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Plewig and Kligman´s Acne and Rosacea [4th ed.]
978-3-319-49273-5;978-3-319-49274-2

Author / Uploaded
Gerd Plewig
Bodo Melnik
WenChieh Chen

Table of contents :
Front Matter ....Pages i-xxvi
Pilosebaceous Follicles: Structure, Biochemistry, and Function (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 1-34
Acne Epidemiology and Genetics (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 35-44
Acne Pathogenesis (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 45-61
Acne Clinic: Morphogenesis (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 63-189
Distinctive Acne Entities (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 191-215
Acne Classification and Disease Burden (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 217-222
Acne Therapy (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 223-292
Acne and Nutrition (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 293-298
Acne-Mimicking Diseases (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 299-410
Acne-Associated Syndromes (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 411-453
Hidradenitis Suppurativa/Acne Inversa/Dissecting Terminal Hair Folliculitis (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 455-500
Rosacea Epidemiology and Genetics (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 501-508
Rosacea Pathogenesis (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 509-516
Rosacea Clinic and Classification (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 517-557
Rosacea Therapy (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 559-572
Demodex Mites and Demodicosis (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 573-594
Acne Research Models (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 595-608
History of Acne and Rosacea (Gerd Plewig, Bodo Melnik, WenChieh Chen)....Pages 609-658
Back Matter ....Pages 659-671

Citation preview

Plewig and Kligman´s Acne and Rosacea Gerd Plewig Bodo Melnik WenChieh Chen Fourth Edition

123

Plewig and Kligman’s Acne and Rosacea

Gerd Plewig • Bodo Melnik • WenChieh Chen

Plewig and Kligman’s Acne and Rosacea Fourth Edition

Gerd Plewig Department of Dermatology and Allergy Ludwig-Maximilian-University Munich Munich Germany WenChieh Chen Department of Dermatology and Allergy Technical University of Munich Munich Germany

Bodo Melnik Department of Dermatology Environmental Medicine and Health Theory University of Osnabrück Osnabrück Germany

ISBN 978-3-319-49273-5 ISBN 978-3-319-49274-2 (eBook) https://doi.org/10.1007/978-3-319-49274-2 © Springer Nature Switzerland AG 1975, 1993, 2000, 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

In Memory of Albert Montgomery Kligman, M.D., Ph.D., Dr. hc. mult. Philadelphia 17 March 1916–Philadelphia 9 February 2010 Mentor—Teacher—Scientist—Physician—Friend (Portrait. Oil on canvas, painted in 1995 by John Boyd Martin, who is born in 1936 Located outside the laboratory named for Albert M. Kligman, Biochemical Research Building, Department of Dermatology, University of Pennsylvania, Philadelphia With kind permission, George Cotsarelis, M.D., Ph.D., Professor and Chairman)

To our wives, Helga, Susanne, and Pei-Hsiu

Preface to the Fourth Edition

More than 50 years have elapsed since the first publication of this book, compiled and written with the brilliant ideas and energy of Albert Montgomery Kligman (1916–2010) from Philadelphia, one of the greatest experimental and clinical dermatologists of his time. Sadly enough, we miss him as an author of this new work but express our deepest gratitude to a lifelong teacher, mentor, and friend. After the English editions (1975, 1993, 2000) and German editions (1978, 1994), time was ready for a new team of authors to continue this monograph. Colleagues the world over encouraged us to bring the vast new information on these common diseases, acne and rosacea, and also demodicosis and acne-associated autoinflammatory diseases into a new volume of text and atlas. The growth of basic knowledge coupled with clinical experience since has been enormous. This has been a joyous enterprise for us. The ability to treat acne and rosacea effectively was accompanied by the vastly expanded understanding of their etiologies and pathogenesis, thanks to the remarkable input of eminent researchers and clinicians worldwide. Acne is not only an eminently treatable disease; even worst cases, for example, acne conglobata and acne fulminans, are actually curable. No case is so severe as to be beyond help with the array of diverse drugs now available. Treatment failure is mostly physician failure. Prevention of acne in highly susceptible children is well possible with topical agents prescribed at the incipient stage, thus preventing the dreaded sequel of scarring. We continue in the beliefs expressed in 1975 regarding our mission. This text and atlas is dedicated to dermatologists and other colleagues who must diagnose and treat these disfiguring, remarkably protean, common diseases. This is a reference work for investigators, including a selective review of the literature. The references we cite have been selected for their relevance to daily practice, for their educational worth, and for their readability and historical impact. This meant for a massive culling of thousands of articles piled up in past decades. We apologize to those authors whose contributions are not listed here. A quote from the first edition epitomizes our current attitude: “We have sought to create a portfolio of still-life pictures of gross and microscopic anatomy of acne and rosacea. This will be a photographic record of what these maladies look like, their usual and unusual features…” The views we present in respect to pathogenesis and treatment are in the first place our own and much less constructed from recommendations of other authorities. Thus, some of our proposals may not meet the stringent requirements of evidence-based medicine. Since this is a practice-orientated text, we have taken on the hazardous responsibility of expressing our personal options and not the many alternatives which can be found in the literature. Consensus conferences and guidelines, based on national or international participation, are helpful but may not be applicable to regional or in loco demands. We do not wish to pretend that no quandaries remain or that everything is simple and straightforward as our style might suggest. Over the past years, new concepts of pathogenesis, new variants, new syndromes of acne, and new therapies have emerged. To name but a few, these include autoinflammatory syndromes of acne associated with arthritis and pyoderma gangrenosum, hidradenitis s uppurativa/ vii

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Preface to the Fourth Edition

acne inversa now redefined as dissecting terminal hair folliculitis, the role of Demodex folliculorum mites in healthy people and diseased state, and the role of microbiota and biofilm. There is evidence to support our hypotheses concerning signal transduction pathways such as the role of FoxO1 and mTORC1 in acne, endoplasmic reticulum stress responses in rosacea, and the T cells and Th17 cells in dissecting terminal hair folliculitis, the impact of hyperglycemic food and milk, and the p53-associated sebocyte apoptosis caused by isotretinoin. Newly introduced drugs and topical remedies were discussed. Many acne-mimicking diseases are commonplace but can be confusing. Acne, syndromic constellations of acne, and rosacea not infrequently coexist in overlap mixtures, which may be present at the same time, with one slowly disappearing and the other emerging. Physicians must keep abreast with this fascinating new wealth of science. Our patients expect that we physicians have enough time for them, listening is as important as looking. Even today, our well-educated patients and their custodians sometimes hold a bag full of irrational folkloristic beliefs and myths, which need to be dispelled. It is well accepted that placebo effects are prominent in medicine and, of course, in acne and rosacea alike. This explains why some popular, unproven remedies seem to work. Even in properly controlled studies, it is astonishing how often the efficacy of the vehicle approaches that of the active drug. Important regular changes took place in the last decades. Acne conglobata and severe inflammatory acne seem to be on the wane, possibly as the result of so effective treatments such as isotretinoin, oral antibiotics, and new topical formulations. Rosacea seems to steadily increase. We speculate that also epidemiological changes reflect the environmental exposure and nutrition. Furthermore, migration across continents and countries with new in loco circumstances of health care and living standards may have their impact on expression of these dermatoses. Fascinating are the enormous steps forward of surgical interventions with lasers, fillers, and peels, as they all revolutionized our treatment possibilities. Highly specialized colleagues have become masters in this field. The reader is referred to the most experienced authorities in this rapidly moving field. Munich, Germany Osnabrück, Germany Munich, Germany

Gerd Plewig Bodo Melnik WenChieh Chen

Acknowledgments

It is with joy that we thank so many highly skilled professionals who generously helped to recreate this book. Our gratitude for their superb collaboration is acknowledged herewith. Our thanks are but a small recompense for their contributions. Mr. Peter Bilek (1936–2009), master of photography, Department of Dermatology, Ludwig- Maximilian-University Munich. Mr. Winfried Neuse, retired photographer, photo designer, and enthusiastic artist with the camera, Department of Dermatology, Heinrich-Heine-University Düsseldorf. Privatdozent Dr. Thomas Jansen, Duesseldorf, contributed faithfully to the 1994 and 2000 editions. Professor Dr. Helmut H. Wolff and Mrs. Elfriede Januschke, medical technician, formerly in the Department of Dermatology, Ludwig-Maximilian-University Munich, contributed to the exquisite transmission electron microscopies. Professor Dr. med., Dr. h.c. mult. Thomas Ruzicka, former chairman of the Munich Department, generously provided unrestricted access to essential sections of the clinic and research facilities to GP after his retirement in 2006, an invaluable help for us three authors. It was and still is a token of friendship. He must be proud to see this monograph coming from his department. Mrs. Carla Ligner, Mrs. Diana Lingk, and Mrs. Claudia Jakobec, the most helpful photographers of our photographic studio, Department of Dermatology, Ludwig-Maximilian- University Munich, went through the transition from celluloid to digital photography, successfully continuing the highest quality of dermatological illustrations. Mrs. Gudrun Kutter, freelance graphic designer in Munich, who from the very start (1975) has been extremely helpful with artwork and reproduction of illustrations. Mrs. Cornelia Hoffmann, dedicated librarian, Ludwig-Maximilian-University Munich, helped with the organization of the historical bibliography. Mrs. Susan Broy, the experienced librarian in our Munich Department, provided otherwise hard to get international papers. Czech & Partners, a Munich offset company, superbly reproduced clinical and microscopic photographs for the 2000 edition, on which this fourth edition is based. Tempora mutantur, nosque mutamur in illis. Truly influenced this hexameter the tradition of book printing. The previous five editions, then printed by Stürtz in Würzburg, a champion- league enterprise, were superbly handled by the distinguished publisher Springer Verlag in Heidelberg. Mr. Willi Bischoff coordinated with his highly professional hands the entire production. This is now taken over by Springer Verlag Italia, Srl Milano. The new professional team consists of the following: Dr. Donatella Rizza, Mrs. Juliette Ruth Kleemann, Milano; Mrs. Ellen Blasig, Heidelberg; and Ms. Madonna Samuel, Manapakkam, India. They responded to our many special questions of an electronic production and printing on demand only. We authors thank them sincerely for their patience and cooperation.

ix

x

Acknowledgments

Last but not least, we witness another change, as for good reasons, the support of the pharmaceutical industry for the production and dissemination of scientific publications as well as support of dermatological residents in the past, has come to an end because of strict regulations. We authors have no conflict of interest and are happy to bear all expenses during the long road of pulling the material together and the final release of the work. Munich, Germany Osnabrück, Germany Munich, Germany

Gerd Plewig Bodo Melnik WenChieh Chen

Contents

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function �� 1 1.1 Anatomy of Follicles�� 1 1.1.1 Terminal Hair Follicles �� 1 1.1.2 Vellus Hair Follicles�� 1 1.1.3 Sebaceous Follicles�� 2 1.2 Sebaceous Glands �� 2 1.3 Sebaceous Gland Functions�� 3 1.4 Sebaceous Lipids and Normal Sebum�� 3 1.5 Facial Pores�� 6 1.6 The Pilosebaceous Unit: The Stage Setting�� 8 1.7 Sebaceous Follicles of the Back and Face�� 10 1.8 A Descent into Follicles�� 12 1.9 Comparative Anatomy of the Face and Back�� 14 1.10 Follicular Filaments and Microcomedones�� 16 1.11 Scanning Electron Microscopic Overview of a Sebaceous Follicle �� 18 1.12 Sampling of Follicles by the Cyanoacrylate Technique�� 20 1.13 Noninvolved Skin of an Acne Patient: A Horizontal View �� 22 1.14 Large Sebaceous Glands in Acne Patients�� 24 1.15 The Sebaceous Filament �� 26 1.16 Comparative Ultrastructure of the Acroinfundibulum and the Infrainfundibulum �� 28 1.17 The Appearances of Sebum�� 30 1.18 The Microflora of Acne�� 32 Bibliography�� 34 2 Acne Epidemiology and Genetics �� 35 2.1 Prevalence of Acne�� 35 2.1.1 Adolescent Acne �� 35 2.1.2 Postadolescent Acne�� 36 2.2 Hereditary Factors in Acne �� 36 2.3 Gene Variations Causing Androgen Excess�� 37 2.4 Retinoid Metabolism�� 37 2.5 Androgen Receptor �� 37 2.6 5α-Reductase Type 1 vs. 2�� 38 2.7 Insulin-like Growth Factor-1�� 38 2.8 Fibroblast Growth Factor Receptor 2�� 38 2.9 Phosphoinositide-3 Kinase Subunit p85 �� 38 2.10 Gene Loci Attenuating TGFβ Signaling �� 38 2.11 c-Myc�� 38 2.12 Mucin 1 �� 39 2.13 Toll-Like Receptor 2 and 4 �� 39 2.14 Tumor Necrosis Factor-α and Tumor Necrosis Factor Receptor 2 �� 39 xi

xii

Contents

2.15 Interleukins 1, 6, and 8�� 39 2.16 Tyrosine Kinase 2�� 40 2.17 Resistin�� 40 2.18 Tissue Inhibitor of Matrix Metalloproteinase 1�� 40 2.19 Proline-Serine-Threonine Phosphatase-Interacting Protein 1�� 40 2.20 l-Selectin�� 40 2.21 TP53�� 40 Bibliography�� 42 3 Acne Pathogenesis�� 45 3.1 Acne Sebum�� 45 3.2 Acne Lipidomics�� 46 3.3 SREBP1c: Key Promoter of Acne Sebum�� 47 3.4 Propionibacterium acnes (P. acnes) �� 47 3.5 Acne Microbiome �� 47 3.6 P. acnes Biofilm�� 48 3.7 Virulence Factors�� 50 3.8 P. acnes Biofilm and Disturbed Follicular Keratinization�� 50 3.9 Comedogenesis �� 50 3.10 Sebofollicular Inflammation �� 51 3.11 Follicular and Comedonal Flora �� 52 3.12 Internal Structures of Old Open Comedones�� 54 3.13 Follicular Fluorescence�� 56 3.14 The Life History of the Comedo�� 58 Bibliography�� 60 4 Acne Clinic: Morphogenesis �� 63 4.1 Dynamics of Comedones�� 64 4.1.1 Evolution of the Comedo�� 64 4.1.2 Dynamics of Primary Comedo�� 64 4.1.3 Dynamics of Secondary Comedo�� 66 4.1.4 Acne Cyst�� 66 4.1.5 Draining Sinuses �� 66 4.1.6 Fistulated Polyporous Comedones�� 67 4.1.7 Cellular Biology of Comedogenesis �� 67 4.2 Dynamics of Inflammation �� 67 4.2.1 Inflammatory Lesions and Sequels �� 69 4.2.2 Acne Conglobata�� 70 4.2.3 Solid Persistent Facial Edema of Acne �� 72 4.3 Dynamics of Scars�� 73 4.3.1 Pitted, Crateriform, and Ice-Pick Scars�� 73 4.3.2 Atrophic Scars�� 73 4.3.3 Hypertrophic Scars�� 73 4.3.4 Keloids�� 73 4.3.5 Perifollicular Papular Scars�� 74 4.3.6 Calcified Scars�� 74 4.3.7 Fistulated Comedones (Polyporous Comedones) �� 74 4.3.8 Linear Scars Associated with Draining Sinus�� 75 4.3.9 Evaluation of Acne Scar and Grading Systems�� 75 4.4 Problems of Classification: Is This Acne Mild or Severe? �� 76 4.5 Closed Comedones�� 78 4.6 Gross and Microscopic Anatomy of Open Comedones�� 80 4.7 Corneocytes: The Bricks of Comedones�� 82 4.8 Patterns of Keratinization in Sebaceous Filaments and Microcomedones: A Horizontal View�� 84

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4.9 Comedogenesis �� 86 4.10 Sebaceous Ducts Keratinize and Become Part of the Comedo�� 88 4.11 Ultrastructural Tableau of the Framework of an Open Comedo�� 90 4.12 Differences Between Corneocytes of Epidermis and Comedones�� 92 4.13 Inside a Comedo �� 94 4.14 Hairs in Comedones�� 96 4.15 Pigment in Comedones �� 98 4.16 Pigment in Comedones Is Melanin �� 100 4.17 The Multiple Faces of Comedones �� 102 4.18 The Evolution of Comedones �� 104 4.19 Profiles of Inflammation �� 106 4.20 Troublesome Acne�� 108 4.21 A Portrait of Acne �� 110 4.22 The Spectrum of Acne�� 112 4.23 Adult Acne or Persistent Facial Acne in Women�� 114 4.24 Inflammatory Acne in Men �� 116 4.25 Folliculitis of Terminal Hair Follicles Versus Fragile Sebaceous Follicles�� 118 4.26 The Hateful Pustule�� 120 4.27 Variegated Histopathology of Pustules, Papulopustules, and Cysts �� 122 4.28 The Old Open Comedo �� 124 4.29 Late Rupture of Comedones �� 126 4.30 Deep-Seated Papules�� 128 4.31 Hemorrhagic Nodules �� 130 4.32 Nodules �� 132 4.33 Late Events of Inflammation�� 134 4.34 Draining Sinus: A Nasty Lesion �� 136 4.35 A Draining Sinus Should Not Be Incised �� 138 4.36 The Misery of Draining Sinuses �� 140 4.37 Cinematographic View of Fistulated Scars �� 142 4.38 Victory Over a Terrible Disease: Acne Conglobata: Before Treatment�� 144 4.39 Four Months Later: Voilà!�� 146 4.40 Acne Conglobata in an Adult�� 148 4.41 Unusual Localizations�� 150 4.42 Acne Scars�� 152 4.43 Variety of Scars �� 154 4.44 Pustules and Scars�� 156 4.45 These Biopsies Came from Scarred Facial Skin�� 158 4.46 Histopathology of a Shallow Scar�� 160 4.47 Atrophic Scar�� 162 4.48 The Hypertrophic Fibrotic Nodule�� 164 4.49 Diagnostic Pitfalls�� 166 4.50 Perifollicular Papular Scars (Closed Comedo-Like Scars) �� 168 4.51 Keloids�� 170 4.52 Widespread Scars�� 172 4.53 Widespread Scars�� 174 4.54 Fistulated (Polyporous) Comedones �� 176 4.55 Fistulated Comedones�� 178 4.56 Cysts�� 180 4.57 Acne Cysts�� 182 4.58 Rupture of Closed Comedones �� 184 4.59 Secondary Comedones�� 186 Bibliography�� 188

xiv

5 Distinctive Acne Entities�� 191 5.1 Acne in Infancy and Childhood�� 191 5.1.1 Acne Neonatorum �� 191 5.1.2 Acne Infantum�� 192 5.1.3 Acne in Preschool and School Age�� 193 5.2 Adult Acne, Postadolescent Acne, Acne Tarda �� 194 5.2.1 Epidemiology�� 194 5.2.2 Clinical Manifestations �� 194 5.2.3 Pathogenesis�� 194 5.2.4 Treatment�� 195 5.3 Acne and Menstrual Cycle�� 195 5.4 Acne in Pregnancy�� 196 5.4.1 Androluteoma Syndrome of Pregnancy (Pregnancy Luteoma) and Gestational Hyperandrogenism�� 196 5.4.2 Treatment of Acne in Pregnancy�� 196 5.5 Peri- and Postmenopausal Acne�� 196 5.5.1 Treatment�� 197 5.6 Bodybuilding and Doping Acne�� 197 5.6.1 Anabolic-Androgenic Steroids�� 198 5.6.2 Growth Hormone (GH), GH Secretagogues, Insulin-Like Growth Factor-1, and Insulin�� 198 5.6.3 Milk Protein Concentrates�� 198 5.7 Acne Neonatorum or Acne Infantum�� 200 5.8 Acne in Newborns and Infancy�� 202 5.9 Acne Infantum and Acne in Childhood�� 204 5.10 Wild Outbreaks of Acne Following Testosterone Injections and Other Anabolics�� 206 5.11 The Toll of Bodybuilding�� 208 5.12 A Bloody Disaster of Anabolic-Induced Acne Fulminans: Destruction of the Skin, Bleeding, and Pain �� 210 5.13 Androluteoma of Pregnancy �� 212 Bibliography�� 214 6 Acne Classification and Disease Burden�� 217 6.1 Classification and Grading of Acne�� 217 6.2 Disease Burden of Acne and Quality of Life�� 219 6.3 Excoriations in Acne �� 219 6.3.1 Excoriations in Acne �� 219 6.3.2 Excoriations in Patients Without Acne�� 219 6.3.3 Treatment�� 220 6.4 Excoriations in Patients Without Acne�� 220 Bibliography�� 222 7 Acne Therapy �� 223 7.1 Topical Acne Therapy �� 224 7.1.1 Topical Retinoids�� 224 7.1.2 Benzoyl Peroxide�� 224 7.1.3 Azelaic Acid�� 224 7.1.4 Topical Antibiotics�� 225 7.1.5 Topical Dapsone�� 225 7.1.6 Topical Olumacostat Glasaretil�� 225 7.2 Systemic Therapy�� 225 7.2.1 Systemic Antibiotics �� 225 7.2.2 Tetracyclines �� 225

Contents

Contents

xv

7.2.3 Macrolides�� 226 7.2.4 Systemic Isotretinoin�� 227 7.2.5 Metformin �� 238 7.2.6 Hormonal Antiandrogenic Therapies�� 238 7.2.7 Combination Oral Contraceptive Pills�� 239 7.2.8 Cyproterone Acetate�� 240 7.2.9 Spironolactone�� 240 7.2.10 Flutamide�� 240 7.2.11 Corticosteroids�� 240 7.2.12 Zinc �� 242 7.3 Topical Therapy�� 242 7.3.1 Chemical Peelings�� 242 7.3.2 Single Agents�� 242 7.3.3 Glycolic Acid�� 242 7.3.4 Lactic Acid�� 242 7.3.5 Mandelic Acid�� 242 7.3.6 Salicylic Acid�� 242 7.3.7 Trichloroacetic Acid (TCA)�� 242 7.3.8 Phenol �� 242 7.3.9 Mixtures�� 243 7.3.10 Jessner’s Solution�� 243 7.3.11 Salicylic Acid (20%) and Mandelic Acid (10%)�� 243 7.4 Photodynamic Therapy �� 243 7.5 Light Therapy�� 243 7.6 An Excellent Therapeutic Result with Tretinoin�� 244 7.7 Topical Tretinoin Loosens Corneocytes�� 246 7.8 Amazing Effect of Systemic Tetracycline and Topical Tretinoin �� 248 7.9 Prior to the Marketing of Isotretinoin, All Kinds of Strategies Were Needed to Help Patients�� 250 7.10 Calcinosis and Bones in the Skin�� 252 7.11 Minocycline Hyperpigmentation�� 254 7.12 Minocycline Hyperpigmentation, Electron Microscopy�� 256 7.13 Oral Isotretinoin, a Powerful Acne Medication�� 258 7.14 Isotretinoin Is the Miracle Drug for Acne Conglobata �� 260 7.15 Excessive Sebum Suppression of Isotretinoin�� 262 7.16 Isotretinoin Stops Sebum Production�� 264 7.17 Isotretinoin Loosens and Expels Corneocytes�� 266 7.18 Isotretinoin Changes Cornification �� 268 7.19 Pyoderma Superimposed on Acne�� 270 7.20 Isotretinoin: Cutaneous Side Effects�� 272 7.21 Therapeutic Adjuncts�� 274 7.22 The Refinements of Comedo Extraction�� 276 7.23 How Beneficial or Detrimental Is Comedo Extraction? �� 278 7.24 Sequelae of Comedo Extraction�� 280 7.25 Comedo Extraction �� 282 7.26 Comedo Extraction Is Often Incomplete, and Refilling Is Fast�� 284 7.27 The Draining Sinus �� 286 Bibliography�� 288 8 Acne and Nutrition�� 293 8.1 History�� 293 8.2 Western Diet and Its Nutrigenomic Effect�� 293 8.3 Western Diet and Its Possible Effect in Polycystic Ovary Syndrome and Prostate Cancer�� 294

xvi

Contents

8.4 Western Diet and Acne: Molecular Pathogenesis �� 294 8.5 Western Diet and Acne: Epidemiological and Clinical Evidence�� 295 8.6 Dietary Intervention in Acne�� 295 8.7 Low Carbohydrate Diets, Ketogenic Diet, Paleolithic Diet�� 295 8.8 Plant-Derived Polyphenols, Polyunsaturated ω-3 Fatty Acids, Vitamin D, and Distinct Gut Microbiota �� 296 8.9 Concerns on the Dietary Intervention in Acne�� 296 Bibliography�� 297 9 Acne-Mimicking Diseases�� 299 9.1 Drug-Induced Acne and Drug-Induced Acneiform Eruptions�� 300 9.1.1 Drug-Induced Acne�� 300 9.1.2 Growth Hormone and Insulin-Like Growth Factor-1 �� 300 9.1.3 Androgens �� 301 9.1.4 Isotretinoin�� 301 9.1.5 Drug-Induced Acneiform Eruptions �� 302 9.1.6 Glucocorticosteroids �� 302 9.1.7 Lithium and Psychotherapeutics �� 303 9.1.8 Halogens �� 303 9.1.9 B-Vitamins�� 303 9.1.10 Antituberculosis Drugs �� 303 9.1.11 Immunosuppressants�� 304 9.1.12 P450-Inducing Agents�� 304 9.1.13 Epidermal Growth Factor Receptor Inhibitors�� 305 9.1.14 RAF and MEK Inhibitors�� 305 9.2 Chloracne�� 305 9.2.1 From Chloracne to MADISH�� 305 9.2.2 Chemistry�� 306 9.2.3 Chemicals Producing Chloracne (Chloracnegens) �� 306 9.2.4 Major Epidemics of Chloracne �� 307 9.2.5 The Route of Contamination�� 308 9.2.6 Clinical Findings�� 309 9.2.7 Histopathology�� 309 9.2.8 Other Dermatological and Nondermatological Manifestations�� 309 9.2.9 Differential Diagnosis and Laboratory Studies�� 309 9.2.10 Treatment and Prevention �� 310 9.3 Acne Venenata�� 310 9.3.1 The Occupational Acnes �� 311 9.3.2 Treatment�� 311 9.3.3 Lip Balm Acne�� 311 9.4 Acne Cosmetica�� 311 9.4.1 Clinical Findings�� 312 9.4.2 Treatment�� 313 9.4.3 Pomade Acne�� 313 9.4.4 Differential Diagnosis and Treatment�� 313 9.5 Acne Mechanica�� 314 9.6 Gram-Negative Folliculitis�� 315 9.6.1 Etiology�� 316 9.6.2 Treatment�� 316 9.7 Malassezia (Pityrosporum) Folliculitis�� 317 9.7.1 Clinical Findings�� 317 9.7.2 Histopathology�� 317

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9.7.3 Differential Diagnosis �� 317 9.7.4 Treatment�� 317 9.8 Acne Necrotica/Necrotizing Lymphocytic Folliculitis �� 318 9.8.1 Historical Background�� 318 9.8.2 Etiology�� 318 9.8.3 Clinical Features �� 318 9.8.4 Histopathology�� 318 9.8.5 Laboratory Findings�� 318 9.8.6 Differential Diagnosis �� 318 9.8.7 Treatment and Prognosis�� 319 9.9 Pseudofolliculitis Barbae�� 319 9.10 Acne Aestivalis/Mallorca Acne/Polymorphous Light Eruption�� 319 9.11 Atrophodermia Vermiculata/Atrophoderma Vermiculatum�� 320 9.11.1 Clinical Manifestations �� 320 9.11.2 Histopathology�� 320 9.11.3 Differential Diagnoses�� 321 9.11.4 Treatment�� 321 9.12 Radiation-Induced Comedones�� 321 9.13 Solar Comedones (Favre-Racouchot Disease)�� 321 9.13.1 Histopathology�� 321 9.13.2 Treatment�� 322 9.14 Unusual Comedones and Comedo-Like Eruptions�� 322 9.14.1 Congenital Comedones �� 322 9.14.2 Childhood Flexural Comedones �� 322 9.14.3 Perianal Comedones�� 322 9.14.4 Familial Dyskeratotic Comedones/Nevoid Follicular Epidermolytic Hyperkeratosis�� 322 9.14.5 Familial Disseminated Comedones Without Dyskeratosis/Familial Multiple Comedones�� 323 9.15 Steatocystoma Multiplex�� 323 9.15.1 Genetics�� 323 9.15.2 Clinical Findings�� 323 9.15.3 Histopathology�� 324 9.15.4 Differential Diagnosis �� 324 9.15.5 Treatment�� 324 9.16 Eruptive Vellus Hair Cyst�� 324 9.16.1 Clinical Findings�� 324 9.16.2 Pathogenesis�� 324 9.16.3 Genetics�� 325 9.16.4 Histopathology�� 325 9.16.5 Differential Diagnosis �� 325 9.16.6 Treatment�� 325 9.17 Trichostasis Spinulosa�� 325 9.17.1 Pathogenesis�� 325 9.17.2 Histopathology�� 325 9.17.3 Diagnosis�� 325 9.17.4 Treatment�� 326 9.18 Dilated Pore and Pilar Sheath Acanthoma�� 326 9.18.1 Histopathology�� 326 9.18.2 Treatment�� 326 9.18.3 Pilar Sheath Acanthoma�� 326 9.18.4 Histopathology�� 326 9.18.5 Differential Diagnosis �� 327 9.18.6 Treatment�� 327

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9.19 Miliary Osteoma Cutis�� 327 9.19.1 Histopathology�� 327 9.19.2 Treatment�� 327 9.20 Contact Acne�� 328 9.21 Oil Acne and Chloracne: Environmental Hazards�� 330 9.22 Contact Acne from Cutting Oil �� 332 9.23 Steroid Acne�� 334 9.24 How Steroid Acne Develops �� 336 9.25 Steroid Acne�� 338 9.26 Acneiform Eruptions�� 340 9.27 Halogens Are Proinflammatory Agents�� 342 9.28 Amineptine Acne�� 344 9.29 Amineptine-Induced Acne Conglobata�� 346 9.30 Acneiform Rashes Induced by EGFR Inhibitor�� 348 9.31 Acneiform Rash Induced by MEK Inhibitor�� 350 9.32 Severe Drug Rash from MEK Inhibitor�� 352 9.33 Necrotizing Lymphocytic Folliculitis �� 354 9.34 Necrotizing Lymphocytic Folliculitis �� 356 9.35 Chloracne: Terrible and Lifelong�� 358 9.36 Chloracne: The Reverse Side�� 360 9.37 Chloracne in Children �� 362 9.38 Chloracne in Children �� 364 9.39 Histopathology of Chloracne�� 366 9.40 Chloracne�� 368 9.41 Chloracne�� 370 9.42 Differential Diagnosis of Closed Comedones�� 372 9.43 Bones in the Skin�� 374 9.44 Pitch Acne �� 376 9.45 Acne Aestivalis (Mallorca Acne) = Polymorphous Light Eruption�� 378 9.46 Solar Comedones = Favre-Racouchot Disease �� 380 9.47 Trichostasis Spinulosa�� 382 9.48 Dilated Pore of Winer �� 384 9.49 Pilar Sheath Acanthoma and Dilated Pore�� 386 9.50 Gram-Negative Folliculitis�� 388 9.51 Gram-Negative Folliculitis�� 390 9.52 Steatocystoma Multiplex and Eruptive Vellus Hair Follicles. Related Cysts, Differing in Size�� 392 9.53 Steatocystoma Multiplex and Eruptive Vellus Hair Cysts. Relatives of a Genetically Determined Malformation of Sebaceous Follicles �� 394 9.54 Familial Steatocystoma Multiplex�� 396 9.55 Steatocystoma Multiplex�� 398 9.56 Atrophodermia Vermiculata: Differential Diagnosis of Acne Scars �� 400 9.57 Atrophodermia Vermiculata, Often Mistaken for Acne Scars�� 402 Bibliography�� 404 10 Acne-Associated Syndromes �� 411 10.1 Acne in Autoinflammatory Syndromes�� 412 10.2 Acne Fulminans�� 412 10.2.1 Clinic�� 412 10.2.2 Pathogenesis�� 413 10.2.3 Differential Diagnosis �� 414 10.2.4 Treatment�� 414 10.2.5 Prognosis�� 414

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10.3 SAPHO Syndrome�� 414 10.3.1 Clinic�� 415 10.3.2 Pathogenesis�� 415 10.3.3 Treatment�� 416 10.4 PAPA Syndrome�� 416 10.4.1 Clinic�� 416 10.4.2 Pathogenesis�� 416 10.4.3 Treatment�� 417 10.5 PASH Syndrome �� 417 10.5.1 Clinic�� 417 10.5.2 Pathogenesis�� 417 10.5.3 Treatment�� 418 10.6 Other Less-Defined Syndromes�� 418 10.6.1 PASS Syndrome�� 418 10.6.2 PAPASH, PsAPASH, and PAC Syndrome�� 418 10.7 Apert Syndrome�� 418 10.7.1 Clinic�� 418 10.7.2 Pathogenesis�� 419 10.7.3 Treatment�� 419 10.8 Acneiform Nevus of Munro�� 419 10.9 Acne-Associated Syndromes Associated with Androgen Excess and Insulin Resistance�� 419 10.10 Nonclassical Congenital Adrenal Hyperplasia�� 419 10.10.1 Clinic �� 419 10.10.2 Laboratory �� 420 10.10.3 Treatment�� 420 10.11 SAHA Syndrome�� 420 10.12 PCO Syndrome �� 420 10.12.1 Clinic �� 420 10.12.2 Laboratory �� 421 10.12.3 Pathogenesis�� 421 10.12.4 Treatment�� 421 10.13 HAIR-AN Syndrome�� 421 10.13.1 Clinic �� 422 10.13.2 Laboratory �� 422 10.13.3 Pathogenesis�� 422 10.13.4 Therapy �� 422 10.14 Acne Fulminans, A Member of the Autoinflammatory Syndromes?�� 422 10.15 Acne Fulminans�� 424 10.16 Acne Fulminans�� 426 10.17 Acne Fulminans�� 428 10.18 Acne Fulminans�� 430 10.19 Acne Fulminans Versus SAPHO Syndrome �� 432 10.20 Acne Fulminans: Clinico-Pathological Correlation�� 434 10.21 PAPA Syndrome�� 436 10.22 PAPA Syndrome�� 438 10.23 PAPA Syndrome�� 440 10.24 PASH Syndrome �� 442 10.25 PASH Syndrome �� 444 10.26 Acne Associated with Mutations of Fibroblast Growth Factor Receptor 2 (FGFR2) �� 446 Bibliography�� 448

xx

11 Hidradenitis Suppurativa/Acne Inversa/Dissecting Terminal Hair Folliculitis�� 455 11.1 Introduction�� 455 11.2 Epidemiology�� 455 11.3 Clinic�� 456 11.3.1 Identifying Acne Inversa/Dissecting Terminal Hair Folliculitis �� 456 11.3.2 Complications �� 457 11.3.3 Associated Syndromes�� 457 11.4 Etiopathogenesis �� 458 11.4.1 Histopathology�� 458 11.4.2 Molecular Pathways�� 460 11.5 Therapy �� 460 11.5.1 Medical Treatment�� 460 11.5.2 Surgical Treatment�� 461 11.5.3 Pre- and Postoperative Care�� 462 11.6 Prognosis�� 462 11.7 Dissecting Cellulitis or Folliculitis of the Scalp/Perifolliculitis Capitis Abscedens et Suffodiens/Dissecting Terminal Hair Folliculitis of the Scalp �� 462 11.7.1 Introduction�� 462 11.7.2 Epidemiology�� 462 11.7.3 Clinic�� 462 11.7.4 Etiopathogenesis �� 462 11.7.5 Therapy �� 463 11.8 Pilonidal Disease�� 463 11.9 Differential Diagnosis �� 463 11.9.1 Folliculitis Scleroticans Nuchae (Acne Keloidalis Nuchae)�� 463 11.9.2 Epidemiology�� 463 11.9.3 Clinic and Etiopathogenesis�� 464 11.9.4 Treatment�� 464 11.10 Anatomy of Apocrine Sweat Glands�� 464 11.11 Hidradenitis Suppurativa/Acne Inversa/Dissecting Terminal Hair Folliculitis: Importance of Proper Biopsies�� 466 11.12 Dissecting Phenomena in Dissecting Terminal Hair Folliculitis�� 468 11.13 Dissecting Terminal Hair Folliculitis: Devastating Inflammation�� 470 11.14 Dissecting Draining Sinuses in Dissecting Terminal Hair Folliculitis�� 472 11.15 Dissecting Terminal Hair Folliculitis: Violent and Generalized �� 474 11.16 Hidradenitis Suppurativa/Acne Inversa/Dissecting Terminal Hair Folliculitis: Differential Diagnosis �� 476 11.17 Hidradenitis Suppurativa/Acne Inversa/Dissecting Terminal Hair Folliculitis �� 478 11.18 Hidradenitis Suppurativa/Acne Inversa/Dissecting Terminal Hair Folliculitis �� 480 11.19 Hidradenitis Suppurativa/Acne Inversa/Dissecting Terminal Hair Folliculitis: A Malicious Disease�� 482 11.20 Hidradenitis Suppurativa/Acne Inversa/Dissecting Terminal Hair Folliculitis: A Determined Surgical Approach�� 484 11.21 Hidradenitis Suppurativa/Acne Inversa/Dissecting Terminal Hair Folliculitis: Genital Involvement�� 486 11.22 Dreadful Disease and Late Complications: Squamous Cell Carcinoma, Metastasizing and Fatal�� 488 11.23 Hidradenitis Suppurativa/Acne Inversa/Dissecting Terminal Hair Folliculitis: A Pitiful Disease�� 490

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11.24 Perifolliculitis Capitis Abscedens et Suffodiens/Dissecting Cellulitis/Folliculitis of the Scalp: Dissecting Terminal Hair Folliculitis of the Scalp �� 492 11.25 Acne Keloidalis Nuchae (Folliculitis Keloidalis Nuchae)�� 494 11.26 Hidradenitis Suppurativa/Acne Inversa/Dissecting Terminal Hair Folliculitis �� 496 Bibliography�� 498 12 Rosacea Epidemiology and Genetics�� 501 12.1 Epidemiology�� 501 12.2 Predisposing Genetic Factors�� 502 12.3 Rosacea Comorbidities Are Linked to ER Stress �� 503 12.4 Inflammatory Bowel Diseases�� 503 12.5 Neuroinflammatory and Neurodegenerative Diseases�� 504 12.6 Type 1 Diabetes Mellitus�� 504 12.7 Rheumatoid Arthritis�� 504 12.8 Metabolic Syndrome and Cardiovascular Disease�� 505 12.9 Cancer �� 505 12.10 Upregulated ER Stress: A Genetic Predisposition to Rosacea?�� 505 Bibliography�� 506 13 Rosacea Pathogenesis�� 509 13.1 ER Stress and the Unfolded Protein Response �� 509 13.2 Disturbed Sebaceous Gland and Epidermal Barrier Function�� 510 13.3 Rosacea Triggers�� 510 13.3.1 Ultraviolet Radiation�� 510 13.3.2 Thermal, Irritant, Mechanical, Nutritive, and Psychological Trigger Factors�� 510 13.4 Inflammation �� 512 13.5 Vascular Hyperactivity�� 512 13.6 Skin Hypersensitivity�� 513 13.7 Angiogenesis and Lymphangiogenesis �� 513 13.8 Fibrosis�� 514 13.9 Demodex Mites �� 514 13.10 Summary �� 514 Bibliography�� 514 14 Rosacea Clinic and Classification�� 517 14.1 Clinical Findings�� 517 14.2 Classification�� 518 14.3 Episodic Erythema (Rosacea Diathesis) �� 518 14.4 Stage I Rosacea �� 518 14.5 Stage II Rosacea�� 518 14.6 Stage III Rosacea�� 518 14.7 Phymas in Rosacea �� 519 14.8 Rhinophyma�� 519 14.9 Ophthalmic or Ocular Rosacea �� 519 14.10 Lupoid or Granulomatous Rosacea�� 520 14.11 Rosacea Conglobata�� 521 14.12 Rosacea Fulminans �� 521 14.13 Steroid Rosacea�� 521 14.14 Halogen Rosacea�� 522 14.15 Gram-Negative Rosacea�� 522 14.16 Persistent Edema of Rosacea�� 522 14.17 Childhood Rosacea �� 522

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14.18 Histopathology�� 523 14.19 Laboratory Findings�� 523 14.20 Differential Diagnosis �� 523 14.21 Portrait of Rosacea�� 524 14.22 Rosacea �� 526 14.23 Facial and Extrafacial Rosacea �� 528 14.24 Extrafacial Rosacea�� 530 14.25 Multiple Facets of Rhinophymas�� 532 14.26 Disfiguring Rhinophyma in a Patient with Rosacea �� 534 14.27 Exuberant Growths of Rosacea�� 536 14.28 Rosacea and Eye Involvement: Ocular or Ophthalmic Rosacea�� 538 14.29 Lupoid or Granulomatous Rosacea�� 540 14.30 Lupoid or Granulomatous Rosacea in a Man versus Rosacea Fulminans in Two Women�� 542 14.31 Incipient Rosacea Fulminans�� 544 14.32 Rosacea at Its Worst. Only One Diagnosis Can Be Made: Rosacea Fulminans �� 546 14.33 Histopathology of Rosacea Fulminans �� 548 14.34 Rosacea Fulminans �� 550 14.35 Persistent Edema of Rosacea: Morbihan Disease�� 552 14.36 Differential Diagnosis of Rosacea�� 554 Bibliography�� 556 15 Rosacea Therapy�� 559 15.1 Topical Treatment �� 559 15.1.1 Metronidazole �� 559 15.1.2 Azelaic Acid�� 560 15.1.3 Ivermectin �� 560 15.1.4 Brimonidine and Oxymetazoline�� 561 15.2 Topical Azithromycin and Cyclosporine�� 561 15.3 Systemic Therapy�� 562 15.3.1 Tetracyclines �� 562 15.3.2 Isotretinoin�� 562 15.4 Special Indications�� 562 15.4.1 Rosacea in Childhood and Pregnancy�� 562 15.4.2 Ocular Rosacea �� 562 15.4.3 Rosacea Fulminans �� 563 15.4.4 Morbihan Disease �� 563 15.4.5 Facial Flushing and Persistent Erythema�� 563 15.4.6 Rosacea Telangiectasia �� 563 15.4.7 Rhinophyma and Other Forms of Phymas�� 563 15.5 Horrendous Rosacea Fulminans �� 564 15.6 Rosacea Is a Treatable Disease �� 566 15.7 Rosacea Can Readily Be Improved by Isotretinoin�� 568 Bibliography�� 570 16 Demodex Mites and Demodicosis �� 573 16.1 Demodex Mites in Humans and Animals�� 573 16.1.1 Introduction�� 573 16.1.2 Diagnostic Techniques�� 574 16.2 Demodicosis�� 574 16.2.1 Epidemiology�� 574 16.2.2 Etiopathogenesis �� 574

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16.2.3 Clinic�� 575 16.2.4 Histopathology�� 575 16.2.5 Therapy �� 575 16.3 Demodex and the Skin�� 576 16.4 Demodicosis in Adults Without Signs of Acne or Rosacea�� 578 16.5 Multiple Presentations of Primary Demodicosis in Women �� 580 16.6 Diagnostic Challenge: Primary Demodicosis �� 582 16.7 Topographical Anatomy of Female and Male Demodex folliculorum�� 584 16.8 Scanning Electron Microscopy of Various Stages of Demodex Mites and Outline Diagrams �� 586 16.9 Demodex Mites: Head, Larva and Female Adults; Right (Scanning Electron Microscopy), Left (Outline)�� 588 16.10 Demodex Mites: Opisthosoma, Nymph and Adult Mites; Right (Scanning Electron Microscopy), Left (Outline) �� 590 16.11 Demodex Mites: Male Adults and Ovum; Right (Scanning Electron Microscopy), Left (Outline)�� 592 Bibliography�� 594 17 Acne Research Models�� 595 17.1 Acne in Animals�� 595 17.2 Canine Acne�� 595 17.3 Feline Acne �� 595 17.4 Syrian Hamster�� 596 17.4.1 Sebaceous Gland Assays�� 596 17.4.2 Flank Organ�� 596 17.4.3 Ears �� 596 17.5 Rabbit Ear �� 596 17.6 Rhino Mouse�� 596 17.7 HR-1 Mouse�� 597 17.8 The Human Sebaceous Gland Organ Culture �� 597 17.9 Primary Human Sebocyte Cultures�� 597 17.10 Immortalized Human Sebocytes Cultures�� 598 17.11 The Syrian Hamster Model�� 600 17.12 The Rabbit Ear Comedogenic Assay�� 602 17.13 The Rhino Mouse�� 604 Bibliography�� 606 18 History of Acne and Rosacea�� 609 18.1 Introduction�� 610 18.2 A Historical Survey�� 610 18.2.1 The Early Years �� 610 18.2.2 The Seventeenth and Eighteenth Centuries: From Speculative Opinion to Scholarly Work �� 611 18.3 The Confusion of Acne and Rosacea�� 612 18.4 Milestones �� 613 18.5 The Twentieth Century: Clinical and Experimental Milestones �� 614 18.6 Early Depictions of Rosacea and Acne by International Leaders in Dermatology �� 618 18.7 Portrait of the Back of a 26-Year-Old Man with Acne �� 620 18.8 Portrait of Acne �� 622 18.9 Acne as Seen by Ferdinand von Hebra in Vienna (1816–1880) �� 624 18.10 Acne as Seen by Ferdinand von Hebra in Vienna (1816–1880) �� 626 18.11 Acne Rosacea as Called by Erasmus Wilson�� 628 18.12 Acne Rosacea as Called by Ferdinand von Hebra�� 630

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18.13 Acne Rosacea, Rhinophyma as Called by Dr. Ferdinand von Hebra �� 632 18.14 Acne Rosacea, Rhinophyma as Seen by Henry Radcliff Crocker�� 634 18.15 Acne and Acne Necrotica (Necrotizing Lymphocytic Folliculits)�� 636 18.16 Early Histopathology of the Nineteenth Century�� 638 18.17 Stereoscopic Viewing of Patients�� 640 18.18 Ulerythema Acneiforme, Today Atrophodermia Vermiculata (or Vermiculatum) Honeycomb Atrophy�� 642 18.19 Keloids, Rosacea and Acne�� 644 18.20 Acne Histopathology and Acne Infantum�� 646 18.21 Röntgen Rays (X-Rays) for the Treatment of Acne�� 648 Bibliography�� 650 Index�� 659

About the Authors

Gerd Plewig, FRCP Medical School University of Hamburg, Graz and Kiel, promotion 1967. Rotating internship 1966–1967 in Germany, and 1967–1968 in Darby/ Philadelphia, USA. 1967–1969 Research Fellow with Professor Albert Montgomery Kligman, MD, PhD, University of Pennsylvania, Philadelphia. Dermatology training as Resident and Associate with Professor Dr. Dr. h.c. mult. Otto Braun-Falco, Department of Dermatology, Ludwig- Maximilian- University Munich 1969–1982. Chairman, Department of Dermatology, Heinrich- Heine- University, Düsseldorf 1982–1991. Chairman, Department of Dermatology, Ludwig-Maximilian-University Munich 1991– 2006. Since 2006 Professor emeritus of his Alma mater. Fellow of the Royal College of Physicians, London 1997. Doctor honoris causa Charles-University Prague, Medical University Wroclaw (Breslau), and Comenius University Bratislava. President European Society for Dermatological Research 1982–1983; Chief Medical Director School of Medicine, Ludwig-Maximilian-University 1999–2005. Bodo C. Melnik Finished his medical studies at the University of Münster with his promotion in 1982. From 1982 to 1984, he was visiting scientist at the Cardiovascular Research Institute, School of Medicine, University of California, San Francisco. From 1984 to 1990, he was resident in dermatology with Professor Dr. Gerd Plewig at the Department of Dermatology, Heinrich-Heine-University, Düsseldorf. In 1989, he received his venia legendi in dermatology and was Felix Hoppe-Seyler Prize awardee of the German Society for Laboratory Medicine. Since 1991, he is senior lecturer at the Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück. He is member of the European Society for Dermatological Research and section editor of the Journal of Translational Medicine.

