hypertrophic scars are commonly treated with intralesional corticosteroid injection but laser therapy (pulsed‐dye, frac­ tional) has also been highlighted. There is moderate‐quality evidence that injectable fillers can improve atrophic acne scars. In a Cochrane Review on atrophic and hyper­ trophic acne scarring, any modality showed sufficient evidence to support them as first‐ line treatment, both for efficacy and safety

49

50

Acne

reasons, though fractional laser, fractional radiofrequency, glycolic acid, phenol, sali­ cylic‐mandelic acid or trichloroacetic acid peeling, injectable filler, and microneedling may have limited benefit according to some studies [83]. Diet, Lifestyle Habits and Environmental Factors At present, no specific regimen has sufficient evidence to be recommended for patients with acne [84]. Although without strong evidence, we may suggest that an integrative approach would benefit from educating the patient about diet and lifestyle habits, always together with the conventional treatment outlined above. As explained, high glycemic index diet and skim milk may synergistically influence acne pathogenesis [35, 36, 48, 49, 52]. Also, adult female acne was found to be associated with lower consumption of vege­ tables, fruits, and fish [51]. Thus, an adequate diet would include a reduction of the glyce­ mic load and skim milk and an increase in the consumption of fish (source of omega‐3 essential fatty acids, with anti‐inflammatory effects), fruits, vegetables, and green tea, which have natural plant‐derived mTORC1 inhibitors, such as Epigallocatechin gallate and resveratrol. The role of vitamin D in the clinical evolution of acne was studied by only one clinical study with 80 patients with acne and 80 healthy controls, where the serum levels of 25‐hydroxyvitamin D were evalu­ ated and the deficiency (set at 10 cases per million that affect women more fre­ quently than man during adulthood. Photosensitivity occurs in approximately half of patients. Homogeneous antinuclear factor is found in 60%, and the anticytoplasmic antibodies anti Ro in 80% and anti_La in 40% of patients. SLE is a systemic disease with multisystem organ inflammation that commonly involves the skin, joints, and vasculature, and is asso­ ciated with immunological abnormalities. The characteristic specific skin sign of LE is malar or butterfly rash, described as discrete erythematous macules, papules, and plaques associated with a congestive erythema in the central areas of the face. However, widespread erythematous macu­ lar and papular lesions are seen in the gen­ eralized form. Lesions predominate on UV‐exposed areas and they usually appear after sun exposure [9]. SLE is associated with antinuclear autoan­ tibodies (ANA) and the fine specificity of the ANA profile helps to distinguish the different clinical subtypes and may be of prognostic value [10]. In terms of the psychological aspect of SLE, a recent study [11] shows SLE individu­ als with insomnia symptoms have high levels of perceived stress and more frequent use of disengaging and emotionally focused coping strategies. This body of evidence suggests that individuals with SLE and comorbid insomnia symptoms may therefore require additional interventions for insomnia. Cutaneous manifestations occur in approx­ imately 80% of patients during the course of the disease and are the first sign of SLE in up to 20% of cases.

Their prompt recognition is important for the clinical diagnosis, which must be con­ firmed by histology, and by a positive lupus band test at direct immunofluorescence. Given the clinical heterogeneity and unpre­ dictable disease course, the management of CLE is highly variable and is usually guided by predominant manifestations [8]. In the purely cutaneous form topical corti­ costeroid therapy can frequently control, and sometimes clear, lesions without systemic treatment. But autoimmune disorders that affect the skin and internal organs with a chronic relapsing course can have a high impact on patients’ general physical condi­ tions, psyche, life span, social life, and also work productivity, and they require a com­ plex, interdisciplinary management due to multiple organ involvement. Treatment options for CLE have increased with the introduction of new biological therapies. However, the majority of the patients still benefit from antimalarials, which remain the cornerstone of treatment. The evaluation and management of CLE patients depend on the clinical findings and associated symptoms. New targeted therapies will allow for more specific, highly effective and less harmful treatments. Recent studies have tried to elucidate the role of cytokines such as interferon‐alpha in SLE to establish targets for treatment; future treatments aimed at correcting the intracel­ lular and intercellular signaling may prove effective in restoring immune tolerance in SLE [12].