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xxvi

About the Authors

WenChieh Chen Medical School at Kaohsiung Medical University Taiwan. Doctorate thesis with Prof. emer. Dr. Prof. h.c. Dr. h.c. Constantin Emmanuel Orfanos, Department of Dermatology and Allergy, Free University of Berlin, Germany 1994–1997. Research Fellow with Prof. emer. Dr. Dr. h.c. mult. Gerd Plewig, Department of Dermatology and Allergy, Ludwig-Maximilian-University Munich 1997–1998. Assistant Professor, Department of Dermatology, National Cheng Kung University Tainan, Taiwan 1998–2003. Chairman and Associate Professor, Department of Dermatology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan 2003–2007. Humboldt Research Award, Germany 2007– 2009. Habilitation with Prof. emer. Dr. Dr. Johannes Ring, Department of Dermatology and Allergy 2010, and since 2014 Adjunct Professor at the Technical University of Munich, Germany.

1

Pilosebaceous Follicles: Structure, Biochemistry, and Function

Core Messages • Three kinds of follicles exist in the face: vellus, sebaceous, and terminal follicles. • Sebaceous follicles are limited to the face, ear lobes, neck, shoulders, upper V-shaped areas of the chest and back, and the lateral aspects of the upper arms. • The sebaceous follicle is characterized by an exceptionally large and multilobulated sebaceous gland, a deep and cavernous follicular canal, and a tiny inconspicuous hair. Acne affects the sebaceous follicles. • Sebaceous glands are found in highest density and size in acne-prone skin areas: the face, the scalp, V-regions of the chest, and upper back. • A typical pilosebaceous unit is composed of a sebaceous gland, the hair follicle, and the arrector pili muscle. • Sebaceous glands are found on the entire surface of the skin except for the palms and soles. • A capillary network connects sebaceous glands to the systemic circulation. • Sebaceous glands are holocrine glands and secrete sebum after programmed sebocyte death. • Their number remains unchanged during lifetime, whereas their size and activity are increased especially after birth and during adolescence. • Sebaceous glands produce sebaceous lipids, predominantly triacylglycerols, wax esters, and squalene. • Monounsaturated fatty acids, especially sapienic acid and oleic acid, which are produced by desaturases, are functionally important constituents of acne sebum.

1.1

Anatomy of Follicles

For a deeper understanding of acne and sebaceous gland- related diseases, it is important to be familiar with the anatomy and physiology of sebaceous follicles. This chapter provides information about sebaceous gland structure and sebaceous lipogenesis. The secretory end product of sebaceous glands is sebum, which plays a key role in the pathogenesis of acne vulgaris.

1.1.2 Vellus Hair Follicles

Three kinds of follicles on the face can be distinguished: terminal, vellus, and sebaceous follicles. The structure of these three kinds of follicles differs in the size and predominance of the hair and sebaceous gland, respectively. Acne is a disease of the sebaceous follicle.

1.1.1 Terminal Hair Follicles Beard and scalp follicles on the face of men are typical terminal follicles. The hair is stiff, thick, and long. Its diameter is wide enough to occupy almost the entire lumen of the follicular canal. Because of its stiffness and its steady growth, the hair keeps the canal free of horny debris. Comedones and acne do not occur in terminal follicles. In terminal follicles, sebaceous glands empty their contents into the follicular canal via short ducts. The region above their insertion is designated the infundibulum. It is lined by an epithelium, which produces sturdy, well-differentiated horny cells similar to those of the adjacent epidermis. Consequently, the horny layer of the infundibulum possesses barrier properties. The horny cells desquamate continuously and invisibly through the orifice. Terminal follicles are not targets for acne, but they are the key targets of acne inversa (dissecting terminal hair folliculitis), formerly called hidradentitis suppurativa and acne inversa.

These are miniatures of terminal follicles in size with disproportionately large sebaceous glands. On the face, they are three to four times more numerous than sebaceous follicles and accordingly contribute appreciably to the pool of skin surface lipids. The hairs and orifices of vellus follicles are

© Springer Nature Switzerland AG 2019 G. Plewig et al., Plewig and Kligman’s Acne and Rosacea, https://doi.org/10.1007/978-3-319-49274-2_1

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2

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

very tiny and can scarcely be seen with the naked eye. Vellus follicles are not targets for acne but are involved in chemical folliculitis and perioral dermatitis.

1.1.3 Sebaceous Follicles Sebaceous follicles are the targets of acne. They have special characteristics, which make them specifically vulnerably to acne. Their sebaceous glands are exceptionally large and multilobulated and enter via short ducts into the bottom of the canal. The canal is deep and cavernous. The pilary unit is tiny and inconspicuous. It produces a wispy hair whose width is less than one-fifths to one-tenth that of the internal diameter of the canal. It is virtually lost in the huge lumen. The terminal portion of the canal is termed the acroinfundibulum and extends about 200 μm downward. The epithelium is similar to that of the infundibulum of terminal follicles. It keratinizes like the contiguous epidermis and functions as a barrier. Below this, the epithelium has exceptional properties. This portion is called the infrainfundibulum. It makes up the greatest part of the epithelial lining of the sebaceous follicle. It also keratinizes but produces only a thin, incomplete horny layer whose cells soon slough. The desquamated corneocytes are fragile and imperfect. Many break open and loose part of their contents. These corneocytes are not well differentiated. In consequence, a loose mass of horny detritus occupies the canal. The sturdy laminae of a true stratum corneum are lacking in the infrainfundibulum. The granular layer can barely be made out, being generally one cell-layer thick and containing only tiny granules. Unlike, normal epidermis, PAS staining discloses glycogen granules in many of the Malpighian cells. The epithelium of the sebaceous ducts keratinizes in much the same way, producing empty looking, flimsy horny cells which float up into the canal in a stream of sebum. In this way, separate streams of keratinized cells are created which correspond to the number of sebaceous ducts. The keratinous envelope that contains the sebum has been called the sebolemmal sheath. The canal itself contains a mixture of sloughed corneocytes and sebum. A variable number of sebaceous follicles show masses of gram-positive bacteria. These bacteria-rich structures comprise sebaceous filaments. When the contents of such follicles are expelled by pressure, cheesy, waxy, whitish wormlike structures emerge. They contain abundant colonies of Propionibacterium acnes. Sebaceous filaments are physiological structures that contain a core of lipid and bacteria encased in a cylinder of coherent horny cells.

1.2

Sebaceous Glands

The pubertal increase in insulin-like growth factor-1 (IGF-1) and androgens enhance sebum secretion, which is a prerequisite in the pathogenesis of acne vulgaris. Almost all acne

patients suffer from seborrhea. Acne vulgaris does not occur when sebum secretion is low. The sebum-suppressive efficacy of systemic isotretinoin and antiandrogens confirms the importance of sebum in the pathogenesis of acne. Sebum is the end product of holocrine secretion of sebocytes. To understand the pathogenesis of acne, it is mandatory to be familiar with the anatomy and physiology of sebaceous glands. Sebaceous glands consist of two cell types, sebocytes and the cells of the excretory duct. The base of the sebaceous gland may represent a niche for skin stem cells. Sebocytes are highly specialized epithelial cells that undergo terminal differentiation and finally die in a DNase2- mediated programmed cell death called holocrine secretion thereby extruding their lipid-enriched content and other cell products into the follicular canal. The lipid-rich product of holocrine sebocyte secretion is called sebum. Sebaceous glands are abundant on the face, the scalp, and the V-shaped area on the chest and back. On the face, high numbers of 400–900 glands per cm2 have been determined. Sebaceous glands are either unilobular or multilobular. Each acinus is associated with a duct that connects to the main sebaceous duct. Three types of sebaceous glands are distinguished, and the smallest are associated with fine vellus hairs. Larger ones are associated with terminal hair follicles, such as those of the scalp. Huge, often multilobulated sebaceous glands of sebaceous follicles are found in the face and acne-prone skin areas. They play a key role in the pathogenesis of acne. Sebaceous glands are not innervated and thus function independently of nerve signals. However, human sebaceous glands express nicotinic acetylcholine receptor α7 (nAchRα7). Acetylcholine increases lipid synthesis in a dose-dependent manner. Sebaceous glands are enveloped by a thin highly vascular, fibrous tissue capsule. This stroma separates various acini and is enriched in capillaries. Sebaceous glands are connected to the blood circulation and are thus able to receive systemic hormonal signals such as IGF-1 and androgens. Sebocytes express steroidogenic enzymes and are able to convert less potent androgens to highly potent dihydrotestosterone. In order to produce sebum in the process of holocrine secretion, the sebocyte undergoes a program of cellular differentiation. A single layer of undifferentiated sebocytes facing the basal lamina represent the germinative cells. They provide a continual flux of proliferating and later differentiating cells. Migrating from the gland’s periphery to the center, the basal cells gradually differentiate into an early differentiated sebocyte, an advanced differentiated cell, a fully differentiated cell, and finally the mature sebocyte. Cell reproduction takes place in the basal layer, just above the basement membrane. These cells are small, flat, or cuboid and are mostly undifferentiated. Electron microscopy already reveals tiny lipid droplets indicating early lipid synthesis. During the differentiation process, the sebocyte increases greatly in size and becomes a round cell. A mature cell may be 100–150 times larger than the basal cells. Lipid synthesis

1.4 Sebaceous Lipids and Normal Sebum

results in great expansion of sebocytes. Mature sebocytes still contain sometimes more than 50 individual lipid vacuoles, separated by fine cytoplasmic strands. The cytoplasm contains a well-developed Golgi apparatus and rough endoplasmic reticulum. Sebocytes also synthesize sparse tonofilaments, which disappear during maturation. At the end of the differentiation process, the organelles and the nucleus are degraded and disappear. The activation of DNAse2 plays a critical role for DNA fragmentation. The cell finally ruptures and releases its content, the sebum, into the sebaceous duct. There is recent evidence that confirms that sebocyte death, like keratinocyte death, which leads to cornification, underlies a well-regulated process of programmed cell death. The time of initial sebaceous lipogenesis and the emergence of sebum is in the range of 1–2 weeks. The cells of the sebaceous ducts have histological and biochemical features of both sebocytes and keratinocytes. They contain lipid droplets and are significantly smaller than mature sebocytes, but they also possess ultrastructural markers of keratinization, e.g., lamellar bodies, keratohyalin granules, and tonofilaments. They produce a thin horny layer composed of fragile, loose corneocytes, which readily shed into the lumen. The capacity to form corneocytes becomes especially evident during comedogenesis.

1.3

Sebaceous Gland Functions

Why do we have sebaceous glands? At the beginning of extrauterine human life, sebaceous glands experience their first growth stimulation and secretory activation via dehydroepiandrosterone sulfate released in high amounts from the fetal adrenal gland. They provide the majority of lipids of the vernix caseosa which functions as a lubricant of the newborn’s convex body surfaces, especially the vertex of the scalp in the process of parturition. Lubrication may also be the physiological reason of free sebaceous glands on the inner surface of the prepuce (Tyson glands), where they may involve in the production of the lipid-rich smegma. Free sebaceous glands are also found on the labia minora and periareolar skin. Remarkably, sebaceous glands produce natural antibiotics such as various defensins and antibacterial lipids, such as lauric acid (C12:0) and sapienic acid (C16:1Δ6) derived from human sebaceous triacylglycerols. Sebaceous lipids are not involved in epidermal barrier function, which primarily relies on functional epidermal lipids, especially ceramides and acylceramides.

1.4

Sebaceous Lipids and Normal Sebum

The pubertal increase in sebum secretion is a prerequisite for the pathogenesis of acne vulgaris. The key growth hormone of puberty responsible for sebogenesis is insulin-like

3

growth factor-1 (IGF-1), which activates the phosphoinositide-3 kinase/AKT/mTORC1 pathway, that via inactivation of the transcription factor FoxO1 enhances the expression of three major transcription factors, which are primarily involved in the biosynthesis of sebum lipids: sterol regulatory element-binding protein 1 (SREBP1), androgen receptor (AR), and peroxisome proliferator-activated receptors (PPARs). In contrast, transforming growth factor-β (TGFβ) inhibits sebaceous gland differentiation and sebaceous lipogenesis. The central hub of cellular lipid metabolism is the kinase mechanistic target of rapamycin complex 1 (mTORC1), which is activated by insulin, IGF-1, essential branched-chain amino acids, and glutamine. During puberty mTORC1 is overactivated by increased IGF-1 and androgen signaling. IGF-1 activates the kinase AKT that stimulates mTORC1 via inhibition of its upstream suppressor tuberin (TSC2). In a similar fashion, androgens attenuate the activity of the natural mTORC1 inhibitor DEP domain-containing mTOR-interacting protein (DEPTOR). Androgens also activate the kinase mTORC2, which is another pathway enhancing AKT-mTORC1 signaling. It has been demonstrated in hamster sebocytes that phosphorylation and thus activation of mTORC1 induces sebum secretion, which is increased by the addition of both IGF-1 and testosterone. IGF-1 promotes adrenal (DHEAS) and gonadal (testosterone) androgen synthesis resulting in increased availability of androgens further increasing androgen receptor activation. SREBP1 acts as the master transcription factor of sebaceous lipogenesis that activates gene expression of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of de novo fatty acid synthesis and squalene synthase (SQS), the rate-limiting enzyme of squalene synthesis, respectively. Furthermore, SREBP1 activates sebaceous gland Δ6-desaturase and stearoyl-CoA desaturase (SCD), which convert palmitic acid (C16:0) to sapienic acid (C16:1Δ6) and stearic acid (C18:0) to oleic acid (C18:1Δ9), respectively. In classical endocrinology textbooks, the main hormones controlling testosterone synthesis in the testis and estrogen synthesis in the ovary at puberty are FSH and LH. IGF-1 can regulate the whole process at different levels but is not the key hormone. Supposedly the same story also happens in sebaceous glands, which can be considered as an endocrine organ. As only LH receptors but not FSH receptors were demonstrated in human sebaceous glands, it remains unclear whether LH and FSH can directly initiate the androgen synthesis in sebocytes. The key role of IGF-1 in androgen synthesis, is probably limited to sebaceous glands (Fig. 1.1). Sebum is the end product of a holocrine secretion process of sebocytes, which has been identified as a special form of DNase2-mediated programmed sebocyte death. Normal human sebum is mainly composed of triacylglycerols, wax esters, squalene, and some free fatty acids with minor

4

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function Puberty Androgen synthesis

IGF-1

Androgen

AKT

FoxO1

mTORC2

FoxOs

AR DEPTOR

mTORC1 SREBP1

ACC

SQS

Monounsaturated FAs C16:1D6 C18:1D9

Saturated fatty acids (FAs) C12:0 C16:0 C18:0

Triacylglycerols

Desaturases

Wax esters

Squalene

Major sebaceous gland lipids

Fig. 1.1 Major signaling pathways regulating the biosynthesis of sebaceous lipids. ACC acetyl-CoA carboxylase; AKT kinase Akt (protein kinase B); AR androgen receptor; FoxO1 forkhead box class O; IGF-1 insulin-like growth factor 1; mTORC1 mechanistic target of rapamycin complex 1; mTORC2 mechanistic target of rapamycin complex 2; SQS squalene synthase; SREBP1 sterol response element regulatory protein 1. Published with kind permission of © Bodo Melnik 2019. All Rights Reserved Table 1.1 Representation of the average relative normal sebum composition Sebum lipid class Triacylglycerols Wax esters Squalene Free fatty acids Cholesterol and sterol esters Diacylglycerols

Mean weight [%] 45 25 12 10 4 2

amounts of cholesterol, sterol esters, and diacylglycerols (Table 1.1). The sebum secretion rate of the mid-forehead of adolescents without acne is on average 3.3 ± 1.8 mg lipid/10 cm2/3 h, whereas acne patients exhibit an increased sebum excretion rate of 5.05 ± 2.5 mg lipid/10 cm2/3 h, respectively. The amounts of total released free fatty acids in acne patients is more than 50% higher than in age-matched controls without acne. The majority of fatty acids in sebum is covalently bound in triacylglycerols. Free fatty acids are released by the action of triacylglycerol lipase, which is a known virulence factor of Propionibacterium acnes in the biofilm form. By the time the sebum reaches the surface of the skin, about one-third of the skin surface lipids are composed of free fatty acids. Sebum contains saturated, unsaturated, and very peculiar branchedchain fatty acids. The most abundant fatty acids of sebum are the saturated fatty acid palmitic acid (C16:0) and the monounsaturated fatty acid sapienic acid (C16:1Δ6) with relative amounts of 25% and 22%, respectively. The absence of a Δ9-desaturase in sebocytes in addition to high expression of Δ6-desaturase promotes the preferred conversion of palmitic acid (C16:0) to sapienic acid (C16:1Δ6). Sapienic acid and lauric acid (C12:0) derived from human sebaceous triacylglycerols are potent antimicrobials found at the human skin surface. Linoleic acid (C18:2Δ9,Δ12), the preferred substrate of Δ6-desaturase in other tissues, undergoes rapid oxidation and degradation in sebocytes, which makes palmitic acid available as the preferred substrate for Δ6-desaturation in the sebocyte. This sebaceous-type reaction is of most critical importance to understand the qualitative change of normal sebum to a proinflammatory and comedogenic acne sebum as outlined later. Free monounsaturated fatty acids, especially sapienic acid (C16:1Δ6) and oleic acid (C18:1Δ9), are critical components of acne sebum that will be discussed in more detail in the next chapter (Fig. 1.2). OH

O H2C HC H2C

OO OO O

Palmitic acid (C16:0)

∆6 COOH CH3

Sapienic acid (C16:1∆6)

O

Stearic acid (C18:0)

OH

Triglyceride

∆9 Oleic acid (C18:1∆9) O OH

Squalene

Fig. 1.2 Functionally important sebum lipids and free fatty acids. Published with kind permission of © Bodo Melnik 2019. All Rights Reserved

O O

Wax ester

1.4 Sebaceous Lipids and Normal Sebum

Sebum lipids, when released into the dermal microenvironment, for example, at rupture of comedones, are involved in the regulation of multiple signaling pathways. They inter-

5

act with Toll-like receptors of macrophages and keratinocytes and thereby contribute to the maintenance of innate immunity.

6

1.5

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

Facial Pores

Ordinarily, only the orifices of the sebaceous follicles are visible. The more numerous vellus follicles are too small to be seen. The diameter of the pore is roughly proportionate to the size of the pilosebaceous unit; hence, people with oily skin and large glands tend to have larger pores. Wide orifices contribute to a coarse appearance and texture Above: Cheek of a young man who had moderate acne. The pores are conspicuous. The larger irregular depressions are small scars from minor acne lesions. All other pores are the openings of acroinfundibula of uninvolved sebaceous follicles. The skin is oily Below: Cheek of a young woman without acne. One can barely make out the pores. The skin is not oily

8

1.6

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

The Pilosebaceous Unit: The Stage Setting

These sketches illustrate the architecture and size differences of the three types of facial follicles Left: Vellus follicle. These are very numerous. Their sebaceous lipids contribute to the surface lipids but are mere bystanders in acne Middle: Sebaceous follicle. This is the theater where the drama of acne is performed. The sebaceous glands are large and multilobular. The puny hair is a flimsy thread in the huge canal which is filled with loose keratinized cells. The sketch shows an anagen follicle Right: Terminal beard hair. The stiff, thick hair fills the canal. These follicles are ignored by all forms of acne except dissecting terminal hair folliculitis, formerly known as acne inversa or hidradenitis suppurativa

9

10

1.7

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

Sebaceous Follicles of the Back and Face

No single sebaceous follicle seems to be identical to the next one. Sebaceous follicles of the back differ from those of the face Above: Sebaceous follicles of the back Left: One normal sebaceous follicle with an acroinfundibulum containing Pityrosporum ovale yeasts, the infrainfundibulum, the pilary portion (peripherally cut in this section), and two large sebaceous lobules draining sebum through sebaceous ducts Right: Sebaceous follicles have one hair apparatus. The thin brownish hair seems to be lost in the spacious infundibulum. Most of the corneocytes from the follicular canal got lost during sectioning Below: Sebaceous follicles of the face Left: The follicular canal is wide and filled with corneocytes. The epithelium has a well-pronounced granular layer. The puny hair is cut tangentially twice. The sebaceous acini are numerous, and all lobules shown here drain into this follicle Right: A tortuous sebaceous follicle. Melanin pigment is produced in the epidermis and in the acroinfundibulum, but not below it. The tiny hair is cut once. Five sebaceous lobules belong to this unit, some of which are located above the draining sebaceous ducts. The contents of the follicular canal correspond to the waxy worms that can be squeezed out from facial skin

12

1.8

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

A Descent into Follicles

Normal-appearing skin from a young man with ongoing mild acne (a–c) and that from a man without acne (d–f) was serially cut in a horizontal fashion a: Close to the skin surface An acroinfundibulum of a sebaceous follicle with pigment in the basal cell layer, a sebaceous filament, and one hair ( To the left is a vellus follicle with its tiny sebaceous gland

).

b: Midinfundibulum The follicular canal is distended by a well-developed sebaceous filament with a central chamber full of bacteria. The sebaceous duct ( ), partly keratinized, is about to merge with the follicular canal. The hair ( ) also joins at this triangular point c: Level of sebaceous glands Two sebaceous acini belong to this follicle, one showing its sebaceous duct ( ). The pilary unit ( sebaceous duct and infundibulum

) is still outside the

d: Close to the skin surface An acroinfundibulum with some melanin pigment in the basal cell layer. A sebaceous filament, two hairs ( ), and a bacteria-filled cavity are seen. The two hairs are from one pilary unit (trichostasis). To the right is a much smaller vellus follicle with one hair e: Midinfundibulum The follicular canal contains a filament with two cavernas filled with bacteria. The hair ( A sebaceous follicle is to the right f: Level of sebaceous gland One sebaceous lobule with multiple trabeculae and undifferentiated cells ( structure ( )

) is just joining the canal.

) in close association with the pilary

a

d

b

e

c

f

*

14

1.9

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

Comparative Anatomy of the Face and Back

The tissue was sectioned horizontally about 0.5 mm below the surface. The photographs were taken at the same magnification Above: Forehead. Vellus and sebaceous follicles are numerous. The latter have large lumina (thick arrows) which often seem empty. The tiny vellus follicles (thin arrows) are about five times more numerous Below: Back. The sebaceous follicles are far apart and often occur in pairs which fuse at the surface. As regards adnexa, the face is an oasis, the back a desert. In consequence, the face is often oily, the back rarely

16

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

1.10 Follicular Filaments and Microcomedones Follicular filaments (sebaceous filaments, follicular casts) are physiological elements and not part of the acne spectrum, whereas microcomedones represent incipient acne lesions Above: Follicular filaments Left: A sebaceous follicle from the back filled with a cocoon of corneocytes. The sebaceous glands below constantly soak the filament with sebum Right: The follicular filament consists of about 30 layers of corneocytes, encompassing a matrix of sebum and dense colonies of Propionibacterium acnes. The follicular epithelium has a well-developed stratum granulosum. This is not a microcomedo, as the accumulation of corneocytes is not large enough. A perpetuous self-cleaning mechanism keeps this follicle well-balanced Below Left: A microcomedo. This type of lesion is clinically not visible. The epithelium is acanthotic, with hypergranulosis, and rapidly producing coherent corneocytes which are no longer discharged through the orifice above. The proliferation-retention hyperkeratosis distends the infundibulum. Usually, dense colonies of Propionibacterium acnes are present, not seen in this particular section. One sebaceous follicle is attached to the lower left Right: Horizontal cut through a follicular filament. This could be the horizontal counterpart to the vertical section above right. The follicular epithelium shows a stratum granulosum and encases a filament of corneocytes. The chambers are full of Propionibacterium acnes; one tiny brownish hair is below

18

1.11

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

Scanning Electron Microscopic Overview of a Sebaceous Follicle

Rarely can one see the full architectural pattern of a sebaceous follicle. Sections of this extent are not easily obtained. This is in the midportion of a normal sebaceous follicle from the back of a young man. The follicular epithelium is in the upper right and lower left corners. The hair with its cuticle is in the center. About 15 layers of corneocytes line the epithelium; the outermost layers detach and desquamate in an amalgam of sebum. Bacteria cannot be seen in this section, though they are present elsewhere in the follicle. Electron microscopy, ×4000

20

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

1.12 Sampling of Follicles by the Cyanoacrylate Technique Cyanoacrylate, also known as crazy glue, is a quick-setting polymer that rips off the outermost layers of the stratum corneum, to which are attached vellus hairs and the horny casts within the upper regions of sebaceous follicles. This technique, sometimes referred to as the follicular biopsy, offers a splendid way of collecting the contents of sebaceous follicles for a variety of studies. These include (a) density and size of microcomedones and casts, quantifiable by image analysis, (b) presence and abundance of Demodex folliculorum mites, (c) follicular density of Pityrosporum ovale and Propionibacterium acnes, (d) presence of fascicles of hairs (trichostasis spinulosa), and (e) composition of lipids within microcomedones. The specimens shown here are mounted in immersion oil Above The inset shows the outermost sheet of stratum corneum removed on a glass slide. On the forehead of a healthy person, the vellus hairs are single and not encased in horny material Below Left: Microcomedo. Here there are two hairs, the tip of one being barely visible. These are encased in a thick, solid mass of corneocytes, which have begun to distend the follicle. Comedones larger than this, i.e., closed comedones, are too firmly anchored to be removed by this technique Right: Two sebaceous filaments. A hair is sheathed in a semi-firm mass of corneocytes which thins out toward the root. The presence of only one hair per horny casts indicates that there is no real obstruction. This specimen was from the cheek of an acne patient in whom these follicular casts are typically numerous and thick. They indicate a predisposition to the formation of comedones, corresponding to the clinical picture of large pores and oiliness

22

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

1.13 Noninvolved Skin of an Acne Patient: A Horizontal View A biopsy of noninvolved skin of the forehead was sectioned horizontally and photographed at the same magnification Several points are noteworthy: • • • • •

The densely arranged sebaceous and vellus follicles The follicular filaments in sebaceous follicles, full of bacteria The large sebaceous acini of sebaceous follicles The pilary portion associated with each follicle The lingering lymphohistiocytic infiltrate

Above Left: Close to the skin surface, there are many vellus follicles ( acini are not at this level Right: Hair papillae and small sebaceous acini ( ceous follicles

) between sebaceous follicles (

). Sebaceous

) of vellus follicles are present next to spacious infundibula of seba-

Below Left: Level of sebaceous acini of sebaceous follicles. The glands are large and multilobulated ( ( ) and cross sections of hairs ( ) Right: Lower level of sebaceous acini with the pilary portion still mostly outside the glands ( ibulbar lymphohistiocytic infiltrate is present

). Sebaceous ducts

). Perivascular and per-

24

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

1.14 Large Sebaceous Glands in Acne Patients These biopsies were obtained from the cheeks of two 17-year-old men, one with smooth skin and no acne, the other with severe inflammatory acne. The tissue was cut horizontally and photographed at the same magnification. Above: Normal skin. Sebaceous lobules rest around their pilary portion Below: Acne skin. The sebaceous gland is at least four times as voluminous in the acne patient as in the normal subject. The pilary portion is above. Acne patients produce more sebum than persons without acne. The more sebum is produced, the more severe the acne tends to be. Sebaceous glands are particularly large in patients with acne conglobata

26

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

1.15 The Sebaceous Filament Above: Squeezed-out sebaceous filaments. These waxy worms were forced out of the sebaceous follicles of the forehead by pinching the skin between the blades of a hemostat. This was a man with skin type VI with oily skin who had had acne in the past. It is much easier to express filaments from the alae nasi of persons with oily skin and large pores. The filament is a cylindrical tube of keratinized cells, actually stratum corneum, enclosing a cheesy mass of sebaceous lipids densely colonized by Propionibacterium acnes. Sebaceous filaments do not evolve into comedones Below: Ultrastructure of the sebaceous filament. This view of the central portion reveals a mixture of bacteria and dehiscing corneocytes. The latter are very irregular in size and shape and more like those in ordinary sebaceous follicles than in normal stratum corneum. Many corneocytes seem empty, possibly artifactual. Others contain lipid droplets. Some are swollen and broken, indicating vast imperfections. The bacteria and horny cells are suspended in a matrix of sebum. Electron microscopy, ×16,600

28

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

1.16 Comparative Ultrastructure of the Acroinfundibulum and the Infrainfundibulum Above: Acroinfundibulum. The keratinizing epithelium is on the left, with prominent keratohyalin granules. Approximately 25 rows of dense corneocytes on the right are compacted into a horny layer. This corresponds to the interfollicular portion of the epidermis. The acroinfundibulum is an extension of the epidermis into the terminal segment of a sebaceous follicle. Electron microscopy, ×28,000 Below: Infrainfundibulum. This epithelium also keratinizes, but the corneocytes have different characteristics. The keratohyalin granules (left) are small and sparse. Adjacent to this diminutive granular layer are three to four rows of poorly formed, jumbled, thin, irregular corneocytes which show signs of disintegration. The amorphous material on the right is sebum. Electron microscopy, ×28,000

30

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

1.17 The Appearances of Sebum Above: Comedo stained for lipid. The framework of a comedo is soaked with sebum. This frozen section was stained with oil-red-O. The lipid is found extracellularly in clefts between the corneocytes and in the channels which conduct it to the surface. Lipid droplets within the corneocytes can only be seen with electron microscopy. Hair shafts are cut tangentially twice at 6 and 12 o’clock

Below Left: Lipid-laden cells (sebocytes). Electronmicroscopic view of mature lipid cells of the sebaceous glands shortly before their rupture. ×6900 Right:

Human sebum is a yellowish, oily liquid at skin temperature. This was collected by ether extraction from the scalp

32

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

1.18 The Microflora of Acne Three organisms are constantly found on the face: Propionibacterium acnes, Staphylococcus epidermidis, and yeasts of the genus Pityrosporum. These panels compare the lightmicroscopic (left) and the electron microscopic (right) appearances of these organisms in tissue at the same magnification. Above: Pityrosporum. These budding yeasts congregate in bead-like patterns at the tip of the comedo and also in the acroinfundibulum of normal follicles. They have a very thick wall. Left, semithin section, PAS stain, ×960; right, electron microscopy, ×3200 Middle: Staphylococcus epidermidis. These bacteria prefer superficial locations in the acroinfundibulum and at the tips of comedones. They are recognized by their round shape. Left, semithin section, methylene blue, ×960; electron microscopy, ×25,000 Below: Propionibacterium acnes. This microaerophilic diphtheroid occupies almost exclusively the deeper portions of the sebaceous follicles and comedones. The bacterium varies a good deal in size and shape, sometimes even showing coccoid forms. Left, semithin section, methylene blue, ×960; electron microscopy, ×64,000

34

1 Pilosebaceous Follicles: Structure, Biochemistry, and Function

Bibliography Bakan I, Laplante M. Connecting mTORC1 signaling to SREBP-1 activation. Curr Opin Lipidol. 2012;23:226–334. Bell M. A comparative study of the ultrastructure of the sebaceous glands of man and other primates. J Invest Dermatol. 1994;62:132–43. Buffoli B, Rinaldi F, Labanca M, et al. The human hair: from anatomy to physiology. Int J Dermatol. 2014;53:331–41. Cunliffe WJ, Perera WD, Thackray P, et al. Pilo-sebaceous duct physiology. III. Observations on the number and size of pilo-sebaceous ducts in acne vulgaris. Br J Dermatol. 1976;95:153–6. Dahlhoff M, Fröhlich T, Arnold GJ, et al. LC-MS/MS analysis reveals a broad functional spectrum of proteins in the secretome of sebocytes. Exp Dermatol. 2016;25:66–7. Dozsa A, Dezso B, Toth BI, et al. PPARγ-mediated and arachidonic acid-dependent signaling is involved in differentiation and lipid production of human sebocytes. J Invest Dermatol. 2014;134:910–20. Eberlé D, Hegarty B, Bossard P, et al. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 2004;86:839–48. Ellis RA, Montagna W, Fanger H. Histology and cytochemistry of human skin. XIV. The blood supply of the cutaneous glands. J Invest Dermatol. 1958;30:137–45. Fischer CL, Blanchette DR, Brogden KA, et al. The roles of cutaneous lipids in host defense. Biochim Biophys Acta. 2014;1841:319–22. Fischer H, Fumicz J, Rossiter H, et al. Holocrine secretion of sebum is a unique DNase2-dependent mode of programmed cell death. J Invest Dermatol. 2017;137:587–94. Ge L, Gordon JS, Hsuan C, et al. Identification of the delta-6 desaturase of human sebaceous glands: expression and enzyme activity. J Invest Dermatol. 2003;120:707–14. González-Serva A. Excretion of sebum is channeled by a keratinous envelope from sebaceous duct origin: the sebolemmal sheath. J Invest Dermatol. 1997;108:376. Gribbon EM, Cunliffe WJ, Holland KT. Interaction of Propionibacterium acnes with skin lipids in vitro. J Gen Microbiol. 1993;139:1745–175. Hinde E, Haslam IS, Schneider MR, et al. A practical guide for the study of human and murine sebaceous glands in situ. Exp Dermatol. 2013;22:631–7. Hoover E, Krishnamurthy K. Physiology, sebaceous glands. Source StatPearls [internet]. Treasure Island, FL: StatPearls; 2018. p. 24. Inoue T, Miki Y, Kakuo S, et al. Expression of steroidogenic enzymes in human sebaceous glands. J Endocrinol. 2014;222:301–12. Ju Q, Tao T, Hu T, et al. Sex hormones and acne. Clin Dermatol. 2017;35:130–7. Li ZJ, Park SB, Sohn KC, et al. Regulation of lipid production by acetylcholine signalling in human sebaceous glands. J Dermatol Sci. 2013;72:116–22. Lopez JM, Bennett MK, Sanchez HB, et al. Sterol regulation of acetyl coenzyme a carboxylase: a mechanism for coordinate control of cellular lipid. Proc Natl Acad Sci U S A. 1996;93:1049–53. Lovászi M, Szegedi A, Zouboulis CC, Törőcsik D. Sebaceous-immunobiology is orchestrated by sebum lipids. Dermatoendocrinology. 2017;9:e1375636. Mangelsdorf S, Otberg N, Maibach HI, et al. Ethnic variation in vellus hair follicle size and distribution. Skin Pharmacol Physiol. 2006;19:159–67. Matsuzaka T, Shimano H, Yahagi N, et al. Dual regulation of mouse Delta(5)- and Delta(6)-desaturase gene expression by SREBP-1 and PPARalpha. J Lipid Res. 2002;43:107–14. McNairn AJ, Doucet Y, Demaude J, et al. TGFβ signaling regulates lipogenesis in human sebaceous glands cells. BMC Dermatol. 2013;13:2. Melnik BC. Linking diet to acne metabolomics, inflammation, and comedogenesis: an update. Clin Cosmet Investig Dermatol. 2015;8:371–88. Melnik BC, Zouboulis CC. Potential role of FoxO1 and mTORC1 in the pathogenesis of Western diet-induced acne. Exp Dermatol. 2013;22:311–5. Míková R, Vrkoslav V, Hanus R, et al. Newborn boys and girls differ in the lipid composition of vernix caseosa. PLoS One. 2014;9:e99173. Nakamura MT, Nara TY. Gene regulation of mammalian desaturases. Biochem Soc Trans. 2002;30:1076–9. Nicolaides N. Skin lipids: their biochemical uniqueness. Science. 1974;186:19–26. Niemann C, Horsley V. Development and homeostasis of the sebaceous gland. Semin Cell Dev Biol. 2012;23:928–36. Otberg N, Richter H, Schaefer H, et al. Variations of hair follicle size and distribution in different body sites. J Invest Dermatol. 2004;122:14–9. Pappas A, Anthonavage M, Gordon JS. Metabolic fate and selective utilization of major fatty acids in human sebaceous gland. J Invest Dermatol. 2002;118:164–71. Plewig G. Follicular keratinization. J Invest Dermatol. 1974;62:308–15. Powell EW, Beveridge GW. Sebum excretion and sebum composition in adolescent men with and without acne vulgaris. Br J Dermatol. 1970;82:243–9. Ricoult SJ, Manning BD. The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep. 2013;14:242–51. Rosignoli C, Nicolas JC, Jomard A, Michel S. Involvement of the SREBP pathway in the mode of action of androgens in sebaceous glands in vivo. Exp Dermatol. 2003;12:480–9. Rudman SM, Philpott MP, Thomas GA, Kealey T. The role of IGF-I in human skin and its appendages: morphogen as well as mitogen? J Invest Dermatol. 1997;109:770–7. Schneider MR. Lipid droplets and associated proteins in sebocytes. Exp Cell Res. 2016;340:205–8. Schneider MR, Paus R. Sebocytes, multifaceted epithelial cells: lipid production and holocrine secretion. Int J Biochem Cell Biol. 2010;42:181–5. Schneider MR, Schmidt-Ullrich R, Paus R. The hair follicle as a dynamic miniorgan. Curr Biol. 2009;19:R132–42. Smith TM, Cong Z, Gilliland KL, et al. Insulin-like growth factor-1 induces lipid production in human SEB-1 sebocytes via sterol response element-binding protein-1. J Invest Dermatol. 2006;126:1226–32. Smith TM, Gilliland K, Clawson GA, Thiboutot D. IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway. J Invest Dermatol. 2008;128:1286–93. Tansey TR, Shechter I. Structure and regulation of mammalian squalene synthase. Biochim Biophys Acta. 2000;1529:49–62. Thody AJ, Shuster S. Control and function of sebaceous glands. Physiol Rev. 1989;69:383–416. Trivedi NR, Cong Z, Nelson AM, et al. Peroxisome proliferator-activated receptors increase human sebum production. J Invest Dermatol. 2006;126:2002–9. Wheatley VR. The sebaceous glands. In: Jarret A, editor. The physiology and pathophysiology of the skin, vol. 9. London: Academic Press; 1986. Zouboulis CC, Picardo M, Ju Q, et al. Beyond acne: current aspects of sebaceous gland biology and function. Rev Endocr Metab Disord. 2016;17:319–34.

2

Acne Epidemiology and Genetics

Core Messages • Acne during adolescence affects approximately 85% of young adults in developed countries with a climax of acne prevalence at the age of 15 years. • There is an increasing early onset of puberty and acne and a rising prevalence in late adolescence on a global scale. • Late adolescent acne exhibits higher prevalence rates in developed versus developing countries. • Acne during adolescence has not been observed in several genetically independent populations that are still exposed to Paleolithic dietary conditions. • Postadolescent acne is divided into persistent acne representing a continuation of acne from adolescence into adult life and late-onset acne occurring after the age of 25 years and predominantly affects women. • Late-onset acne is more frequently associated with endocrinological or metabolic abnormalities. • Single hereditary factors play a significant role in the pathogenesis of acne but cannot explain the epidemic occurrence of acne in developed countries. • Twin studies have confirmed the hereditability of acne and the association of a positive family history associated with an increased risk of developing acne. • The severity of acne, magnitude of sebum production and inflammation, extension of the disease, regional variations, clinical course, and response to treatment are influenced by genetic factors. • Acne-associated mutations and gene polymorphisms cluster in three major pathways: IGF-1-mTORC1 signaling, androgen signaling or inflammation. There is substantial evidence that hereditary factors play an important role in acne pathogenesis. They enhance the risk for disease or aggravate its course and outcome and modify the time of onset, persistence after puberty, response to treatment, tissue remodeling and healing, the extent of scaring, and the disposition for keloid. Acne genetics have been overestimated during the last decades because a single genetic polymorphism or a rare mutation cannot explain the high and

fast raising prevalence rates in adolescents living in developed countries. The high acne prevalence in developed countries underlines the predominance of environmental factors including Western-style nutrition.

2.1

Prevalence of Acne

2.1.1 Adolescent Acne Acne vulgaris, an inflammatory disease of the human sebaceous follicle, affects the vast majority of adolescents in Westernized populations. According to the Global Burden of Disease (GBD) study, acne vulgaris affects approximately 85% of young adults aged 12–25 years. The climax of acne prevalence is observed at the age of 15 years. The acne vulgaris-associated disease burden exhibits global distribution and has continued to grow in prevalence from 1990 to 2010. Acne vulgaris is primarily a disease of wealthy countries and exhibits higher prevalence rates in developed compared to developing countries (http://vizhub.healthdata.org/gbd-compare/) (Fig. 2.1). In developed countries, acne presents at a younger age associated with an accelerated onset of puberty, especially in girls. Early onset of menarche is clearly associated with increased body mass index (BMI). According to the National Health and Nutrition Examination Survey (NHANES), increased milk consumption during the second and fourth year of life promotes a higher BMI in children. Multiple epidemiological studies report an increased prevalence of acne in patients with skin of color. Acne is more prevalent in African American and Hispanic women than in Continental Indian, Caucasian, and Asian women. All racial groups display equal prevalence of acne with the exception of Asians, for whom inflammatory acne was more prevalent than comedonal acne and, in Caucasians, for whom comedonal acne was more prevalent than inflammatory acne. Prevalence of acne in the Chinese population is lower than that in Caucasian populations. No acne was found in Chinese subjects less than 10 years of age, and only 1.6% in the

© Springer Nature Switzerland AG 2019 G. Plewig et al., Plewig and Kligman´s Acne and Rosacea, https://doi.org/10.1007/978-3-319-49274-2_2

35

36

2 Acne Epidemiology and Genetics

PREVALENCE DALY

5.5

Developed countries

5.0

4.5

GLOBAL

4.0

Developing countries 1990

1995

2000 YEAR

2005

2010

Fig. 2.1 Acne prevalence in the age range of 15–19 years for both sexes determined by disability-adjusted life years (DALY) modified according to Lynn et al. (2016). Published with kind permission of © Gerd Plewig 2019. All Rights Reserved

10-year-old group had acne. Prevalence then increased rapidly with age, up to 47% in the 19-year-old group declining gradually with age. In Brazil (Sao Paulo), the prevalence of acne during adolescence in the age range between 10 and 17 years was 96.0% and increased with age over 14 years. The most prevalent form of acne in Brazil was comedonal (61.1%), followed by mild (30.6%) and moderate papulopustular (7.6%), which affected mostly the face (97.5%). Cordain and coworkers found no acne in non-Westernized populations still living under Paleolithic dietary conditions constraining hyperglycemic carbohydrates, milk, and dairy products. Adolescent Kitavan islanders of Papua New Guinea and Aché hunter-gatherers of Paraguay in the age range of 15–25 years exhibited no case of acne. Within a decade, the fast transition of the Eskimo population of Canada from the status of a hunting society to that of a town-based population has been associated with a rapid increase of acne prevalence. An increase in acne prevalence has also been observed in Okinawans and Chinese after leaving their traditional dietary habits. In contrast to high acne prevalence rates in urban areas of Brazil (96%), rural areas such as the tropical Purus Valley showed a very low prevalence of acne (2.7%). Thus, civilization factors, especially exposure to the Westernized nutrition, have an impact on acne prevalence rates.

2.1.2 Postadolescent Acne It is generally believed that in the majority of adolescents, acne resolves after puberty. In Westernized countries, acne persists into the 20s and 30s in around 60% and 40% of individuals, respectively. Postadolescent acne is a common disorder that is often defined as acne that occurs in individuals aged 25 years or older. Postadolescent acne is divided into per-

sistent acne, which represents a continuation of acne from adolescence into adult life, and late-onset acne, which refers to acne occurring after the age of 25 years. Postadolescent acne predominantly affects women. In a community-based study of adults aged 25 years or older in the United Kingdom, clinically significant acne was detected in 12% of women, but only 3% of men. In a prospective study of 2895 women (aged 10–70 years) performed in the United States, England, Italy, and Japan, the prevalence of acne in women steadily decreased with age. Women aged 21–30 had 45%, women aged 31–40 had 26%, and women aged 41–50 had 12% acne, respectively. Women with inflammatory acne were younger than those with comedonal acne, and postmenopausal women had less acne than age-matched peers. According to the criteria used in different studies, the prevalence of adult acne in women ranges from 10 to 60%. A community-based study in the United Kingdom estimated the prevalence of facial acne in adult women aged between 26 and 44 years to be 14%. The large majority (>90%) of women with adult acne exhibit facial comedones. The most common predominant sites of involvement are the cheeks, chin, temples, and mandibular area. In patients with late-onset acne, the number of comedones, total number of acne lesions, and proportions of comedones were significantly less than in patients with early-onset acne. According to an Italian study, comedonal postadolescent acne is correlated with cigarette smoking. Especially patients with late-onset acne may represent a subgroup, who have underlying abnormalities of ovarian, adrenal, or local androgen metabolism that require further endocrinological investigations.

2.2

Hereditary Factors in Acne

The roles of genetic inheritance and special genetic susceptibility for acne have been suggested for over 100 years, but their identification and determination started only in the 1990s. To date, an increasing number of genetic polymorphisms and mutations affecting the expression and function of genes associated with acne have been determined. Hecht in 1960 was the first who studied the role of heredity in acne and demonstrated that if one of the parents has presented with acne in youth, the child who resembled the parent most had an 80% probability of developing acne. Data from family studies further suggested familial clustering. Several twin studies supported this observation. Higher correlations of the rate of sebum excretion have been found in monozygotic versus dizygotic twins. The proportion of branched fatty acids in the fraction of sebaceous wax esters more highly correlates in monozygotic compared with dizygotic twins. Apolipoprotein A1 serum levels were significantly lower in acne twins. Heredity as a prognostic factor for acne has been evaluated in a French prospective epidemiologic study, which confirmed the importance of heredity as a prognostic factor for acne and showed that a family history of acne is associated with earlier occurrence of the disease and

2.5 Androgen Receptor

increased number of retentional lesions as well as therapeutic difficulties. Especially, the risk for a relapse after oral isotretinoin treatment is significantly higher in the population of patients with a positive family history of acne. The severity of teenage acne at three body sites, i.e., the face, chest, and back, in 778 pairs of twins revealed that heritability of acne on the back was very high. At age 14 years, facial acne in girls was less influenced by genetic factors than in boys and was significantly influenced by environmental factors. The majority of gene polymorphisms and aberrations in gene expression associated with acne contribute to pathogenesis at some point of the complex signaling cascade that drives increased IGF-1-mTORC1 activity, increased androgen signaling, and inflammation. This results in excessive sebum production as well as gene regulatory mechanisms promoting inflammatory responses and disordered infundibular keratinization.

2.3

ene Variations Causing Androgen G Excess

The cytochrome P450 17A1 gene (CYP17A1) is critically involved in adrenal and gonadal androgen metabolism. CYP17A1 encodes a steroid 17α-monooxygenase that is found in the zona reticularis and zona fasciculata of the adrenal cortex and gonadal tissues. It has 17α-hydroxylase and 17,20-lyase activities and is a key enzyme in the steroidogenic pathways that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens. An association of CYP17 −34 (T>C) single nucleotide polymorphism (SNP) has been reported in Chinese acne patients. CYP17 SNP was not associated with acne in the Polish population. HSD3B1 and HSD17B3 are genes involved in cutaneous androgen metabolism. HSD3B1 encodes 3β-hydroxysteroid dehydrogenase/ Δ5-Δ4-isomerase type I. HSD17B3 encodes 17β-hydroxysteroid dehydrogenases, which catalyze the dehydrogenation of 17-hydroxysteroids in steroidogenesis. This gene is involved in the interconversion of DHEA and androstenediol, androstenedione and testosterone, estrone and estradiol, respectively. SNPs of HSD3B1 and HSD17B3 have been found to increase the susceptibility to acne in Han Chinese. CYP17 T-34C and CYP19 TA) SNP among Caucasians. In the Pakistani population, TNF −308 (G>A) and TNF −238 (G>A) SNPs exhibited an association with acne. Furthermore, severe acne showed an increased frequency of mutant TNF genotypes at −308 and −238 compared with patients with less severe acne. TNFR2 is the gene encoding tumor necrosis factor receptor 2 (TNFR2) is a membrane receptor that binds TNFα. The 196M allele of TNFR2 M196R has recently been identified as risk factor for acne vulgaris in Chinese Han population.

2.15 Interleukins 1, 6, and 8 Several proinflammatory interleukins (ILs) are upregulated in lesional skin of acne patients such as interleukin-1α (IL- 1α), IL-1β, IL-6, IL-8, and IL-17. TLR2 signaling activated by sebum-derived free fatty acids and diacylglycerols and P. acnes membrane components activate the NLRP3 inflammasome resulting in increased secretion of IL-1β, which activates the Th17 cell response with production of IL-17. IL-17+ cells have been detected in the perifollicular infiltrate of comedones. SNPs of certain interleukin genes may enhance the inflammatory response and tissue destruction in acne. IL1α is a proinflammatory cytokine of the interleukin 1 family encoded by the IL1A gene. IL-1α is produced mainly by activated macrophages, as well as neutrophils, and keratinocytes. It binds to the IL-1 receptor and activates TNFα. IL-1α has been detected in open comedones and implicated to play a role in comedogenesis. A positive association was found between the minor T allele of the IL1A +4845 (G>T) SNP and acne in the Caucasian population. A −889 (C>T) IL1A SNP predisposes to acne vulgaris in the Polish and Pakistani population. Triggering or exacerbating effects of diet on acne have been related to IL1A (−889) gene polymorphism. Among the 47 patients who reported diet as a risk factor for triggering or exacerbating their lesions, 62.5% had TT genotype. IL-6 is a proinflammatory cytokine encoded by the IL6 gene. IL-6 is secreted by T cells and macrophages to stimulate innate immunity in response to pathogen-associated molecular patterns that activate TLRs such as P. acnes- activated TLR2. An association of IL6 –572 (G>C) SNP with acne has been found in the Pakistani population.

40

IL-8 is a chemokine produced by TLR-stimulated macrophages and epithelial cells and is encoded by the IL8 gene. IL-8 is a mediator of the innate immune system response and is an important neutrophil chemotactic factor that plays a role in pustule formation in acne lesions. Increased IL-8 plasma levels have been found in acne patients compared with healthy subjects. Elevated IL-8 levels and the IL8 –251 (T>A) SNP has been reported in Pakistani acne patients.

2.16 Tyrosine Kinase 2 A phenome-wide association study using research participants’ self-reported data provides insight into the Th17, and IL-17 pathway found an association of the variant encoding p.I684S in the gene TYK2, encoding tyrosine kinase 2, with the occurrence of adolescent acne.

2.17 Resistin Resistin is a cysteine-rich adipose-derived peptide hormone in humans encoded by the RETN gene. Sebocytes secrete various adipokines including resistin. Resistin enhances the expression of proinflammatory cytokines including IL-1, IL-6, IL-12, and TNF-α. RETN −420 (C>G) SNP was significantly associated with acne in patients compared with healthy controls. The minor allele G at −420 was more prevalent in cases versus controls. The RETN −420 (C>G) SNP was significantly associated with severity of acne. The RETN gene rs1862513 SNP is a novel predisposing marker for familial acne vulgaris in a Pakistani population. RETN polymorphisms (RETN +299G > A and −420C > G) is expected to boost resistin expression increase the risk of developing acne. Resistin via inhibiting AMP-activated protein kinase (AMPK) promotes mTORC1 activation linking increased resistin expression to mTORC1-driven acne pathogenesis.

2.18 T issue Inhibitor of Matrix Metalloproteinase 1 Gene expression of matrix metalloproteinases MMP-1 and MMP-3 are activated in lesional skin of acne patients. They promote inflammatory matrix remodeling, which may enhance deeper tissue destruction in acne such as acne conglobata. P. acnes stimulates pro-MMP-2 expression through TNFα in human dermal fibroblasts. P. acnes via activation of protease-activated receptor 2 on keratinocytes mediates the expression of MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13. Facial sebum of acne patients contains MMP-1, MMP-13, and tissue inhibitor of MMP-1 (TIMP-1) and TIMP-2. The TIMP2 –418 CC genotype was nearly two times more common in Turkish acne patients compared to

2 Acne Epidemiology and Genetics

controls. Extracellular matrix remodeling is balanced by the action of MMPs and their inhibitors.

2.19 Proline-Serine-Threonine Phosphatase-Interacting Protein 1 Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant inherited autoinflammatory disorder associated with increased production of IL-1β. Three known missense mutations A230T, E250Q, and E250K in the gene PSTPIP1 encoding proline- serine-threonine phosphatase-interacting protein 1 (PSTPIP1) cause this syndrome. Mutant PSTPIP1 interacts with pyrin that activates the ASC pyroptosome, which recruits and activates caspase-1 resulting in increased production of IL-1β. Anakinra, an IL-1 receptor antagonist, was effective in treating a fraction of patients with PAPA syndrome. Acne in PAPA syndrome is not congenital but develops during puberty, a life period with increased AKT signaling. Increased IL-1β signaling of PAPA syndrome obviously synergizes with sebuminduced inflammasome activation. A PSTPIP1 mutation with a homozygous nucleotide exchange 773 (G>C) in a patient with a PAPA-like syndrome with acne has been observed successfully treated with canakinumab, a human anti-IL-1β monoclonal antibody.

2.20 l-Selectin l-selectin is encoded by the gene SELL. l-selectin is a cell surface component that is a member of a family of adhesion receptors that play important roles in lymphocyte-endothelial cell interactions. SELL is involved in the regulation of cutaneous inflammation and upregulated in acne lesions. In the Chinese Han population, a new acne susceptibility locus 1q24.2 (rs7531806) covers a gene cluster including SELL.

2.21 TP53 Increased frequencies of the TP53 SNP72 C allele and the genotype SNP 72 CC have been observed in patients with synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. SAPHO syndrome may be linked to an imbalance between mouse double minute 2 (MDM2) and p53 regulation resulting in weak p53 signaling. Table 2.1 summarizes all known gene polymorphisms and mutations that increase the disposition for acne in various populations. It becomes clear that there is no Mendelian inheritance in acne. Genetic variations cluster around the IGF-1-PI3K-AKT-mTORC1 pathway, androgen-AR signal transduction pathways, or inflammatory cytokine regulation that either increases sebum production or enhances inflammatory responses (Fig. 2.2).

2.21 TP53

41

Table 2.1 Gene polymorphisms and gene mutations associated with acne Polymorphism/gene mutation +4889 (A > G) +6235 (T > C) CYP17 −34 (T > C) CYP17 TC; CYP19 TT HSD3B1 rs6428829 HSD17B3 Haplotype H8 AR Shorter CAG repeats

Gene CYP1A1

Potential acneigenic effects Retinoid metabolism Retinoid metabolism Androgen conversion

Increased AR activity Increased 5α-reductase type 2 Reduced AR degradation (?)

References Paraskevaidis et al. (1998) Paraskevaidis et al. (1998) He et al. (2006) Chamaie-Nejad et al. (2018) Yang et al. (2013) Yang et al. (2013) Sawaya and Shalita (1998), Pang et al. (2008) and Yang et al. (2009) Pang et al. (2008) Hu et al. (2018) Yang (2014a, b) and He et al. (2014)

Increased IGF-1 expression with enhanced PI3K/Akt signaling

Tasli et al. (2013) Rahaman et al. (2016) Mina-Vargas et al. (2017)

Androgen conversion Androgen conversion Increased AR transcriptional activity

PIK3R1

Shorter GGN repeats (TA)n > 6 rs747650 rs1060573, 11p11.2 CA repeat polymorphisms, 192 bp allele rs10515088

FGFR2

S252W mutation

p85 subunit expression of phosphoinositide-3 kinase Increased FGFR2-Akt signaling

FGFR2 TGFB2 OVOL1 FST MYC MUC1 TLR2

P253R 1q41 11q13.1 5q11.2 rs4133274 on 8q24 Long tandem repeats +2258 (G > A) R753G +896 (A > C) +1196 (C > T) −238 (G > A) −238 (G > A) −308 (G > A)

Increased FGFR2-Akt signaling Decreased TGFβ signaling Decreased TGFβ signaling Decreased TGFβ signaling Increased c-Myc signaling Increased PI3K/Akt signaling Increased TLR2 signaling Increased TLR2 signaling Increased TLR4 signaling Increased TLR4 signaling Increased TNFα signaling Increased TNFα signaling Increased TNFα signaling

−857 (C > T) −863 (C > A) −1031 (T > C) M196R +4845 (G > T) Long tandem repeat −889 (C > T)

Increased TNFα signaling Increased TNFα signaling Increased TNFα signaling Increased TNF-R signaling Increased IL-1α signaling Increased IL-1α signaling Increased IL-1α signaling

AR SRD5A2 DDB2 IGF1

TLR4 TNFA

TNFR2 IL1A

−572 (G > C) −251 (T > A) −420 (C > G) +299(G > A) TIMP2 −418 (G > C) PSTPIP1 A230T E250Q E250K 773 (G > C) SELL rs7531806; 1q24.2 TP53 G72C TYK2 p.I684S

IL6 IL8 RETN

Increased IL-6 signaling Increased IL-8 signaling Increased resistin signaling Matrix metalloproteinase Pyrin-mediated IL-1β release Pyrin-mediated IL-1β release Pyrin-mediated IL-1β release Pyrin-mediated IL-1β release l-selectin-induced inflammation Weak p53 signaling Tyrosine kinase 2; Th17 axis

Ahmed et al. (2008), Munro and Wilkie (1998) and Melnik et al. (2008) Ibrahim (2001) Navarini et al. (2014) Navarini et al. (2014) Navarini et al. (2014) Zhang et al. (2014) Ando et al. (1998) Koreck et al. (2006) Tian et al. (2010) Koreck et al. (2006) Koreck et al. (2006) Sobjanek et al. (2009) Szabó et al. (2010) and Aisha et al. (2016) Baz et al. (2008), Sobjanek et al. (2009), Szabó et al. (2010), Agodi et al. (2012), Al-Shobaili et al. (2012) and Aisha et al. (2016) Szabó et al. (2010) Szabó et al. (2010) Szabó et al. (2010) Tian et al. (2010) Szabó et al. (2010) Szabó et al. (2010) Sobjanek et al. (2013), Younis and Javed (2015) and Ibrahim et al. (2019) Younis and Javed (2015) Hussain (2015a, b) Hussain (2015a, b) Younis et al. (2016) Yaykasli et al. (2013) Wise et al. (2002) Wise et al. (2002) Lindwall et al. (2015) Geusau et al. (2013) He et al. (2014) Wang et al. (2015) Assmann et al. (2010) Ehm et al. (2017)

42

2 Acne Epidemiology and Genetics PIK3R1

Insulin FGFR2 TGFB2

AR

IGF1 IGF-1

PI3K Akt

SMAD

LXRa

PPARy

TP53

mTORC1

RETN

S6K1

TGFB2

SREBP1a

∆6D

SRD5A2 DDB2

Androgens mTORC2

Fox01

AR

MUC1

Sebum TG synthesis ↑

P. acnes growth and biofilm

C16:0 ↑

TG lipase

SCD

Monounsaturated FAs ↑

C18:1 ↑

TG lipase

Free C16:0

Free C18:1

TLR2 activation

Disturbed keratinocyte Ca2+ gradient

LTA

TLR2

NLRP3 activation

PSTPIP1

IL-1b

IL-1a

IL1A

Th17

TNFA IL6, IL8 SELL

INFLAMMATION

IL-17

COMEDOGENESIS

Fig. 2.2 Synopsis of genetic variations related to acne pathogenesis. Genetic variations either increase sebaceous lipogenesis and sebum fatty acid desaturation or enhance the magnitude of downstream proinflammatory and comedogenic signals. Genetic aberrations associated with increased acne risk affecting IGF-1-PI3K-AKT-mTORC1 signaling are presented in light blue boxes, genetic variations modifying androgen signaling pathways are presented by light violet boxes, and gene polymorphisms enhancing proinflammatory cytokine signaling are depicted by pink boxes. Akt kinase AKT; IGF-1 insulin-like growth factor-1; FoxO1 forkhead box O1 transcription factor; mTORC1 mecha-

nistic target of rapamycin complex 1; S6K1 S6 kinase 1; AR androgen receptor; PPARγ peroxisome proliferator-activated receptor-γ; LXRα liver X receptor-α; SREBP1c sterol regulatory element binding protein 1c; Δ6D Δ6-desaturase; SCD stearoyl-CoA desaturase; TG triacylglycerol; FA fatty acid; C16:0 palmitic acid; C18:1 oleic acid; P. acnes Propionibacterium acnes; LTA lipoteichoic acid; TLR2 Toll-like receptor 2; NLRP3 NLR family, pyrin domain-containing 3; IL interleukin; TP53 p53. For further gene symbols, see Table 2.1. Published with kind permission of © Bodo Melnik 2019. All Rights Reserved

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43 Herane MI, Ando I. Acne in infancy and acne genetics. Dermatology. 2003;206:24–8. Holzmann R, Shakery K. Postadolescent acne in females. Skin Pharmacol Physiol. 2014;27(Suppl 1):3–8. Hu X, Ding W, Jin X, et al. Longer TA repeat but not V89L polymorphisms in the SRD5A2 gene may confer acne risk in the Chinese population. Adv Dermatol Allergol. 2018;35:33–8. Hussain S, Iqbal T, Sadiq I, et al. Polymorphism in the IL-8 gene promoter and the risk of acne vulgaris in a Pakistani population. Iran J Allergy Asthma Immunol. 2015a;14:443–9. Hussain S, Faraz A, Iqbal T. The RETN gene rs1862513 polymorphism as a novel predisposing marker for familial acne vulgaris in a Pakistani population. Iran J Basic Med Sci. 2015b;18:526–8. Ibrahim AA, Salem RM, El-Shimi OS, et al. IL1A (−889) gene polymorphism is associated with the effect of diet as a risk factor in acne vulgaris. J Cosmet Dermatol. 2019;18:333–6. Imperato-McGinley J, Gautier T, Cai LQ, et al. The androgen control of sebum production. Studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity. J Clin Endocrinol Metab. 1993;76:524–8. Khunger N, Kumar C. A clinico-epidemiological study of adult acne: is it different from adolescent acne? Indian J Dermatol Venereol Leprol. 2012;78:335–41. Kirk KM, Evans DM, Farthing B, Martin NG. Genetic and environmental influences on acne in adolescent twins. Twin Res. 2001;4:190. Koreck A, Kis K, Szegedi K, et al. TLR2 and TLR4 polymorphisms are not associated with acne vulgaris. Dermatology. 2006;213:267–9. Kovács D, Lovászi M, Póliska S, et al. Sebocytes differentially express and secrete adipokines. Exp Dermatol. 2016;25:194–9. Li L, Wu Y, Li L, et al. Tumour necrosis factor (TNF)-α is considered to play a central role in the pathogenesis of acne. Clin Exp Dermatol. 2015;40:682–7. Lichtenberger R, Simpson MA, Smith C, et al. Genetic architecture of acne vulgaris. J Eur Acad Dermatol Venereol. 2017;31:1978–90. Lindwall E, Singla S, Davis WE, Quinet RJ. Novel PSTPIP1 gene mutation in a patient with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome. Semin Arthritis Rheum. 2015; 45:91–3. Lynn DD, Umari T, Dunnick CA, Dellavalle RP. The epidemiology of acne vulgaris in late adolescence. Adolesc Health Med Ther. 2016;7:13–25. Melnik BC. Role of FGFR2-signaling in the pathogenesis of acne. Dermatoendocrinology. 2009;1:141–56. Melnik BC. Acneigenic stimuli converge in phosphoinositol-3 kinase/Akt/FoxO1 signal transduction. J Clin Exp Dermatol Res. 2010;1:10. Melnik B, Vakilzadeh F, Aslanidis C, Schmitz G. Unilateral segmental acneiform naevus—a model disorder towards understanding fibroblast growth factor receptor 2 function in acne? Br J Dermatol. 2008;158:1397–9. Meng X, Pei G, Bai Y, et al. Prevalence of acne vulgaris in Chinese adolescents and adults: a community-based study of 17,345 subjects in six cities. Acta Derm Venereol. 2012;92:40–4. Mina-Vargas A, Colodro-Conde L, Grasby K, et al. Heritability and GWAS analyses of acne in Australian adolescent twins. Twin Res Hum Genet. 2017;20:541–9. Munro CS, Wilkie AOM. Epidermal mosaicism producing localized acne: somatic mutation in FGFR2. Lancet. 1998;352:704–5. Navarini AA, Simpson MA, Weale M, et al. Genome-wide association study identifies three novel susceptibility loci for severe acne vulgaris. Nat Commun. 2014;5:4020. Osterle LS, Rumsby HP, et al. Carrier status for steroid 21-hydroxylase deficiency is only one factor in the variable phenotype of acne. Clin Endocrinol. 1998;48:209–15. Pang Y, He CD, Liu Y, et al. Combination of short CAG and GGN repeats in the androgen receptor gene is associated with acne risk in north East China. J Eur Acad Dermatol Venereol. 2008;22:1445–151.

44 Papakonstantinou E, Aletras AJ, Glass E, et al. Matrix metalloproteinases of epithelial origin in facial sebum of patients with acne and their regulation by isotretinoin. J Invest Dermatol. 2005;125:673–84. Paraskevaidis A, Drakoulis N, Roots I, et al. Polymorphisms in the human cytochrome P-450 1A1 gene (CYP1A1) as a factor for developing acne. Dermatology. 1998;196:171–5. Perkins AC, Cheng CE, Hillebrand GG, et al. Comparison of the epidemiology of acne vulgaris among Caucasian, Asian, Continental Indian and African American women. J Eur Acad Dermatol Venereol. 2011;25:1054–60. Perkins AC, Maglione J, Hillebrand GG, et al. Acne vulgaris in women: prevalence across the life span. J Womens Health (Larchmt). 2012;21:223–30. Rahaman SM, De D, Handa S, et al. Association of insulin-like growth factor (IGF)-1 gene polymorphisms with plasma levels of IGF-1 and acne severity. J Am Acad Dermatol. 2016;75:768–73. Raina D, Kharbanda S, Kufe D. The MUC1 oncoprotein activates the anti-apoptotic phosphoinositide 3-kinase/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts. J Biol Chem. 2004;279:20607–12. Sawaya ME, Shalita AR. Androgen receptor polymorphism (CAG repeat length) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg. 1998;3:9–15. Schaefer O. When the Eskimo comes to town. Nutr Today. 1971;6:8–16. Seattle WI. GBD compare. Seattle: University of Washington; 2013. Shen Y, Wang T, Zhou C, et al. Necropsies on Okinawans: anatomic and pathologic observations. Arch Pathol. 1946;42:359–80. Shoham NG, Centola M, Mansfield E, et al. Pyrin binds the PSTPIP1/ CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A. 2003;100:13501–6. Silswal N, Singh AK, Aruna B, et al. Human resistin stimulates the proinflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway. Biochem Biophys Res Commun. 2005;334:1092–101. Singh PK, Hollingsworth MA. Cell surface-associated mucins in signal transduction. Trends Cell Biol. 2006;16:467–76. Skroza N, Tolino E, Mambrin A. Adult acne versus adolescent acne: a retrospective study of 1,167 patients. J Clin Aesthet Dermatol. 2018;11:21–5. Smith TM, Gilliland K, Clawson GA, Thiboutot D. IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3 kinase/Akt pathway. J Invest Dermatol. 2008;128:1286–93. Sobjanek M, Zabłotna M, Nedoszytko B, et al. Lack of association between the promoter polymorphisms at positions −238 and −308 of the tumour necrosis factor alpha gene and acne vulgaris in Polish patients. J Eur Acad Dermatol Venereol. 2009;23:331–2. Sobjanek M, Zablotna M, Glen J, et al. Polymorphism in interleukin 1A but not in interleukin 8 gene predisposes to acne vulgaris in Polish population. J Eur Acad Dermatol Venereol. 2013;27:259–60. Sobjanek M, Zabłotna M, Dobosz-Kawałko M, et al. Polymorphisms in the cytochrome P-450 (CYP) 1A1 and 17 genes are not associated with acne vulgaris in the Polish population. Postepy Dermatol Alergol. 2015;32:323–6. Szabó K, Tax G, Kis K, et al. Interleukin-1A +4845 (G>T) polymorphism is a factor predisposing to acne vulgaris. Tissue Antigens. 2010;76:411–5. Szabó K, Tax G, Teodorescu-Brinzeu D, et al. TNFα gene polymorphisms in the pathogenesis of acne vulgaris. Arch Dermatol Res. 2011;303:19–27. Tasli L, Turgut S, Kacar N, et al. Insulin-like growth factor-I gene polymorphism in acne vulgaris. J Eur Acad Dermatol Venereol. 2013;27:254–7. Tian LM, Xie HF, Yang T, et al. Association study of tumor necrosis factor receptor type 2 M196R and toll-like receptor 2 Arg753Gln

2 Acne Epidemiology and Genetics polymorphisms with acne vulgaris in a Chinese Han ethnic group. Dermatology. 2010;221:276–84. Trivedi NR, Gilliland KL, Zhao W, et al. Gene array expression profiling in acne lesions reveals marked upregulation of genes involved in inflammation and matrix remodeling. J Invest Dermatol. 2006;126:1071–9. Walton S, Wyatt EH, Cunliffe WJ. Genetic control of sebum excretion and acne—a twin study. Br J Dermatol. 1988;118:393–6. Wang D, Höing S, Patterson HC, et al. Inflammation in mice ectopically expressing human pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome-associated PSTPIP1 A230T mutant proteins. J Biol Chem. 2013;288:4594–601. Wang H, Guo M, Shen S, et al. Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population. J Dermatol. 2015;42:378–81. Wilkie AOM, Slaney SF, Oldridge M, et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995;199:165–72. Williams C, Layton AM. Persistent acne in women: implications for the patient and for therapy. Am J Clin Dermatol. 2006;7: 281–90. Wise CA, Gillum JD, Seidman CE, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet. 2002;11: 961–9. Xu SX, Wang HL, Fan X, et al. The familial risk of acne vulgaris in Chinese Hans—a case-control study. J Eur Acad Dermatol Venereol. 2007;21:602–5. Yang Z, Yu H, Cheng B, et al. Relationship between the CAG repeat polymorphism in the androgen receptor gene and acne in the Han ethnic group. Dermatology. 2009;218:302–6. Yang XY, Wu WJ, Yang C, et al. Association of HSD17B3 and HSD3B1 polymorphisms with acne vulgaris in Southwestern Han Chinese. Dermatology. 2013;227:202–8. Yang JK, Wu WJ, Qi J, et al. TNF-308 G/A polymorphism and risk of acne vulgaris: a meta-analysis. PLoS One. 2014a;9:e87806. Yang JK, Wu WJ, He L, Zhang YP. Genotype-phenotype correlations in severe acne in a Han Chinese population. Dermatology. 2014b;229:210–4. Yaykasli KO, Turan H, Kaya E, Hatipoglu OF. Polymorphisms in the promoters of MMP-2 and TIMP-2 genes in patients with acne vulgaris. Int J Clin Exp Med. 2013;6:967–72. Yentzer BA, Hick J, Reese EL, et al. Acne vulgaris in the United States: a descriptive epidemiology. Cutis. 2010;86:94–9. Yeon HB, Lindor NM, Seidman JG, Seidman CE. Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q. Am J Hum Genet. 2000;66:1443–8. Yiu ZZ, Madan V, Griffiths CE. Acne conglobata and adalimumab: use of tumour necrosis factor-α antagonists in treatment-resistant acne conglobata, and review of the literature. Clin Exp Dermatol. 2015;40:383–6. Younis S, Javed Q. The interleukin-6 and interleukin-1A gene promoter polymorphism is associated with the pathogenesis of acne vulgaris. Arch Dermatol Res. 2015;307:365–70. Younis S, Blumenberg M, Javed Q. Resistin gene polymorphisms are associated with acne and serum lipid levels, providing a potential nexus between lipid metabolism and inflammation. Arch Dermatol Res. 2016;308:229–37. Yu JW, Fernandes-Alnemri T, Datta P, et al. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol Cell. 2007;28:214–27. Zhang M, Qureshi AA, Hunter DJ, Han J. A genome-wide association study of severe teenage acne in European Americans. Hum Genet. 2014;133:259–64.

3

Acne Pathogenesis

Core Messages • Increased sebum secretion has been regarded as “the flame of acne” by Albert Kligman. Sebum excess together with monounsaturation of sebum fatty acids drives comedogenesis and sebofollicular inflammation. • Sebaceous lipid synthesis and sebocyte desaturase expression depend on the activity of lipogenic transcription factor SREBP1c, which is upregulated by insulin-like growth factor-1 (IGF-1), mechanistic target of rapamycin complex 1 (mTORC1), and androgens. • Endocrine changes of puberty superimposed by nutrigenomic effects of Western diet increase IGF-1/mTORC1 and androgen signaling and decrease p53 activity. • In contrast to common belief, acne patients harbor less Propionibacterium acnes (P. acnes), recently reclassified as Cutibacterium acnes (C. acnes), than healthy individuals. • Distinct microbiome changes at the species and P. acnes strain level explain increased expression of P. acnes virulence factors in acne vulgaris. • Metagenomic elements shape the overall virulence property of follicular microbiota in acne-promoting P. acnes biofilm and antibiotic resistance. • Free fatty acids of acne sebum released by virulence factor P. acnes lipase promote P. acnes biofilm, comedogenesis, and follicular barrier disturbance allowing the penetration of proinflammatory sebum lipids into the dermis. • Free fatty acids are danger signals activating monocytemacrophage NLRP3 inflammasome with increased production of interleukin-1β (IL-1β). • IGF-1 stimulates sebocyte synthesis of proinflammatory IL-1β promoting Th17/IL-17 signaling attracting neutrophils into inflammatory lesions. Four major factors are involved in the pathogenesis of acne: (1) increased sebum production with altered lipid composition, (2) metagenomic modifications of the P. acnes

microbiome favoring P. acnes biofilm, (3) deviated acroinfundibular keratinization leading to comedogenesis, and (4) inflammasome activation with infiltration of inflammatory cells into the perifollicular dermis. All four factors are interdependent. In our opinion quantitative and qualitative alterations of sebum represent the initial event driving all other related pathological features of acne.

3.1

Acne Sebum

Sebum is not sebum. It is of critical importance to realize that normal sebum of acne-free individuals and sebum from acne patients differ in quantity and quality. Sebum excretion has generally been accepted as an important factor in the development of acne vulgaris. The pubertal increase in sebum secretion is a prerequisite for acne pathogenesis. Almost all acne patients suffer from seborrhea. Acne does not occur when sebum secretion is low. The sebum-suppressive efficacy of systemic isotretinoin and anti-androgens confirms the importance of sebum in the pathogenesis of acne. Collective data across multiple studies demonstrate that the projected sebum reduction required to achieve 50% reduction in acne ranged from 30 to 50%. Not only the total amount of sebum matters but its composition. The synthesis of increased amounts of monounsaturated fatty acids, which ignite proinflammatory and comedogenic reactions in the sebaceous follicle, plays a critical role. The majority of sebum lipids are bound in triacylglycerols. Albert Kligman already realized that triacylglycerols are harmless and do not induce acne. Certain free fatty acids released by the action of P. acnes triacylglycerol lipase are potent inducers of comedogensis, P. acnes biofilm generation, and inflammation. The amount of total released free fatty acids in acne patients is more than 50% higher than in age-matched controls without acne. By the time the sebum reaches the surface of the skin, about one third of the skin surface lipids is hydrolyzed to free fatty acids. In comedones

© Springer Nature Switzerland AG 2019 G. Plewig et al., Plewig and Kligman’s Acne and Rosacea, https://doi.org/10.1007/978-3-319-49274-2_3

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3 Acne Pathogenesis

more than 90% of triacylglycerols are hydrolyzed explaining the high prevalence of free fatty acids in acne.

3.2

Acne Lipidomics

To appreciate the changes from a normal noninflammatory, noncomedogenic sebum to a proinflammatory, comedogenic sebum of acne, one has to understand the pathways of sebaceous lipogenesis, which are involved in the production of total sebaceous lipids including saturated and monounsaturated fatty acids. The key transcription factor of lipogenesis, sterol regulatory element-binding protein-1c (SREBP1c), controls total sebaceous triacylglycerol synthesis, squalene synthesis, as well as fatty acid desaturation. This explains the close relationship between total sebaceous triacylglycerol synthesis and the rate of fatty acid desaturation generating sapienic acid (C16:1Δ6) and oleic acid (C18:1Δ9), respectively. The endocrine regulation of SREBP1c by the insulinlike growth factor-1 (IGF-1) and androgens and nutritional upregulation of insulin/IGF-1 signaling by Western diet are of importance for the generation of acne sebum. Plasma levels of IGF-1, the key hormone of puberty, correspond to the magnitude of sebum secretion and the clinical course of acne, much better than androgens, which persist at high plasma levels despite the clinical involution of acne after puberty. IGF-1 not only enhances adrenal and gonadal androgen synthesis but via induction of 5α-reductase (5α-R) promotes the conversion of testosterone to ten times more active dihydrotestosterone (DHT), thereby increasing androgen/androgen receptor signaling. Both, IGF-1 and androgens promote the expression of SREBP1c, the key transcription factor of sebaceous lipogenesis. In patients without acne, SREBP1c expression is low due to its suppression by the transcription factor FoxO1 and low activity of the kinase mechanistic target of rapamycin complex 1 (mTORC1). Nuclear FoxO1 is upregulated during starvation, a condition that is associated with low sebum production. During puberty and times of nutrient excess, insulin and IGF-1 activate the kinase AKT that via phosphorylation of FoxO1 reduces FoxO1’s nuclear localization, thereby increasing SREBP1c activity. Androgens also activate AKT and stimulate SREBP1c activity. FoxO1 suppresses the transcriptional activity of androgen receptor. The hormones insulin, IGF-1, and androgens in concert with mTORC1 upregulate SREBP1c transcriptional activity. The kinase AKT controls the activity of the transcription factor p53, called the guardian of the genome. AKT-mediated phosphorylation of mouse double minute 2 (MDM2) promotes p53 degradation and thereby attenuates p53 signaling. p53 inhibits gene expression of IGF-1 receptor, androgen receptor, and SREBP1c. In addition, p53 reduces the activity of mTORC1 but promotes the expression of FoxO1. At

ultiple checkpoints, p53 operates as a negative regulator of m the AKT-mTORC1 signaling pathway (Fig. 3.1). IGF-1- and androgen-mediated activation of AKT attenuates p53, an important step promoting the expression of multiple genes involved in anabolism and lipogenesis. mTORC1 orchestrates growth factor signals and amino acid availability and enhances SREBP1c expression for lipid biosynthetic pathways under conditions for optimized growth. This explains why high sebaceous gland mTORC1 activation responds to endocrine signals of puberty as well as exaggerated insulin/ IGF-1 signaling of Western diet. mTORC1 is significantly upregulated in the skin and sebaceous glands of acne patients compared with acne-free controls. Acne is a member of mTORC1-driven diseases of civilization including obesity,

Puberty

Western diet

Adrenal and gonadal androgen synthesis

IGF-1 IGF1R

MDM2

5aR

AKT FoxO1

DHT p53

p53

NFkB mTORC1

SREBP1c

AR

p53

PPARg

Sebaceous lipogenesis Fatty acid desaturation Ductal hypoxia

Free fatty acids

HIF-1a

P. acnes biofilm

C18:1 C16:1D6 C16:0

TG lipase

Disturbed keratinization Barrier disruption COMEDOGENESIS

IL-1a

IL-1b Th17 Æ IL-17

INFLAMMATION

Fig. 3.1 Increased IGF-1 and androgen signaling of puberty superimposed by insulin/IGF-1 signaling of Western diet. Activated AKT/ mTORC1 signaling upregulates the transcription factor SREBP1c, which increases total sebaceous lipid synthesis and fatty acid desaturation. Acne sebum is characterized by increased amounts of monounsaturated fatty acids including oleic acid (C18:1) and sapienic acid (C16:1Δ6). High sebum and monounsaturated fatty acids promote ductal hypoxia and P. acnes biofilm and disturb barrier function and keratinization. Enhanced activation of AKT via activation of mouse double minute 2 (MDM2) attenuates p53, the key negative regulator of androgen receptor and the IGF-1-AKT-mTORC1 signaling cascade. IGF-1 directly stimulates the expression of proinflammatory cytokines including interleukin-1β (IL-1β), which induces Th17 cell differentiation. Bold arrows indicate increased activity and dotted lines decreased activity. AKT kinase AKT (protein kinase B); AR androgen receptor; DHT dihydrotestosterone; FoxO1 forkhead box class O transcription factor; HIF-1α hypoxia-inducible factor 1α; IGF-1 insulin-like growth factor-1; IL interleukin; mTORC1 mechanistic target of rapamycin complex 1; NFκB nuclear factor kappa B; 5αR 5α-reductase type 2; p53 transcription factor p53; PPARγ peroxisome proliferator-activated receptor-γ; SREBP1c sterol regulatory element-binding protein 1c; Th17 Th17 cell. Published with kind permission of © Bodo Melnik 2019. All Rights Reserved

3.5 Acne Microbiome

insulin resistance, type 2 diabetes mellitus, and certain cancers. A significant decrease of cutaneous SREBP1 expression was observed in acne patients after a diet low in carbohydrates associated with low serum levels of insulin and free IGF-1. In contrast, high glycemic load diet increased serum IGF-1 levels in acne patients. Peroxisome proliferator-activated receptors (PPARs) are further lipogenic transcription factors that enhance human sebum production. PPARs bind specific lipid ligands activating their transcriptional activity in a mode of action that is comparable to androgen binding to androgen receptor. PPAR ligands such as thiazolidinediones or fibrates increase sebum production in humans. In accordance with androgen receptor, the transcriptional activity of PPARγ is also suppressed by FoxO1. Insulin- and IGF-1-mediated FoxO1 suppression thus control PPARγ activity. In analogy to SREBP1c, PPARα and PPARγ protein expression also depend on mTORC1 activity. Nuclear levels of FoxO1 are decreased in sebaceous glands of acne patients, whereas mTORC1 activity is increased in skin and sebaceous glands of acne patients resulting in increased expression of lipogenic transcription factors SREBP1c, androgen receptor, and PPARγ.

3.3

REBP1c: Key Promoter of Acne S Sebum

SREBP1c activates the expression of acetyl-CoA-carboxylase, the rate-limiting enzyme of saturated fatty acid de novo synthesis in the sebocyte. SREBP1c critically controls the production of palmitic acid (C16:0) and stearic acid (C18:0), which are subsequently incorporated into sebocyte triacylglycerols. The acetyl-CoA-carboxylase inhibitor olumacostat glasaretil suppressed sebaceous lipogenesis in hamster ear model. SREBP1c is not only involved in the production of sebum lipids such as triacylglycerols, squalene, and wax esters but critically controls sebum fatty acid desaturations. SREBP1c enhances the expression of the sebaceous desaturases Δ6-desaturase and stearyl-CoA desaturase. Δ6-desaturase has been identified as a functional marker of sebocyte differentiation and is detectable in sebocytes with full lipid synthetic capacity. High expression of SREBP1c results in excessive sebaceous lipid synthesis and increased fatty acid desaturation explaining the reduced ratio of saturated/monounsaturated fatty acids of skin surface triacylglycerols in correlation with sebum secretion and acne lesion counts. High follicular sebum outflow is associated with an increase in the proportion of sebum monounsaturated fatty acids such as sapienic acid and oleic acid. A correlation between total sebum triacylglycerol synthesis and the amount of sapienic acid was demonstrated. In contrast, transforming growth factor-β (TGFβ) is a negative regulator of sebocyte differentiation and inhibits the expression of

47

Δ6-desaturase. This is of importance since a genome-wide association study identified decreased expression of components of the TGFβ pathway in patients with severe acne vulgaris. Increased insulin/IGF-1 and androgen signaling in acne via upregulation of SREBP1c promote hyperseborrhea and fatty acid monounsaturation, a lipidomic condition that increases P. acnes biofilm synthesis. IGF-1 directly stimulates the expression of proinflammatory cytokines including IL-1β, IL-6, IL-8, and TNFα in primary human sebocytes (Fig. 3.1).

3.4

Propionibacterium acnes (P. acnes)

In 1896, Paul Gerson Unna described the Bacillus acnes when studying histological sections of comedones. In 1922, this gram-positive diphtheroid bacterium was first classified in the genus Corynebacterium and in 1933 transferred to the genus Propionibacterium. Propionibacterium acnes (P. acnes) together with P. humerusii, P. granulosum, and P. avidum belongs to the phylum Actinobacteria. Acne is not a transmitted bacterial skin disease such as pyoderma. In 2004, the characterization of the complete genome sequence of P. acnes encoding 2333 putative genes allowed insights into its role in the pathogenesis of acne. P. acnes classification changed on the basis of genetic variations. According to sequence comparison of tly and recA genes, P. acnes has been classified into three major genetic phylotypes IA, IB, and III. Based on multilocus sequence typing, P. acnes has been further subdivided into closely related clusters IA1, IA2, IC, II, and III or clades I-1a, I-1b, II, and III. P. acnes strains have been defined by genetic differences of the 16S rRNA gene, which is universally present in all prokaryotes and contains highly conserved regions as well as hypervariable regions enabling phylogenetic categorization into ribotypes (RTs). Among the top ten major P. acnes ribotypes, RT1, RT2, and RT3 were the most abundant and found in both healthy individuals and acne patients with no significant differences. However, RT4, RT5, and RT8 were enriched in acne patients, while RT6 was found mostly in healthy individuals. In 2016, genomic and metagenomic investigations resulted in the reclassification of P. acnes to Cutibacterium acnes (C. acnes). We prefer to stay with P. acnes.