­Scleroderma Scleroderma is a disorder of an autoimmune etiology which can be limited to the skin, as in the localized morphea or scleroderma, or be associated with vascular abnormalities, connective tissue sclerosis, and atrophy and autoimmune changes characterizing pro­ gressive systemic sclerosis.

91

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Autoimmune Skin Disorders

In systemic scleroderma, ANA specific to centromers are characteristic to the diffuse form with prominent, mainly acral sclerosis of the skin. In contrast, IgG against topoi­ somerase (Scl‐70) is characteristic to the diffuse form which is associated with a more severe course (nephrosclerosis, pulmonary sclerosis, and myocardial fibrosis).

­Dermatomyositis Dermatomyositis is a clinical spectrum of cutaneous symptoms on the one hand and myositis on the other hand. The cardinal cutaneous symptoms are heliotrope facial erythema, red to purple papules over the knuckles and sometimes the interphalangeal Joints (Gottron’s sign) and nail fold hyper­ keratosis and teleangectasia (Keining sign). Myositis‐specific ANA (anti‐Jo1, anti‐Mi‐2) are less sensitive (50% of patients with CU examined [62]. However, the observation that sera from a large part of patients with CSU induce significant activation of mast cells lacking the high‐affinity IgE receptor, irrespective of the autoreactivity status or of the pres­ ence/absence of circulating autoantibodies, suggests that other mechanisms may be involved in the pathogenesis of the disease [63, 64]. Studies showed that low‐molecu­ lar‐weight circulating factors (molecular weight about 30 kDa) may be involved in the activation of mast cells in CU patients, [65, 66]. In the US practice parameters, CIU is ­considered to have an autoimmune basis in many, but not all, patients. Other underlying causes of CIU have been proposed, including food intolerance, infections, and autoallergy [8, 52].

149

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Urticaria

­ ole of Autologous Serum R Skin Test (ASST) Since the reactivity of ASST is mainly due to serum factors responsible for histamine release and vasodilatation that are controlled by antihistamines, ASST is widely used in the diagnosis of CU in order to evaluate an auto­ immune origin of the disease. ASST seems sufficiently specific for CU, as normal sub­ jects do not show skin reactivity [67], although they may score positive for CIU such as cold urticaria [68], multiple hyper­ sensitivity, and multiple drug allergy syn­ drome to non‐steroidal anti‐inflammatory drugs [69, 70]. However, the ASST scores positive in only about one‐half of CU patients [71, 72], leaving almost another half of patients not showing any autoreactivity despite their potentially severe and/or ongoing disease. The role of ASST as a marker for the disease is controversial. Some studies claimed there was a longer duration of urticaria or higher disease activity in ASST‐­ positive patients than that in ASST‐negative patients; while other studies did not support this point in terms of disease duration, severity, and qual­ ity of life scores [9, 73–75]. Interestingly, a study showed that ASST reactivity was a ­significant predictor of well‐controlled CU during the six‐month stepwise treatment, and the results of the ASST may be a useful parameter for monitoring therapeutic response and predicting response to treat­ ment in patients with CU. The authors hypothesized that ASST‐positive patients are expected to achieve a well‐controlled state within six months of treatment [76].

­Endothelium and Coagulation System in CSU Besides the chemokine system, the endothe­ lium plays a critical role in influencing cel­ lular trafficking and controlling the passage of fluid into the tissue [77]. In the skin,

endothelium dysfunction might increase vascular permeability before a proinflamma­ tory response. The soluble forms of adhe­ sion molecules, such as intercellular adhesion molecule (ICAM‐1) and vascular cellular adhesion molecule‐1 (VCAM‐1), are widely used as biomarkers of endothelial dysfunction, and their increase in skin biop­ sies and circulation [49] seems to reflect a proinflammatory endothelium phenotype in several skin diseases, including CSU [17, 49, 78, 79]. The detection of increased levels of pro­ thrombin fragment 1 + 2, factor VIIa, and D‐ dimer in CSU suggests that, following endothelial cell activation, tissue factors are released with consequent activation of the extrinsic coagulation cascade and secondary fibrinolysis [80, 81]. It is thus presumed that thrombin is a potent inducer of mast cell degranulation and can increase vascular per­ meability, at least in experimental models [82]. Furthermore, the plasma levels of D‐ dimer are frequently elevated in patients with severe CSU and seem to decrease ­following treatment with omalizumab [83], suggesting a link between activation of coag­ ulation, circulating autoantibodies, and fibrin degradation in severe CSU. The D‐ dimer level is also significantly associated with acute urticaria, suggesting its role as a marker of disease severity in both forms of urticaria. [84] The observation that the autologous plasma skin test (APST) may score positive in some ASST‐negative patients [85] has prompted investigation of the coagulation system in patients with CU. Specific studies have shown that the coagulation cascade is activated in CU and involves the extrinsic pathway first and the intrinsic pathway ­second [80–82, 85–87]. The process seems to be triggered by the high expression of tissue factors by activated eosinophils [88]. IgG autoantibodies to the low‐affinity IgE recep­ tor FcεRII, present on the membrane of eosinophils, have been detected in quite a large proportion of patients (about 65%) with CU [89]; activation of such cells with subsequent

­Role of Angiogenesis in CS

release of MBP and other mediators cause mast cell degranulation. The activation of the coagulation cascade might play an important role in the pathogenesis if one considers that thrombin is a potent inducer of mast cell degranulation and can remarkably increase the vascular permeability in experimental models. The activation of the coagulation cascade occurs in other skin disorders char­ acterized by an increase of vascular permea­ bility, such as bullous pemphigoid and angioedema due to C1‐inhibitor deficiency [90, 91], and in a wide spectrum of systemic diseases, such as disseminated intravascular coagulation [92], endotoxemia [93], and deep venous thrombosis [94], all prothrombotic conditions that are not characterized by urti­ caria or edema. Parallel to the coagulation/fibrinolysis pathways, an imbalance in pro‐ and anti‐ inflammatory adipokines in CSU patients has been also observed. In particular, Lipocalin‐2 (LCN2) might be used as a marker not only of the clinical response to antihistamine treatment but also of disease activity [37], suggesting new approaches to response to therapy and monitor disease progression in CSU patients.

­Role of Angiogenesis in CSU Angiogenesis is the growth of new blood ­vessels from pre‐existing ones. It is a multi­ step and highly orchestrated process involv­ ing endothelial cell migration, vessel sprouting, tube formation, proliferation, and survival [95, 96]. Under physiologic condi­ tions, angiogenesis depends on the balance of negative and positive angiogenic media­ tors within the vascular microenvironment and requires the functional activities of a number of molecules, including extracellular matrix proteins, angiogenic factors, proteo­ lytic enzymes, and adhesion receptors [95, 96]. Angiogenesis is also correlated with pathologic conditions as a direct response to tissue demands, such as fibrosis, chronic inflammation, and tumor growth. [96]

Numerous inducers of angiogenesis have been identified, including members of the vascular permeability factor/vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) family, transforming growth factor alpha and beta (TGF‐α and TGF‐β), angiogenin, platelet‐derived growth factor (PDGF), hepatocyte growth factor/ scatter factor (HGF/SC), TNF‐α, granulocyte macrophage colony‐stimulating factor (GM‐ CSF), and angiopoietin‐1 and angiopoietin‐2. Among them, VEGF is the most potent direct‐acting regulator of angiogenesis, and its expression is often excessive in chronic inflammatory diseases. VEGF induces migra­ tion, proliferation, and tube formation of endothelial cells and promotes secretion of interstitial matrix metalloproteinase‐1 (MMP‐1) and the expression of chemokines and von Willebrand factor, as well as leuko­ cyte adhesion molecules, such as VCAM‐1, ICAM‐1, and E‐selectin [97]. Increased lev­ els of VEGF have been observed in the circu­ lation and in the tissue of CSU patients [98]. Since VEGF is mainly produced by inflam­ matory cells, it is hypothesized that infiltrat­ ing eosinophils, mast cells, and basophils present in skin lesions might contribute to the release of VEGF with a consequent increase in neoangiogenesis and vascular permeability. On the other side, eosinophils, mast cells, and basophils might be targets for VEGF, leading to amplification and perpetu­ ation of the inflammatory processes [99]. The functional activity of VEGF is also tightly regulated by endogenous antiangiogenic mediators produced mostly by the degrada­ tion of extracellular matrix (ECM) compo­ nents such as thrombospondin‐ (TSP‐) 1 and endostatin (ES). Increased levels of TSP‐1 and ES in the sera of CSU patients were reported, although no association with dis­ ease activity was found [100]. TSP‐1 and ES also exert roles in skin remodeling. TSP‐1 on the cells destabilizes contact between endothelial cells, leading to skin vasodilation and consequent extravasation [101]. ES acts as a vasoactive mediator via nitric oxide (NO) synthesis on endothelial cells [102].