3.5

Acne Microbiome

P. acnes is the predominant bacterial species in sebaceous and non-sebaceous areas of human skin. Highest presence is found in sebaceous gland-rich skin such as the glabella region where Propionibacteria species and Staphylococci

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species predominate. Sebaceous follicles of the face, scalp, chest, and back produce substantial amounts of sebum and provide a preferred microenvironment for this lipophilic anaerobe. Immediately after holocrine secretion of the sebocyte, sebum predominantly contains triacylglycerols, which do not serve as a nutrient substrate for P. acnes. After triacylglycerol hydrolysis mediated by bacterial lipases, free fatty acids can be utilized as energy source for P. acnes. A contribution of P. acnes in the pathogenesis of acne vulgaris, especially to the genesis of inflammatory acne lesions and eventually comedones, has long been suggested. Evidence confirming P. acnes pathogenic contribution has only been circumstantial. Many in vitro studies with P. acnes isolates added to immortalized sebocyte or blood mononuclear cell cultures do not reflect the complex sebofollicular reality and cannot represent the multiple metabolic and gene regulatory interactions of all known bacterial species, strains, and metagenomic elements of follicular residents involved in acne pathogenesis. For a long time, there was no direct proof of a causal link between P. acnes numbers and acne. Recently, the dogma changed that excessive sebum production increased P. acnes numbers. Contrary to what was previously thought, proliferation of P. acnes is not the trigger of acne as patients with acne do not harbor more P. acnes in follicles than normal individuals. Metagenomic shotgun sequencing analysis exhibited differentially expressed metagenomic elements of the skin microbiome of acne patients compared with the microbiome of healthy individuals. Certain metagenomic elements have been identified that determine P. acnes virulence, transmission of antibiotic resistance, and biofilm production.

3.6

P. acnes Biofilm

Genomic, transcriptomic, and phylogenetic studies allow a better understanding of P. acnes ability to produce a biofilm. Biofilm is a common process of most bacteria during which bacteria irreversibly attach to and grow on a surface and produce extracellular polymers facilitating adherence and matrix formation. Direct visualization studies including vertical and transversal sectioning of skin biopsies identified four patterns of P. acnes biofilm: (1) attachment of P. acnes to the follicle wall, (2) attachment to the hair shaft, (3) spreading over the full lumen of the hair follicle, and (4) matrix-encased biofilms localized in the center of the hair follicle (Fig. 3.2). Biofilm can extend over 1000 μm and is

not accessible by commonly used sampling techniques including swab, tape stripping, and cyanoacrylate gel. It is technically not easy to detect follicular P. acnes biofilm, and its existence has been overlooked for decades. An increased incidence of P. acnes biofilm has been found in acne patients. Follicular P. acnes was demonstrated in 47% of samples from patients with acne vulgaris but only in 21% from control subjects. Thirty-seven percent of samples from patients with acne vulgaris exhibited large macrocolonies/biofilms in sebaceous follicles compared with only 13% in control samples. P. acnes in acne skin shows a higher prevalence of follicular colonization and greater numbers of bacteria in macrocolonies/biofilms than in control samples. The P. acnes genome includes genes involved in biofilm biosynthesis. In comparison to single planktonic bacteria, biofilms are composed of sessile bacterial communities associated with changes in gene expression. Bacteria in biofilms express specific resistance genes and genes that increase bacterial virulence such as bacterial lipase. Biofilm is regulated by a bacterial communication system called quorum sensing (QS). QS is a universal bacterial signaling system by which bacteria produce and detect molecules and thereby coordinate their behavior and gene expression in a cell densitydependent manner. QS and biofilm allow fast gene regulatory responses of bacteria to environmental changes such as nutrient excess or alterations of oxygen tension. Grampositive bacteria including P. acnes regulate biofilm via a signaling molecule called autoinducer-2 (AI-2). The complete genome sequence of P. acnes has revealed three separate clusters of genes that encode enzymes involved in the synthesis of extracellular polymeric substances required for biofilm. QS allows an immediate bacterial response to environmental changes. AI-2 signaling increases bacterial virulence. The gene GehA encoding triacylglycerol lipase is regarded as an important virulence factor of P. acnes. Biofilm generation occurs in subsequent steps. At the beginning, a conditioning film is formed by the adsorption of organic or inorganic nutrients, which enhances initial attachment of bacteria. The monounsaturated fatty acid oleic acid increases P. acnes adherence and cell-to-cell aggregation. Increases in total sebum production and sebum fatty acid desaturation enhance the availability of free oleic acid in sebum, a critical factor initiating P. acnes biofilm. Oleic acid also promotes biofilm in other bacteria such as S. aureus. After the initial sebum-induced attachment step, bacteria change their exopolysaccharide matrix and adhere more firmly. Increased expression of biofilm polysaccharides enhances the immunogenicity of P. acnes.

3.6 P. acnes Biofilm

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a

b

c

d

Fig. 3.2 Confocal microscopic images of transversely sectioned skin biopsies highlighting different patterns of P. acnes colonization in hair follicles. P. acnes labeling in green, keratin labeling in red, and blue labeling of host cells. (a) Attachment of P. acnes to the follicle wall, scale bar 2 μm. (b) Attachment of P. acnes to the hair shaft; arrow heads point toward the hair shaft, scale bar 2 μm. (c) P. acnes biofilm spreading over nearly the entire lumen of the hair follicle with a diameter of

200 μm in the longest direction, scale bar 10 μm. (d) Matrix-encased P. acnes biofilm without obvious attachment to the follicle wall, scale bar 20 μm. With kind permission of O.A. Alexeyev reproduced from Jahns AC, Alexeyev OA. Three dimensional distribution of Propionibacterium acnes biofilms in human skin. Exp Dermatol. 2014;23:682–9. Published with kind permission of © Jahns AC and Alexeyev OA 2019. All Rights Reserved

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P. acnes exhibits favorable growth in continuous cultures at very low oxygen tensions. Ductal hypoxia resulting from excess sebum has been proposed to promote biofilm, which is associated with antibiotic resistance, a growing problem in the treatment of acne. The oxygenizer benzoyl peroxide is the only topical anti-acne agent used over decades that showed no signs of antibiotic resistance.

3.7

Virulence Factors

Sessile P. acnes produce more lipase and QS molecule AI-2. P. acnes lipase is a virulence factor that provides increased amounts of free oleate, which promotes P. acnes adherence initiating biofilm. The P. acnes triacylglycerol lipase gene GehA plays a pivotal role in biofilm-dependent gene expression. Evidence from in vitro studies suggests that QS enables P. acnes to upregulate its hydrolysis of sebum triacylglycerols by its bacterial lipase, releasing increased amounts of free palmitic acid, oleic acid, and diacylglycerols (DAGs). DAGs activate protein kinase C, which mediates various cellular responses of proinflammatory cytokines including TNFα or IL-1. Free palmitic acid and oleic acid are danger signals that sensitize dendritic cells to augment the secretion of Th1/Th17-instructive cytokines upon proinflammatory stimulation. Enhanced Th17/IL-17 signaling has been observed in acne lesions. Human monocytes respond to P. acnes and secrete mature IL-1β partially via the NLRP3mediated pathway. Free palmitic acid, oleic acid, and DAGs act as danger-associated molecular patterns activating tolllike receptor 2 (TLR2). In vivo expression of TLR2 and TLR4 is increased in the epidermis of acne lesions. One of P. acnes membrane-derived natural ligands of TLR2 is lipoteichoic acid. DAG-containing glycolipids exhibit similarities with lipoteichoic acid of gram-positive bacteria. DAG-bound oleic acid activates T-lymphocyte functions via calcium influx. Gram-positive bacterial lipoglycans based on a glycosylated DAG lipid anchor are microbe-associated molecular patterns recognized by TLR2. Subsequent TLR2-mediated inflammasome activation with IL-1β release activates T-helper (Th)-driven immunity with expression of Th1-/ Th17-associated inflammatory cytokines (Fig. 3.1). Proteomic studies demonstrated that P. acnes express several exogeneous proteases. P. acnes culture supernatant induces calcium signaling in keratinocytes via proteinaseactivated receptor 2 (PAR-2). This stimulates keratinocyte mRNA expression of IL-1α, IL-8, TNF-α, and various matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13). It has been shown in human dermal fibroblasts that P. acnes increased expression of pro-matrix metalloproteinase (proMMP)-2 mRNA and protein. Overexpression of PAR-2 combined with an increase in global protease activity has been observed in acne lesions.

3.8

P. acnes Biofilm and Disturbed Follicular Keratinization

P. acnes has been isolated from comedones. It has been suggested but not yet proven that P. acnes biofilm may form an adhesive glue leading to the binding and retention of infundibular corneocytes resulting in microcomedo formation. Due to higher lipase expression of P. acnes biofilm, increased amounts of free fatty acids including oleic acid and palmitoleic acid are in closer contact to infundibular keratinocytes. These monounsaturated fatty acids are highly comedogenic in the rabbit ear model. Oleic acid induces abnormal keratinization, which is associated with increased production of IL-1α by keratinocytes. This cytokine has been detected in the majority of open comedones in acne vulgaris. P. acnesinduced intracellular calcium fluctuations have been implicated in abnormal follicular keratinization and comedo formation. Biofilm-derived QS molecules also affect eukaryotic host cells to express proinflammatory cytokines such as IL-1α and IL-6 as well as cyclooxygenase 2. P. acnes biofilm adhering to infundibular keratinocytes contributes to abnormal keratinization and inflammation (Fig. 3.1).

3.9

Comedogenesis

A pivotal factor of acne pathogenesis is abnormal follicular keratinization with increased proliferation of acroinfundibular keratinocytes promoting comedones. Albert Kligman showed human sebum triacylglycerols and waxes only have weak comedogenic effects. In contrast, comedogenic factors are free fatty acids that are released from sebum triacylglycerols by the action of P. acnes lipase. Early studies found that interleukin-1α (IL-1α), which was detected in the majority of open comedones, plays a role in comedogenesis. Free oleic acid enhances calcium influx into epidermal keratinocytes, increases keratinocyte proliferation, and induces abnormal keratinization and barrier function, associated with increased release of IL-1α. Free palmitic acid, the most abundant free fatty acid of comedones, acts as a stimulating ligand of TLR2, which activates the NLRP3 inflammasome. Free palmitic acid, oleic acid, and DAGs function as danger signals activating the innate immune response. Another fact supporting the causative role of acne sebum in comedogenesis comes from the observation that comedonal acylceramides contain higher amounts of palmitic acid and sapienic acid and much less linoleate than acylceramides isolated from the skin surface. Sapienic acid is a unique fatty acid of exclusive sebaceous origin. It has to be incorporated by infundibular keratinocytes to generate keratinocytederived sapienyl-ceramides. Replacement of linoleate in acylceramides of infundibular keratinocytes disturbs infundibular barrier function with increased transepidermal water

3.10 Sebofollicular Inflammation

loss. In adolescent acne patients, a reduction of ceramides chain length and increase in unsaturated free fatty acids, that contributed to an altered lipid organization and decreased skin barrier function, have been reported. These observations underline the intimate link between disturbed sebum processing in acne, comedogenesis, and impaired epithelial barrier function. Excessive SREBP1c-mediated production of high amounts of sebum squalene and monounsaturated fatty acids enhances total amounts of lipids with double bonds increasing the chance for lipid peroxidation. Higher amounts of squalene peroxide have been detected in acne patients compared to acne-free controls. Ultraviolet radiation enhances the capacity of human sebum to produce comedones in the external ear canals of rabbits. Squalene peroxides as well as peroxides of oleic acid are highly comedogenic. The production of monounsaturated sebum in acne patients and subsequent lipid peroxidation increases comedogenesis. UV-generated squalene photooxidation products of skin surface lipids induce metabolic and inflammatory responses of keratinocytes.

3.10 Sebofollicular Inflammation Acne vulgaris is an inflammatory skin disease. Activation of the NLRP3 inflammasome was reported in inflammatory acne lesions. Free palmitic acid and oleic acid are danger

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signals that sensitize dendritic cells to augment the secretion of Th1/Th17-instructive cytokines upon proinflammatory stimulation. Enhanced Th17/IL-17 signaling was also observed in acne lesions. Human monocytes respond to P. acnes and secrete mature IL-1β partially via the NLRP3mediated pathway. Free palmitic acid, oleic acid, and DAGs act as danger-associated molecular patterns activating TLR2. In vivo expression of TLR2 and TLR4 is increased in the epidermis of acne lesions. One of P. acnes membranederived natural ligands of TLR2 is lipoteichoic acid (LTA). DAG-containing glycolipids exhibit similarities with LTA of gram-positive bacteria. DAG-containing oleic acid activates T-lymphocyte functions via calcium influx. P. acnes has been shown to activate the inflammasome of human peripheral neutrophils. Free palmitic acid, oleic acid, and DAGs activate the NLRP3 inflammasome. Consecutive release of IL-1β orchestrates the Th17 lymphocyte response with enhanced secretion of IL-17. In primary human sebocytes, addition of IGF-1 significantly enhanced the synthesis of IL-1β which is a major inducer of Th17 cell differentiation associated with increased synthesis of IL-17. Significantly increased numbers of Th17 cells and CD83 dendritic cells have been detected in acne lesions. Substance P, which is a major neuroendocrine factor detected in acne lesions, as well enhances Th17 polarization. Activated Th17 cells via secretion of IL-17 attract neutrophilic granulocytes promoting the development of papules and pustules (Fig. 3.1).

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3.11 Follicular and Comedonal Flora The deep anaerobic or semianaerobic recessus of follicular structures are an El Dorado for bacteria, richly nourished by the constant flow of sebum Above Left:

A normal sebaceous follicle of a person without acne. The follicular filament is saturated with solid colonies of bacteria, most of which are Propionibacterium acnes and Staphylococcus epidermidis. Sebaceous glands provide nutrition. Gram stain

Right: An old open comedo has multiple spacious cavernas ( ) in its inner structure, providing space and ample living conditions for Propionibacterium acnes. Between the lamellae of corneocytes at the tip, numerous Pityrosporum ovale yeasts ( ) enjoy undisturbed growth. They have nothing to do with the acne process. The pilary portion is to the lower left. PAS stain Below Left: Horizontal section through a biopsy from the cheek of a person with moderate acne on the back. Multiple large sebaceous follicles and their adjacent sebaceous lobules are seen. The blue stain signals bacterial colonization. Every follicle is colonized. Gram stain Right: Higher magnification of two follicular canals of sebaceous follicles. The follicular filament is a cast of corneocytes, with multiple channels in the center full of bacteria. Each channel is the draining system of a sebaceous duct below. Propionibacterium acnes loves this nutrient broth. The hairs ( ) enter the follicular canal at this level. Gram stain

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3.12 Internal Structures of Old Open Comedones Comedones removed with comedo extractors were cut horizontally. Despite their compact external appearance, large open comedones are often full of holes like Swiss cheese Above: In very large, aged comedones, there are rows of chambers, all exiting into a single giant cavity. Finger-like projections of corneocytes divide the gallery. These chambers were full of Propionibacterium acnes, most of which fell out during histological preparation Below: The individual cavernas are sealed by concentric layers of tightly adherent corneocytes. Masses of Propionibacterium acnes are trapped, floating in a sea of sebum. The cavernas communicate at other levels of the comedo, while they meander to the comedonal core

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3.13 Follicular Fluorescence Propionibacterium acnes produces porphyrins which fluoresce under Wood’s light. The characteristic orange-red fluorescence can be visualized in follicles harboring a dense population of these microorganisms. Sebum itself fluoresces slightly yellow Above Left:

Fluorescent follicles are easily observed on the nose. The cheesy “worms” that can be pressed out of the alae nasi fluoresce brilliantly and contain millions of propionibacteria. The percentage of brightly fluorescing follicles varies greatly from person to person. Fluorescence is a rough but useful indicator of the quantity of Propionibacterium acnes. Persons who show bright fluorescence over their forehead and cheeks invariably have high numbers of these microaerophilic microorganisms. As a rule, acne patients show intense and widespread fluorescence compared with unaffected subjects. After antibiotic or antimicrobial treatment, fluorescence diminishes greatly owing to suppression of P. acnes. This can be used to evaluate the efficacy of antibiotics in acne

Right: Fluorescent colonies of Propionibacterium acnes on agar. Only the surface colonies fluoresce brightly

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3.14 The Life History of the Comedo Above Left:

A normal sebaceous follicle with its extravagant glands, minuscule hair (telogen stage), and cavernous canal

Middle: Early microcomedo. The canal has begun to distend with coherent layers of corneocytes. Inside these are bacteriafilled channels (stained blue), reaching well into the sebaceous ducts. The hair is an anagen Right: Late microcomedo. The epithelium is hyperplastic. A horny impaction has dilated the follicle. This is still too small to be visible with the naked eye. The sebaceous ducts are also hyperkeratotic. Regression of the sebaceous acini has started. Gram-positive rods (Propionibacterium acnes) have densely colonized the central channels Below Left:

Mature, closed comedo. The pore is microscopic. Horny squamae are densely packed into concentric lamellae, though whorling has jumbled the pattern. The channels are larger and more irregular than in microcomedones. They contain solid masses of Propionibacterium acnes. The glands are small. The pilary portion is intact, with several hairs trapped in the horny mass

Right: Open comedo. There are now numerous bacteria-filled spaces which belie the solid appearance of the comedo. The sebaceous glands are very small but never absent. The pilary portion is normal and continues to shed hairs into the comedo. Here and there are cross-sectional cuts of trapped vellus hairs. Yeasts (Pityrosporum ovale) are congregated at the tip. A comedo is a melange of corneocytes, bacteria, yeasts, hairs, and sebaceous lipids All drawings are of the same magnification

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3 Acne Pathogenesis Fischer H, Fumicz J, Rossiter H, et al. Holocrine secretion of sebum is a unique DNase2-dependent mode of programmed cell death. J Invest Dermatol. 2017;137:587–94. Fitz-Gibbon S, Tomida S, Chiu BH, et al. Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol. 2013;133:2152–60. Franz S, Simon JC, Saalbach A. Free fatty acids sensitize dendritic cells to amplify TH1/TH17-immune responses. Eur J Immunol. 2016;46:2043–53. Gan Y, Zhou M, He C, et al. Lipidomics reveals skin surface lipid abnormity in male youth acne. Br J Dermatol. 2018; 179:732–40. Ganceviciene R, Böhm M, Fimmel S, Zouboulis CC. The role of neuropeptides in the multifactorial pathogenesis of acne vulgaris. Dermatoendocrinology. 2009;1:170–6. Ge L, Gordon JS, Hsuan C, et al. Identification of the delta-6 desaturase of human sebaceous glands: expression and enzyme activity. J Invest Dermatol. 2003;120:707–14. Guo JW, Lin TK, Wu CH, et al. Human sebum extract induces barrier disruption and cytokine expression in murine epidermis. J Dermatol Sci. 2015;78:34–43. Hall JB, Cong Z, Imamura-Kawasawa Y, et al. Isolation and identification of the follicular microbiome: implications for acne research. J Invest Dermatol. 2018;138:2033–40. Holland C, Mak TN, Zimny-Arndt U, et al. Proteomic identification of secreted proteins of Propionibacterium acnes. BMC Microbiol. 2010;10:230. Isard O, Knol AC, Ariès MF, et al. Propionibacterium acnes activates the IGF-1/IGF-1R system in the epidermis and induces keratinocyte proliferation. J Invest Dermatol. 2011;131:59–66. Jahns AC, Alexeyev OA. Three dimensional distribution of Propionibacterium acnes biofilms in human skin. Exp Dermatol. 2014;23:687–9. Jahns AC, Lundskog B, Ganceviciene R, et al. An increased incidence of Propionibacterium acnes biofilms in acne vulgaris: a case-control study. Br J Dermatol. 2012;167:50–8. Jahns AC, Eilers H, Ganceviciene R, Alexeyev OA. Propionibacterium species and follicular keratinocyte activation in acneic and normal skin. Br J Dermatol. 2015;172:981–7. Jahns AC, Eilers H, Alexeyev OA. Transcriptomic analysis of Propionibacterium acnes biofilms in vitro. Anaerobe. 2016;42:111–8. Janiczek-Dolphin N, Cook J, Thiboutot D, et al. Can sebum reduction predict acne outcome? Br J Dermatol. 2010;163:683–8. Jasson F, Nagy I, Knol AC, et al. Different strains of Propionibacterium acnes modulate differently the cutaneous innate immunity. Exp Dermatol. 2013;22:587–92. Ju Q, Tao T, Hu T, et al. Sex hormones and acne. Clin Dermatol. 2017;35:130–7. Jugeau S, Tenaud I, Knol AC, et al. Induction of toll-like receptors by Propionibacterium acnes. Br J Dermatol. 2005;153:1105–13. Kasimatis G, Fitz-Gibbon S, Tomida S, et al. Analysis of complete genomes of Propionibacterium acnes reveals a novel plasmid and increased pseudogenes in an acne associated strain. Biomed Res Int. 2013;2013:918320. Katsuta Y, Iida T, Inomata S, Denda M. Unsaturated fatty acids induce calcium influx into keratinocytes and cause abnormal differentiation of epidermis. J Invest Dermatol. 2005;124:1008–13. Kelhälä HL, Palatsi R, Fyhrquist N, et al. IL-17/Th17 pathway is activated in acne lesions. PLoS One. 2014;9:e105238. Kim H, Moon SY, Sohn MY, Lee WJ. Insulin-like growth factor-1 increases the expression of inflammatory biomarkers and sebum production in cultured sebocytes. Ann Dermatol. 2017;29:20–5.

Bibliography Kistowska M, Gehrke S, Jankovic D, et al. IL-1β drives inflammatory responses to propionibacterium acnes in vitro and in vivo. J Invest Dermatol. 2014;134:677–85. Kligman AM, Wheatley VR, Mills OH. Comedogenicity of human sebum. Arch Dermatol. 1970;102:267–75. Kwon HH, Yoon JY, Park SY, Suh DH. Analysis of distribution patterns of Propionibacterium acnes phylotypes and Peptostreptococcus species from acne lesions. Br J Dermatol. 2013;169:1152–5. Li ZJ, Choi DK, Sohn KC, et al. Propionibacterium acnes activates the NLRP3 inflammasome in human sebocytes. J Invest Dermatol. 2014;134:2747–56. Lomholt HB, Kilian M. Population genetic analysis of Propionibacterium acnes identifies a subpopulation and epidemic clones associated with acne. PLoS One. 2010;5:e12277. Lomholt HB, Scholz CFP, Brüggemann H, et al. A comparative study of Cutibacterium (Propionibacterium) acnes clones from acne patients and healthy controls. Anaerobe. 2017;47:57–63. Lwin SM, Kimber I, McFadden JP. Acne, quorum sensing and danger. Clin Exp Dermatol. 2014;39:162–7. Mattii M, Lovászi M, Garzorz N, et al. Sebocytes contribute to skin inflammation by promoting the differentiation of T helper 17 cells. Br J Dermatol. 2018;178:722–30. McDowell A. Over a decade of recA and tly gene sequence typing of the skin bacterium Propionibacterium acnes: What have we learnt? Microorganisms. 2017;6:E1. McNairn AJ, Doucet Y, Demaude J, et al. TGFβ signaling regulates lipogenesis in human sebaceous glands cells. BMC Dermatol. 2013;13:2. Melnik BC. Acne vulgaris: an inflammasomopathy of the sebaceous follicle induced by deviated FoxO1/mTORC1 signalling. Br J Dermatol. 2016;174:1186–8. Melnik BC. p53: key conductor of all anti-acne therapies. J Transl Med. 2017;15:195. Melnik BC. Acne vulgaris: the metabolic syndrome of the pilosebaceous follicle. Clin Dermatol. 2018;36:29–40. Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol. 2009;18:833–41. Mills OH, Porte M, Kligman AM. Enhancement of comedogenic substances by ultraviolet radiation. Br J Dermatol. 1978;98:145–50. Mirdamadi Y, Thielitz A, Wiede A, et al. Insulin and insulin-like growth factor-1 can modulate the phosphoinositide-3-kinase/Akt/ FoxO1 pathway in SZ95 sebocytes in vitro. Mol Cell Endocrinol. 2015;415:32–44. Monfrecola G, Lembo S, Caiazzo G, et al. Mechanistic target of rapamycin (mTOR) expression is increased in acne patients’ skin. Exp Dermatol. 2016;25:153–5. Navarini AA, Simpson MA, Weale M, et al. Genome-wide association study identifies three novel susceptibility loci for severe acne vulgaris. Nat Commun. 2014;5:4020. Ottaviani M, Camera E, Picardo M. Lipid mediators in acne. Mediators Inflamm. 2010;2010:858176. Pappas A, Anthonavage M, Gordon JS. Metabolic fate and selective utilization of major fatty acids in human sebaceous gland. J Invest Dermatol. 2002;118:164–71.

61 Perisho K, Wertz PW, Madison KC, et al. Fatty acids of acylceramides from comedones and from the skin surface of acne patients and control subjects. J Invest Dermatol. 1988;90:350–3. Plewig G, Fulton JE, Kligman AM. Cellular dynamics of comedo formation in acne vulgaris. Arch Dermatol Forsch. 1971;242:12–29. Powell EW, Beveridge GW. Sebum excretion and sebum composition in adolescent men with and without acne vulgaris. Br J Dermatol. 1970;82:243–9. Qin M, Pirouz A, Kim MH, Krutzik SR, et al. Propionibacterium acnes induces IL-1β secretion via the NLRP3 inflammasome in human monocytes. J Invest Dermatol. 2014;134:381–8. Schneider MR, Paus R. Sebocytes, multifaceted epithelial cells: lipid production and holocrine secretion. Int J Biochem Cell Biol. 2010;42:181–5. Scholz CF, Kilian M. The natural history of cutaneous propionibacteria, and reclassification of selected species within the genus Propionibacterium to the proposed novel genera Acidipropionibacterium gen. nov., Cutibacterium gen. nov. and Pseudopropionibacterium gen. nov. Int J Syst Evol Microbiol. 2016;66:4422–32. Seleit I, Bakry OA, Abdou AG, Hashim A. Body mass index, selected dietary factors, and acne severity: are they related to in situ expression of insulin-like growth factor-1? Anal Quant Cytopathol Histpathol. 2014;36:267–78. Selway JL, Kurczab T, Kealey T, Langlands K. Toll-like receptor 2 activation and comedogenesis: implications for the pathogenesis of acne. BMC Dermatol. 2013;13:10. Smith TM, Gilliland K, Clawson GA, Thiboutot D. IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway. J Invest Dermatol. 2008;128:1286–93. Stelzner K, Herbert D, Popkova Y, et al. Inflammasome activation by Propionibacterium acnes: the story of IL-1 in acne continues to unfold. J Invest Dermatol. 2014;134:595–7. Stewart ME, Grahek MO, Cambier LS, et al. Dilutional effect of increased sebaceous gland activity on the proportion of linoleic acid in sebaceous wax esters and in epidermal acylceramides. J Invest Dermatol. 1986;87:733–6. Tomida S, Nguyen L, Chiu BH, et al. Pan-genome and comparative genome analyses of propionibacterium acnes reveal its genomic diversity in the healthy and diseased human skin microbiome. MBio. 2013;4:e00003–13. Wang Y, Kuo S, Shu M, et al. Staphylococcus epidermidis in the human skin microbiome mediates fermentation to inhibit the growth of Propionibacterium acnes: implications of probiotics in acne vulgaris. Appl Microbiol Biotechnol. 2014;98:411–24. Zhou BR, Zhang JA, Zhang Q, et al. Palmitic acid induces production of proinflammatory cytokines interleukin-6, interleukin-1β, and tumor necrosis factor-α via a NF-κBdependent mechanism in HaCaT keratinocytes. Mediators Inflamm. 2013;2013:530429. Zouboulis CC, Jourdan E, Picardo M. Acne is an inflammatory disease and alterations of sebum composition initiate acne lesions. J Eur Acad Dermatol Venereol. 2014;28:527–32.

4

Acne Clinic: Morphogenesis

Core Messages • Acne dynamics involves primary and secondary comedo, papule, pustule, nodule, abscess, draining sinus, and scar in a long-standing progressive and overlapping manner. • The comedo is the initial primary lesion of acne, while comedogenesis is an active process. Primary comedones begin with invisible microcomedo due to retention hyperkeratosis in infrainfundibulum of sebaceous follicles or sebaceous ducts. Closed comedones take several months to reach maturity, and then they either rupture inciting an inflammation or they gradually enlarge into open comedones. Open comedo (blackhead) is a stable structure containing shed hairs and can remain for years. The pigment is melanin. • Secondary comedo shows histological signs of a prior inflammation and asymmetry. They are exceedingly variable in size and shape, caused by once or repeatedly focal rupture, inflammatory infiltration and re-encapsulation, with loose concentric scar as ultimate clue. Secondary comedones are progressive and of different stages, with three distinctive entities: acne cyst, draining sinus, and fistulated polyporous comedo. • Acne cysts are typical manifestation of acne conglobata, chiefly on the back and to a lesser extent the face and neck. Without epithelial lining, acne cysts are different to trichilemmal cysts or epidermal cysts. They never disappear spontaneously, can exist for many years, and rupture at any time. • Draining sinus is monstrous, long, deep-seated fistulated sinus tract occurring on the face of patients with acne conglobata, acne fulminans, and acne inversa/dissecting terminal hair folliculitis, rosacea conglobata, and rosacea fulminans. It erupts at unforeseeable intervals with progressive scarring. • Fistulated (polyporous) comedo is typical for acne conglobate, with several to hundreds of these communicating comedones predominantly on the back. It is caused by

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over years of repeatedly focal rupture, inflammatory infiltration, and re-encapsulation, with diverticulum extending to adjacent sebaceous follicles. The collapse of small closed comedo gives rise to the deep-seated, long-lasting papule, starting with accumulation of neutrophils and followed by granulation tissue and scarring. The pustule represents a partial breakdown of the comedo. Small pustules may resorb and heal, while some burst out pustules may for secondary comedones, and after repeated rupture and re-encapsulation, eventually lead to large acne cysts. The nodule represents the total breakdown and fuse of two or more adjacent comedones, with huge abscess and hemorrhage extensively destroying the surrounding tissues. Acne conglobata is a rare and progressive, highly inflammatory disease mainly of adult men with nodules on the back, usually beginning at puberty and recurring for years to decades. Scarring is inevitable with a full spectrum of various acne scars. Pathogenesis remains unclear. Treatment of choice is oral isotretinoin, preceded or accompanied with systemic steroids initially. Persistent solid facial edema occurs predominantly in men, without or with a prior clinical history of mild papulopustular acne, starting in adolescence or early adulthood, characterized by a constantly hard non-pitting swelling of the mid third of the face, and increasing in severity with time. Pathogenesis is unknown and treatment is challenging. We prefer low-dose isotretinoin combined with ketotifen daily over a period of 6–12 months. Scars are the hallmark of acne after comedones. Spontaneous scars may present as small atrophic pitted/crateriform/ice-pick scars on the face or large flat atrophic scars on the back, hypertrophic scars, keloids, perifollicular papular scars, calcified scars, fistulated polyporous comedones, and linear scars associated with draining sinus in

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4 Acne Clinic: Morphogenesis

the face. Several grading systems are proposed for assessment of acne scar severity and for comparison of treatment results.

4.1

Dynamics of Comedones

4.1.1 Evolution of the Comedo The comedo is the initial, primary lesion of acne. It is an impaction of corneocytes within sebaceous follicles. Comedones develop through the following stages.

4.1.1.1 Primary Comedones The microcomedo is an early distention of the follicle by corneocytes. Its existence can be verified only in histological sections. The closed comedo, or whitehead, is the first visible lesion, a firm whitish nodule resembling a milium, generally 1–2 mm in diameter. The pore is tiny and generally cannot be seen with the naked eye. The dilatation of the orifice by a protruding mass of darkly pigmented horny material marks the onset of the open comedo, or blackhead. The pigment is melanin. Open comedones may attain a diameter of 5 mm, sometimes even larger. 4.1.1.2 Secondary Comedones The rupture and re-encapsulation of comedones creates secondary comedones. The same comedo may experience focal blowups many times. Secondary comedones can usually be differentiated because they have irregular shapes, are generally larger than the primary ones, and show histological signs of a prior inflammatory episode. Three types of secondary comedones are sufficiently specialized to warrant specific designations. The acne cyst is a large, skin-colored, rubbery nodule, resembling a trichilemmal cyst (synonyms are atheroma or wen), 5–20 mm in diameter, occurring mainly on the back and sometimes on the cheeks of individuals with acne conglobata. Pressure or puncture releases a cheesy, crumbly material consisting of corneocytes, hairs, bacteria, and sebum. A late sequel, probably starting with a primary comedo, then engulfing other follicles, comedones, papules, and abscesses, results in a draining sinus. The fistulated (polyporous) comedo looks like a cluster of two or more blackheads, occurring mainly on the back in acne conglobata. These are interconnected and share common openings. Fistulated comedones can also be viewed as a peculiar type of scar. The latter two will be dealt with in the chapter on scars (p. 67, 74).

4.1.2 Dynamics of Primary Comedo Two tactics have been of inestimable value for observing the anatomical changes of the evolving disease: these are biopsy and serial sectioning of the apparently uninvolved areas of acne-bearing skin. Without these the earliest changes cannot be seen, and without serial sections one can catch only glimpses. One section of the same specimen may look almost normal, while elsewhere there may be startling alterations. Heterogeneity is quite characteristic of acne. A peculiar change in the pattern of keratinization of the infrainfundibulum, where the sebaceous duct joins the hair follicle, marks the onset of comedo. A granular layer appears, sturdier corneocytes are produced and, most important of all, these begin to stick together to form a coherent kernel made up of well-defined horny lamellae. The microcomedo originates from follicles harboring sebaceous filaments; these might be regarded as precomedones. It is very important to appreciate that sebaceous filaments do not inevitably evolve into comedones. In fact, they usually do not, since they are common in adults with oily skin who no longer have acne. Moreover, sebaceous filaments are common on the nose, where comedones are rare. They are simply a stage through which the sebaceous follicles pass on their way to comedo. The filament has an outer envelope of compacted corneocytes, literally a thick horny layer, encasing a softish amalgam of sebum, sloughed empty sebocytes, and undifferentiated cells from sebaceous acini, and flimsy corneocytes from sebaceous ducts or the lower portion of the infrainfundibulum. A paramount finding is masses of Propionibacterium acnes within the core of the filament. These play a crucial and active role in the formation of the comedo. The lumen is congested through the orifice, and never blocks, as erroneously stated occasionally. Sebum issues through the orifice. The transformation of a sebaceous filament into a microcomedo is a continuous process. The key change is decreased dehiscence or increased cohesiveness of corneocytes. They stick together tightly like bricks and form a solid compact mass which steadily expands. The intercellular cement must change in some way so as to act as a nondegradable glue. Probably there are qualitative and quantitative alterations of the intercellular lipids, in particular the ceramides. Perhaps lytic enzymes are no longer secreted into the intercellular spaces to weaken the cement. More evidence is required to prove this hypothesis. In any case, the cells become permanently tied together. Speculation concerning these events centers around the keratinosomes or membrane-coating granules. These are lysosome-like structures which extrude their lipid-rich contents into the intercellular spaces. These lipids are essential for the barrier function of the stratum corneum and also apparently

4.1 Dynamics of Comedones

regulate desquamation in some unknown fashion. Membranecoating granules are numerous in the normal infrainfundibulum, but they have been reported to decrease in number when comedones form, suggesting that shedding of corneocytes becomes limited in their relative absence. This is a disputed subject. Another component of importance for the cell-to-celladhesion, not only in the living epidermis but also in the stratum corneum (or comedones), are desmosomes. Corneodesmosomes are modified desmosomes in the stratum corneum. Corneodesmosome breakdown and corneocyte shedding are closely related. Kallikreins, in particular KLK5 and KLK7, are serine proteases with trypsin or chymotrypsin-like activity that are involved in epidermal desquamation after complete cornification. After release from the lamellar bodies at the apical side of the stratum granulosum, they are activated through proteolysis in the intercorneocyte space and target corneodesmosomes by cleaving the structural proteins corneodesmosin, desmocollin, and desmoglein. Little is known about the details of these changes in comedones. The failure of corneocytes to slough normally produces a hyperkeratosis of the retention type. There is also an increased production of corneocytes. The upper follicular epithelium becomes hyperproliferative. Both processes, increased production and increased retention of corneocytes, contribute to the distention of the infundibulum by horny impactions. This hyperkeratosis is not simply a result of irritation. Toxic substances characteristically produce loose horny layers that fall apart rapidly in contrast to comedogenic agents, which cause cohesion. For example, propionic acid is very irritating and noncomedogenic, while oleic acid is comedogenic and only mildly irritating. It awaits clarification whether acne-prone patients have a higher content of oleic acid in the follicular epithelium. It is the better part of wisdom not to offer any mechanistic explanation for comedo formation. We do not know how this happens or why, among the hundreds of sebaceous follicles, only a few evolve into comedones. The customary belief regarding how a comedo forms is a fanciful misconception. It is always said that it begins with an obstruction of the orifice. After the orifice becomes blocked, a bag of sebum collects. This might be called the plug or cork version. Nothing like this happens; indeed, quite the opposite. The acroinfundibulum or pore region does not participate at all. If the acroinfundibulum became hyperkeratotic, the orifice would dilate from the very start; the first visible lesion would be an open, not a closed, comedo. This never happens in acne vulgaris. It can be brought about artificially when a potent comedogenic agent such as coal tar is applied. In that case, the acroinfundibulum becomes immediately involved in retention hyperkeratosis. The horny mass distends and protrudes

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through the pore. The first visible lesion is then an open and not a closed comedo as in acne vulgaris. In acne vulgaris only the infrainfundibulum participates in comedo formation. Hence the follicle swells below and the orifice does not dilate. Instead of a cork at the outlet, the whole follicular canal becomes filled with compact corneocytes. Acne would be an easier disease to treat if the cork conception were true. Advertisements promoting the sale of abrasives and peeling agents are often based on uncapping this superficial plug. Comedogenesis is an active process but not the result of passive occlusion. Closed comedones ordinarily do not grow beyond about 2 mm. They take approximately 2–5 months to reach this degree of maturity. The larger ones sometimes contain two hairs, rarely more, which is evidence of their youth. Closed comedones (microcomedones in their start-up stage) suffer one of two fates: either they rupture and incite an inflammatory lesion or they gradually enlarge into open comedones. Autoradiographic studies show that the production of corneocytes does not slow down as the comedo enlarges; hence, if it does not explode, continued accumulation of corneocytes will force the orifice to dilate. The tip of the horny mass will then be exposed, giving birth to the open comedo. At first, the pigmented tip may be no more than 1 mm wide. As the orifice dilates, the core of protruding horn gets thicker and may eventually reach a size of 5 mm or more. The open comedo has a very long career, being a rather stable structure. Unlike the closed comedo, horny material continuously moves through the orifice in a glacier-like fashion and is eroded away. Semiliquid substances such as sebum can still escape to the surface. Drainage of sebum and products excreted by masses of Propionibacterium acnes is almost completely obstructed in the closed comedo, hence its tendency to rupture. The closed comedo has been dubbed the time bomb of acne. As the open comedo enlarges, the pilary portion continues to produce and shed hairs. These are of course retained and become curled and tangled within the horny matrix. Mediumsized blackheads generally contain six to seven hairs. An aged comedo may contain as many as 15 hairs. Allowing 80 days for a complete anagen-telogen hair cycle, the longevity of such a comedo would be over 3 years. It is important to note that 80–100 days refer to the hair cycle of terminal follicles, while the hair cycles of vellus follicles and sebaceous follicles remain ill-defined. During that time, of course, the horny mass would have been replaced or turned over many times. Throughout the life of a comedo, the shrunken sebaceous lobules continue to secrete sebum, which streams to the surface through tortuous, bacteria-filled central channels. In aged blackheads, the channels tend to fuse and become large cavities containing dense communities of Propionibacterium acnes. It is likely that bacterial enzymes, mainly proteases, contribute to the widening and

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merging of the channels. That products of these bacteria can lyse horny material can be shown in a very simple way; clear zones form around colonies of Propionibacterium acnes growing on agar plates seeded with keratinized scales. Further characterization of the proteases/peptidases is lacking. It is not known whether lipases also play a role in lysing the intercellular lipids of adhering corneocytes or not.

4 Acne Clinic: Morphogenesis

Rupture, abscess, and re-encapsulation are the key sequences which underlies the creation of secondary comedones. These can arise only when rupture is partial, and generally not from nodules. Substantial segments of comedonal epithelium must survive the inflammatory storm. Because focal rupture and re-encapsulation may happen once or many times, secondary comedones cannot be placed in such neat categories as primary ones; they are exceedingly variable in size and shape. Some of them may look like closed or open comedones. Secondary comedones can be identified with certainty only by histological examination and their asymmetry. Diagnosis is made by finding evidence of an earlier inflammatory event. If this was recent, there will be hyperplasia of the epithelium and a chronic inflammatory reaction. Later there may be but a scattering of lymphocytes. The connective tissue presents the ultimate clue, a scar consisting of fine, parallel bundles of collagen. The fibers are arranged in loose laminae, often in concentric patterns. Within the scarred tissue, all elastic fibers have been destroyed. An elastic stain is therefore helpful to delineate the extent of scarring. Taken together, secondary comedones are progressive and of different stages. Following repeated episodes of rupture and re-encapsulation, the internal structure of the comedo becomes altered. The horn is not so dense; the lamellae are looser and not in such neat concentric patterns. The bacteria are sparser; the habitat seems less hospitable to Propionibacterium acnes. Three varieties of secondary comedones are clinically distinctive.

usually 7–15 mm large, but they may attain as much as 2–5 cm in diameter. Large cysts are lesions up to 5–10 years old. There is some confusion regarding nomenclature. Torpid nodules and abscesses, typical of acne conglobata, are often called cysts. They are not true cysts and lack epithelial lining. Strictly speaking, they are acne cyst different to sebaceous cyst, trichilemmal cyst, or epidermal cyst. Acne cysts will release a cheesy to waxy material (corneocytes with bacteria, debris from previous inflammatory episodes) when squeezed out or nicked. Deep puncture with a scalpel will yield more of these contents. Discharge can also occur spontaneously. The contents often have the offending odor of foul, rotten material. Hairs are typically few or may even be absent in large, old cysts. In this case, the pilary unit and sebaceous glands have been destroyed by successive inflammatory episodes. Acne cysts are like time bombs; one never knows when they will rupture. This can be limited to a small segment of the epithelium with swift re-encapsulation, or it can be a total explosion. Large, very painful abscesses can develop within a few days. The overlying and neighboring skin and subcutis is edematous, red, very tender, and painful when the patient is leaning against a chair or lying on his back, for example. It is a common mistake to diagnose a boil (furuncle). Cultures are generally sterile, with no evidence of Staphylococcus aureus infection. Histopathologically, an epithelial-lined cystic cavity with an apical opening is seen, mostly small, sometimes requiring serial sections to visualize. The epithelium keratinizes to form corneocytes, associated with a well-developed stratum granulosum. Sebaceous acini are absent. Occasionally, small buds of undifferentiated sebaceous glands cling to the cyst epithelium. The pilary portion is almost always destroyed, so that few or no hairs are within the cavity. Pericystic fibrosis is always present. Cysts never disappear spontaneously. They have only two fates: rupture with abscess, leaving a bad scar, or surgical removal of the cyst wall. Of course, surgery is preferable and the results gratifying, but surgical intervention is underused in acne.

4.1.4 Acne Cyst

4.1.5 Draining Sinuses

True cysts have an epithelial lining. While the opening is not very evident in most of them, some have a clearly visible punctum. Cysts are almost always part of the scenery of acne conglobata. Their chief territory is the back, from the shoulders straight down to the hips, and to a lesser extent the face, neck, nape, and earlobes. Acne cysts are smooth, dome-shaped, elevated, freely movable, skin-colored, round to ovoid structures. They are

A somewhat similar series of events leads to a draining sinus. This is nothing but a monstrous, long, and particularly deepseated fistulated sinus tract which empties to the surface. It most often occurs in patients with severe forms of acne, such as acne conglobata, acne fulminans, and acne inversa/dissecting terminal hair folliculitis. It is also seen in patients with severe forms of rosacea, such as rosacea conglobata and rosacea fulminans. In contrast to acne cysts and fistulated

4.1.3 Dynamics of Secondary Comedo

4.2 Dynamics of Inflammation

comedones, it prevails on the face: cheeks, saddle of the nose, chin, and submandibular region. There may be one or two tracts, rarely more. Inflammation is much more extensive than with the fistulated comedo. Like a volcano, it erupts at unforeseeable intervals. Of course, there is progressive scarring as with fistulated comedones.