151

152

Urticaria

Therefore, both ES and TSP‐1 might contrib­ ute to the vascular leakage in CSU, leading to the development of its clinical manifesta­ tions, such as flare and wheals formation. Parallel to ECM fragments, some members of matrix metalloproteinases (MMPs) are increased in the circulation of CSU patients [103]. For example, MMP‐9, an endopepti­ dase involved in ECM degradation during tissue remodeling, inflammation, and angio­ genesis, is increased in the peripheral blood of CSU patients in children and in adults [104]. Some, but not all studies, reported a correlation between plasma concentration of MMP‐9 and disease activity [103–106]. It is likely that MMP‐9 contributes to the patho­ genesis of CSU and that of other chronic dis­ eases (i.e. asthma) where tissue remodeling and inflammation take place.

­Diagnosis The characteristic skin finding of urticaria is the presence of pink or red, edematous, pru­ ritic wheals of variable shape and size, and a lack of any epidermal changes such as crust/ scale. Individual lesions typically fade within 24  hours. Angioedema generally involves swelling of the lower dermis and subcutis, with frequent involvement of severe periph­ eral edema or the proximal mucus mem­ branes (lip or ocular edema). Severe swellings may be painful, and most cases of angi­ oedema typically may take up to 72 hours to resolve [3, 8]. It is universally recommended to begin the diagnostic process with a thorough investiga­ tion of patient history and a physical exami­ nation [3, 8]. Where indicated by patient history, provocation tests (e.g. use of a der­ mographometer to elicit symptomatic der­ mographism or exposure to cold stimulus if cold‐contact urticaria is suspected) can be used to confirm the threshold and relevance of triggers in patients who have a physical/ inducible form of CU [8]. It is important to note that not all possible causative factors

need be investigated in all patients [3]. It is unlikely to identify causes in the majority of CSU cases and efforts to identify underlying causes should be limited to patients with longstanding and/or severe CSU [8]. Skin biopsies should be considered only when autoinflammatory disease, vasculitis, or another immunologic condition that can present with hive‐like lesions (e.g. bullous pemphigoid, etc.) is suspected [8]. No reliable biomarker for management and evaluation of CSU patients is yet availa­ ble. Based on the review of the literature, among the clinical clues studied, higher age at onset, being female, long disease duration, and aspirin/nonsteroidal anti‐inflammatory drug (NSAID) hypersensitivity may be linked to both severe CSU and a prolonged time to spontaneous remission [107]. In addition, a positive ASST may be associated with severe CSU, and comorbidity of CIU and concomi­ tant recurrent angioedema may be linked to longer CSU duration. Potential biomarkers of CSU severity and/or duration include basophil count and its susceptibility to acti­ vation, inflammatory markers, markers of activation of the extrinsic coagulation path­ way, immunoglobulin E, and vitamin D.

Therapy Antihistamines, not structurally related to histamine and not competitive antagonists of histamine, bind to different sites from hista­ mine on H1 receptors [33]. Therefore, these antihistamines are inverse agonists rather than receptor antagonists [33, 108, 109]. They are referred to as “H1 antihistamines” rather than “histamine antagonists” [33]. When H1 antihistamines are bound to H1 receptors, they interfere with histamine action on small blood vessels and sensory neurons, directly downregulating allergic inflammation. This downregulation also occurs indirectly through calcium ion chan­ nels and transcription factor nuclear factor‐κB [110].