4.1.6 Fistulated Polyporous Comedones Like the cyst, the polyporous comedo is a typical feature of acne conglobata; again, it predominates on the back. Usually there are several lesions, and it is not rare to encounter a patient whose back is studded with hundreds of these communicating comedones. Fistulated comedones always have fairly wide openings, with pigmented tips protruding through the pore. Their formation takes place over years, after a complete series of ruptures and encapsulations. Histopathologically, a localized rupture occurs which, by encapsulation, becomes a lateral diverticulum lined with keratinizing epithelium. By means of subsequent ruptures, the diverticulum extends in length and finally breaks into a nearby follicle, which also becomes or may have been the site of a double comedo. Groups of two or more follicles become linked up in this fashion. When there are two openings, the term double comedo is used. One could likewise refer to a triple comedo. Fistulated comedones evolve through inflammatory stages from ordinary comedones and therefore have to be classified as secondary comedones. They could also be placed into the category of scars. The scar tracks and tunnels are stuffed with a comedo-like paste of corneocytes. Fistulated comedones are dealt with again in the chapter on scars.

4.1.7 Cellular Biology of Comedogenesis The primary biological event initiating comedogenesis remains largely unknown. Saurat et al. proposed that sebaceous gland progenitor cells or sebaceous gland stem cells, as identified by staining with leucine-rich repeats and immunoglobulin-like domain protein 1 (LRIG1) in mice, are the root of comedo switch. As acne vulgaris is a unique disease of human sebaceous follicles, more evidence is needed to confirm whether the data deriving from mice terminal hair follicles can apply to humans. Even unclear is why only a small portion of sebaceous follicles is involved in any acne patient and which sebaceous follicles will first enter the socalled acne cycle. Diverse factors triggering comedogenesis have been discussed. The causative role of Propionibacterium acnes in comedogenesis has been controversially discussed, while the existing evidence can neither prove nor disprove it.

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The classical view of the lipases in Propionibacterium acnes generating irritative free fatty acids can be reexamined by study of the different virulent strains and biofilm formation of Propionibacterium acnes. Lipid peroxidation, especially squalene peroxides, induced by ozone, long UVA rays or cigarette smoke, was found to relate to comedogenesis. Expression of different cytokines including IL-1alpha, tumor necrosis factor-alpha, interferon-gamma, and epidermal growth factor/transforming growth factor-alpha and the activation of Toll-like receptor 2 have also been demonstrated in comedogenesis. Perifollicular infiltrates of inflammatory cells, particularly CD3+ and CD4+ T cells and macrophages, can be detected in uninvolved acne skin without evidence of ductal hyperproliferation or microcomedo, casting doubt that inflammation precedes but not pursues comedogenesis. In a proteomic analysis of sebaceous follicular casts, normal samples showed a predominance of anti-oxidative proteins such as prohibitins and peroxiredoxins, while acne-affected skin exhibited proteins involved in inflammation, wound healing, and tissue remodeling, such as myeloperoxidase, lactotransferrin, neutrophil elastase inhibitor, vimentin, and specific factors associated with Propionibacterium acnes surface proteins. The unique efficacy of retinoic acid in acne treatment indicated abnormal metabolism of retinoids with local vitamin A deficiency leading to hyperproliferation rather than differentiation of infundibular keratinocytes. It remains to be determined whether the activation of the AhR pathway by xenobiotics, as happens in chloracne, also involves comedogenesis of normal acne.

4.2

Dynamics of Inflammation

It is a popular conception that free fatty acids formed by the hydrolysis of triglycerides in sebum within sebaceous follicles are irritants which attack the follicular epithelium, thus causing breaks in the lining. Presumably, sebum then flows out and provokes an inflammatory reaction. This is an oversimplified view that is no longer acceptable. Theoretically, a pustule could spring up in this way from a normal sebaceous follicle. With rare exceptions, pustules originate from preexisting comedones, whether these are visible or not. There is no doubt that sebum is a toxic material. Intradermal injection of a dilute suspension provokes within 24 h a tender, intensely red papule, lasting for many days. There is no proof that the normal follicular epithelium is leaky because of the toxicity of sebum. Many other factors contribute to the breakdown of the follicular lining. Comedones are not clinically evident when one looks at pustules or papules. The reason for this is that comedones usually burst before becoming large enough to be visible. Besides, the inflammatory reaction itself tends to mask the underlying comedo. Expressing the contents of pustules

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often makes it possible to tease out the horny kernel. The most conclusive demonstration is by histopathological evaluation. We have done this hundreds of times. A comedo, often very small but sometimes also of much larger size, is invariably present. The tendency for small closed comedones to blow up has led to their being called the time bombs of acne. This sobriquet is well earned. The comedo is a bag of toxic substances encompassing sebum, hairs, bacterial products, and corneocytes. These toxic materials cannot get out easily through the microscopic pore. By contrast, open comedones are relatively inert. When they do occasionally rupture, their large size and pigmentation make it easy to discover them within the infiltrate. Inflammatory lesions arising from open comedones tend to be rather limited. The reaction is usually not strong enough to expel the comedones. The more a comedo matures, the less likely it is to rupture. Mature, old comedones have very small sebaceous glands, which provide only minuscule amounts of fuel for explosion. This is why one sometimes sees patients whose lesions are mainly comedones with but a scattering of pustules. Open comedones are stable end stages. In patients with numerous inflammatory lesions, comedones are usually not prominent. As a rule, there is an inverse relationship between the visibility of comedones and the prominence of inflammatory lesions. In acne conglobata, for example, open comedones are hard to find. These patients have such fragile microcomedones that early collapse is almost inevitable, once horny distention is under way. In patients with many papulopustules, rupture usually occurs at the microcomedo stage. Of course, some patients have both comedones and papulopustules, and in these, some follicles get past the fragile stage. Little is unknown who is predisposed to noninflammatory comedonal acne and who is susceptible to inflammatory acne. Patients predisposed to highly inflammatory acne keeps that state for a long time. The follicular population is heterogeneous. Why some follicles are more susceptible than others are a mystery. Microcomedones are not visible; thus manual extraction is not feasible for prophylaxis. The removal of visible closed comedones is helpful in moderating acne papulopustulosa. However, the manual extraction itself usually induces inflammation afterward. The extraction of open comedones is cosmetically satisfying but does not alter the course of the disease. As always, however, there are exceptions. Application of cyanoacrylate to remove early follicular impactions is possible, but not as a routine procedure. The inflammatory lesions that make up the characteristic repertoire of acne vulgaris are papules, pustules, papulopustules, and nodules, all ending in scars, visible or not. Factors triggering rupture of comedones remain unclear. Pressure is not an important factor in the rupture of comedones. Various other cystic lesions such as steatocystoma

4 Acne Clinic: Morphogenesis

multiplex, eruptive vellus hair cysts, and trichilemmal cysts which reach much larger size would rupture even more readily. The latter usually have very thin walls but they stay intact. The earliest event in the development of an inflammatory lesion can be discovered only by chance. This requires taking random biopsies of apparently uninvolved skin from patients with numerous inflammatory lesions. This is of course a hit-and-miss technique; sometimes the histopathological findings are normal. Occasionally, however, one catches the earliest change. This consists of the accumulation of a few neutrophils hard up against the outside of the follicular epithelium. At this stage the lining seems intact, although leukotrienes and other proinflammatory substances may have leaked out at that focus. Subsequently, the neutrophils invade the epithelium and create spongiotic foci. The epithelial cells swell and detach from each other. Neutrophils soon begin to pool on the inner side of the epithelium within the comedo. The epithelium at that site then degenerates. This is the event specified by the term rupture. The contents of the follicle leak out and masses of neutrophils are called forth, extending well beyond the rupture. An intrafollicular and perifollicular abscess is thus formed. The massive pooling of neutrophils inside and outside the comedo is archetypal of acne vulgaris. The segment of epithelium which undergoes necrosis is of variable length. It may be so tiny as to never surface clinically. Minor border incidents of this kind are fairly common in biopsies of comedones which show no trace of inflammation clinically. These tiny breaks heal swiftly and would remain entirely undetected except for histopathological observations. Comedones that are clinically visible frequently show traces of these little “brush fires,” with variable degrees of fibrosis when examined histopathologically. It is possible that rupture of certain comedones may first happen after many break-healing cycles. These tiny scars contribute to an uneven texture in later life. The capacity of the epithelium to restore continuity after a break is very impressive. We have pushed sterile needles completely through closed and open comedones expecting to incite a pustule. With two and even three such perforations, the comedo usually remained quiescent. In histopathology, these artificial breaks healed within several days. A small nest of neutrophils collected outside the perforation; the epithelial edges quickly linked up. We envision that toxic substances, particularly those produced by Propionibacterium acnes, accumulate in the comedo. These attack a weak point in the epithelial lining, permitting diffusion into the dermis. Neutrophils rush to the scene and destroy the epithelium completely, forming an intrafollicular abscess. The solid and soluble components of the comedo now pour into the surrounding tissue and initiate a perifollicular abscess.

4.2 Dynamics of Inflammation

The molecular pathway steering the fate of comedones remains incompletely understood. In progression to inflammatory papules, recruitment of IL-17A-positive T cells was found, with activation of Th17-related cytokines such as IL-1β, IL-6, TGF-β, and IL23. There are significant changes in the sebum lipids, proinflammatory cytokines and chemokines, Th1 markers, T regulatory cell markers, IL-17-related antimicrobial peptides, and Toll-like receptors, especially in response to the high virulent strains of P. acnes. The interplay and balance between the activated IL-17 pathway and the IL-10/Tregs seem to determine the progression or demarcation of the inflammation and eventually resolution of the lesions.

4.2.1 Inflammatory Lesions and Sequels 4.2.1.1 Papules The collapse of the comedo gives rise to the deep-seated, long-lasting papule. The papule may be regarded as a small nodule. The destruction of the epithelial lining is complete in most cases. The comedonal core is often not discharged to the surface and remains within the tissue as a foreign body. The horny core floats in a huge sea of inflammatory cells. During the ensuing inflammation, fragments of corneocytes and other debris are sequestered in the dermis. Hairs, too, are dumped out. The skin has no effective means of rapidly removing lipids, keratinized detritus, and hair fragments; hence the devastating property of the papule. Tissue enzymes are not suited for this type of mop-up. A foreign-body granuloma is provoked within a week or so that takes many weeks and months to resolve. The violent inflammatory response extends widely in all directions. The neutrophilic flood may lap against neighboring sebaceous follicles and down into the subcutaneous fat as well. It may break into nearby follicles or form comedones. Further out, it still seeps along vascular channels encircling the secretory coil of eccrine sweat glands. Here and there are thickened, irregular remnants of the follicular epithelium, struggling vainly to link up with other epithelial islands. These are all necrotic and heavily infiltrated with neutrophils. Nuggets of horny material are sometimes scattered far away from the destroyed follicle. Fragments of vellus hairs litter the scene, sometimes swallowed by foreign-body giant cells. Trichogranulomas are particularly persistent pestilential sequels. Later the infiltrate consists of a mixture of neutrophils, lymphocytes, histiocytes, and Langhans’ foreignbody giant cells. Eventually, granulation tissue forms, with many new vessels and fibroblasts. Histopathological evidence of inflammatory activity persists long after the lesion has become clinically quiescent, usually for months. Scarring is inevitable, macroscopically as well as microscopically.

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4.2.1.2 Pustules Pustules frequently start as solid lesions, i.e., papules, which soon liquefy. These are hybrids for which the term papulopustule is more exact, though not favored. The pustule represents a partial breakdown of the comedo. A variable segment of the epithelial lining survives and will reconstitute itself. Blowouts close to the epidermis are less serious than deeper ones in the dermis and create smaller, more elevated lesions. Usually, the roof of the pustule bursts, allowing pus to escape. The battered remnants of the comedo are then discharged. Healing occurs in a very characteristic way, not differing from normal wound repair. The severed ends of the follicular epithelium, literally immersed in a pool of pus, begin to thicken and soon send out irregular, hyperplastic sheets of undifferentiated epithelial cells. This migrating epithelium cleaves its way through the tissue around the periphery of the abscess, searching for viable dermis on which to implant itself. The epithelial ends link up and a continuous lining is re-established. The abscess thus becomes re-encapsulated. Hyperplasia gradually diminishes, and re-differentiation into a keratinizing epithelium occurs. What happens to the comedonal core? Fortunately, it is usually not extruded into the dermis; enough epithelium remains to keep it in place. Neutrophils partially liquefy and disperse the horny matrix. Hydrolytic enzymes of the neutrophils, especially proteases, attack corneocytes and break them down. This is described in more detail in the chapter on channels within comedones (p. 58, 65). Small pustules may resorb without retaining horny fragments. Following re-encapsulation, the polymorphous neutrophils slowly disappear. About 10 days after rupture, lymphocytes and histiocytes become prominent. A loose, cell-rich connective tissue surrounds the reformed epithelium. The presence of concentrically arranged fine collagen fibers with many fibroblasts always indicates an earlier rupture. Inflammatory cells remain on the spot for an extraordinarily long time, at least several weeks after clinical healing. Eventually, nothing is left but a histological scar. By tattooing the vicinity of pustules and then taking biopsies at various times after their clinical disappearance, much can be learned about their fate. This field requires more investigation. Two outcomes have been observed, excluding serious scarring: 1. The epithelium may resume the production of coherent corneocytes; the comedo then continues its growth after a brief inflammatory interlude. Thus the secondary comedo is born. Re-encapsulation inevitably results in a variable enlargement of the lesion. Depending on the place and extent of rupture, the outline of the secondary comedo will be variably irregular. The appearance may be that of a simple outward pouching, a tubular diverticulum, a bal-

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loon, or other odd shapes. The same comedo may rupture repeatedly. Large cystic lesions can arise from this. 2. The sebaceous follicle may be reconstituted, usually with some distortion in architecture. The sebaceous glands reform but are peculiarly shaped. The epithelium reverts to the production of loose horny material. The life of the comedo is terminated. This is probably the more usual outcome. As a rule, pustules heal without much visible scarring, although the site can often be found with a magnifying glass.

4.2.1.3 Nodules The nodule represents the total disintegration of a comedo with far-reaching consequences. Two or more adjacent comedones often break down and fuse to create these monstrous lesions (giant papules). While the papule is a relatively localized explosion, the nodule is a volcanic eruption that destroys a large surrounding territory. A huge abscess engulfs neighboring follicles or comedones and destroys these, too. The dissolution of adjacent pilosebaceous units propagates the inflammatory reaction. Hemorrhage and pools of serum are always part of this violent reaction. The abscess dissects well down into the subcutaneous tissue; panniculitis is always prominent. Every living structure within a radius of 10–30 mm is destroyed – sweat glands, vellus follicles, sebaceous follicles, nerves, and vessels. Fragments of hairs and comedonal kernels float like flotsam in the necrotic tissue. Foreign-body giant cells are numerous. Acute inflammation slowly gives way to a chronic state with many mononuclear cells and histiocytes. Histopathological activity lasts for many months. Granulation tissue finally forms and scarring is, of course, massive. 4.2.1.4 Draining Sinus in Acne The draining sinus is a truly malevolent hybrid lesion featuring the combination of nodules and scars at the same time. It develops in the face, especially in the nasolabial folds and the neck. It is a huge, tender lesion which periodically drains and crusts. In this case remnants of follicular epithelium somehow manage to survive. These dissect through the necrotic tissue and create tunnels of hyperplastic epithelium. They form a complicated, bizarre labyrinth of galleries which connect with the surface at various places. Because it is constantly breaking down, the sinus tracts are not completely lined with epithelium. The lesion thus propagates itself, often extending linearly to form huge inflammatory ridges several centimeters long. The tunnels lie in a matrix of chronic granulation tissue composed of a variable mixture of neutrophils, lymphocytes, histiocytes, and foreign-body giant cells. The epithelium lining the tunnels is very restless and sends out buds, ribbons, and tongues to form striking patterns which often suggest hamartomatous growths. Here

4 Acne Clinic: Morphogenesis

and there, ruptures occur and epithelium immediately encapsulates the new areas of necrosis. Sebaceous lobules and pilary units persist for a variable period but are destroyed with time. There are constantly alternating episodes of rupture and repair. It may grow relentlessly for years, intermittently calming down only to start draining again. Spontaneous healing hardly ever occurs. It is to note that the acne draining sinus is not entirely analogous to the sinus tracts seen in hidradenitis suppurativa/ acne inversa, even if they may look very similar in the advanced stage. The former derives from sebaceous follicles, while the latter begins in terminal hair follicles. Treatment is a real challenge and very difficult. It is done conservatively with aspiration of the hemorrhagic contents and injection of a corticosteroid crystal suspension, with tightly fitting compression bandages worn for several days thereafter. We often favor oral corticosteroids, which can also be tried for several weeks. Oral antibiotics are nearly always ineffective. Isotretinoin provides only temporary and inconsistent relief. In most cases, only surgical excision of the entire labyrinth provides a final cure.

4.2.2 Acne Conglobata Acne conglobata is a rare and progressive, highly inflammatory disease characterized by comedones, cysts, abscesses, draining sinuses, and irregular scarring. It is mainly a disease of adult men with conspicuously oily skin, although cases usually have their onset in adolescence. The disorder has also been encountered in women, although rarely. Acne conglobata is more common among Caucasians than Asians or in people of color.

4.2.2.1 Clinical Findings Chronicity and progression are marked features of acne conglobata. Lesions begin at puberty. Severity increases over the years, reaching a crescendo in late adolescence. In contrast to common belief, acne conglobata does not subside after adolescence. It characteristically persists, sometimes in a vivid and exuberant form, for many decades; in other cases it smolders lifelong. Subsidence is slow with periodic flares. Sometimes scars cover one third of the skin surface, and scattered lesions continue to appear episodically. The archetypal lesion of acne conglobata is the nodule, a large, succulent, tender, red, elevated, dome-shaped mass, at first firm, later becoming soft or even fluctuant. Nodules often fuse to form odd-shaped aggregates, sometimes several centimeters long. The lesions take many months to regress and invariably leave scars. They may evolve into a draining sinus, a labyrinth of tunnels which periodically releases a serous or suppurative exudate at one or more openings. The

4.2 Dynamics of Inflammation

draining sinuses typically remain active for years with occasional blowups. Inflammatory lesions dominate the landscape. Nodules are conspicuous, and there may be many persistent papules. Pustules are variable in number and usually not prominent. Open and closed comedones are curiously not common and never conspicuous. On the other hand, two types of secondary comedones are characteristic of long-standing acne conglobata: the whitish, firm, cyst-like secondary comedones, and polyporous comedones which look like clusters of huge blackheads but are actually scars. Acne conglobata flourishes on the trunk, especially the back, and is typically much less severe on the face. Acne conglobata limited to the face is actually uncommon, if at all, almost exclusively observed in women. In many patients only the back is involved. It usually extends beyond the territory of acne. The buttocks and even the thighs are often afflicted. Lesions encroach on the neck, earlobes, auditory canal, nape of the neck, and hairy scalp. Sometimes this fearful disease is generalized, with lesions occurring wherever there are sebaceous follicles. Scarring is inevitable and never superficial. The full spectrum of scars can be found in any given patient. Atrophic scars, thin as cigarette paper, often more than 3–5 cm wide, with ectatic blood vessels shining through, may cover large areas. Hypertrophic scars may be intermingled: these are elevated, hard, fibrotic nodules of varying size, sometimes suggesting keloids. On the back these may occur as discrete, small, whitish, firm papular scars localized to follicles. These are frequently confused with closed comedones. When nicked with a sharp instrument, nothing comes out. On the face crateriform, ice-pick-like scars, troughs, tunnels, and other bizarre defects disfigure the surface. Sometimes inflammatory lesions blow up in old scars, e.g., pustules, papules, or nodules in either the atrophic or hypertrophic varieties. Some patients with acne conglobata may develop episodes of arthritis, affecting mainly the larger joints of the arms and legs and the axial skeleton. Ankylosing spondylarthritis and erosive arthritis have been reported. This is further expanded in the chapter on the SAPHO syndrome (p. 418).

4.2.2.2 Pathogenesis The cause of acne conglobata is unknown. Although considered by some to be a severe suppurative variant of acne vulgaris, it is generally regarded as a distinct entity because of its almost exclusive appearance in adult men and its chronic, intermittent course. Patients with acne conglobata often have a family history, but definitive proof for the importance of hereditary factors is lacking. Individuals with the XYY genotype have been reported to have acne conglobata, but we are not sure if this is a real phenomenon and actually doubt it. Patients with acne conglobata and Klinefelter’s syndrome have also been reported.

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4.2.2.3 Histopathology The histopathological changes are those of acne vulgaris with numerous comedones and follicular horny plugs, accompanied by a dense perifollicular inflammatory infiltrate of lymphocytes, plasma cells, and polymorphonuclear leukocytes. Intra- and perifollicular abscesses are frequently observed. Downward epidermal proliferation occurs, with the formation of interconnecting sinus tracts. Scarred skin often shows a remarkable degree of inflammatory activity with engorged vessels, mononuclear infiltrates, and foreignbody granulomas. 4.2.2.4 Treatment Our program consists in the comprehensive use of topical and oral drugs. We often show before-and-after pictures of previous therapeutic success. This alone often greatly lifts the spirits and ensures cooperation. 4.2.2.5 Systemic In almost all cases, systemic isotretinoin provides a beneficial response unrivaled by that of any other therapeutic modality. It is clearly the drug of choice in acne conglobata. The dosage should not be less than 0.5 mg/kg daily and the duration of treatment no shorter than 3–5 months. In most instances, the inflammatory reaction can be significantly lessened or even abolished, but recurrences tend to be more common than in acne vulgaris. Sinus tracts are hardly affected by systemic isotretinoin treatment. Systemic corticosteroids, e.g., 0.5–1.0 mg/kg of prednisolone, are beneficial in the initial treatment of acne conglobata, especially if ulcerations are present or develop during isotretinoin treatment. We often start with corticosteroids for 2 weeks before we add isotretinoin. It seems evident that isotretinoin combined with systemic corticosteroids, in the beginning or after 2–4 weeks of therapy, is the optimal treatment for acne conglobata, although controlled clinical studies are lacking. Prior to the availability of systemic isotretinoin, sulfones such as diaminodiphenylsulfone (dapsone) were quite often used. These compounds may be tried in treatment-resistant cases. The dose is 50–150 mg daily for a few weeks or months. Treatment must be carefully supervised. Intense systemic antibiotic therapy is indicated to combat secondary infection when present. Nonsteroidal anti-inflammatory drugs may be needed to control the musculoskeletal symptoms in acne conglobata. 4.2.2.6 Topical High-potency corticosteroids may be used for several weeks to moderate the inflammatory process. Retinoids are useful in combination with oral isotretinoin.

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4.2.2.7 Additional Options The contents of the larger hemorrhagic nodules can be aspirated with a thick needle and syringe. Small incisions with a lancet or scalpel also allow drainage but are not preferred by us. Corticosteroid crystalline suspensions such as triamcinolone acetonide can be injected into the lesions; this leads to notable flattening within a few days. Cryotherapy is another option for indurated hemorrhagic nodules and fistulous abscesses. Surgical excision and skin grafting of chronically involved areas offer a positive approach to the eradication of this disease. There is growing interest in the use of biologics, such as the tumor necrosis factor-alpha antagonists. Only single cases are reported, especially in the syndrome-associated acne conglobata. Response rate and long-term therapeutic efficacy are unknown. Paradoxically, acne conglobata induced by adalimumab has been reported.

4.2.3 Solid Persistent Facial Edema of Acne Edema is not a typical expression of acne. In February 9, 1966, Carney presented probably the first case of acne-associated facial edema at the Los Angeles Dermatological Society under the diagnosis of lymphoma. The presence of mast cells was described, and treatment with X-ray irradiation was discussed. It was not until a report in 1985 from the Mayo Clinic, which gave it the name of solid facial edema, that clinicians became alerted to its occurrence.

4.2.3.1 Clinical Findings Persistent solid facial edema occurs predominantly in men. Many, but not all, patients have a history of acne which predates the edema by 2–5 years. Age of onset is in adolescence or early adulthood. Usually, it is low-grade papulopustular acne that gives rise to solid persistent facial edema, and not highly inflammatory acne papulopustulosa or acne conglobata. The clinical picture is characteristic. There is a hard nonpitting swelling of the mid third of the face without scaling or the peau d’orange phenomenon. The skin does not indent when firmly pressed with finger. There is little day-to-day variation. The swelling is localized mainly on the forehead, upper eyelids, nasal bridge, nasolabial folds, and cheeks. It persists indefinitely, often increasing in severity with time. The condition does not involute spontaneously. Subjective complaints are slight, except for deformed facial contours. The appearance is grotesque, presenting a grave threat to self-esteem. 4.2.3.2 Pathogenesis Nothing is known about the pathogenesis. It is speculated that chronic inflammation of any cause, including bacterial infection, leads to lymphatic stasis, a theory which we do not

4 Acne Clinic: Morphogenesis

favor. The lack of a beneficial effect of antibiotics contradicts the bacterial etiology. The numerous mast cells found in the infiltrate may be responsible for fibrosis, as in other conditions such as neurofibromatosis. There is no evidence for an allergic or a traumatic origin.

4.2.3.3 Histopathology The clinician, not the pathologist, makes the diagnosis. The histopathology is uncharacteristic. A mild edema in the mid and deep dermis is found, along with ectatic lymph vessels and occasionally a sparse to dense perivascular lymphohistiocytic infiltrate. Remarkably, many mast cells are seen. The key feature is a fibrosis with thickening of the connective tissue up to 2–4 times its normal size, extending into the fibrous strands of the subcutaneous fat. 4.2.3.4 Differential Diagnosis At first glance, the condition may mimic streptococcal erysipelas. However, constitutional symptoms, increased local temperature, or even pain are absent, and oral antibiotics have no effect. Pareiitis granulomatosa (MelkerssonRosenthal syndrome) is often considered, but this diagnosis cannot be sustained in the absence of scrotal tongue, lip edema, or peripheral facial nerve involvement. Allergic reaction or contact dermatitis is often a misdiagnosis but should be excluded. Rarely can persistent facial and periorbital edema be the first manifestation of acquired angioedema, systemic lupus erythematosus, or underlying malignancies, such as lymphoma or cutaneous angiosarcoma. A similar solid edema occurs in rosacea, and even in patients who have neither acne nor rosacea. Perhaps the pathogenesis is the same, related to lymphatic obstruction or to fibrosis induced by mast cells. Rosacea tends to occur in an older age group and presents other signs such as flushing, blushing, or telangiectasia. In our opinion, the Morbihan disease, as first reported as a distinct entity in 1957 by Degos, and the chronic lymphedema, or solid facial edema in acne or rosacea, very likely describe the same chronic refractory condition. The name Morbihan came from the French district along the coastline of Bretagne, where Degos observed this condition in fishermen. 4.2.3.5 Treatment Treatment of solid persistent facial edema is largely unsatisfactory. The underlying acne or rosacea should be treated. Clinicians have tried almost everything imaginable in the past, including X-rays and high doses of antibiotics. Compression garments are unwieldy and usually not effective. Daily lymph massage deserves more study, as it might be valuable, but lack of evidence. Systemic corticosteroids have been reported to reduce the facial swelling but have been ineffective in our experience. Our tentative

4.3 Dynamics of Scars

recommendation is low-dose isotretinoin, 0.1–0.2 mg/kg body wt. daily, combined with 2 mg ketotifen daily over a period of 6–12 months. The ketotifen has effects on mast cells, and this is the reason for its use. Preliminary results are encouraging, but treatment failure and advocation of high doses are both reported in literature. Clofazimine may be worth a trial. The dosage is 100 mg four times a week. A combination of clofazimine and isotretinoin has also been reported to be helpful. Low-dose doxycycline or minocycline for long-term use over 3 months has been demonstrated to be effective in patients from Japan.

4.3

Dynamics of Scars

Next to comedones, scars are the hallmark of acne. Permanent scarring is the most dreaded outcome of this disease. Scarring can be the natural consequence of inflammatory lesions, or the result of self-manipulation; the latter is too often overlooked. Both types may coincide. In this chapter only spontaneous scars will be discussed; a separate chapter is devoted to self-inflicted scars (p. 217). The spectrum of scars extends from invisible to severely mutilating.

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4.3.2 Atrophic Scars Small, flat atrophic scars can occur on the face. Much larger ones, several centimeters in size, may develop over the shoulder blades or anywhere on the upper parts of the back. Atrophic scars are the insignia of acne conglobata. Fresh ones are pink to red, older ones alabaster-white to yellowish. Some of them are cigarette-paper thin, wrinkled, and transparent. As the collagen bed is extremely thin and atrophic, the blood vessels are visible through the thin overlying tissue. All skin adnexa are completely wiped out by the fibrotic process. Under magnification, not a single opening of follicle remnants or sweat glands can be seen on the surface.

4.3.2.1 Histopathology Quite distinctive is the extremely flattened-out, thin epidermis, void of rete ridges. Within the dermis there are numerous ectatic lymph and venous vessels with fine horizontally arranged collagen bundles, numerous fibroblasts, and irregular foci of lymphohistiocytic cells. Remnants of arrector muscles of hair, nerves, clusters of debris, giant cells, calcification, or even bone formation are variably present. No adnexal structures remain.

4.3.1 Pitted, Crateriform, and Ice-Pick Scars These are typical examples of one variety of acne scars. Exclusively confined to the face, they are variably shaped crater-like depressions (also known as boxcar scars), pits, and ice-pick scars (reminiscent of steep-sided pits in a glacier from an ice pick). Pitted scars may become confluent to form broad, retiform, extremely ugly scars, also known as rolling scars. Some experts suggest classification by the size, rather by the shape, for a more objective evaluation in the course of treatment. The rim of the scar can be steep or shallow. This makes a real difference to the bearer. Steep rims throw shadows and cause the scars to be conspicuous. Beveled rims allow light to flood the base with light shadows only. These scars are less noticeable.

4.3.1.1 Histopathology The picture is variable, but horn-filled canals are always seen, lined by an irregularly thickened epithelium budding off into ribbons. Signs of foreign-body granulomas are present, with mixtures of inflammatory cells. There are variable inflammatory changes, inevitably accompanied by a surrounding fibrosis. In short, scars are extremely pleomorphic, depending on their stage and on the severity of the preceding inflammatory lesion. These are not atrophic scars in histology and should better be described as depressed acne scars clinically.

4.3.3 Hypertrophic Scars Hypertrophic scars are also called fibrotic nodules. They are preceded by deep inflammatory nodules of acne conglobata, most common on the back, the shoulder, or over the sternum. The lesions are large, often 1–2 cm wide, dome-shaped, and elevated 5–10 mm above the surface. First they are fiery-red, later becoming porcelain yellowish-white and very hard and lumpy. The surface is shiny, without follicular openings. With time these lesions flatten, a process that may take years. Itching is frequently reported.

4.3.3.1 Histopathology A low-power view is diagnostic. The scar is exclusively composed of dense collagen bundles of varying size and in complete disarray. Most of the collagen is stratified horizontally. The skin adnexa have all been destroyed, and elastic fibers are absent or sparse. Vessels are scarce. This is the picture of extreme fibrosis.

4.3.4 Keloids Keloids are a terrible form of scars that occur more often in people of color than in Caucasians. Preferred sites are the sternum, breasts, lateral sites of the upper arms, shoulders, back of neck, and the V-shaped area of the back. Keloids do

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not arise spontaneously but start with trauma, often minor. In acne they follow inflammatory lesions which may simply be papulopustules but more often are inflammatory nodules in acne conglobata. Keloids are often mistaken for hypertrophic scars. The two are not interchangeable, as many seem to think. True keloids extend far beyond the original zone of inflammation. They are thick, raised, lobulated fibrotic plaques, with a strong tendency to recur after removal. Some look like lobsters with threatening pairs of claws. They hardly flatten with time. Elevated, hard scars in white persons are often hypertrophic scars. The color is deep red to brownish, with a shiny surface. After many years they become skin-colored especially in hypertrophic scars. No fine texture, wrinkles, or pores are visible. Itching, sometimes associated with pain, is very common. Keloids never regress spontaneously, even after decades, as may happen with hypertrophic scars, though they may become flat with time.

4.3.4.1 Histopathology Nothing very specific can be seen histopathologically, except for densely packed, whorled, mostly horizontally arranged collagen bundles. In between are ectatic blood vessels and sparse lymphohistiocytic infiltrates. Elastic tissue is completely absent, as in all scars. Any search for adnexal structures will be in vain. Histopathology may fail to appreciate the fact that keloids can be distinguished from hypertrophic scars. The fibrous tissue in the former is arranged in nodules, with circumferential bands of collagen delimiting each nodule. This architecture is absent in hypertrophic scars, where the collagen is in disarray.

4.3.5 Perifollicular Papular Scars Perifollicular papular scars are elevated, firm, hard growths prevalent on the back, rarer on the chest, and even rarer on the face. The scars are round to oval, white, slightly elevated lesions. Several terms are used to describe them: papular acne scars, perifollicular elastolysis, and post-acne anetoderma-like scars. They resemble closed comedones, hence the name closed comedo-like scar. We prefer the term perifollicular papular scars. These are best seen when the skin is pinched together between the fingers. They are frequently mistaken for closed comedones. Puncturing the apex with a pointed scalpel differentiates them from comedones: nothing comes out. Differential diagnosis may include papular elastorrhexis, disseminated lenticular dermatofibrosis, eruptive collagenoma, nevus anelasticus, mid-dermal elastolysis, postinflammatory elastolysis, anetoderma, pseudoxanthoma elasticum, and cutis laxa.

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4.3.5.1 Histopathology The extent of the scar is best visualized by staining of elastic fibers. The perifollicular papular scar is larger than it appears clinically. The elastic fibers are completely destroyed, and those surrounding it mark the borders of the scar. Generally, the adnexa have been destroyed, although sometimes a hairbearing unit survives with a fine hair protruding, hence the name perifollicular papular scar. Fibrosis is evidenced by dense bundles of collagen with straggly vessels.

4.3.6 Calcified Scars One of the late sequelae of severe inflammatory acne is calcification. Even bone formation (osteoma) may occur. The contents of these scars are not diagnosed clinically. Preferred sites are the face, especially the cheeks and chin, followed by the upper back. X-rays show many opacities, often an accidental finding. Sometimes calcified nodules can be suspected in a badly scarred face, when densities hard as stone are felt by palpation. Modern imaging techniques also revealed these bony depositions.

4.3.6.1 Histopathology Small or large calcified nodules are dispersed throughout the corium. Multinuclear giant cells often bear calcified deposits. Osteoma cutis is described elsewhere (p. 252, 331).

4.3.7 F istulated Comedones (Polyporous Comedones) Fistulated comedones are described elsewhere (p. 67, 176, 178). They are sequelae to acne conglobata, located mainly on the back, and they achieve their final form over many years of inflammatory activity. Quite often, dozens or even hundreds of clusters of comedo-like lesions are spread over the upper trunk. Each cluster is a system of interconnected horn-filled galleries. Between 2 and 20 openings may show on the surface of these complex units. A blunt probe inserted into one opening may issue from others nearby, indicating that one is dealing with a labyrinth of epithelium-lined channels. A comedo-like kernel can be pushed out; its surface is often dark black. The pigment is melanin. There is a smoldering low-grade inflammation, causing tender abscesses to form off and on. The bacteriology is that of the normal skin flora. Dumping of foreign material into the dermis, e.g., corneocytes, trapped hairs, and epithelial remnants, accounts for abscesses and foreign-body granulomas. Other stigmata of acne conglobata with atrophic and

4.3 Dynamics of Scars

hypertrophic scars are often in close proximity. Fistulated comedones never heal spontaneously and stay with the bearer for the rest of his life. Incision with fine scissors unroofs each gallery. The horny impactions fall out and do not reform. The opened lesions are allowed to heal by secondary intention. The cleanup of hundreds of fistulated comedones is a herculean task, though rewarding. Elimination of the rancid odor is in itself very gratifying to patients.

4.3.7.1 Histopathology Tunneled galleries, interconnected with each other, with a variable number of gully-like openings, are lined with keratinizing epithelium. Sebaceous lobules are usually destroyed, though occasionally a bizarrely shaped acinus is connected with the labyrinth. The tunnels are densely packed with corneocytes. Inflammatory pockets, small or large, are part of the spectrum. Melanin is produced around the openings, so that the horny material becomes black.

4.3.8 L inear Scars Associated with Draining Sinus Draining sinus is the most grotesque and disturbing lesion of the acne repertoire. Typically, these inflammatory tunnels are located in the face, notably the nasolabial folds, cheeks, bridge of the nose, chin, and sides of the neck. Suppurative material drains to the surface more or less continually. These are sausage-like thickenings which are linear, often several centimeters long. They are tender, smelly, and offensive with their periodic foul discharges.

4.3.8.1 Histopathology Multiple openings on the skin surface connect a set of galleries traversing the middle and deep corium. The tunnels are

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lined with a restless epithelium forming odd patterns with innumerable sprouts and ribbons. The appearance varies with each cut. Trapped in the tunnels are loose corneocytes, parakeratotic debris, all kinds of inflammatory cells, and sometimes curled-up hairs. The perilesional collagen is fibrotic. One finds pockets of inflammation with a variable mixture of lymphohistiocytes and granulocytes, and sometimes calcification. Actively smoldering draining sinuses can be treated by intralesional injection of corticosteroids, usually triamcinolone acetonide crystals (p. 138, 239, 290). Unfortunately, flare-ups are common. Final cure can be achieved only by surgery; the entire gallery has to be excised, resulting of course in a linear scar. Plastic surgeons can sometimes do wonders in excising and repairing draining sinuses.

4.3.9 E valuation of Acne Scar and Grading Systems Several grading systems are proposed for assessment of acne scar severity and for comparison of treatment results. They are mainly based on the morphology, size, and number of the scars. Review of the pigmentation, dynamic change and course should also be included. Due to the great variety of scar subtypes, their common coexistence in the same patient, particular predilection to different body regions, and high numbers of lesions in severe disease, a universal, precise, valid and applicable system is yet to be established. Recent efforts have been made to predict the liability to and risks of acne scar.

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Problems of Classification: Is This Acne Mild or Severe?

This boy has many closed and some open comedones. Many would call this mild (grade I) acne because there are only a few scar-forming inflammatory lesions. However, grading of acne requires evaluation of the quantity as well as the quality of the lesions. When hundreds of closed comedones are present, as in this case, the affliction falls into the serious category (grade IV) and deserves intensive therapy. Closed comedones are often more easily felt than seen. Patients know this very well, since they examine every corner of their face minutely. This boy’s skin is worse than it appears to the casual observer

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Closed Comedones

Above: Macrophotography of acne-bearing skin reveals many closed comedones, some of them in an intermediate stage to open comedones. The central pore is tightly constricted like a pouch Below: The histopathological counterpart reveals a microcomedo to the left, a fully developed closed comedo in the center, and an oblique cut through a microcomedo to the far right. No inflammation disturbs the scene

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Gross and Microscopic Anatomy of Open Comedones

In some patients open comedones sit silently in the skin, do not become inflamed, and reach old age, often remaining for years. The comedonal opening is more or less patent, exposing the pigmented apical portion, which makes the lesion look ugly Above Left:

Macrophotography opens a new dimension of viewing skin surface structures and follicular disorders. The comedo is wide open, with only a veil-like stretch of epidermis locking it firmly into its cavity

Right: An open comedo of this stature has reached old age; approximately 1–2 years of maturation can be assumed. The opening reveals a compacted pigmented core; the cystic cavity is much broader, almost 5 mm. The comedo causes bulging at the skin surface, a characteristic typical of old lesions Below Left:

Histopathology of an open comedo with no signs of inflammation. The wall is stretched out but bears no signs of leaks or inflammatory pockets. The sebaceous lobules are still quite large, indicating that the lesion is not extremely old. The sebum exits through sebaceous ducts, one of which is seen in this section. The sebum then flows in channels through the comedo. This is the favored location for bacterial chambers

Right: An old, compacted, open comedo, also not inflamed. The sebaceous glands dedifferentiate

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Corneocytes: The Bricks of Comedones

The bricks of the horny framework of comedones are corneocytes. Those from the interfollicular epidermis form the stratum corneum of the skin, those from the follicular infundibula of sebaceous follicles the comedones. The intercorneocyte material is the mortar, cementing the bricks properly together. This brick-and-mortar model is employed to explain epidermal barrier functions. Cellular adhesion is also provided by desmosomes, which in the horny layer are called corneodesmosomes The morphology of corneocytes is quite distinct. In this plate epidermal and comedonal corneocytes are compared. Suspensions are best prepared from triton-X-100 scrubs, vortexed, and stained with crystal violet and rhodamine B Above: Epidermal corneocytes are mostly of a regular, often even a symmetrical shape. Hexagonal and pentagonal patterns prevail. The cells have no nuclei and overlap at the edges. The sizes of corneocytes differ because of regional variations and effects of age. The surface area of epidermal corneocytes on the chest of an adult is about 1000 μm2. The cells increase in size, e.g., from about 900 μm2 in the newborn to about 1150 μm2 in the octogenarian Left:

Monolayer of corneocytes from the shoulder

Right: A single corneocyte from a darkly pigmented patient shows a central cluster of melanin granules Below: Comedonal corneocytes, the bricks from follicular filaments or comedonal kernels, are of a different quality than their epidermal counterparts. Variable size and shape, with convex and concave borders, and thin translucent fragile cells prevail. There are often nuclei or nuclear remnants. Above all, they are much larger than those from the epidermis, i.e., 50–70 μm in diameter Left:

A single corneocyte from a comedo. It contains numerous lipid-like droplets

Right: Individual corneocytes from a closed comedo. Irregular configurations, large size, nuclei, and nucleolar remnants are typical features

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atterns of Keratinization in Sebaceous Filaments and Microcomedones: P A Horizontal View

The waxy worms that can be squeezed out from spacious sebaceous follicles are either normal impactions in large follicles or the intermediate stage to microcomedones. In this plate the architecture of a microcomedo from a patient with oil acne is compared with that of a sebaceous filament in normal skin from an acne patient Above: Oil acne. Oil acne is the result of improper exposure to comedogenic compounds of various industrial oils and greases, including cutting fluids Left:

Microcomedo. About 30 densely packed corneocytes form a cylinder around the horizontally cut hair, with little sebaceous matter and debris between the hair and the concentric layers of corneocytes. Bacteria are absent, a characteristic feature of oil acne. Electron microscopy, ×10,500. Semithin methylene blue section on opposite page, left

Right: The follicular epithelium (acroinfundibulum) immediately adjacent to the epidermis is to the right, with keratohyalin granules. It produces dense and coherent corneocytes, indistinguishable from interfollicular epidermis. The toxic material responsible for oil acne inhibits bacterial growth. Electron microscopy, ×15,000 Below: Sebaceous filaments (synonymous with follicular filaments or follicular casts) are numerous and well developed in the oily skin of patients with acne Left:

The hair is to the left. Loose cellular debris, swollen corneocytes, lipid droplets, and bacteria form a soft, pasty material. Electron microscopy, ×8900. Semithin methylene blue section on opposite page, right

Right: The periphery of the filament consists of about 15 layers of corneocytes, 5 of which are shown here. They are swollen and show a few lipid inclusions. Many bacteria are embedded in an amalgam of sebaceous matter and biofilm. Electron microscopy, ×11,600

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Comedogenesis

All stages of primary comedogenesis can be studied in this panel Above Left:

A large sebaceous follicle with a follicular filament full of bacterial cavernas is on the left. A microcomedo is on the right. The keratinization of the sebaceous duct is typical for rapidly growing comedones

Right: A closed comedo is on the left with a tight opening and dedifferentiating sebaceous lobules. A large sebaceous follicle with debris but no appreciable keratinization in its three sebaceous ducts is on the right Below Left:

Every sebaceous follicle has its one sewage canal system. This large sebaceous follicle is drenched by three channels, each one directly associated with a sebaceous duct (*)

Right: An open comedo, densely filled with corneocytes. The sebaceous lobules are but a small bud, the pilary unit is still functioning

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4.10 Sebaceous Ducts Keratinize and Become Part of the Comedo With slow enlargement of open and closed comedones, the sebaceous glands gradually disappear. The formerly large sebaceous lobules become small buds with only a few sebocytes. The sebaceous ducts are integrated into the comedonal epithelium Above: The sebaceous ducts are the most vulnerable section of follicles and comedones. Often, small foci of inflammation are found here. The sebaceous duct is distended by parakeratotic and orthokeratotic debris (*) Below: This open comedo in the center has only small sebaceous glands left in its base compared with the large sebaceous lobules of a sebaceous follicle (right). The sebaceous ducts keratinize like the rest of the comedonal epithelium. The more the comedo becomes inflated by its growing kernel, the more are sebaceous ducts integrated into the comedo wall

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4.11 Ultrastructural Tableau of the Framework of an Open Comedo Corneocytes comprise the hard skeleton of the comedo. Electron microscopy reduces the artifactual spaces seen by light microscopy. Here the corneocytes are tightly packed. The narrow interspaces contain lipids and sugars, the so-called cement substance which is responsible for cohesion. The complex lipids form laminated membranes. The biochemistry and structural arrangement of this intercellular mortar is fairly well known. Laminated disks of ceramides and sphingolipids are their major components. Also desmosomes, those in the stratum corneum sometimes referred to as corneodesmosomes, contribute to cell-to-cell-adhesion. A portion of an epithelial cell with dark keratohyalin granules is at the lower right The moth-eaten internal structure of some of the corneocytes is an artifact. It is extremely difficult to obtain authentic images of the stratum corneum without artifacts. Electron microscopy, ×22,000. Semithin methylene blue section on opposite page

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4.12 Differences Between Corneocytes of Epidermis and Comedones The complex structure of the stratum corneum has come to light only recently. Special staining methods and electron microscopy are required to show details which are hidden under routine light microscopy. Even so, artifacts are abundant Above: Stratum corneum of normal epidermis. The granular layer at the bottom contains prominent keratohyalin granules. The corneocytes are densely packed with fibrous proteins, compacted into a stratum corneum about 15 cell layers thick. The spaces between the corneocytes are rich in lipids and sugars. This mixture is thought to keep the cells together, providing a barrier to inward diffusion of external substances as well as to outward diffusion of water. Also evident are electron-dense disks (desmosomes, sometimes called cementosomes or corneodesmosomes in the stratum corneum), which provide strong cell-to-cell attachments. The brick (corneocytes)-and-mortar model can be appreciated from this electron-microscopic picture. Electron microscopy, ×22,000. Semithin methylene blue section on opposite page Below: Comedonal corneocytes. There are tightly compacted, densely filled corneocytes with variably sized lipid droplets, reflecting rapid turnover. The empty spaces contain bilaminar membranes made up of various lipid classes. Electron microscopy, ×18,000. Semithin methylene blue section on opposite page

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4.13 Inside a Comedo The core of a comedo is a skeleton of tightly packed corneocytes. In the horny layer of the epidermis, they are stratified and stacked; in a comedo, stacking and disarray concur Above: Swirled corneocytes. The cells seem to push each other into meandering patterns. Electron microscopy, ×10,000 Below: In the central chambers of the comedonal kernel, detached corneocytes swim in an amalgam of sebum and debris. Electron microscopy, ×21,800. Semithin methylene blue section on opposite page

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4.14 Hairs in Comedones Above Left:

This is a whole biopsy which has been cleared with methyl salicylate to allow a three-dimensional view of the shape and contents of an open comedo. Coiled-up hairs of different diameters and lengths are trapped in the horny impaction. The tip of one has wondrously managed to extrude through the orifice. Major rupture of a comedo with displacement of hairs, horn, and lipids into the dermis provokes persistent indurated papules and nodules. Large, open comedones are end-stage lesions which rarely rupture

Right: The wispy, puny hairs that are trapped in comedones are easily overlooked. When the comedonal epithelium ruptures, they are translocated into the connective tissue Cross-section of an extracted comedo. The corneocytes are laid down in concentric lamellae. A number of hairs are cut in cross-section Below: An immersion-oil squash mount of an open comedo. The corneocyte matrix becomes transparent and allows visualization of individual hairs, which can be teased out and counted. The latter are tangled and coiled

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4.15 Pigment in Comedones Pigment in comedones, seen macroscopically in open but only microscopically in closed ones, is melanin and not dirt Above Left:

In this darkly pigmented subject, not only melanocytes but also the basal keratinocytes of the acroinfundibulum and interfollicular epidermis are packed with melanin. The lower part of the infundibulum does not contain melaninsynthesizing cells. Silver stain

Right: All four comedones, lifted up with a comedo extractor, display a melanin-pigmented cap and a whitish, unpigmented lower portion and tail. Unstained Below: Melanin-synthesizing cells are confined to the acroinfundibulum and the interfollicular epidermis. The closed comedo to the right bears no pigment. The pigmented hair trapped in the comedo is cut twice tangentially. Silver stain

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4.16 Pigment in Comedones Is Melanin The black cap decorating to varying degrees open but not closed comedones is neither dirt nor oxidized lipid matter, but melanin. Melanin is produced in the apical portion of the comedonal epithelium and then transferred into the corneocytes. Giant melanosomes, i.e., large packages of clumped melanin, ride with the corneocytes. Hundreds of condensed corneocytes provide enough pigment to produce a deep brown-black color Above: Tip of an open comedo with many giant melanosomes within corneocytes. Electron microscopy, ×35,000 Below: For comparison corneocytes from a benign pigmented skin lesion (lentigo senilis) are shown x35.000. Likewise, giant melanosomes ride upward with the corneocytes. Electron microscopy, x32.000 (Courtesy of Prof. Dr. Wilhelm Stolz, Munich, Germany)

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4.17 The Multiple Faces of Comedones The faces of comedones are variegated; no two look alike. Yet there is always something present that is specific to the key histopathological features Above Left:

A well-matured comedo which was never blasted by inflammatory episodes. This can be said because it is symmetrical, and whirled patterns of the comedonal core and pericomedonal fibrosis are absent. The sebaceous glands have all regressed. The pilary unit is intact, with one hair shed into the comedo. A few lymphocytes linger at the site where the sebaceous lobules once resided

Right: The opening of this comedo is spatulate. The core consists of densely packed corneocytes, with only a few bacteria in between. The large sebaceous lobule below still connects with the comedo, as was judged from serial sections Below Left:

The slight asymmetry, the pericomedonal fibrosis, remnants of parakeratotic corneocytes mixed with debris from granulocytes and lymphocytes (right upper portion), and multiple cross-sections through hairs all indicate that this comedo is old and has undergone several inflammatory episodes, from which it recovered. It is bizarre that two sebaceous lobules are still releasing sebum into the comedo

Right: A very mature open comedo. Its belly is hollow like an old tree. Multiple cystic cavernas make up a good portion of the kernel; they are all densely filled with bacteria, most of which are Propionibacterium acnes. The comedo seems to lift itself up graciously: this is an artifact from the pressure of the anesthetic injection

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4.18 The Evolution of Comedones Above: A beautiful example of a closed comedo is on the right. Its pore is tight, the epithelium stretched out and thin, the sebaceous gland atrophic, and the comedonal kernel tightly packed. It was never inflamed. For comparison, a normal sebaceous follicle can be seen on the left Below: This is also a closed comedo, but more specifically a macrocomedo or epithelial cyst. Its pore is tight, though artificially distended for histotechnical reasons. The epithelium is extremely thin. No sebaceous glands can be detected, even in step sections. The pilary portion has been destroyed. Perilesional fibrosis indicates earlier inflammatory phases. If left alone, these lesions can become very old, persisting for years or even decades

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4.19 Profiles of Inflammation A wide variety of inflammatory lesions arise from the rupture of comedones. All figures drawn from various histological sections Above: The closed comedo is the first visible lesion in acne. There are masses of Propionibacterium acnes in the central channels. Products of this invariably incite rupture. A normal sebaceous follicle is shown on the left; two vellus follicles and one eccrine sweat gland are on the right Middle Left:

The pustule. Disintegration of the upper epithelial lining has created an intrafollicular abscess with a perifollicular inflammatory reaction. The basal portion of the comedo is intact. Healing will occur by re-encapsulation; while a scar will form, it will generally not be clinically apparent, except for some minor distortion of the orifice

Right: The papule. The comedo has totally collapsed and the epithelial lining has been completely destroyed. Neutrophils have spread far into the tissue and even into the subcutaneous fat. Such lesions persist for several weeks and heal slowly, leaving a depressed scar Below: The nodule. The comedo has been shattered. Remnants of horn and hairs have been extruded into the tissue. The acute neutrophilic phase will give way to a chronic foreign-body granuloma, remaining in place for weeks or even months. An ugly permanent scar is certain. A vellus follicle is to the left, a sebaceous follicle with incipient inflammation to the right. If the nodule links up with the sebaceous follicle, a fistulated comedo is created

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4.20 Troublesome Acne This girl is 15 years old but already has bad acne. Few follicles are spared in this intensive affliction. The full spectrum of lesions is present, e.g., closed comedones, small papules, and pustules. The chest and back are also involved. Extreme seborrhea forms the background for the unusually numerous lesions. Aggressive therapy is indicated to prevent progression to an even more frightening disease. The emotional impact of acne on this girl is understandably disabling

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4.21 A Portrait of Acne The face is rich in sebaceous follicles, which are the site of acne lesions. The dynamics of acne can be appreciated from this picture, which shows various stages. Small, hardly perceptible, closed comedones, here in the nasolabial fold and on the temples (not to be confused with a few milia on the left lower eyelid), are primary lesions. Sooner or later these turn into inflammatory (secondary) lesions, the papules and pustules present here mainly on the cheeks and forehead. A few more indurated nodules hide below the mandible

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4.22 The Spectrum of Acne Above Left:

This woman’s complexion is not good. Her face is obviously oily and papules pop up, leaving scars. Excoriations inflicted by her fingers add another facet to the disease. Hormonal treatment, especially with antiandrogens, in combination with isotretinoin can be indicated

Right: Although not as severe as in the picture to the left, this is nonetheless troublesome acne. Inflammatory papules and deep, persistent nodules are mingled with the initial comedones Below Left:

Acne conglobata in a 16-year-old adolescent. This is serious acne, programmed to run for years and decades unless appropriately treated. In the middle of the cheek, confluent abscesses dissect the skin; a draining sinus can result from this. Systemic corticosteroids and isotretinoin are indicated

Right: This is the picture of sadness. The young woman has conglobate acne. Immediate action is required to prevent physical and mental scarring. Isotretinoin is indicated, provided that all contraindications are ruled out and guidelines are strictly followed

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4.23 Adult Acne or Persistent Facial Acne in Women This is sometimes called acne tarda, most of which appears in adulthood. Cases of this type of nasty, therapy-resistant inflammatory acne in women warrant an endocrinological workup. Hyperandrogenic conditions, including polycystic ovary disease or adrenal hyperplasia, may lurk in the background. One should also inquire about intake of anabolic steroids. Treatment should include oral contraceptives of the antiandrogen type where available and isotretinoin Above: The jawline is a typical area, where persistent inflammatory lesions predominate. This woman did not respond to conventional therapy. She was successfully treated with low-dose isotretinoin (0.2 mg/kg body wt) in combination with the antiandrogen cyproterone acetate prescribed as an oral contraceptive. Her face cleared completely in 7 months with no recurrence thereafter Below: This woman is only 19 years old, but she suffers miserably from closed comedones, scars, and confluent conglobate papules and nodules. Oral isotretinoin along with a contraceptive containing 2 mg cyproterone acetate and 35 μg ethinyl estradiol led to a permanent cure

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4.24 Inflammatory Acne in Men Above Left:

Irrespective of grading systems, anyone can easily see that this is bad acne. Face, neck, and shoulders bear papules and nodules, even hemorrhagic ones. Many closed comedones on the maxilla complete the varied spectrum of lesion

Right: A much milder course of acne, but troublesome. The patient has had this acne for years. It is now mostly inflammatory. The facial pores are wide, the skin are oily, and fine scars are already present. The dusky red hue of his nose may be a very early sign of a rosacea diathesis, a disease which can follow acne Below Left:

These many superficial and deep papules and nodules are aggressive and violent. Some persist for many weeks. Seborrhea is a typical feature. This is not the picture of gram-negative folliculitis, and no gram-negative organisms were cultured despite several attempts

Right: Bad and severe acne with confluent and conglobate lesions. The young man definitely suffers

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4.25 Folliculitis of Terminal Hair Follicles Versus Fragile Sebaceous Follicles Folliculitis, usually of the impetigo type (impetigo follicularis Bockhart), is a pyoderma that can be misinterpreted as an acne pustule Above: Staphylococcal folliculitis Left:

This lesion is a typical bacterial infection of a terminal hair follicle. Staphylococcus aureus is retrieved in great numbers from such lesions. The entire follicular canal is filled with granulocytes. There is no comedonal kernel

Right: Bacterial folliculitis with minimal accumulation of corneocytes swimming as an eosinophilic flotsam in a sea of pus. As in the lesion to the left, the sebaceous glands of the terminal hair follicle are intact Below: Fragile sebaceous follicles. Some acne patients, particularly those with acne conglobata and acne fulminans, have very fragile follicles. They rupture at an early stage before a substantial comedo can build up. Such lesions harbor Propionibacterium acnes and Staphylococcus epidermidis, but no pyogenic organisms Left:

A fragile follicle from a patient with acne conglobata. The follicle has ruptured to the upper right. The comedonal kernel has been partially lost during sectioning, but loose corneocyte debris is still present. The pilary portion is to the left

Right: A fragile follicle from a patient with acne fulminans. The canal is filled with granulocytes and debris, with a microcomedo close to the sebaceous ducts

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4.26 The Hateful Pustule Pustules are very conspicuous lesions and therefore hated by acne patients Above: A large, succulent pustule. Acne pustules arise from comedones; the latter are usually invisible. Here, the brownish comedonal core floats on a yellow sea of pus, surrounded by erythema Below: The histopathological counterpart is an abscess with a horny kernel. Only a short segment of the comedonal epithelium to the right is still intact, too small to re-encapsulate the entire inflammatory lesion

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4.27 Variegated Histopathology of Pustules, Papulopustules, and Cysts Open, but much more often closed, comedones undergo focal areas of inflammation. Depending on the site and degree, variable pustular elements are the result Above Left:

A quite old, open comedo with a dense central core, multiple bacterial cavities, a thin comedonal epithelium, and almost completely regressed sebaceous lobules has become inflamed. Pockets of granulocytes are dissecting along the entire comedonal epithelium, with a major collection of pus subcorneally. It is expected that this comedo will survive to become a secondary comedo

Right: Deep papulopustule. The comedonal kernel is in the center. The entire comedonal epithelium has been destroyed. The inflammatory infiltrate extends far beyond the original lesion. Healing will be slow, leaving a bad scar without reconstitution of a follicle Below Left:

This aged open comedo ruptured in its bottom portion. The comedonal epithelium has been reconstituted. Pericomedonal inflammation attacks the sebaceous lobules and pilary unit. It is assumed that they will survive

Right: An old closed comedo has been shattered at various points along the epithelial lining and is now a papulopustule. The pilary unit and the sebaceous lobules are destroyed; a cyst is born

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4.28 The Old Open Comedo Histopathological view of a large, long-standing open comedo. Old blackheads often show small segments of inflammation along their borders. Sometimes the epithelial lining is very thin or absent. Pericomedonal fibrosis indicates that rupture and repair have occurred many times. The inflammatory reaction is limited, because the really toxic soluble contents of the comedo are bottled up in the central chambers. The periphery of this comedo constitutes a dense capsule of corneocytes, which is an effective barrier The blue-stained amorphous material in the large multiloculated central cavities is a dense population of Propionibacterium acnes. Fortunately, mature open comedones rarely rupture and thus do not spill their toxic contents into the dermis, an event that would of course wreak havoc. The horny capsule almost seals off the internal contents, although not completely, as evidenced by the pericomedonal neutrophilic infiltrate

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4.29 Late Rupture of Comedones Above Left:

A microcomedo, just on its way to becoming a closed comedo, has ruptured. The biopsy is from a patient with acne conglobata. The still small comedonal core is layered between inflammatory cells and the severed, acanthotic comedonal epithelium. It is a poor sign that the abscess has dissected deep down into the dermis. There is much more inflammation than suspected clinically

Right: In contrast to the picture on the left, this is an old open comedo with a wide pore. Parts of the comedo are bacteriafilled chambers. The comedonal epithelium is extremely thin, almost absent on the right side. The pilary portion, but not the sebaceous lobules, is intact. Pericomedonal edema and fibrosis signal multiple earlier inflammatory episodes which the comedo survived Below: A quite symmetrical closed comedo has ruptured, for the first time, on its upper right side. The inflammation is localized mainly in the apical portion, classifying it clinically as a pustule. Healing will be fast, with almost no scarring. For comparison, a normal sebaceous follicle with sebaceous lobules, a pilary unit, and one hair in the follicular canal is seen on the left

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4.30 Deep-Seated Papules Papules are histologically hybrids, and therefore papulopustules. Superficially located lesions often drain to the skin surface and leave less trouble behind than deep-seated ones Above: A comedo has ruptured at its lower pole. One third of its bottom lining has been destroyed. The comedonal contents exploded far into the surrounding skin. This lesion will persist for many weeks or months until all of this inflammatory disaster has been cleared away. Scarring is inevitable Below Left:

The entire comedonal epithelium has been dissolved. The comedonal contents are exposed to the vasculature and connective tissue, inciting an inflammatory response. A bystanding sebaceous follicle to the left has already been attacked

Right: Higher magnification reveals the comedonal kernel with bacterial chambers. The bacteriology of papulopustules can be studied only if this comedonal kernel is secured. It will take months for this acne lesion to calm down, and scarring is inevitable and will be substantial

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4.31 Hemorrhagic Nodules Some patients with acne conglobata and acne fulminans react at the peak of the stormy disease with frank bleeding into the skin. Intact hemorrhagic nodules, and dome-shaped elevations form, or the skin ulcerates early on, leaving wide open bloody craters. Rarely are biopsies taken from these severely afflicted patients; this one is from the upper back Above: Two dome-shaped hemorrhagic nodules on top of an atrophic scar. Multiple other scars are seen in this patient with acne fulminans Below: Biopsy from a similar lesion. A hemorrhagic abscess occupies the middle and lower dermis. Gelatinous material is in the center, dissecting toward all directions. The dermis is totally necrotic. The debris is surrounded by a dense infiltrate. The contents of such hemorrhagic skin necrosis is sterile

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4.32 Nodules Patients with severe acne can develop nodules of fantastic size and at the most unusual locations Above Left:

A preferred site is the earlobes. The nodules persist for a long while and can re-erupt intermittently. They cause discomfort and pain. Aspiration yields a reddish or brownish viscous fluid. Unfortunately, refilling occurs within a few days. Sometimes intralesional injection of triamcinolone acetonide crystal suspension is helpful. The best treatment is with oral corticosteroids. Otherwise, nodules have to be excised, if possible, once they have come to a temporary rest Right: The bridge of the nose is another choice location for hemorrhagic nodules. Sometimes nodules turn into draining sinuses

Below Left:

The extensive tissue destruction can be seen in this low-power view. The abscess extends below the lateral and lower margin of this photograph. The remnant of the comedonal kernel is in the center. No comedonal epithelium has survived

Right: The ruptured comedo and parts of its epithelium are still alive. The abscess spreads far into all directions

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4.33 Late Events of Inflammation Biopsies from the skin of acne patients taken weeks or months after the acute inflammatory phase may disclose peculiar leftovers Above: Several weeks previously, this was the site of a papulopustule. The location was carefully identified and biopsied 10 weeks later. Clinically, it was a fairly fresh, slightly red scar. Histopathology showed more than was anticipated. Remnants of the comedo are present as foreign material. A whole string of multinucleated giant cells slowly digest the debris and corneocytes. Chronic, lymphocytic perivascular, and diffuse infiltrates, as well as ectatic venules, remain as a sign of the ongoing inflammation. The follicle that once held the comedo has been eradicated Below: More than 12 weeks previously, a deep-seated tender papule developed, persisted, and at the time of biopsy still showed inflamed skin. Deep in the dermis are spectacular inflammatory elements. Quite a large portion of the comedo, though devoid of its epithelium, drifts around. Two segments of epithelium (*) float in a sea of pus. The lymphocytic infiltrate reaches far beyond the boundaries of this section

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4.34 Draining Sinus: A Nasty Lesion Above: An illustrative example of a draining sinus that runs more than 5 cm from the nose to the corner of the mouth. It is still inflamed and tender, with stretches of atrophic scarring Below: Histopathology of a similar lesion explains why a draining sinus cannot come to rest. The tunnel is completely epithelialized, opens at multiple sites into the epidermis, and is chronically inflamed

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4.35 A Draining Sinus Should Not Be Incised Draining sinuses are too often misdiagnosed, resulting in inappropriate surgical intervention. While draining sinuses and nodules inevitably leave a scar, incisions produce far worse scarring. Intralesional injection of triamcinolone acetonide is the preferred local approach, sometimes combined with systemic corticosteroids and isotretinoin Above: Bilateral draining sinuses in a 14-year-old girl, an unusual presentation, to say the least. Acne lesions on her forehead provided the diagnostic clue. Within the next 4 years, she developed severe inflammatory acne on her face and back Below: Examples of detrimental effects of incision and drainage Left:

The draining sinus in a young girl received an incision 2 cm long elsewhere. The lesion not only refilled but also left an ugly scar. She also had open and closed comedones in the nasolabial folds and maxillary region

Right: Deep incisions (above) of a large draining sinus on the cheek of a 16-year-old girl elsewhere. Unfortunately, an unsightly scar (below) remained

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4.36 The Misery of Draining Sinuses Above Left:

The boy suffers not only from acne conglobata but also from draining sinuses on the bridge of the nose, the right nasolabial fold, and the chin

Right: A bulging abscess, linear in configuration, is a draining sinus Below: Acne conglobata has left variable scars on the cheek of this patient. The linear scar is a draining sinus, producing discharge from multiple openings and re-erupting occasionally like a volcano

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4.37 Cinematographic View of Fistulated Scars Serial sections of scars disclose striking patterns that are not expected clinically. Scars, like this one from the chin, may have surprising extensions. Epithelium-lined sinus-like tracts traverse the skin. The epithelium is bizarre, pouching out in various directions. Fistulated scars connect multiple follicles. This scar originated from a draining sinus. Most of the inflammation has cooled off, leaving a dense scar deep in the dermis with horizontally arranged collagen bundles and a chronic perivascular inflammation. Stiff beard hairs pinch through the scar, making clean shaving a problem. Acne is still present with comedones, as seen in the bottom section

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4.38 Victory Over a Terrible Disease: Acne Conglobata: Before Treatment This 15-year-old boy had terrifying acne conglobata. A great mixture of inflammatory lesions and scars coexist. There are also linear draining sinuses alongside the nose, on the glabella, and in the nasolabial folds. In addition to being disfiguring, these lesions are tender and painful. The devastated figure of Job depicted in the Bible could not have been more pitiful

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4.39 Four Months Later: Voilà! Even before 1979, when isotretinoin first became available, acne conglobata could be successfully treated, as exemplified by this patient. All that remains are some pustules An all-out therapeutic program was mounted in this horrendous case: • • • •

Tretinoin was applied twice daily The nodules were injected with triamcinolone acetonide, some two or three times Dapsone (DDS), 100 mg daily, was given for 3 months This was accompanied by a dose of 1000 mg tetracycline twice daily for several months

This patient has been satisfactorily maintained on topical tretinoin alone Today such a patient would be started on oral and topical corticosteroids, followed by isotretinoin

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4.40 Acne Conglobata in an Adult Contrary to common belief, acne does not always disappear in early adulthood. Acne conglobata, in particular, can rage on for a lifetime, even into old age. This is the case in the 52-year-old man shown here His back is a mess. Wide atrophic scars are everywhere along with black, polyporous comedones, papules, nodules, abscesses, and scars. The huge abscess on the neck is particularly painful when he is lying down. Movement is handicapped. Underwear and shirts are constantly soiled. This man became a social recluse. Nowadays, this fate can be avoided by systemic therapy with corticosteroids and isotretinoin

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4.41 Unusual Localizations Practically every region except the palms and soles may be involved when acne is very severe Above: While the face and shoulders are typical acne sites, the neck and the hairy scalp may also be seriously affected. Lesions on the neck are often very painful. Collars may aggravate the lesions mechanically. Here the lesions are mainly deep-seated papulopustules and nodules, each one persisting for many months Below Left:

The back of the ear, though hidden from view, is often involved to a surprising degree. Large open comedones on the ventral side of the ear may be numerous, as shown here

Right: Acne behind and in the ears. There are numerous large secondary closed comedones behind the ear and over the mastoid. These persist for years and occasionally rupture, causing painful abscesses

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4.42 Acne Scars One of the questions most often asked by acne patients is: Can my scars be removed or improved? Various techniques are available, including dermabrasion, chemical peels, punch elevation, punch replacement, collagen injections, and laser treatment, to name but a few Above Left:

Shallow depressions are the most common scars. These are highly amenable to surgical techniques. Ongoing inflammatory lesions should be treated first

Right: Numerous deeper scars call for expert evaluation. Soft tissue augmentation with collagen is an option. Replacement punch biopsies from postauricular skin are another Below: A fantastic variety of scars remain in the wake of inflammatory acne. In addition to comedones, scars are a hallmark of the disease. Multiple crisscross, pitted, and crateriform scars distort the face of this unfortunate man. His neck is similarly afflicted. Another late sequela of acne is the huge horn-filled cyst on the left side of the neck

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4.43 Variety of Scars This man, well into his adulthood, suffered serious attacks of acne more than 30 years ago. It is easy to see where he fought the disease. This photographic portrait documents more than any number of words. His entire face and neck are scarred, even his nose. The facial pores are wide; his skin is oily, despite the destruction of many sebaceous glands during the active phase of the disease. Ingrown beard hairs are an additional problem. The similarity to atrophodermia vermiculata is striking

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4.44 Pustules and Scars Most pustules and papulopustules in acne patients will leave a scar, histopathologically and clinically Above: A localized papulopustule with trapped remnants of the comedo kernel. The pus will soon be discharged. The lower portion of the comedonal epithelium will stay intact and could leave a scar, as depicted below Below: A pit in the skin with steep sides and loosely arranged corneocytes. This cannot be camouflaged. Histopathology reveals the extent and disaster of such scars. The base of the scar connects with strands of epithelium traversing the skin. The dermis is scarred with horizontally arranged fine fibrils, many lymphocytes, and histiocytes

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4.45 These Biopsies Came from Scarred Facial Skin Above: A shallow scar. Clinically, this is only a slightly depressed scar, which throws no shadows due to its gentle slopes. Beneath the epidermis, a remarkable scar is identified. It extends beyond the right and bottom margins of this figure. The collagen is dense and rich in blood vessels, which are surrounded by lymphocytes. The adnexa have been wiped out Below: A trough-like scar. Clinically, this is a cumbersome scar. Its sides are steep, allowing for phenomena of light and shadow. Histopathologically it is a fairly punched-out limited defect. One sebaceous follicle is connected with its base, as are sprouts of epithelium, possibly remnants of sebaceous lobules. The collagen beneath is horizontally arranged, with little inflammation

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4.46 Histopathology of a Shallow Scar Above: Clinically, this was a shallow scar on the cheek of an acne patient. Histologically, the scar is easily identified. Surprising are its depth and the dense chronic inflammatory reaction extending beyond the margins of the section Below: The special stain for elastic tissue reveals that the scar is void of elastic fibers. All adnexa have been destroyed. Von kossa stain

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4.47 Atrophic Scar Above: Huge irregular scars are eloquent evidence of the tendency of acne conglobata to engulf large areas of skin. Through fusion of lesions, only islands of normal skin remain. Most of the scarring on the back of this 16-year-old boy is of the flat, cigarette-paper, atrophic kind. The destruction has not yet come to an end, as there are still hemorrhagic crusts covering necrotic tissue (far left) Below: The normal tissue is to the left of the arrows. The scar has an atrophic epidermis with loss of rete ridges. The skin adnexa have been destroyed. Numerous ectatic vessels, a chronic lymphohistiocytic infiltrate, a few multinucleated giant cells, fibroplasia, and interstitial edema characterize the scar

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4.48 The Hypertrophic Fibrotic Nodule Above: This irregular, massive, hard, lumpy growth is a sequela of inflammatory nodules in acne conglobata. Fibrotic nodules are most common on the back, shoulders, or upper arms. With time they slowly flatten. The process can be accelerated by injecting corticosteroids intralesionally Below: Low-power view of a fibrotic nodule. Collagen bundles are in disarray but mostly horizontally arranged and of variable size. Thin-walled, dilated vessels are numerous and characteristic. The skin adnexa have all been destroyed. The scar extends further down than shown by this photograph

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4.49 Diagnostic Pitfalls The chest (above) and upper back (below) of this man with long-standing, severe acne are covered with hundreds of small, white dome-shaped papules, associated with inflammatory acne lesions. They are all scars and commonly mistaken for closed comedones. One can also call these closed comedo-like scars. They almost never occur on the face. While these scars may flatten a little after many years, no effective treatment is available. The scars are sequelae of prior inflammatory lesions. This man also displays larger hypertrophic scars, scattered among active inflammatory lesions

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4.50 Perifollicular Papular Scars (Closed Comedo-Like Scars) These small, elevated, hard growths prevail on the skin of the back and chest. In contrast, atrophic, depressed scars are more likely on the face. For better visualization of the lesions, the skin should be compressed between two fingers Above Left:

These round, white, elevated lesions are often mistaken for closed comedones. In most of them, a centrally or eccentrically located fine hair reveals the follicular origin

Right: The photograph reveals a pilary unit in the center, though tortured from previous inflammation, hence the name perifollicular papular scar. The scar extends far beyond the right, left, and lower margins of this picture with swirled collagen bundles, ectatic blood vessels, and a chronic lymphohistiocytic infiltrate Below: The comedo-like scar is larger than it appears clinically. Its true extent can be determined by staining for elastic fibers. The latter are generally destroyed and do not regenerate. The original elastic fibers are found only beyond the boundaries of the scar (arrows). The collagen bundles are rather coarse, densely packed, and eosinophilic. There are many dilated vessels of variable size in a disorderly arrangement typical for scars. The adnexa have been destroyed

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4.51 Keloids The spectrum of acne scars includes unusual forms. True keloids are more common in people of color than in caucasians; they are uncommon and hardly ever develop in the face. Inflammatory lesions may be followed by thick, elevated, lobulated, fibrotic plaques which resemble true keloids. They are hypertrophic scars and less likely to recur when excised. Preferred sites are the V-shaped area of the chest and back, particularly over the sternum, breasts, lateral aspects of the upper arms, and shoulders Above: In this 18-year-old man, the keloids are limited to the areas of previous acne: chest, arms, and shoulders Below: Confluent, huge expanding fibrous plaques on the back establish the unequivocal diagnosis of keloids. Unlike hypertrophic scars, keloids are extremely difficult to treat and tend not to flatten with time. The acne is still smoldering with inflammatory papules and pustules. Early and comprehensive treatment can prevent these extensive scarring

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4.52 Widespread Scars Above: This young man has acne conglobata. Thick, raised, red, itchy, and painful growths stud his back, shoulders, and chest (not shown here) Below: Close-up of upper back showing ongoing inflammatory lesions in need of continuing treatment

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4.53 Widespread Scars Above: The skin of the chest, neck, and upper back is a mess. The V-shaped area of the chest bears multiple, shallow, trough-like scars, closed comedo-like scars, and a few papules Below: The back, on closer inspection, is also badly scarred. Open comedones, fistulated comedones retaining heavily pigmented corneocyte impactions, and scattered papules are a burden

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4.54 Fistulated (Polyporous) Comedones Fistulated comedones can be classified as secondary comedones or, eventually, as scars. They have a complicated history and take a long time to develop. Rare on the face but common on the back, they are late and permanent sequelae of acne conglobata Above: This adult man seems to have many giant blackheads. On closer inspection, it can be seen that the comedones are distributed in clusters. Indeed, each comedo is a member of a complex system of interconnected horn-filled galleries. Other stigmata of acne conglobata are also present: Atrophic and hypertrophic scars and, invariably, a few hot spots where the disease refuses to die, even after decades Below: A probe inserted in any opening can be made to issue from any of the others in the complex. A part of the horny plug has been pushed out. These comedones are really specialized scars filled with corneocytes. The pigment is melanin. The gaping and irregular outlines are telltale signs of scarring

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4.55 Fistulated Comedones Fistulated comedones, also called polyporous comedones, have two or more openings. Sometimes there are 20 outlets. The whole structure may be compared to a rabbit warren. Fistulated comedones are actually scars Above: Much of the skin of the back of this adult man has been mutilated by innumerable inflammatory episodes in the past. The inflammatory battle is over; what is left are hundreds of thick, dark comedonal structures full of dense horn. The black comedo-like impactions are dry, solid masses of corneocytes. These are interconnected complexes with two to more than a dozen openings. The pigment is melanin. The only effective treatment is the dissection of the overlying epithelial bridges, setting free the keratinized debris Below: The way polyporous comedones originate is illustrated here. Two sebaceous follicles have fused via an inflammatory process, leaving a joint horn-filled cavity below with two chimneys above. There is a diffuse inflammatory process going on, with fibrosis surrounding the comedo. The sebaceous acini have been destroyed or are reduced to small undifferentiated epithelial buds, shown at the base. For comparison, there are two intact sebaceous follicles on the left

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4.56 Cysts The term cystic acne is somewhat of a misnomer. Cysts are epithelial-lined cavities. The cysts in acne are a result of repeated ruptures and re-encapsulations, best defined as large secondary comedones Above: Cysts can be found everywhere in the territory of acne, mostly on the trunk. However, the face is not spared. This black man has one cyst behind his ear (left) and many on his cheeks (right). Puncture reveals a cheesy, horny material. The epithelial sac can be removed with a small curette, putting a permanent end to the cyst Below: Cysts are soft and fluctuant. They have a widespread distribution in this man, occurring on his face, chest, shoulders, and back. They slowly enlarge over time, some attaining gigantic size. At that stage the epithelial wall becomes quite thin and can easily rupture by trauma. Ruptured cysts leave abscesses in their wake. Patients are well advised to have their cysts shelled out to prevent rupture and subsequent inflammatory nodules Left:

Multiple cysts on the temple, cheek, chin, and chest

Right: This white man in his late fifties has had acne all his life, which is not unusual for acne conglobata. He has many scars, secondary open comedones, and cysts

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4.57 Acne Cysts The repertoire of acne is vast, and some of the actors are strange characters; among them are cysts Above Left:

The cyst is a late lesion of acne conglobata but not a burned-out inflammatory lesion. It is a soft, seemingly lifeless, flesh-colored, round mass which, on close inspection, sometimes shows a central dimple or pore. In fact, it is a huge secondary comedo formed by repeated rupture and re-encapsulation

Right: After puncture, or with pressure alone, a string of whitish, curdy horny material can be forced out. To prevent reformation the epithelial sac must also be delivered or excised completely Below Left:

A single cyst shelled out by blunt dissection

Right: Histopathology shows a huge epithelium-lined sac containing loose horny matter. There are no hairs, the pilary unit having been destroyed long ago. Though a pore was not visible clinically, there is a tiny orifice. A localized inflammatory reaction is going on at the bottom of the lesion like a brushfire

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4.58 Rupture of Closed Comedones A complete rupture blew up this closed comedo, dispersing some of its contents into the corium. This is clinically equivalent to a deep persistent papule or nodule Above: The comedonal core is in place. The comedonal epithelium has ruptured to the left and right, is now acanthotic, and tries to reconnect. Pericomedonal inflammation is far-flung Below: Close-up of the breach shown in the upper photograph, which are now lying outside the comedo. A foreign-body reaction will persist for many weeks or months before this alien material has been completely resorbed, showing tangential cuts through three hairs

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4.59 Secondary Comedones Secondary comedones are always postinflammatory stages of open or closed comedones. Their fate is variable. Some remain in the category of open or closed comedones, and others develop into cysts and even others into fistulated comedones. The worst outcome would be a draining sinus. Two of these possibilities are presented here Above: Fistulated comedo. A large comedo has sustained a bad blowup; miraculously it survived. The comedo is sandwiched between inflammatory debris. The comedo wall is acanthotic and sends out tongues of epithelium. The widespread and heavy chronic infiltrate with many multinucleated giant cells shows that the cleanup job is still to be done. An innocent neighboring sebaceous follicle to the right became involved in the abscess and is now permanently linked with its aggressor. Thus a fistulated complex is formed. If more than two follicles or comedones are linked up, there is always the danger of a draining sinus ensuing Below: Cyst. This comedo also escaped total destruction by the previous inflammatory episode. Its wall is sealed again, locking up the comedo core and debris. However, none of the sebaceous glands or the pilary unit survived. Only a minuscule bud of epithelium (arrow) remains to show where the sebaceous follicle once prospered. The area surrounding the cyst is still inflamed

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Acne Conglobata Balakirski G, Neis MM, Megahed M. Acne conglobata induced by adalimumab. Eur J Dermatol. 2017;27:320–1. Grech I, Giatrakos S, Damoraki G, Kaldrimidis P, et al. Impact of TNF haplotypes in the physical course of acne vulgaris. Dermatology. 2014;228:152–7. Hennes R, Mack A, Schell H, Vogt HJ. 13-cis-retinoic acid in conglobate acne: a follow-up study of 14 trial centers. Arch Dermatol Res. 1984;276:209–15. Marcusson JA, Tyden G. Acne conglobata in transplant patients treated with isotretinoin. Br J Dermatol. 1988;118:310–2.

Bibliography Rebora A, Dallegri F, Patrone F. Neutrophil functions in acne conglobata. Dermatologica. 1979;159:217–20. Rosner IA, Richter DE, Huettner TL, Kuffner GH, et al. Spondyloarthropathy associated with hidradenitis suppurativa and acne conglobata. Ann Intern Med. 1982;97:520–5. Sosis AC, Panet-Raymond G, Goldenberg DM. XYY chromosome complement in a patient with nodulocystic acne. Dermatologica. 1973;146:222–8. Wilkins JW Jr, Voorhees JJ. Prevalence of nodulocystic acne in white and negro males. Arch Dermatol. 1970;102:631–4. Wollenberg A, Wolff H, Jansen T, Schmid MH, et al. Acne conglobata and Klinefelter’s syndrome. Br J Dermatol. 1997;136:421–3.

Solid Persistent Facial Edema of Acne Camacho-Martinez F, Winkelmann RK. Solid facial edema as a manifestation of acne. J Am Acad Dermatol. 1990;22:129–30. Carney JW. Solid edema of face (??). Arch Dermatol. 1966;94:664–6. Choi WT, Stetsenko GY, Zhang J, et al. Cutaneous angiosarcoma clinically presenting as progressive solid facial edema in a 43-year-old male. Dermatol Online J. 2013;19:20409. Connelly MG, Winkelmann RK. Solid facial edema as a complication of acne vulgaris. Arch Dermatol. 1985;121:87–90. Dragan LR, Baron JM, Stern S, Shaw JC. Solid facial edema preceding a diagnosis of retro-orbital B-cell lymphoma. J Am Acad Dermatol. 2000;42(5 Pt 2):872–4. Friedman SJ, Fox BJ, Albert HL. Solid facial edema as a complication of acne vulgaris: treatment with isotretinoin. J Am Acad Dermatol. 1986;15:286–9. Helander I, Aho HJ. Solid facial edema as s complication of acne vulgaris: treatment with isotretinoin and clofazimine. Acta Derm Venereol (Stockh). 1987;67:535–7. Jungfer B, Jansen T, Przybilla B, Plewig G. Solid persistent facial edema of acne: successful treatment with isotretinoin and ketotifen. Dermatology. 1993;187:34–7.

189 Okubo A, Takahashi K, Akasaka T, Amano H. Four cases of Morbihan disease successfully treated with doxycycline. J Dermatol. 2017;44:713–6. Tosti A, Guerra L, Bettoli V, Bonelli U. Solid facial edema as a complication of acne vulgaris in twins. J Am Acad Dermatol. 1987;17: 843–4. Yell JA, Mbuagbaw J, Burge SM. Cutaneous manifestations of systemic lupus erythematosus. Br J Dermatol. 1996;135:355–62.

Dynamics of Scars Ali FR, Kirk M, Madan V. Papular acne scars of the nose and chin: an under-recognised variant of acne scarring. J Cutan Aesthet Surg. 2016;9:241–3. Clark AK, Saric S, Sivamani RK. Acne scars: how do we grade them? Am J Clin Dermatol. 2018;19:139–44. Kang S, Lozada VT, Bettoli V, Tan J. New atrophic acne scar classification: reliability of assessments based on size, shape, and number. J Drugs Dermatol. 2016;15:693–702. O’Brien L, Pandit A. Silicon gel sheeting for preventing and treating hypertrophic and keloid scars. Cochrane Database Syst Rev. 2006;1:CD003826. Tan J, Thiboutot D, Gollnick H, Kang S. Development of an atrophic acne scar risk assessment tool. J Eur Acad Dermatol Venereol. 2017;31:1547–54. Thomé EP, Steglich RB, Meotti CD, et al. Case for diagnosis. Papular elastorrhexis. An Bras Dermatol. 2012;87:651–3. Varadi DP, Saqueton AC. Perifollicular elastolysis. Br J Dermatol. 1970;83:143–50. Watson JB. Monoporous and polyporous acne. Arch Dermatol. 1959;80:167–70. Wilson BB, Dent CH, Cooper PH. Papular acne scars. A common cutaneous finding. Arch Dermatol. 1990;126:797–800. Wortsman X, Claveria P, Valenzuela F, et al. Sonography of acne vulgaris. J Ultrasound Med. 2014;33:93–102.

5

Distinctive Acne Entities

Core Messages • Distinctive acne entities refer to acne in certain period of life before puberty or after menopause in women, in which acne is induced by excessive endogenous or exogenous androgens. • Acne neonatorum is not uncommon but usually mild. The etiology remains unclear and is probably associated with intrinsic hormonal dysfunction in newborns. Differential diagnoses may include acne venenata induced by ointments and oils, acne or acneiform eruptions due to drugs given to the mother during pregnancy, milia, and neonatal cephalic pustulosis or Malassezia furfur pustulosis. • Acne infantum usually occurs from the third to the sixth month of life and tends to be more severe and persistent for many months or even years. The lesions may vary from a few comedones to conglobate acne. An underlying hormonal disturbance should be excluded in severe cases. In contrast to acne neonatorum, treatment is required and even with systemic isotretinoin and prednisone under close surveillance. • Prepubertal acne warrants special attention when other changes of precocious puberty are present. Steroid acne can be observed in children on topical or systemic glucocorticoid treatment. Children are susceptible to chloracne and suffer from its long-term complications. • Adult acne seems to show an increasing prevalence in women, with a typical distribution on the lower face. Perioral dermatitis and rosacea are the most important differential diagnoses, while concurrence is possible. Low-dose oral isotretinoin is the most effective treatment, but implementation is not always easy. • Premenstrual periodicity or exacerbation of acne is not uncommon. The etiopathogenesis remains unclear. The use of combined oral contraceptives can help. • The prevalence and course of acne in pregnancy is less studied. Severe acne seems rare, and gestational hyperandrogenism such as androluteoma should be ruled out. Differentiation

to rosacea fulminans should be kept in mind. Treatment decision should consider embryonal toxicity. • Data about peri- and postmenopausal acne are very limited. It is not uncommon and usually of low grade and burns out in their 70s. Coexistence with facial hirsutism, if remarkable, indicates possible androgen excess. Worsening of acne and hair loss has been observed in women under certain hormone replacement therapy. • Bodybuilding with increased intake of milk protein concentrates and doping acne with abuse of anabolic- androgenic steroids are associated with increased mTORC1 activity, attenuation of p53 signaling, anabolism, and insulin resistance. The induced acne preferentially affects the trunk and ranges from acne vulgaris to conglobate acne and even in rare instances acne fulminans.

5.1

Acne in Infancy and Childhood

We generally think of acne as a disease which begins in adolescence. Its presentation in the neonatal period or during infancy is disturbing but rarely serious. The following synopsis of acne shows the great spectrum of acne diversities and variations.