Therapy

Second‐generation H1 antihistamines were highly selective for H1 receptors and were devoid of anticholinergic activity [33]. However, because of differences in drug specificity for active transporter proteins (e.g. P‐glycoprotein) across the blood–brain barrier, some second‐generation agents may enter the CNS to a greater extent than others [33, 111]. Desloratadine, cetirizine, and loratadine, especially at high dosages, are potentially more sedating than levocetirizine and fexofenadine [33, 112]. Another major drawback for some second‐ generation agents was significant cardiotox­ icity. That is, terfenadine and astemizole were shown to block the delayed rectifier K+ current (IKr), which is essential for cardiac repolarization [33]. This gave rise to the potential for life‐threatening ventricular arrhythmias such as torsade de pointes and QT interval prolongation. Such cardiotoxic potential is now well established [33]. Further modifications then led to the intro­ duction of other second‐generation agents. For example, knowledge of the metabolism pathway of loratadine led to the development of desloratadine, and stereoselective investi­ gation led to levocetirizine. Rupatadine is a dual PAF and histamine H1 receptor antago­ nist, which undergoes extensive hepatic metabolism to produce active metabolites, including desloratadine [113, 114]. High‐dosage bilastine (40 or 80 mg once daily), in line with EAACI/GA2LEN/EDF/ WAO guidelines [3], has demonstrated effi­ cacy in the treatment of urticaria [115]. In a study in patients with acquired cold urticaria, bilastine was well tolerated and there wasn’t evidence of an increased incidence of seda­ tion at doses up to 80 mg per day [115]. The US practice parameters recommend adding an additional second‐generation H1‐ antihistamine and/or H2‐antagonist to H1‐ antihistamine therapy. Data comparing the safety and efficacy of combination therapy versus updosing of a single agent are scarce [116, 117]. As a general principle, it is likely to be safer to adjust the dosing of a single drug rather than complicating management

with several antihistamine classes [118–120]. Oral corticosteroids are frequently used in patients with CU not adequately controlled with antihistamine therapy, yet no con­ trolled study has been performed [8, 121]. A large retrospective study showed that 50% of patients with antihistamine‐resistant CU treated with a single course of prednisone (25 mg per day for three days, de‐escalated to 12.5 mg per day for three days and 6.25 mg per day for four days) had a remission, and an additional 9% of patients responded after a second course [122]. The main concern with the use of corticosteroids is the risk of adverse effects, thus only short‐term use to help manage exacerbations should be ­considered [3, 8]. Leukotriene‐modifying agents (LTMAs) such as zafirlukast and montelukast, are reportedly effective for the treatment of CU as monotherapy or in combination with H1‐ antihistamines, with the strongest evidence for montelukast (10 mg per day), although the treatment effect observed was small [123–127]. Results of clinical studies have been inconsistent; some showing superiority [124, 128, 129], and others demonstrating poorer responses from LTMAs than antihis­ tamines [125] or even a lack of efficacy com­ pared to placebo [130]. When symptoms of patients do not respond to prior antihistamine therapy, agents with H1‐ and/or H2‐antagonist activ­ ity such as cyproheptadine, hydroxyzine, or doxepin, which have considerable sedating effects, are also options [3, 8]. Compared with other antidepressants such as nortrip­ tyline, amitriptyline, and mirtazapine, clini­ cal evidence is strongest for doxepin (at doses from 10–25 mg three times daily) [8, 131, 132]. However, electrocardiographic effects at doses >100  mg, sedation, and numerous drug–drug interactions may limit its use [8, 133]. Of the available biologics recommended for patients with refractory CU, omalizumab (Xolair®, Genentech, Inc.), an anti‐IgE ­antibody, has the most robust data suppor­ ting its use [134]. Although omalizumab

153

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Urticaria

(administered as subcutaneous injections every four weeks at doses of 150, or 300 mg) has a favorable risk/benefit ratio and was well tolerated in clinical studies [135–137], it has infrequently been correlated with ana­ phylaxis [137]. Omalizumab has also been shown to be an efficacious treatment alone or as an add‐on therapy to H1‐antihistamine plus an H2‐antihistamine or LTMA, or a combination of these for patients with CIU refractory to antihistamine treatment in three Phase 3 studies [135–137]. However, the requirement for subcutaneous adminis­ tration in a physician’s office, the cost of treatment, and anaphylaxis concerns may limit its use [8, 125]. Cyclosporine A (CsA) is an immunosup­ pressant that has been shown to be an effec­ tive treatment for CU (at dosages of 3–5 mg kg d for up to four weeks) in placebo‐con­ trolled studies as a solo treatment and in combination with second‐generation H1‐ antihistamines [138, 139]. Both the interna­ tional guidelines and the US practice parameters recommend consideration of CsA for patients with refractory CU [3, 8]. There is a relatively high incidence of mild adverse effects in treatment with CsA includ­

ing paresthesia, gastrointestinal distur­ bances, and infections [138, 139]. These adverse effects were transient and mild for patients with CU using low‐dose CsA (