5.1.1 Acne Neonatorum Acne neonatorum is certainly a good deal more common than the approximately 200 related publications reported so far would lead us to believe. Pediatricians are familiar with it and regard it casually because of its short duration. The incidence may be more than 20% if one includes the presence of only a few comedones. Acne neonatorum occurs at birth or in the first weeks of life. This type of acne seems to occur clinically more often in boys than in girls, although this has not been carefully

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studied. Closed comedones, sometimes accompanied by a few open ones, and often a scattering of papules or pustules are usually confined to the cheeks but occasionally affect the chin and forehead. In contrast to adolescent acne, the chest and back are not affected. The eruption is generally mild and normally regresses spontaneously within several months. The pathophysiology of acne neonatorum is probably related more to the infant’s intrinsic hormonal milieu rather than to maternal hormonal influence. At birth and for the first 6–12 months of life, infant boys have early pubertal levels of luteinizing hormone (LH) and testosterone. In both boys and girls, the neonatal adrenal gland is hyperactive. Although both boys and girls have an adrenal contribution to their elevated androgens, boys in addition have testicular androgen derived from testosterone synthesis and are thus more vulnerable to neonatal and infantile acne. Steroid synthesis in the fetal ovary is relatively limited. Rarely an in utero virilization secondary to androgenic tumors or associated with certain medical treatments can act as triggers. It remains to be determined if neonates of low birth weight or on bottle-feeding are especially predisposed to neonatal acne. It is important to differentiate acne venenata induced by ointments and oils, acne infantum, acne or acneiform eruptions due to drugs given to the mother during pregnancy (diphenylhydantoin, lithium), milia, and neonatal cephalic pustulosis or Malassezia furfur pustulosis. In mild cases of acne neonatorum, treatment is usually unnecessary; comforting words will do. If required, topical retinoids or other keratolytic agents are sufficient. Newborns tolerate comedolytic agents quite well. Inflammatory lesions are best treated with low-strength benzoyl peroxide (2.5%). Because of potential absorption, clindamycin is not used due to the theoretical risk of pseudomembranous colitis. Exogenous oil such as baby oils and lotions may aggravate this disorder and should be avoided.

5.1.1.1 Fetal Hydantoin Syndrome Women who take diphenylhydantoin/phenytoin, during early pregnancy, may give birth to premature babies with the fetal hydantoin syndrome. This is characterized by growth retardation, peculiar facies, variable limb defects, and dry hair. Acne neonatorum may also be a feature of this syndrome. This acneiform eruption is provoked by transplacental transfer from the mother to the fetus. It resolves spontaneously within the first months of life. Carbamazepine and valproic acid are two other drugs deserving special attention because they can induce hyperandrogenism in treated women.

5 Distinctive Acne Entities

5.1.2 Acne Infantum The term acne infantum has been applied to a type of acne that generally does not make its appearance until the third to the sixth month of life and tends to be more severe and persistent, lasting for many months or even years. More boys than girls are affected. The lesions are confined to the face. They may be fairly numerous, and comedones often predominate, mainly on the cheeks. Inflammatory lesions such as papules and pustules are frequent, and, on rare occasions, nodules may be apparent. Occasionally, healing with scars is observed. We feel that severe acne infantum may be predictive of severer acne in the adolescent period. On the other hand, family history of severe acne appears to be a risk factor for acne infantum. The course of acne infantum varies considerably. The lesions may be limited to a few comedones that clear after a few weeks. Most cases disappear within the first 2–3 years of life. Others have been reported to persist into puberty. In some children, severe or persistent acne may be a mark of underlying hormonal abnormalities, including premature adrenarche, congenital adrenal hyperplasia, gonadal or adrenal tumors, Cushing’s syndrome, and true precocious puberty. The best screening evaluation is probably of bone age, i.e., an X-ray of the knee or wrist, which is a good physiological measurement of androgenicity. If available, a growth chart is another valuable tool, as children with high androgens will have accelerated growth across standardized growth percentiles. Laboratory evaluations may include serum total and free testosterone, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), LH, follicle-stimulating hormone (FSH), 17alpha-hydroxyprogesterone, and prolactin. If evidence of hormonal imbalance or precocious puberty is found, the child should be referred to a pediatric endocrinologist for more specific hormonal evaluation. Differential diagnosis includes acne neonatorum (in newborns only) and acne venenata (from comedogenic oils, creams, or lotions applied by parents). Infantile type of eosinophilic pustular folliculitis or eosinophilic pustulosis of infancy should be suspected in infants of Asian descent, with scalp involvement or showing recalcitrance to acne treatment. Blood or tissue eosinophilia in histology and good response to topical steroids further support the diagnosis. Acne infantum requires decisive treatment and can be a real challenge. A comedolytic agent such as tretinoin, isotretinoin, or adapalene is usually helpful. Topical antibacterials such as benzoyl peroxide or erythromycin may be tried as adjuncts to the comedolytic agent. Oral antibiotics, espe-

5.1 Acne in Infancy and Childhood

cially erythromycin, may have to be added to bring the process under control. All the tetracyclines must be avoided, since they will cause permanent tooth discoloration at least up to 8 years of age. Intralesional steroids may be tried for deep inflammatory lesions. Parents must be informed that treatment may be prolonged.

5.1.2.1 Acne Conglobata Infantum Rarely, acne conglobata may occur in infants. The lesions are confined to the face, which is disfigured by papules, pustules, nodules, and draining sinuses. Depressed scars are a dreaded result and an indication for aggressive treatment. The disease may endure and last right into puberty. Differential diagnosis is limited to pyodermas and panniculitis of various origins. Otherwise, the picture is so dramatic that no other form of acne needs to be considered. Treatment is the same as for severe acne infantum. Topical and systemic modalities may be started at the same time. We suggest oral corticosteroids, starting with about 1.0 mg/kg body weight and then slowly tapering it. Once the inflammation has cooled off, oral isotretinoin may be considered for several months, at a daily dose of 0.2–0.5 mg/kg. A parallel start with systemic glucocorticoids and isotretinoin can also be considered. The effect of isotretinoin on growth and ultimate height potential must be discussed with the families. Data in the literature support the concept that isotretinoin in doses of 0.5–1.0 mg/kg daily for up to 6 months has no side effects on bone density, but this dose is not used by us for pediatric patients. This therapeutic regimen is followed by topical retinoids or other keratolytic agents to prevent relapse. Resistant nodules can be treated with intralesional injections of triamcinolone at a concentration of 1–2 mg/mL. 5.1.2.2 Acne Venenata Infantum This is contact acne, which is a sequela of topically applied comedogenic substances. These are often greasy salves, creams, pomades, and oils, applied by parents and grandparents. Ethnic and cultural peculiarities determine the prevalence of acne venenata infantum in different groups. The condition is more common in Mediterranean countries and among African Americans. Clinically, within the first 3–4 months of life, but not at birth, dense crops of tiny closed and open comedones spring up on cheeks, nose, forehead, and temples, but rarely on the trunk or extremities. Differential diagnosis includes acne infantum, acne venenata from other sources, or steroid acne induced by topical use of corticosteroids. Removing the contactant terminates the problem, but the time to clearing may be long. In some cases, topical retinoids or other keratolytic agents are effective. Treatment should be kept as simple as possible.

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5.1.3 Acne in Preschool and School Age Acne after infancy and before puberty can be grossly divided into two groups, preschool age and school age, based on the age onset. As children in the preschool age do not normally produce significant levels of adrenal or gonadal androgens, acne in this age group is rare and warrants special attention. Precocious puberty is a spectrum disorder including premature thelarche, pubarche, adrenarche, and menarche. A trend toward an earlier onset of puberty has been observed, with an increasing number of children displaying precocious puberty. Possible reasons under discussion may include the global socioeconomic improvement across different populations, changes of lifestyles and nutrition ways, and the action of endocrine-disrupting chemicals. Central precocious puberty due to CNS abnormalities, congenital adrenal hyperplasia, adrenocortical and gonadal sex hormone secreting tumors, and exogenous source of androgens need to be excluded. Collaboration with pediatric endocrinologists and a systemic workup is indispensable. On the contrary, acne in the school age, especially in the preadolescent period at 9–12 years, appears more and more commonly observed. Premature adrenarche is defined as the appearance of clinical signs of hyperandrogenism, most pronounced with pubic/axillary hair, but also acne, seborrhea, osmidrosis/bromhidrosis, and excessive growth, before the age of 8 years in girls or 9 years in boys, associated with high concentrations of adrenal androgen precursors abnormal for the chronologic prepubertal age. The prevalence is higher in girls than in boys, and the affected children are often overweight and taller than their peers. Association with a later development of metabolic syndrome or polycystic ovarian syndrome has been an issue of intense investigation during the last decades. A careful checkup is likewise necessary. Topical, oral, or inhaled corticosteroids induce steroid acne. Children are unusually susceptible to these agents. Examples may include children with nephrotic syndrome, rheumatoid diseases, severe therapy-resistant asthma or atopic dermatitis, and posttransplantation. Crops of inflammatory papulopustules should arouse suspicion. Treatment entails withdrawal of the offending steroid. The eruption responds best to retinoids and/or benzoyl peroxide. Chloracne has been considered an epidemiological marker of exposure to dioxin, and children are at special risk to ingest toxins of contaminated soil by swallowing dust while playing. For more details please refer to the chapter of chloracne (Table 5.1).

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5 Distinctive Acne Entities

Table 5.1 Acne in infancy Disease Fetal hydantoin syndrome and acne neonatorum Androluteoma syndrome of pregnancy and masculinized female fetuses Acne neonatorum Acne infantum Acne conglobata infantum Acne venenata Variants of acne venenata Steroid acne Pomade acne

Age Newborns Newborns

Sex m + f f

Cause Hydantoin therapy of the mother during pregnancy Virilizing luteoma (androluteoma) in pregnancy

Newborns >3 months >3 months >3 months

m + f m + f m + f m + f

Maternal and infantile and first weeks of life androgens? Androgens of child? Androgens of child? Contact with comedogenic compounds

>1 year Newborns

m + f m + f

Local or systemic corticosteroids Comedogenic care products and infants

m: male, f: female

5.2

dult Acne, Postadolescent Acne, A Acne Tarda

According to dermatological dogma, acne vulgaris regresses in most patients in early adulthood. This is not true for women and neither for men. Low-grade acne may persist for decades past adolescence (persistent type), while moderate acne appears more and more common. Acne can spring up in women who have escaped adolescent acne (late-onset or de novo type), and the trend goes upward. Both types can be observed in adult women, while the late-onset type appears rare in adult men.

5.2.1 Epidemiology Adult acne is delineated when acne occurs after 25 years of age, an arbitrary definition. Exact figures of prevalence are varying, since epidemiological studies based on general population are scarce, and questionnaire studies are mostly unreliable. It is estimated about one fourth to one third of adult women in general still suffer from acne. Men and women seem equally affected in persistent adult acne, while late-onset form predominates in women. More and more women are seeking consultation, with rising ages and long-lasting courses of acne, in our impression. Routine examination of the face regardless of the chief complaint will show that this is a rather common problem. The importance of identifying this type of acne lies in the fact that it may be misinterpreted as acne cosmetica. Originally, it was thought that adult acne was due to acnegenic substances in cosmetics and skin care products, especially moisturizers and sunscreens. As many as 50% of cosmetic products were found to be comedogenic in the rabbit-ear assay. This neatly explained the limitation of the disorder to women. It turns out that cosmetic acne has been overdiagnosed. Cosmetics do not account for most of the

cases of adult acne in women. Experience has taught us that withholding suspected cosmetics is largely of no avail. For a long time major manufacturers of cosmetics are very sensitive to safety issues and routinely test their products for acnegenic potential. Comedogenic cosmetics have virtually been eliminated, but this cleanup has had no perceivable effect on the prevalence of acne, exactly the opposite.

5.2.2 Clinical Manifestations The distinguishing features of genuine acne cosmetica are fairly dense crops of closed and open comedones located in the areas of application. Papulopustules are also fairly numerous, sometimes without a preceding microcomedo (chemical folliculitis). Of course, it is not permissible to make a diagnosis of acne cosmetica in women who rarely or never use cosmetics or who select only brands made by reliable manufacturers. History is telling. By contrast, in adult acne, the lesions tend to be less numerous, and the comedones are small and of the closed type. Papulopustules are scattered and generally show a preexisting horny mass when the contents are expressed. The typical distribution is in the lower part of face, especially submandibular and submental areas. Premenstrual flares and premenstrual tension syndrome are frequent. We view this as true acne vulgaris of endogenous origin. Rosacea and perioral dermatitis are the most common differential diagnoses, and the possibility of coexistence is higher in this age group.

5.2.3 Pathogenesis The etiology is not understood. Androgen story is inconsistent. Association with hyperandrogenemia has been controversially

5.3 Acne and Menstrual Cycle

demonstrated, in which ethnic difference deserves attention. Some metabolites of circulating androgens, such as androsterone glucuronide, were found to increase in adult women with moderate acne, but not confirmed in other studies. Polycystic ovary syndrome should be explored, especially when the patients also show hirsutism and/or androgenetic alopecia. A small group of patients with persistent adult acne was diagnosed as nonclassical congenital adrenal hyperplasia, but the exact prevalence is unknown. Stress is certainly of higher significance in adult acne, especially the late-onset form, but quantitative analysis is difficult. Familial factors seem to influence more the individual susceptibility to adult persistent acne. Many women report recurrence or exacerbation of acne after discontinuation of contraceptives or change from combined oral contraceptives to contraceptive rings. Smoking plays a role, especially in manifestation as multiple densely populated comedones, but the study about the quantity and duration is inconclusive. Whether obesity or nutrition influences more adult than adolescent acne is unclear.

5.2.4 Treatment Evidence-based data are scarce. Adult acne is generally more resistant to treat than adolescent acne, probably due to multiplex persisting triggering factors. For mild cases, topical treatment combining different active ingredients deserve consideration. For moderate acne, oral antibiotics usually help little, and recurrence rates seem higher, and the associated vaginal candidiasis more common than those in the adolescent group. We recommend low to very low doses of isotretinoin, e.g., 10 mg/day, or 10 mg on 3 days/week, at least for 6 months. Ideal duration of treatment remains to be determined, given the chronic recurrent course of adult acne. Precautions to avoid pregnancy must be declared and reminded at each visit, because many women at this age are hesitating to take oral contraceptive pills, and some of them may wish to have children in the near future.

5.3

Acne and Menstrual Cycle

A variety of distressing symptoms occur in many women just prior to menstruation. Nervousness and irritability (premenstrual tension) are often attributed to psychological influences. Objective changes also occur, such as weight gain and breast enlargement. These are not so easily passed off as having an emotional origin. Similarly, premenstrual exacerbation of acne is a genuine phenomenon, experienced by at least one third of

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patients. There may be two subgroups of patients: premenstrual acne in women otherwise without acne and premenstrual exacerbation of acne in women prone to acne. Typically, these women notice an increase in papules/pustules about a week or so before menstruation. These spring up rapidly and, like all other inflammatory lesions, are due mainly to the rupture of invisible closed comedones (microcomedones). The phenomenon is most evident in comparatively mild papulopustular acne, far less so when numerous deep-seated papules are present. An outcropping of five to ten pustules every month, more or less regularly, is bound to be noticed, though the overall effect may not strike an outside observer. Some physicians have even doubted the existence of premenstrual acne. Although lesion counts rarely increase greatly, the fixed rhythm of the process can scarcely be overlooked. Fingering the lesions owing to heightened tension is not the cause, though it may of course intensify the reaction. There is no good explanation for the peculiar periodicity. There are unproved and false claims, we believe, that sebum secretion varies with the menstrual cycle, the increase occurring at just the right time to explain the flare. Others have been persuaded that free fatty acids in the surface lipids increase at this time. It is exceedingly unlikely that the amount or composition of sebum is affected by the menstrual cycle. Even so, such changes would not explain a sudden outcropping of inflammatory lesions. Another observation, fanciful in our opinion, is that the follicular orifice becomes smaller between days 15 and 20 of the menstrual cycle. This supposedly impedes the outflow of sebum, laying the groundwork for an exacerbation 3–4 days later. Some believe that the flares occur only in those patients who show premenstrual weight gain. This, too, may be questioned. Premenstrual flares often develop in women whose weight remains steady and whose breasts do not become edematous. It has been found that diuretics have no more prophylactic effect than placebos, whether or not there is demonstrable weight gain. Influence of hormone changes on the inflammation and the virulence of P. acnes can be an interesting hypothesis. There is some evidence that progesterone mediates premenstrual acne in some unknown way. The omission of progestin in contraceptive regimens has avoided flares which otherwise occurred regularly. On the other hand, there is evidence suggesting that progesterone can increase sebum synthesis and promote inflammation, while progesterone receptor, especially type B, has been demonstrated in sebaceous glands. We have no special treatment for premenstrual acne. We do not recommend diuretics. We take note of the phenomenon and treat the acne vulgaris according to its severity. When acne improves from contraceptive pills, preceding menstrual flares generally diminish or disappear.

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5.4

5 Distinctive Acne Entities

Acne in Pregnancy

Data about the prevalence and course of acne in pregnancy are very limited. A questionnaire study on a total of 378 pregnant women from France showed a median prevalence rate of 42.3%, among them 86.6% had acne previously, with relapse of cured acne in 35.1% and persisting acne since adolescence in 51.5% of cases. Among the latter women, 59.7% reported acne worsening during their pregnancy, 9.1% an improvement, and 31.2% no change. Among the 137 multiparous patients, 65.9% reported acne flares during previous pregnancies. While 35.2% of the women had only facial lesions, the proportion of women with lesions on the trunk was 87.2%. Inflammatory lesions predominated. In a prospective observational study of facial acne in 35 pregnant women from Taiwan, the average number of acne was highest in the second trimester. Primigravida, female gender, and low birth weight for gestational age of the newborn were associated with higher numbers of acne in the second and third trimester. Severe acne in pregnancy seems rare, and differentiation to rosacea fulminans should be made. Treatment should be based on the benefits and risks of a particular drug by referring to the new FDA Pregnancy and Lactation Labeling Rule (PLLR).

5.4.1 A ndroluteoma Syndrome of Pregnancy (Pregnancy Luteoma) and Gestational Hyperandrogenism A persistent corpus luteum with excessive testosterone production causes severe abnormalities based on androgen excess. The mother becomes masculinized with seborrhea, hirsutism, deepening of the voice, acne papulopustulosa, and even acne conglobata. Female fetuses are at risk and can be born with signs of masculinization, including acne. This tumor is rare, with only a few cases reported in the literature so far. Diagnosis is based on ultrasound identification of the tumor in the ovary and excess androgenic hormone levels in the peripheral blood. Surgical removal of the androgen-producing corpus luteum during pregnancy is curative. Hyperreactio luteinalis is another condition associated with hyperandrogenism in late pregnancy, which is supposed to arise from ovarian hyperstimulation by a high-level of β-hCG during pluripara or gestational trophoblastic diseases. The resulting hypertrophy and luteinization of the theca interna cells induce hyperandrogenism with maternal virilization which can occur in 20–30% of cases.

Cushing syndrome is an extremely rare event in pregnant women, and its diagnosis and treatment are a medical challenge. Adrenal origin with adrenal adenoma is the most frequent cause, in contrast to ACTH-secreting corticotroph adenomas of the pituitary gland, which account for 70% of the usual cases. Aromatase converts androgens into estrogen, and placental aromatase deficiency can induce ambiguous genitalia in the female fetus and maternal virilization during the pregnancy including acne and hirsutism. Fetal congenital adrenal hyperplasia is an additional cause of gestational hyperandrogenism and acne.

5.4.2 Treatment of Acne in Pregnancy Acne should be treated during pregnancy to prevent worsening, scarring, or psychological impairment of the mother. Systemic tetracycline, doxycycline, minocycline, and isotretinoin are contraindicated. Topical benzoyl peroxide and topical azelaic acid are safe options. For severe cases, systemic macrolides such as erythromycin or azithromycin can be considered from the second trimester in cooperation with the gynecologists. Mechanical peeling or chemical peeling with glycolic or alpha-hydroxy acids may be of some help for mild acne, but salicylic acid, trichloroacetic acid, or phenol peels should be avoided. Topical retinoids, the best studied tretinoin, are not recommended during pregnancy. In humans, no long-term treatment with topical tretinoin was found to affect the endogenous levels of retinoic acid or its metabolites. A meta-analysis ruled out a major increase in the rates of major congenital malformations, spontaneous abortions, low birth weight, and prematurity associated with exposure to topical retinoids in the first trimester. The management of acne in pregnancy is complicated by the lack of clinical studies and pharmacokinetic data in this patient population.

5.5

Peri- and Postmenopausal Acne

The literature rarely mentions peri- or postmenopausal acne. Postmenopausal acne was discovered coincidentally in older women seeking medical counseling for a variety of facial problems, including hyperpigmentation, seborrheic keratoses, large pores, trichostasis spinulosa, wrinkles, and other signs of photodamage. Epidemiological surveys are lacking, and the prevalence of postmenopausal acne is not known. We think it is quite common, as can be easily ascertained by questioning about breakouts. It is most frequently seen in women with thick, darker, oilier skin.

5.6 Bodybuilding and Doping Acne

Postmenopausal acne affects women mostly within the first 2 years after ovarian failure. In fact, it may presage the last menstruation, often in association with other menopausal symptoms such as hot flashes. Perhaps a better title would be perimenopausal acne. We propose the following explanation: As the ovaries no longer produce enough estrogens but continue to synthesize androgens, as do the adrenals, a state of unopposed hyperandrogenism comes into play. Hormonal imbalance incites menopausal acne, thus making it a member of the expanding list of hyperandrogenic syndromes. Postmenopausal acne is low-grade acne with scattered small, closed comedones which become visible when the lax skin is stretched. Open comedones are rare. Small, sparse papulopustules are also part of this picture. The disease smolders for many years, an annoying problem which detracts from the patients’ appearance. The low-grade acne eventually burns out when the women are in their 70s. Most of these women do not exhibit scarring from adolescent acne and give no account of having suffered from it. They do have large facial pores, especially on the nose and malar areas. A fair number complain of oiliness, but others insist that their skin is dry. There seems to be an association with postmenopausal hirsutism of the chin and upper lip. Some women wax to remove unsightly hair or use bleaching agents. Vellus hairs of the beard area of the cheeks tend to be long, creating an unwelcome fuzz. Not all hirsute women have postmenopausal acne. Circulating androgen levels are usually within normal range. When postmenopausal acne and hirsutism occur together with other virilization signs, it is imminent to exclude hyperandrogenemia associated with androgen-secreting tumors or hyperfunctional state of adrenals or ovaries. Hyperandrogenism in PCOS women may persist after the menopausal transition. Ovarian stromal hyperthecosis and iatrogenic hyperandrogenemia are special causes to be considered. The administration of dehydroepiandrosterone or testosterone to improve sexual function or menopausal symptoms in postmenopausal women may cause concern of androgenic side effects including acne flare-up. We have witnessed some cases, but relevant studies based on dermatological observations are limited. Concomitant frequent heavy use of cosmetics in this age group is uncommon. Perimenopausal acne is not likely to be confused with acne cosmetica. The latter shows a higher density of comedones and larger inflammatory lesions. Multiple miliary osteoma cutis of the face, especially on the forehead, can occur in postmenopausal women with or without significant acne history. A careful differentiation to closed comedones is necessary. Many of these women, being older, exhibit

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dermatoheliosis from chronic excessive exposure to sunlight. These are probably coincidental findings. Many show the usual stigmata of photodamage, popularly called photoaging, including wrinkles, blotches, growths, or leathery yellow skin.

5.5.1 Treatment Since comedones dominate the scene, tretinoin or other retinoids are the drugs of choice. A 0.025% tretinoin cream formulation is advised to begin with. A 0.1–0.3% adapalene formulation is less irritating. Clearing of comedones can be anticipated within 4–5 months. When tolerance develops, usually in about 1 month, a 0.05% formulation is recommended. Alternatively, other retinoids or other comedolytic agents can be used. Antimicrobial agents, including benzoyl peroxide and topical antibiotics, are not indicated.

5.6

Bodybuilding and Doping Acne

Prevalence of abuse of anabolic-androgenic steroids in individuals of the general population has reached alarming dimensions. Use of androgens is no longer limited to competitive sports, but has spread to leisure and fitness sports, bodybuilding, and individuals motivated to increase muscular mass and physical attractiveness. Especially adolescents are at risk for doping acne. Androgens are combined with recombinant growth hormone, insulin, and insulinotropic milk protein-fortified drinks that potentiate health risks of androgen abuse. A survey of 484 recreational athletes in 11 German gyms in the area of Frankfurt/ Main showed that 12.9% of the men and 3.6% of the women reported to take anabolic drugs. They consumed anabolic- androgenic steroids (AAS, 35% p.o.; 71% parenterally), stimulants (14%), and growth hormone (GH, 5%). Disappointingly, 28% of the suppliers were physicians. Abusers of doping substances primarily intended to increase muscle size (86%) and strength (61%). A recent report of 180 patients, who visited a specialized anabolic-androgenic steroids (AAS) outpatient clinic in the Netherlands between 2011 and 2016 showed that AAS abuse started at a median age of 23 years. Ninety-five percent used AAS in cycles (median of 4 cycles) and completed them after 10 weeks. Cycles consisted of a median of three different AAS, most commonly testosterone, nandrolone, and trenbolone. GH was used by 34% in addition to AAS. Side effects during ASS cycles occurred in 96% of patients, mainly acne (38%), gynecomastia (34%), agitation (27%), decreased libido (34%), and erectile dysfunction (20%). Onset of aggravation of acne is a typical clinical feature of AAS and whey protein abuse especially in the body-

198

building scene. In doping acne, the clinical picture ranges from the initial manifestation of acne vulgaris or a worsening of preexistent acne up to features of acne conglobata or the sudden occurrence of acne fulminans. Whey proteininduced acne has been reported to preferentially affect the trunk.

5.6.1 Anabolic-Androgenic Steroids One of the first visible clinical side effects of androgen abuse is bodybuilding acne, which is the most commonly reported visible adverse effect of AAS misuse. It is well known that androgens lead to hypertrophy of sebaceous glands together with increased sebum excretion, enhanced production of skin surface lipids, increased population of P. acnes, and finally the development of acne. Androgens enhance the expression of SREBP1c, the key lipogenic transcription factor of sebaceous lipogenesis. In addition, androgens promote the expression of miRNA-125b, which is a key negative regulator of TP53 mRNA. Thus, androgens activate SREBP1c and suppress p53 expression, critically involved in acne pathogenesis.

5.6.2 G rowth Hormone (GH), GH Secretagogues, Insulin-Like Growth Factor-1, and Insulin Recombinant growth hormone (GH), GH secretagogues, insulin-like growth factor-1 (IGF-1), and insulin are available from Internet stores and the black market. They all stimulate the somatotropic axis and increase anabolism and muscle mass. Both GH and IGF-1 appear on the World Anti-Doping Agency (WADA) list of prohibited substances. GH secretagogues stimulate hypothalamic GH secretion. GH stimulates hepatic IGF-1 secretion, the key signal promoting the activation of AKT and mTORC1. IGF-1 directly via activation of the kinase AKT promotes the expression of the lipogenic transcription factor

5 Distinctive Acne Entities

SREBP1c and via activation of mouse double minute 2 (MDM2) downregulates cellular levels of p53, a critical transcription that suppresses cell proliferation and SREPB1c-mediated lipogenesis. GH stimulates proliferation and differentiation of sebaceous glands. Furthermore, IGF-1 stimulates sebaceous lipogenesis, gonadal and adrenal androgen synthesis, as well as the activity of 5α-reductase, which converts testosterone to its ten times more active dihydrotestosterone. Insulin and IGF-1 via AKT-mediated phosphorylation of the transcription factor and nuclear androgen receptor (AR) suppressor FoxO1 enhances androgen signaling.

5.6.3 Milk Protein Concentrates Milk protein concentrates, either whey protein or casein protein powder, are used to increase muscle mass in the bodybuilding and fitness gyms. Acne induced or aggravated by high intake of whey protein has been reported in the literature. The market provides these fortifiers for muscle gain in buckets of 5 kg or even more. Easily accessible Internet-provided recipes recommend daily addition of 80 g whey protein powder added to 1 L milk, so-called whey smoothies. Casein and whey protein are highly enriched in branched-chain amino acids (BCAAs) such as leucine comprising 14% and 10% of total whey and casein protein, respectively. BCAAs and glutamine are crucial activators of mTORC1. It has been shown that increased mTORC1 activity and the glutaminolysis pathway play pivotal roles in sebaceous lipogenesis. In pancreatic β-cells, these insulinotropic amino acids via mTORC1 activation enhance insulin secretion. The highly soluble and fast hydrolyzed whey proteins increase plasma BCAA and peak insulin levels already after 20 min. Casein acts more slowly within hours and preferentially stimulates hepatic synthesis of IGF-1. Milk consumption increases plasma levels of GH, IGF-1, and insulin, which all activate the kinase AKT with resultant increase of SREBP1c activation and downregulation of p53.

5.6 Bodybuilding and Doping Acne

199 Milk Whey

Insulin

GH sectetagogues Recombinant GH

Casein

Insulin ≠

IGF-1 ≠

IR

IGF1R

Recombinant IGF-1

FoxO1 Ø

p53Ø

PI3K≠

Androgens

PTEN TP53

p53 Ø

AR

AR ≠

p53Ø p53 Ø

P

P FoxO1 Ø

AKT ≠

MDM2 ≠

p53 Ø

AR-dependent target genes MIR125B

Sebaceous lipogenesis and sebocyte survival ≠ BCAAs

mTORC1 ≠

Th17 cell differentiation and IL-17 secretion ≠ Protein synthesis and muscle cell growth ≠

Fig. 5.1 Synergistic interplay of androgens and doping agents that enhance insulin/IGF-1 signaling including milk, dairy protein concentrates, growth hormone (GH), GH secretagogues, recombinant IGF-1, and insulin. These compounds enhance the activity of the kinase AKT that activates mouse double minute 2 (MDM2), the key negative regulator of p53. Reduced p53 activity enhances the expression of androgen receptor (AR), which promotes the expression of AR-dependent target genes including MIR125A, a key negative regulator of TP53 expression. Insulin/IGF1-signals and androgen stimuli converge in p53 suppression,

which allows anabolism and growth resulting in muscle gain and sebaceous gland hypertrophy. Branched-chain amino acids (BCAAs), major constituents of dairy proteins, enhance the activity of mTORC1, which promotes muscle protein synthesis, sebaceous lipogenesis, and Th17 cell proliferation with increased secretion of interleukin 17 (IL-17). Abbreviations: FoxO1 forkhead box O1, IGF-1 insulin-like growth factor-1, IGF1R insulin-like growth factor-1 receptor, IR insulin receptor, PI3K phosphoinositide-3 kinase, TP53 p53 gene. Published with kind permission of © Bodo Melnik 2019. All Rights Reserved

In cultured peripheral blood mononuclear cells, the addition of BCAAs increased the production of reactive oxygen species and activated AKT-mTORC1 signaling suggesting that high concentrations of BCAA could contribute to the proinflammatory and oxidative status. Furthermore, BCAAmediated mTORC1 activation enhances the Th17 cell population and secretion of proinflammatory interleukin 17, a signature cytokine found to be highly expressed in the skin of acne patients (Table 5.2; Fig. 5.1).

Table 5.2 Commonly used anabolic-androgenic steroids in the fitness environment according to Boos et al. (1998) Anabolic-androgenic steroid Methenolone Testosterone Stanozolol Methandrostenolone Oxandrolone Nandrolone

Average daily dose [mg] 75.6 58.5 37.4 36.6 25.0 4.0

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5.7

5 Distinctive Acne Entities

Acne Neonatorum or Acne Infantum

Above: This baby developed inflammatory papules and papulopustules soon after birth. Excessive androgen production by the newborn, typical for this period, is blamed for the eruptions. Most babies lose their acne spontaneously within a few months. Tiny follicular papules or pustules, but no comedones, are typical for this setting. Malassezia furfur folliculitis is a good differential diagnosis Below: A very similar picture as seen in the above illustration is present. The diagnosis is acne neonatorum, mostly with slightly raised tiny papules on both cheeks and the chin, spontaneously disappearing

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b

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5.8

5 Distinctive Acne Entities

Acne in Newborns and Infancy

It is not unusual for newborns to present some signs of acne in their face. Also in early childhood, acne can appear with many variations. Above Left: Acne neonatorum. Many papulopustules and small comedones cover the face of this boy. The skin is oily, signifying androgen-stimulated sebaceous gland activity Right: This could pass as acne neonatorum or acne infantum but is actually acne venenata in a 5-month-old infant. Some mothers have an irresistible urge to grease the skin with exotic salves. In this case an unidentifiable ointment had been applied several times daily. Aggregations of comedones always suggest an exogenous cause. As a rule, infants and children, who have immature follicles, are relatively resistant to acne Below Left: Acne infantum. Indurated deep papules and nodules persist for many months, with new lesions coming up periodically Right: Acne conglobata, the severest form of acne infantum. Understandably, the parents of this girl worry about the outcome of this severe inflammatory variant of acne. Scarring is inevitable. Laboratory workup is necessary to rule out endocrine disorders

a

b

c

d

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5.9

5 Distinctive Acne Entities

Acne Infantum and Acne in Childhood

Above Left: The young boy has painful grouped inflammatory nodules on both cheeks. The ones on the left cheek are interconnected and form a draining sinus. There are no comedones. The nodules are not caused by bacterial infection. Treatment is mandatory with systemic steroids for a short while and an oral antibiotic of the macrolide type. Scarring is a feared complication Right: Grouped inflammatory nodules on both cheeks, here pictured the left side. They are most likely connected forming a draining sinus. No other acne lesions are present. These children should be observed at regular intervals in case they develop acne, mostly of very early onset around puberty Below Left: Acne infantum of painful nodular lesions on both cheeks. Treatment is indicated as stated above. Peculiar is the inflammatory granulomatous lesion on the lower left eyelid. The literature contains reports that such patients may bear heralding signs of rosacea developing later in adulthood, presenting in childhood with such lesions. It remains open if this is true. The hematoma on the chin and hemorrhagic crust came from an earlier injury while playing Right: The boy is approaching puberty. Earliest clinical sign of beginning puberty is the onset of smelly armpits (you should ask the mother). He developed multiple tiny closed comedones and a few open ones on the forehead, cheeks, and chin. Topical therapy is recommended. The diagnosis as idiopathic facial aseptic granulomas as proposed by French authors can be considered in the three boys depicted above and below left, given the absence of comedones

a

b

c

d

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5 Distinctive Acne Entities

5.10 Wild Outbreaks of Acne Following Testosterone Injections and Other Anabolics Contrary to former belief, sebaceous glands in young adult men are not maximally stimulated by endogenous androgens. Excessive doses of androgens not only increase sebum production but can cause severe inflammatory and scarring acne. Above: Bodybuilding acne Left: This 21-year-old man had had only mild facial acne since the age of 14 years. Two months before these pictures were taken, he started a bodybuilding program together with illegal medication of anabolics and vitamin-B cocktails. His face, chest, back, shoulders, and upper arms broke out with deep inflammatory papules, conglobate nodules, and pustules. Hypertrophic and keloid scars were seen a year later. Thus, doping causes acne conglobata Right: Close-up of the left shoulder and upper arm showing the conglobate nature of the disease Below: Anabolic-induced acne fulminans. The young man wanted to build up muscle mass. One side effect was the sudden outbreak of acne fulminans on the chest (and back, not shown here), finally leaving scars

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5 Distinctive Acne Entities

5.11 The Toll of Bodybuilding Fitness studios and men’s health facilities propagate bodybuilding programs. Impressive looks can unfortunately be accompanied by deleterious side effects. Above: Acne fulminans, mostly on the chest, persisted for many weeks and months before the patients consulted a dermatologist for help. He had used various undisclosed drugs and nutrients. Thick painful and oozing plaques permit a prima vista diagnosis. Atrophic scars are the late sequelae of such lesions, indicating the long history of similar lesions Below: The back is studded with inflammatory papules, crusts, and scars

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b

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5 Distinctive Acne Entities

5.12 A Bloody Disaster of Anabolic-Induced Acne Fulminans: Destruction of the Skin, Bleeding, and Pain Above and below: Vegetating, mushy, and bleeding vascular granulation tissue. New lesions spring up, and old ones are crusted and finally leave a flat scar

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5.13 Androluteoma of Pregnancy An androgen-producing tumor can turn an otherwise healthy person into a severely sick person within weeks. This woman had been working as a model until her first pregnancy. She was overwhelmed in the first trimester by unusual skin changes completely unknown to her: seborrhea; hirsutism on her face, chest, and abdomen; and eruption of papules, pustules, and abscesses, leaving behind unsightly scars. A masculinizing syndrome was suggested by deepening of her voice. Her gynecologist suspected an androluteoma of pregnancy. Removal was followed by slow regression of all these lesions, leaving mild scars. A healthy boy was delivered several months later. Androgenization of newborn girls is a worrisome complication of androgen excess. Above Left:

Severe inflammation, seborrhea, and hirsutism disfigure this woman

Right: Acne conglobata-like hemorrhagic draining sinuses behind the earlobe Middle Left:

The acne-prone area of the chest is also involved

Right: Increased hair growth and scattered papules and pustules on the abdomen are part of this syndrome Below Left:

Inflammatory papules and pustules on the back

Right: Close-up of a highly inflamed papulopustule on the back

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Bibliography

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Adult Acne Carmina E, Godwin AJ, Stanczyk FZ, et al. The association of serum androsterone glucuronide with inflammatory lesions in women with adult acne. J Endocrinol Invest. 2002;25:765–8.

5 Distinctive Acne Entities Di Landro A, Cazzaniga S, Cusano F, et al. Adult female acne and associated risk factors: results of a multicenter case-control study in Italy. J Am Acad Dermatol. 2016;75:1134–1141.e1. Goulden V, McGeown CH, Cunliffe WJ. The familial risk of adult acne: a comparison between first-degree relatives of affected and unaffected individuals. Br J Dermatol. 1999;141:297–300. Han XD, Oon HH, Goh CL. Epidemiology of post-adolescence acne and adolescence acne in Singapore: a 10-year retrospective and comparative study. J Eur Acad Dermatol Venereol. 2016;30:1790–3. Rademaker M, Wishart JM, Birchall NM. Isotretinoin 5 mg daily for low-grade adult acne vulgaris—a placebo-controlled, randomized double-blind study. J Eur Acad Dermatol Venereol. 2014;28:747–54. Shen Y, Wang T, Zhou C, et al. Prevalence of acne vulgaris in Chinese adolescents and adults: a community-based study of 17,345 subjects in six cities. Acta Derm Venereol. 2012;92:40–4. Svensson A, Ofenloch RF, Bruze M, et al. Prevalence of skin disease in a population-based sample of adults from five European countries. Br J Dermatol. 2018;178:1111–8. Trakakis E, Papadavid E, Dalamaga M, et al. Prevalence of non-classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Greek women with acne: a hospital-based cross-sectional study. J Eur Acad Dermatol Venereol. 2013;27:1448–51.

Acne and Menstrual Cycle Boyanova L. Stress hormone epinephrine (adrenaline) and norepinephrine (noradrenaline) effects on the anaerobic bacteria. Anaerobe. 2017;44:13–9. Cabeza M, Miranda R. Stimulatory effect of progesterone and 5 betaprogesterone on lipid synthesis in hamster flank organs. Steroids. 1997;62:782–8. Evans J, Salamonsen LA. Inflammation, leukocytes and menstruation. Rev Endocr Metab Disord. 2012;13:277–88. Kariya Y, Moriya T, Suzuki T, et al. Sex steroid hormone receptors in human skin appendage and its neoplasms. Endocr J. 2005;52:317–25. Pochi PE. Acne in premature ovarian failure. Reestablishment of cyclic flare-ups with medroxyprogesterone acetate therapy. Arch Dermatol. 1974;109:556–7.

Acne in Pregnancy Bechstein SK, Ochsendorf F. Akne und Rosazea in der Schwangerschaft. Hautarzt. 2017;68:111–9. Brown SM, Aljefri KA, Waas R, Hampton PJ. Systemic medications used in treatment of common dermatological conditions: safety profile with respect to pregnancy, breast feeding and content in seminal fluid. J Dermatolog Treat. 2017;16:1–53. Caimari F, Corcoy R, Webb SM. Cushing’s disease: major difficulties in diagnosis and management during pregnancy. Minerva Endocrinol. 2018;43:435–45. Dréno B, Blouin E, Moyse D, et al. Acne in pregnant women: a French survey. Acta Derm Venereol. 2014;94:82–3. Hakim C, Padmanabhan V, Vyas AK. Gestational hyperandrogenism in developmental programming. Endocrinology. 2017;158: 199–212. Kaňová N, Bičíková M. Hyperandrogenic states in pregnancy. Physiol Res. 2011;60:243–52. Meredith FM, Ormerod AD. The management of acne vulgaris in pregnancy. Am J Clin Dermatol. 2013;14:351–8. Wadzinski TL, Altowaireb Y, Gupta R, et al. Luteoma of pregnancy associated with nearly complete virilization of genetically female twins. Endocr Pract. 2014;20:e18–23.

Bibliography Yang CC, Huang YT, Yu CH, et al. Inflammatory facial acne during uncomplicated pregnancy and post-partum in adult women: a preliminary hospital-based prospective observational study of 35 cases from Taiwan. J Eur Acad Dermatol Venereol. 2016;30:1787–9.

Peri- and Postmenopausal Acne Achilli C, Pundir J, Ramanathan P, et al. Efficacy and safety of transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder: a systematic review and meta-analysis. Fertil Steril. 2017;107:475–82.e15. Elraiyah T, Sonbol MB, Wang Z, et al. Clinical review: the benefits and harms of systemic testosterone therapy in postmenopausal women with normal adrenal function: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2014;99:3543–50. Kligman AM. Postmenopausal acne. Cutis. 1991;47:425–6. Rothman MS, Wierman ME. How should postmenopausal androgen excess be evaluated? Clin Endocrinol (Oxf). 2011;75:160–4. Scheffers CS, Armstrong S, Cantineau AE, et al. Dehydroepian drosterone for women in the peri- or postmenopausal phase. Cochrane Database Syst Rev. 2015;1:CD011066.

Body Building and Doping Acne Anderson LJ, Tamayose JM, Garcia JM. Use of growth hormone, IGF-I, and insulin for anabolic purpose: pharmacological basis, methods of detection, and adverse effects. Mol Cell Endocrinol. 2018;464:65–74. Boos C, Wulff P, Kujath P, Bruch HP. Medikamentenmißbrauch beim Feizeitsportler im Fitneßbereich. Dtsch Ärztebl. 1998;95:A953–7. Cengiz FP, Cevirgen Cemil B, Emiroglu N. Acne located on the trunk, whey protein supplementation: is there any association? Health Promot Perspect. 2017;7:106–8. Collins P, Cotterill JA. Gymnasium acne. Clin Exp Dermatol. 1995;20:509. Dorrell HF, Gee TI. The acute effects different quantities of branchedchain amino acids have on recovery of muscle function. Sports Nutr Ther. 2016;1:115. Downie MM, Kealey T. Human sebaceous glands engage in aerobic glycolysis and glutaminolysis. Br J Dermatol. 2004;151:320–7. Goldman A, Basaria S. Adverse health effects of androgen use. Mol Cell Endocrinol. 2018;464:46–55. Guha N, Dashwood A, Thomas NJ, et al. IGF-I abuse in sport. Curr Drug Abuse Rev. 2009;2:263–72. Guha N, Cowan DA, Sönksen PH, Holt RI. Insulin-like growth factor-I (IGF-I) misuse in athletes and potential methods for detection. Anal Bioanal Chem. 2013;405:9669–83. Hartgens F, Kuipers H. Effects of androgenic-anabolic steroids in athletes. Sports Med. 2004;34:513–54.

215 Heydenreich G. Testosterone and anabolic steroids and acne fulminans. Arch Dermatol. 1989;125:571–2. Holt RI, Sönksen PH. Growth hormone, IGF-I and insulin and their abuse in sport. Br J Pharmacol. 2008;154:542–56. Huang G, Basaria S. Do anabolic-androgenic steroids have performance-enhancing effects in female athletes? Mol Cell Endocrinol. 2018;464:56–64. Kraus SL, Emmert S, Schön MP, Haenssle HA. The dark side of beauty: acne fulminans induced by anabolic steroids in a male bodybuilder. Arch Dermatol. 2012;148:1210–2. Melnik BC. Androgen abuse in the community. Curr Opin Endocrinol Diabetes Obes. 2009;16:218–23. Melnik BC. Evidence for acne-promoting effects of milk and other insulinotropic dairy products. Nestle Nutr Workshop Ser Pediatr Program. 2011;67:131–45. Melnik BC. Acne vulgaris: the metabolic syndrome of the pilosebaceous follicle. Clin Dermatol. 2018;36:29–40. Melnik B, Jansen T, Grabbe S. Anabolikamissbrauch und BodybuidingAkne: eine unterschätzte gesundheitliche Gefährdung. J Dtsch Dermatol Ges. 2007;5:110–7. Nicholls AR, Holt RI. Growth hormone and insulin-like growth factor-1. Front Horm Res. 2016;47:101–14. Nieschlag E, Vorona E. Mechanisms in endocrinology: medical consequences of doping with anabolic androgenic steroids: effects on reproductive functions. Eur J Endocrinol. 2015;173:R47–58. Perez M, Navajas-Galimany L, Antunez-Lay A, Hasson A. When strength turns into disease: acne fulminans in a bodybuilder. An Bras Dermatol. 2016;91:706. Pontes Tde C, Fernandes Filho GM, Trindade Ade S, Sobral Filho JF. Incidence of acne vulgaris in young adult users of protein-calorie supplements in the city of João Pessoa—PB. An Bras Dermatol. 2013;88:907–12. Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35:341–75. Raschka C, Chmiel C, Preiss R, Boos C. Doping bei Freizeitsportlern. Eine Untersuchung in 11 Fitnessstudios in Frankfurt am Main. MMW Fortschr. 2013;155(Suppl 2):41–3. Razavi Z, Moeini B, Shafiei Y, Bazmamoun H. Prevalence of anabolic steroid use and associated factors among body-builders in Hamadan, West province of Iran. J Res Health Sci. 2014;14:163–6. Simonart T. Acne and whey protein supplementation among bodybuilders. Dermatology. 2012;225:256–8. Silverberg NB. Whey protein precipitating moderate to severe acne flares in 5 teenaged athletes. Cutis. 2012;90:70–2. Smit DL, de Ronde W. Outpatient clinic for users of anabolic androgenic steroids: an overview. Neth J Med. 2018;76:167. Traupe H, von Mühlendahl KE, Braamswig J, Happle R. Acne of the fulminans type following testosterone therapy in three excessive tall boys. Arch Dermatol. 1988;124:414–7.

6

Acne Classification and Disease Burden

Core Messages • There is no unifying international standard for classification and grading of the severity of acne. This renders comparison of epidemiological data and treatment efficacy infeasible. No simple global grading system or numerical counting can encompass the great variety of acne expressions. • Our empirical approach is to first classify facial acne into its three main subtypes: acne comedonica, acne papulopustulosa, and acne conglobata. Each subtype will be divided into grades I to IV, in ascending order of severity. • Acne is the single skin disease of highest impact in the evaluation of global disease burden study measured by disability-adjusted life years from 306 diseases and injuries. • Different scoring systems are proposed to evaluate the impact of acne on the quality of life concerning psychological disability in workplace, social and sexual relationships, depression, and anxiety. Disparity exists between objective inspector-directed assessment and subjective patient-centered perception. • Excoriations in acne differ from excoriations in patients without acne. The former is the manipulation of acne, more commonly in girls, including squeezing, picking, rubbing, and crushing, which leads to polymorphic lesions, hyper- or hypopigmentation, and scars diffusely distributed over the entire face. • The latter is observed mainly in women in their 30s and 40s without obvious acne, though they may have had acne in the past. It is characterized by self-induced scars not limited to the face, accompanied with psychosomatic, psychiatric, or personality disorders, and can be considered as a subtype of pathologic skin picking. Treatment is resistant and requires collaboration with specialists.

6.1

Classification and Grading of Acne

Nosology does not rank high among the interests of acne researchers. Yet the lack of a common international standard for classifying and grading the severity of acne has been a distressing source of confusion and controversy. The result is that epidemiological data and classifications from different sources cannot be compared because the criteria are different. This adversely affects every field of investigation, for example, surveys concerning the prevalence of acne in different countries. At present we have no definite information about whether acne is more prevalent in meat eaters than in vegetarians, in cold climates compared with warm ones, in different ethnic groups, etc. What dermatologists may classify as severe acne in Japan might be considered mild by American dermatologists. There is an embarrassing degree of controversy regarding the efficacy of anti-acne medication. Widely divergent views are held. Perhaps worse than differences among observers is the problem of inconsistencies by the same observer. In the absence of objective criteria, the same physician seeing the same patient at different times is highly susceptible to biased readings. The extraordinary effectiveness of placebo therapy (vehicle) in many studies doubtlessly stems from the subjective way in which the severity of acne is judged. The most widely used grading systems are unsatisfactory, enduring only because of their simplicity. For example, patients are commonly classified as having mild, moderate, or severe acne. This is usually based on the dominant lesions. Comedonal acne, even when the face is densely studded, is generally graded as mild. Papulopustular acne is deemed moderate, while nodules imply severity. But one may ask who is worse off, the patient with hundreds of closed comedones or the patient with three nodules? We must take into account not only the quality of the lesions but their quantity as well. No simple global rating (mild to severe) or numerical system (grades I–IV) can encompass the great variety of clinical

© Springer Nature Switzerland AG 2019 G. Plewig et al., Plewig and Kligman´s Acne and Rosacea, https://doi.org/10.1007/978-3-319-49274-2_6

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expressions. Our empirical approach may be summarized as follows: With reference to facial acne, the first step is to divide the disease into its three main subtypes:

• • • •

1. Acne comedonica 2. Acne papulopustulosa 3. Acne conglobata

We must admit that the numbers mentioned above are just estimates and can deviate in different grading, depending on the individual study design. As a rule, the higher grades are associated with fewer comedones. Moreover, there will be a greater number of larger, harder, deeper, and persistent papules. In severe inflammatory acne, microcomedones blow up before they mature into clinical comedones, hence the inverse relationship. Acne conglobata is a spectacular disease and can be easily identified. It is never mild. The disease is at the far end of the spectrum of acne and its nosologic position is explicit. The severity of acne conglobata can be further classified based on its affected areas and progressions.

Different to the preference of some authors, we don’t use the term “nodulocystic acne,” because the nodular lesions rarely occur alone and usually become confluent soon, while the fluctuant lesions are not true cysts without epithelial linings in histology. It is challenging to evaluate the whole face with numerous acne lesions, and there are no standard methods. As the distribution is not always symmetrically face-split right-and-left even, the counting of only a half face can sometimes be misleading. We find it practical to divide the whole face roughly into three compartments: the upper one third (hairline, forehead, temple, orbital), the middle one third (nose, cheeks, preauricular), and the lower one third (perioral, chin, jaw/ mandible, submandible). Each part can be further evaluated in consideration of the grading system proposed below, and the results summated in toto. Certain acne variants show predilection sites. Adult acne tends to accumulate in the lower third, and acne draining sinus along the nasolabial folds in the middle third, while acne-related persistent facial swelling in the upper third of the face. In acne comedonica, the dominant lesions are open and closed comedones. Inflammatory lesions may also be present but are not numerous. We recognize four grades, in the order of increasing severity: • • • •

Grade I: Fewer than 10 comedones Grade II: 10–25 comedones Grade III: 26–50 comedones Grade IV: More than 50 comedones

The majority of cases fall into grades I and II. It is encountered chiefly when the disease makes its debut around puberty. What starts as acne comedonica often evolves into inflammatory disease. Older adolescents sometimes have mainly grade III or IV acne comedonica. The disease is usually apparent first on the nose and then on the forehead, descending to the chin over months or years. Acne papulopustulosa is by far the most common type in mid-adolescence or beyond. It is a mixture of comedones and inflammatory lesions, which can be further divided into papules and pustules. Papules are actually pustules when evaluated histopathologically. We routinely combine these under the designation of papulopustules. Assignment to this category is based solely on the prevalence of inflammatory lesions, regardless of the number of comedones. Classification of the severity of acne papulopustulosa can follow suit:

Grade I: Fewer than 10 papulopustules Grade II: 10–25 papulopustules Grade III: 26–50 papulopustules Grade IV: More than 50 papulopustules

• Grade I: Confined to only one of the following body regions—face and neck, chest, back, or buttock • Grade II: Involvement of more than two body regions • Grade III: Presence of draining sinuses • Grade IV: Scar (hypertrophic or atrophic) Another classification proposed by Cunliffe and coworkers used 10 grades for facial acne and later, in a modified grading system, 12 grades for facial acne and 8 for the back and chest. We feel that this is too complex and literally requires training in their clinic. On the other hand, when high-resolution color photos are available for reference, as provided by the Leeds group around Cunliffe, this system has its merits. Wherever situated, one must always have a complete set of photos that are exactly alike. For all practical purposes, acne grading can best be accomplished using a pattern-diagnosis system, which includes a global, semiquantitative estimate of lesion density. In severe inflammatory acne, additional descriptions are used, such as pain, drainage, hemorrhage, and ulceration. The most destructive forms of the disease, acne conglobata and acne fulminans, are never mild. These entities are easily recognized and belong to the category of very severe acne. Acne comprised only of comedones, even when they are present in large numbers or are extensively distributed, can rarely be designated as severe acne, in the biological view of inflammatory response. This approach is based on the reasonable assumption that grading in experienced hands is fairly reliable and may facilitate evaluation by eliminating counting, a procedure which is far more precise than commonly supposed. The reproducibility of lesion counts is quite poor. Regulatory authorities understandably favor counts, no matter how unreliable, for purposes of statistics. In 2005 FDA published guidance for industry and recommended the inclusion of the “Investigator Global Assessment” to investigate the

6.3 Excoriations in Acne

therapeutic effect on acne s everity. In our opinion, the main task remains how to make compromise between convenience and precision in designing the evaluation systems. A strictly quantitative definition of severity cannot be established and is impracticable because of the variable expression and dynamic course of acne. The approach with quantitative 3D skin imaging analysis can be a valuable tool. The clinical diagnosis of severe acne should be based on the presence of any of the following characteristics: extensive papulopustular disease, persistent or recurrent inflammatory nodules, ongoing scarring, persistent purulent and/or serosanguineous drainage from lesions, or the presence of sinus tracts. Recent efforts have been made to evaluate severity of acne scars, mainly for the treatment decision and the followup of treatment results. There is also a growing concern on acne in the extrafacial body regions and to include it in the evaluation of disease severity. Significant truncal acne in women can mean a greater severity and requires examination of hormone disturbance. Doping acne in men usually shows an extensive involvement of the chest and back. Acne in the décolleté can be annoying to women in the social occasions.

6.2

isease Burden of Acne and Quality D of Life

In the 2013 global disease burden study measuring disability-adjusted life years from 306 diseases and injuries, skin conditions contributed 1.79% to the global burden of disease, with acne as the single highest-impact disease contributing to 0.29%, after dermatitis (atopic, contact, and seborrheic dermatitis) contributing to 0.38%. Another dimension of severity deserves more attention, namely, the individual psychosocial consequences of the disease. Psychological disability concerns the workplace, social and sexual relationships, depression, and anxiety. Scoring systems proposed to evaluate impact of acne on the quality of life may include general evaluation like RAND 36-Item Health Survey, Dermatology Life Quality Index (DLQI), and Skindex-29. Examples of more disease-specific evaluation are Cardiff Acne Disability Index (CADI) and Acne-Specific Quality of Life Questionnaire (Acne-QoL). Disparity between objective inspector-directed severity grading and subjective patient-based perception of the disease impact is known, best exemplified by acne excoriée. Consideration and integration of both doctor’s opinion and patient’s feeling can help for a more appropriate treatment decision.

6.3

Excoriations in Acne

Dermatologists seem to delight in pedantic nomenclature. Textbooks refer to this disorder by its French title acné excoriée des jeunes filles. The ordinary term is excoriations in acne. These terms are confounded, however, by the fact that

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not all the patients do show acne, since acne lesions are often just a pretext for manipulating the face. Acne that is unusually resistant to treatment or atypical in its presentation should raise the suspicion that underlying psychopathology exists.

6.3.1 Excoriations in Acne This disorder usually begins in the teens, when the patients start to see comedones or minor inflammatory lesions. Girls are more susceptible than boys, perhaps because the psychosocial consequences of acne are more serious for the former. Anxious patients often cannot leave the lesions alone and attack them in different ways. It is more like an impulsive control disorder, in which the manipulation of acne usually occurs automatically and rapidly without being able to control oneself, and patients usually feel relieved for some time afterward. Ways of attack vary. Squeezing is most common. The patients take satisfaction in popping out comedones and suppurative material from inflammatory lesions, painful as this might be. Pickers are under less compulsion to manipulate and cause less damage. Others rub, but the really menacing maneuver is crushing between the fingers, thereby dispersing the contents into the dermis. Picking hours, mostly unconsciously, are either during the day when studying, reading, or working, or during the morning or the evening toilet in front of a mirror. Magnifying mirrors turn even the slightest acne lesion into a deep crater. Lesions are diffusely distributed over the entire face, which may have been severely disfigured. They are always polymorphic, including oozing excoriations, hemorrhagic crusts, hyper- or hypopigmentation, and scars.

6.3.2 Excoriations in Patients Without Acne The difference to the abovementioned variant is that the patients do not have any obvious acne lesions, though they may have had acne in the past. It is usually seen in women in their 30s and 40s. They usually insist on the presence of prior lesions, which are no longer recognizable to the observer, having been obliterated by the fingers. Even careful inspection will not disclose acne lesions such as comedones, papules, or papulopustules. Every day the skin is gouged out with the fingernails, leaving a wide variety of lesions, including erosions, superficial ulcerations, hemorrhagic crusts, stellate scars with a dry scab, and hyper- or hypopigmented bizarrely shaped scars. It is easy to differentiate these linear, self-induced scars from those due to acne itself. This is one of the compulsive skin-picking disorders and related skin damaging syndromes and can be considered as a subtype of pathologic skin picking (dermatillomania). Association with bodily focused anxiety or even body dysmorphic disorder can occur and make the patients standing hours in front of the mirror feeling waste of time. The report of multiple family members in a four generation with trichotillomania, skin-picking disorder, and nail biting, without other obvious

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psychiatric disorders, speculated genetic role in this group of body-focused repetitive behavior disorders. Excoriations are not limited to the face, but are often found on the chest, back, and lateral aspects of the upper portion of arms as far as the fingers can reach. The damage is too great to be discounted as a kind of unconscious tic-like action. Some patients are disturbed in their psychosexual adjustments and have many unsolved problems which engender a variety of neurotic ways of acting. They may have no self-confidence and self-esteem, be emotionally labile, and pity themselves. The excoriating habit may go on for decades. The skin then becomes leathery, with a pebbled, scarred surface and spotty pigmentation. Anxiety disorders, including the obsessive-compulsive disorder, may be encountered in these patients. Personality disorders, i.e. borderline or narcissistic personality disorder, depressive disorders with self-mutilation as a component, and delusional disorders including delusions of parasitosis, are sometimes present and not uncommon in patients of elder age. Body dysmorphic disorder is a condition in which the affected patients become obsessively preoccupied with a real or imagined defect. These patients often present with minimal disease but have substantial psychiatric morbidity and rarely even attempt suicide.

6.3.3 Treatment Treatment is challenging in daily busy dermatological practice. In general, topical therapy is ineffective, especially for

6.4

excoriation in patients without acne. The most important thing is to explain the vicious cycle to the patient. Once excoriations are stopped, hemorrhagic scabs, stellate scars, and unpleasant hyper- and hypopigmentation will disappear. Often the patients have consulted many dermatologists who either missed the diagnosis or have a distaste for psychological confrontation. These patients have tried a great variety of medicaments; they do not need a prescription but rather a frank consultation. We have two simple approaches. First, we carefully count fresh and old excoriations and write down these figures in the presence of the patient. When the patient returns, we count them again. Usually, the patient will be relieved by the gradually decreasing number of lesions. Second, we take full facial photographs, front and lateral, and show them at the next appointment. No topical remedy is prescribed during the first consultation. If there is underlying acne, use the appropriate topical therapy. The correction of scarring by dermabrasion, intralesional injection of collagen, or lasers should not be considered until there is evidence that the patient has regained self-control. When anxiety is high or depression is evident, it may be desirable to try sedatives and psychotropic drugs through collaboration with psychiatrists. If everything fails, referral to a psychotherapist or psychiatrist is indicated. Behavioral therapy is sometimes helpful in stopping the manipulation. This disease can be mutilating to skin and psyche.

Excoriations in Patients Without Acne

Patients sometimes have an irresistible urge to pick and scratch what they misinterpret as early acne lesions. The patients are mostly young women who do not have appreciable acne. This behavior reveals a neurotic preoccupation with the face Above Left: Asymmetry is typical for excoriations. These are variable in size and shape and do not correspond to any natural distribution of disease, including acne. Hyperpigmentation is often a troublesome problem, particularly in dark skinned people Right: At first glance this looks like acne. However, no comedones are present. All the lesions have been provoked by her own manipulations. Frenzies of ferocious picking may occur at times of stress Below Left: In addition to picking and squeezing, this patient has used her fingernails to scratch the skin. Linear, shallow lesions are diagnostic of excoriations Right: This patient had severe acne in adolescence at which time she became an obsessive picker and squeezer. The habit deepened into severe attacks on the face after the acne cleared, leaving disfiguring scars. Psychosomatic evaluation is indicated for self-destructive manipulations of this severity. Depression is common

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Disease Burden of Acne and Quality of Life

Acne Classification and Grading

Barnes LE, Levender MM, Fleischer AB Jr, Feldman SR. Quality of life measures for acne patients. Dermatol Clin. 2012;30:293–300. Dréno B. Assessing quality of life in patients with acne vulgaris: implications for treatment. Am J Clin Dermatol. 2006b;7:99–106. GBD 2013 DALYs and HALE Collaborators, Murray CJ, Barber RM, et al. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet. 2015;386:2145–91. Hayashi N, Miyachi Y, Kawashima M. Prevalence of scars and “miniscars”, and their impact on quality of life in Japanese patients with acne. J Dermatol. 2015;42:690–6. Karimkhani C, Dellavalle RP, Coffeng LE, et al. Global skin disease morbidity and mortality: an update from the global burden of disease study 2013. JAMA Dermatol. 2017;153:406–12. Md ZAL. Psychosocial issues in acne management: disease burden, treatment adherence, and patient support. Semin Cutan Med Surg. 2015;34(5 Suppl):S92–4.

Allen BS, Smith JG Jr. Various parameters for grading acne vulgaris. Arch Dermatol. 1982;118:23–5. Burke BM, Cunliffe WJ. The assessment of acne vulgaris – the Leeds technique. Br J Dermatol. 1984;111:83–92. Cook CH, Centner RL, Michaels SE. An acne grading method using photographic standards. Arch Dermatol. 1979;115:571–5. Doshi A, Zaheer A, Stiller MJ. A comparison of acne grading systems and proposal of a novel system. Int J Dermatol. 1997;36:416–8. Dréno B. Assessing quality of life in patients with acne vulgaris: implications for treatment. Am J Clin Dermatol. 2006a;7:99–106. Kang S, Lozada VT, Bettoli V, et al. New atrophic acne scar classification: reliability of assessments based on size, shape, and number. J Drugs Dermatol. 2016;15:693–702. Lucky AW, Barber BL, Girman CJ, et al. A multirated validation study to assess the reliability of acne lesion counting. J Am Acad Dermatol. 1996;35:559–65. Motley RJ, Finlay AY. How much disability is caused by acne? Clin Exp Dermatol. 1989;14:194–8. O’Brien SC, Lewis JB, Cunliffe WJ. The Leeds revised acne grading system. J Dermatol Treat. 1998;9:215–20. Parish LC, Witkowski JA. The acne scoreboard. Int J Dermatol. 1978;17:490–1. Petit L, Zugaj D, Bettoli V, et al. Validation of 3D skin imaging for objective repeatable quantification of severity of atrophic acne scarring. Skin Res Technol. 2018;24:542–50. Petukhova TA, Foolad N, Prakash N, et al. Objective volumetric grading of postacne scarring. J Am Acad Dermatol. 2016;75:229–31. Report of the Consensus Conference on Acne Classification. Washington, DC, March 24 and 25, 1990. J Am Acad Dermatol. 1991;24:495–500. Samuelson JS. An accurate photographic method for grading acne: initial use in a double-blind clinical comparison of minocycline and tetracycline. J Am Acad Dermatol. 1985;12:461–7. Shalita AR, Leyden JJ, Kligman AM. Reliability of acne lesion counting. J Am Acad Dermatol. 1997;37:672. Tan JK, Jones E, Allen E, et al. Evaluation of essential clinical components and features of current acne global grading scales. J Am Acad Dermatol. 2013;69:754–61. Tan J, Frey MP, Knezevic S, et al. The relationship between dermatologist- and patient-reported acne severity measures and treatment recommendations. J Cutan Med Surg. 2015;19:464–9. Witkowski JA, Parish LC, Guin JD. Acne grading methods. Int J Dermatol. 1980;116:517–118.

Excoriations in Acne Bach M, Bach D. Psychiatric and psychometric issues in acne excoriée. Psychother Psychosom. 1993;60:207–10. Fruensgaard K. Psychotherapeutic strategy and neurotic excoriations. Int J Dermatol. 1991;30:198–203. Gieler U, Consoli SG, Tomás-Aragones L, et al. Self-inflicted lesions in dermatology: terminology and classification–a position paper from the European Society for Dermatology and Psychiatry (ESDaP). Acta Derm Venereol. 2013;93:4–12. Gupta MA, Gupta AK, Schork NJ. Psychosomatic study of self-excoriative behavior among male acne patients: preliminary observations. Int J Dermatol. 1994;33:846–8. Gupta MA, Gupta AK, Schork NJ. Psychosomatic correlates of selfexcoriative behavior among women with mild to moderate facial acne vulgaris. Psychosomatics. 1996;37:127–30. Gupta MA, Vujcic B, Gupta AK. Dissociation and conversion symptoms in dermatology. Clin Dermatol. 2017;35:267–72. Kenyon FE. Psychosomatic aspects of acne. Br J Dermatol. 1966;78:344–51. Khumalo NP, Shaboodien G, Hemmings SM, et al. Pathologic grooming (acne excoriee, trichotillomania, and nail biting) in 4 generations of a single family. JAAD Case Rep. 2016;2:51–3.

7

Acne Therapy

Core Messages • Topical treatment is the mainstay for mild to moderate acne. • Topical retinoids, especially all-trans retinoic acid and adapalene, are essential components to treat comedones. • Topical benzoyl peroxide efficiently suppresses Propionibacterium acnes (P. acnes) and exhibits no bacterial resistance, which makes it very suitable for combination therapies. • Topical clindamycin shows significant anti-inflammatory properties; topical erythromycin exhibits increasing levels of P. acnes resistance. • Antibiotics as monotherapy is no longer recommended due to growing evidence of antibiotic resistance, and combination therapies often show synergistic effects. • Oral antibiotics, especially doxycycline, are indicated for inflammatory acne but should not exceed treatment periods of 3–4 months. • Severe and treatment-resistant acne papulopustulosa and nodulocystic acne favorably respond to oral isotretinoin. • The desired sebum-suppressive effect of isotretinoin is via sebocyte apoptosis. Most adverse drug effects including teratogenicity are as well linked to apoptosis. • Off-label use of metformin improves acne in polycystic ovary syndrome associated with insulin resistance. • Antiandrogens have moderate sebostatic effects and can be prescribed in women suitable for antiandrogen treatment. • Translational evidence indicates that therapeutic effects of anti-acne drugs in clinical use converge in upregulation of the transcription factor p53. This chapter provides a unifying model for acne therapy on the basis of transcriptomic regulation. Evidence from the literature will be presented that treatment-induced overexpression of the transcription factor p53, known as the guardian of the genome, is the critical effector of anti-acne therapies, which controls IGF-1 and androgen signaling, sebocyte homeostasis, and sebum production.

Acne is one of the most common worldwide disorders treated by dermatologists and other healthcare providers. Over the decades, clinical acne therapy developed empirically and is believed to affect all major pathogenetic mechanisms such as excessive sebum production, disturbed acroinfundibular proliferation and keratinization, metagenomic changes of P. acnes including biofilm synthesis, as well as follicular and perifollicular inflammation. The crucial anabolic and pro-survival pathway of acne is exaggerated phosphoinositide-3 kinase (PI3K)/AKT signaling that decreases nuclear activity of FoxO transcription factors and p53, thereby enhancing the activity of mechanistic target of rapamycin complex 1 (mTORC1) (see Chap. 3). This prompted us to suggest that anti-acne agents exert their therapeutic activity either via upregulation of FoxO transcription factors (FoxO1 and FoxO3) or attenuation of mTORC1 signaling. The transcription factor p53, which is regarded as the guardian of the genome, interacts with FoxO1, FoxO3, and mTORC1 signaling and is of importance for the induction of cell cycle arrest and apoptosis. p53 induces the expression of FoxO1, FoxO3, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which plays a key role in isotretinoin-mediated sebocyte apoptosis. FoxO3 increases the expression of sestrin 1 and 2, which activate AMP protein kinase (AMPK). Activated AMPK, a well-known target of metformin, inhibits mTORC1. Chronic activation of p53 in mice resulted in mTORC1 inhibition and loss of sebaceous glands. To understand the transcriptomics of acne and its therapeutic modification, it is necessary to appreciate the intricate molecular interplay between p53, insulin-like growth factor-1 (IGF-1), and androgen signaling. p53 attenuates the expression of IGF-1 receptor and thereby reduces mTORC1 activity as well as the expression of the anti-apoptotic protein survivin, which is a negative regulator of caspase 3. In contrast, androgen signaling via upregulation of microRNA-125b suppresses p53 and B lymphocyte-induced maturation protein 1 (BLIMP1). The latter is a negative regulator of c-MYC-driven sebocyte differentiation. Low p53 activity promotes sebocyte survival and differentiation and attenuates TRAIL-mediated sebocyte apoptosis.

© Springer Nature Switzerland AG 2019 G. Plewig et al., Plewig and Kligman’s Acne and Rosacea, https://doi.org/10.1007/978-3-319-49274-2_7

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FoxOs and p53 are extensively upregulated in response to oxidative stress. Increased androgen receptor (AR) expression is a marker of sebocyte differentiation. Both FoxO1, which acts as a nuclear cosuppressor of AR, and p53 attenuate AR signaling. p53 directly inhibits AR gene expression and AR transcriptional activity.

7.1

Topical Acne Therapy

7.1.1 Topical Retinoids Retinoids are the core of topical acne therapy because they are comedolytic, resolve precursor microcomedone lesions, and are anti-inflammatory. All-trans retinoic acid (ATRA), the prototype of topical retinoids inaugurated by Kligman et al. (1969), has been studied extensively and is known to suppress keratinocyte differentiation and to inhibit formation of cornified envelopes. In the rhino mouse, a model of comedogenesis, topical ATRA transforms horn-filled into normal follicles. ATRA downregulates epidermis-specific caspase-14, which is thought to play a crucial role during terminal keratinocyte differentiation and epidermal barrier homeostasis. In human keratinocytes, ATRA increases the expression of p53 and pro-apoptotic caspases and sensitizes keratinocytes to apoptosis. Compared to sebocytes, keratinocytes exhibit much lower susceptibility for ATRA-induced apoptosis. ATRA-induced upregulation of p53 reduces the magnitude of AR signaling associated with increased acroinfundibular keratinization. Topical retinoids approved for acne treatment comprise tretinoin (all-trans retinoic acid, ATRA), isotretinoin (13-cis retinoic acid) first reported by Plewig et al. (1981), as well as the synthetic third-generation polyaromatic retinoids adapalene and tazarotene, the latter being approved for acne treatment in the United States only. Four active agents are available: tretinoin (0.025–0.1% in cream, gel, or microsphere gel vehicles), isotretinoin (0.05% in gel, 0.05% or 0.1% in cream), adapalene (0.1%, 0.3% cream, or 0.1% lotion), and tazarotene (0.05%, 0.1% cream, gel, or foam). Each retinoid binds to a different set of retinoic acid receptors (RARs): tretinoin to RARα, RARβ, and RARγ and tazarotene and adapalene, selectively, to RARβ and RARγ, thereby conferring slight differences in activity, tolerability, and efficacy. Retinoids are ideal for comedonal acne and, when used in combination with other agents, for all acne variants and should be applied to skin in the evening because some formulations of tretinoin are not photostable. Common side effects including dryness, peeling, erythema, irritation, and increased risk of photosensitivity are better tolerated during nighttime. Side effects can be mitigated by reducing the frequency of application. According to our personal experience, adapalene is better tolerated than tretinoin. Tretinoin and adapalene are pregnancy category C, while tazarotene is category X; therefore,

women should be counseled on these pregnancy risks when starting a topical retinoid. Topical retinoids are available in fixed combination with other anti-acne agents: adapalene 0.1% and 0.3% with benzoyl peroxide (BPO) 2.5% and tretinoin 0.025% with clindamycin 1.0%. It has been shown in inflammatory acne lesions that the combined treatment of adapalene with BPO decreased the expression of the proliferation marker Ki67 as well as proinflammatory cytokines more efficiently than treatments with single compounds pointing to a synergistic pharmacological effect of adapalene and BPO.

7.1.2 Benzoyl Peroxide Benzoyl peroxide (BPO) is an antibacterial agent that kills P. acnes through the release of free oxygen radicals and is also mildly comedolytic. BPO is available as topical washes, foams, creams, or gels and can be used as leave-on or wash-off agents. Concentrations available for acne therapy range from 2.5% to 10%. Besides its antibacterial activity, the exact molecular mechanisms underlying its mode of action in the sebaceous follicle are not fully understood. BPO is a potent inducer of oxidative stress increasing the intracellular ratio of oxidized to reduced glutathione (GSSG/GSH) in treated keratinocytes. BPO interacts with mitochondria, inhibits mitochondrial respiration, and induces mitochondrial swelling. p53 is activated upon oxidative stress and in turn inhibits cell proliferation and growth through induction of specific target genes such as sestrin 1 and 2, which inhibit mTORC1. In addition, activation of oxidative stress-inducible kinases increases nuclear FoxO levels promoting sestrin 3-mediated activation of AMPK, thereby inhibiting mTORC1. Both retinoid- and BPO-mediated upregulation of p53 have a synergistic effect in the treatment of acne as demonstrated for the combination of adapalene with BPO. Side effects of BPO therapy are concentration-dependent skin irritation, staining and bleaching of fabric, and uncommon contact allergy. No resistance to this agent has been reported, and the combination of BPO with topical or systemic antibiotic therapy reduces resistance development of P. acnes. Anaerobic follicular microenvironment promotes P. acnes virulence. Future research should unravel BPO’s impact on P. acnes biofilm. In preliminary trials, topical hydrogen peroxide (H2O2) as well reduced the number of inflammatory and noninflammatory acne lesions.

7.1.3 Azelaic Acid Azelaic acid (C9-dicarboxylic acid, AZA) 20% is mildly effective as a comedolytic, antibacterial, and anti-inflammatory agent. AZA disturbs mitochondrial function increasing oxidative stress, which results in upregulation of p53. AZA is used in patients with sensitive skin or of Fitzpatrick skin types

7.2 Systemic Therapy

IV or greater because of the lightening effect of the product on hyperpigmentation. AZA is category B in pregnancy.

7.1.4 Topical Antibiotics Topical antibiotics for acne, which accumulate in the sebaceous follicle, work through anti-inflammatory mechanisms and via antibacterial effects. Due to increasing resistance of P. acnes, the use of topical erythromycin available in 2% and 4% concentration as a cream, gel, or lotion continuously declines. Clindamycin 1% solution or gel is currently the preferred topical antibiotic for acne therapy. Monotherapy with topical antibiotics in the management of acne is not recommended because of the development of antibiotic resistance. Fixed combinations of these antibiotics with BPO significantly reduce the development of resistant bacterial strains. Agents are available with erythromycin 3%/BPO 5%, clindamycin 1%/BPO 5%, and clindamycin 1%/BPO 3.75%. Macrolides such as erythromycin and clindamycin inhibit the p450 enzyme CYP3A that catalyzes intracellular degradation of ATRA. The resulting increase of cellular ATRA levels explains ATRA-mediated upregulation of p53 expression.

7.1.5 Topical Dapsone Dapsone (4,4′-diaminodiphenylsulfone) is an aniline derivative belonging to the group of synthetic sulfones. Dapsone’s mechanisms of action in acne are poorly understood, and we do not use or recommend topical dapsone for the treatment of acne.

7.1.6 Topical Olumacostat Glasaretil Olumacostat glasaretil (OG) is an inhibitor of acetyl coenzyme A (CoA) carboxylase (ACC), the enzyme that controls the first rate-limiting step in fatty acid biosynthesis. OG treatment reduced saturated and monounsaturated fatty acyl chains across lipid species, including di- and triacylglycerols, phospholipids, cholesteryl esters, and wax esters in hamster sebocytes. One study in patients with moderate to severe facial acne vulgaris showed greater reductions in inflammatory and noninflammatory lesions compared to OG-free vehicle. A phase III failure in acne treatment was announced later. We have no personal experience with OG.

7.2

Systemic Therapy

7.2.1 Systemic Antibiotics Acne is not an infectious disease, although antibiotics have been a mainstay of acne treatment for decades. It is well

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established that tetracyclines and macrolides are effective and have a long history of safe use in the treatment of acne. Doxycycline and minocycline are the most commonly used oral antibiotics in the treatment of acne. Antibiotics reduce the population of Propionibacterium acnes (P. acnes) by 90% or more, accompanied by a decrease of about 50% in the proportion of free fatty acids in the skin surface lipids. The decrease in free fatty acids is either related to the reduction of the P. acnes population or direct inhibition of bacterial lipases. Tetracyclines inhibit the enzymatic activity of bacterial lipases more effectively than macrolides. Antibiotics can also suppress the synthesis of bacterial lipase. Several studies underline that tetracyclines and macrolides suppress ATRA-catabolizing p450 enzymes, thereby enhancing cellular concentrations of ATRA, the critical inducer of p53. Systemic antibiotics in acne act to: • Directly suppress the number of P. acnes and inhibit bacterial lipases. • Decrease comedogenic and proinflammatory free fatty acids. • Reduce inflammation and inhibit matrix metalloproteinases. • Increase intracellular ATRA levels via p450 inhibition activating p53, which controls inflammation (NFκB) and matrix metalloproteinase expression (MMP-13). P. acnes is extremely susceptible in vitro to every antibiotic which is active against gram-positive organisms. At the same time, follicular fluorescence from P. acnes-produced porphyrins under Wood’s light disappears. Perhaps the most dependable measure of antibiotic effects is the decrease of free fatty acids in the skin surface lipids, although determination of follicular fluorescence is a much simpler alternative.

7.2.2 Tetracyclines The tetracycline class is considered the first-line therapy in moderate to severe acne. Tetracyclines inhibit protein synthesis by binding the 30S subunit of bacterial ribosomes. Lipophilic tetracyclines, such as minocycline, penetrate better into the lipid-rich domain of sebaceous follicles and microcomedones. It is still a matter of debate whether minocycline is superior to doxycycline at equivalent dosages. Clinical studies have shown that minocycline and doxycycline are equally effective. Doxycycline is effective in the 1.7–2.4 mg/kg dose range. Doxycycline or minocycline is usually given 50 mg twice daily (100 mg). Subantimicrobial dosing of doxycycline (20 mg twice daily to 40 mg daily) showed equal efficacy as doxycycline 100 mg for the treatment of inflammatory lesions in moderate and severe acne. This supports our opinion that P. acnes growth restriction is less important than tetracycline’s anti-inflammatory mode of

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action. Lymecycline is the favored antibiotic used for acne in Switzerland and France. Sarecycline, a narrow-spectrum tetracycline antibiotic, is recently approved by FDA to treat moderate to severe acne. Its long-term benefit remains to be confirmed.

7.2.2.1 Contraindications and Adverse Effects Tetracyclines are contraindicated during pregnancy, in children with an age under 8 years, or in patients with known tetracycline intolerance. Photosensitivity is a major issue for all tetracyclines with doxycycline exhibiting a stronger photosensitizing potential than minocycline. Doxycycline is more frequently associated with gastrointestinal disturbances. Minocycline has been associated with dizziness, tinnitus, and pigment deposition of the skin, mucous membranes, and teeth, more common in patients taking higher doses for longer periods. Minocycline in comparison to other tetracyclines exhibits more serious adverse events such as drug reaction with eosinophilia and systemic symptoms (DRESS), drug-induced lupus, and other hypersensitivity reactions. Lymecycline is claimed to be as effective as minocycline or doxycycline but with much fewer side effects such as esophagitis and phototoxicity. We have no experience with this compound. Pseudotumor cerebri is a rare phenomenon associated with tetracyclines, hypervitaminosis A, and systemic isotretinoin indicating a common underlying pathogenic mechanism.

7.2.3 Macrolides Erythromycin and azithromycin have also been used in the treatment of acne. Their antibacterial mechanism relates to their binding to the 50S subunit of the bacterial ribosome and subsequent inhibition of bacterial protein biosynthesis. Erythromycin, 500 mg thrice daily (1500 mg/day), is the recommended dose. Oral erythromycin can be used for the treatment of severe acne during pregnancy. Antibiotic resistance has been seen most commonly with erythromycin, and such organisms share a cross-resistance to clindamycin. P. acnes resistance to tetracyclines especially minocycline is rare. The widespread use of topical formulations of erythromycin and clindamycin has resulted in a wide dissemination of cross-resistant P. acnes strains. Azithromycin for the treatment of acne has been studied in various pulse dosing regimens ranging from three times a week to 4 days a month and demonstrated beneficial effects. A randomized controlled trial comparing 3 days per month of azithromycin to daily doxycycline showed that doxycycline was superior.

7.2.3.1 Adverse Effects Erythromycin is associated with a higher incidence of diarrhea, nausea, and abdominal discomfort than azithromycin. Macrolides may cause cardiac conduction abnormalities and rarely hepatotoxicity. Macrolides can decrease cyclosporine metabolism. Cutaneous hypersensitivity reactions have been

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reported during the treatment with azithromycin. Vaginal candidiasis and drug eruptions can occur with any antibiotic. Suppression of gram-positive cocci and coryneforms by oral antibiotics may lead to their replacement by gram-negative bacteria. This is one possible explanation of gram-negative folliculitis, in which an ecological niche is created by suppression of the dominant gram-positive organisms.

7.2.3.2 Duration of Systemic Antibiotic Treatment Antibiotic use should not exceed 3–4 months. According to international acne treatment guidelines, oral antibiotics should be used in combination with BPO or a topical retinoid. Oral antibiotic combined with BPO decreases the risk of antibiotic resistance. Furthermore, combined treatments have synergistic effects in terms of enhanced p53 signaling. Limiting systemic antibiotic use is urged because of the possible associations of Candida vulvovaginitis, pharyngitis, inflammatory bowel disease, and Clostridium difficile infection. 7.2.3.3 Antibiotic Resistance The worldwide prevalence of antibiotic-resistant P. acnes is increasing. Resistant strains of coagulase-negative staphylococci within the resident skin flora increase with duration of antibiotic acne therapy. Acne patients represent a considerable reservoir of resistant strains of these important nosocomial pathogens which can be transferred to close contacts. Resistance of P. acnes has received growing attention, considering its involvement in acne pathogenesis. Isolates resistant to one or more antibiotics have been reported worldwide. The reason for the difference in the antibiotic resistance patterns of P. acnes among different countries may be attributed to different antibiotic prescribing habits, varying use of topical agents, methodological differences of bacterial sampling, or even different P. acnes populations. The clinical role of P. acnes antibiotic resistance is challenged by the fact that subantimicrobial dosing of doxycycline showed equal efficacy as conventional antibacterial doxycycline doses. P. acnes resistance is clinically not equally related to treatment failure (Table 7.1). P. acnes biofilm observed in higher prevalence in hair follicles of acne patients deserves special attention. Biofilmassociated virulence factors have been identified that increase P. acnes antibiotic resistance. Attacking the P. acnes biofilm is important to avoid resistance development of P. acnes. Table 7.1 Guidelines to reduce the risk of antibiotic resistance Do not prescribe antibiotics if nonantibiotic treatment will suffice Short intervening courses of topical treatment with an antibacterial agent such as benzoyl peroxide may help to eliminate any resistant propionibacteria that have been elected Avoid simultaneous oral and topical use of chemically different antibiotics to reduce the risk of resistance developing to both Stress the importance of good compliance Reeducate patients not to expect an endless supply of alternative medications

7.2 Systemic Therapy

We speculate that BPO via modifying the anaerobic follicular conditions may attenuate biofilm, a reasonable explanation for the reduced risk of antibiotic resistance in antibiotic acne treatment combined with BPO. Patients with moderate to severe acne, who do not appropriately respond to oral antibiotics, should be considered for treatment with oral isotretinoin, which significantly suppresses P. acnes population density indirectly by suppressing its favorable lipid-enriched, anaerobic follicular microenvironment.

7.2.4 Systemic Isotretinoin Isotretinoin (13-cis retinoic acid) is a mainstay of the dermatologist for the treatment of severe forms of acne. This retinoid represents the cis-configuration of all-trans retinoic acid (ATRA, tretinoin).

7.2.4.1 Historical Note In 1971, Bollag discovered isotretinoin (13-cis retinoic acid) while searching for anticarcinogenic retinoids with less severe side effects than tretinoin. By 1976, isotretinoin had been found to be highly effective for disorders of keratinization, including Darier’s disease, lamellar ichthyosis, and pityriasis rubra pilaris. It happened that one patient with severe acne responded dramatically. This serendipity led to the discovery of a drug which is incomparably effective in acne conglobata. Credit must go to Peck and his colleagues at the National Institutes of Health, who showed conclusively that isotretinoin could suppress and even cure severe inflammatory nodulocystic acne.

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7.2.4.2 Indications In the United States, the Food and Drug Administration (FDA) specifies the use of isotretinoin for severe, recalcitrant nodular, and inflammatory acne, especially after other treatments have failed, including oral antibiotics. In Germany, the spectrum is broader, including acne conglobata, severe inflammatory acne not responding to conventional therapy, and acne fulminans. Despite the exhortations of the regulators, physicians have made up their own mind regarding the patients for whom they will prescribe isotretinoin. The sale of the drug is much greater than could be accounted for by the narrow indications of the package inserts. At educational conferences, international experts have shared their indications for the use of isotretinoin and discussed the type of patients who will benefit from its use. In the United States, isotretinoin is indicated by the FDA only for the treatment of severe recalcitrant nodulocystic acne or for patients with severe inflammatory acne whose condition has failed to respond to oral antibiotics (Tables 7.2 and 7.3). 7.2.4.3 Pharmacology The drug is rapidly absorbed after oral administration, producing peak levels of 180–460 ng/mL 1–6 h (average 3.2 h) after a single dose of 80 mg. Bioavailability is rather low, about 25%. Absorption may be increased by administration with a fatty food. Therefore, intake is recommended with or after the main meal of the day. Isotretinoin is more than 99% bound to plasma albumin. It is metabolized by cytochrome P450 family 26 (CYP26) enzymes in the liver to its main metabolite 4-oxo-isotretinoin. There is also some isomerization of isotretinoin to ATRA. In comparison to

Table 7.2 Practical guidelines for isotretinoin treatment Establish correct diagnosis and severity of acne Explain the drug, modes of action, and anticipated side effects Hand out a brochure provided by the manufacturer, which lists all details patients should know about, including indications and contraindications. The physician but not the patient assumes great responsibility in prescribing this potent drug. Take enough time to explain benefits and risks Minors should be accompanied by parent or guardian. The drug must not be given without written parental consent Blood chemistry before initiation of therapy and at control visits at 6 and 12 weeks and thereafter if necessary: hemoglobin, erythrocytes, leukocytes, SGOT, SGPT, GGTP, LDH, triglycerides, cholesterol, and bilirubin Pay attention to the detailed program for women of childbearing age (see below) Determine the patient’s body weight to adjust the dose Discuss concomitant topical and systemic therapy. Patients should not take vitamin A supplementation, in order to avoid additive hypervitaminosis Unmedicated emollients (basis ointments preferred) should be used to comfort dry skin, lips, and nose. Hydrophobic moisturizers (petrolatum) are most effective, though greasy. Next best are water-in-oil emulsions. Sunscreens should be used when solar exposure is extensive Hand over the prescription only if laboratory results are normal and to women only after completion of a special checklist Acute exacerbation of acne is occasionally seen during the first 2–4 weeks of treatment. Possible flare-ups of acne should be explained to the patient A reduced tolerance to contact lenses may require a switch to glasses It is recommended that patients do not donate blood during therapy or for 1 month after cessation of therapy (theoretically, transfer of a teratogenic blood level to a woman of childbearing potential is possible) Be cheerful. Most patients and parents are shocked after they have read the package insert with its long account of potential problems Do not push the drug; await full acceptance by the patient

228 Table 7.3 Criteria for prescribing isotretinoin in less severe acne Less than 50% improvement in acne after 6 months of conventional oral antibiotic and topical combination therapy Prone to acne scars Acne with significant psychological distress Acne that significantly relapses during or quickly after conventional therapy

other cells in the body, sebocytes exhibit a high capability for isotretinoin isomerization to ATRA, which is of key importance for its pharmacological effects in acne. Much of the drug is eliminated via biliary excretion, with some enterohepatic recirculation. The terminal elimination half-life of isotretinoin and its metabolites ranges from 7 to 36 h. Equal amounts of a dose appear in the feces, mainly as unchanged drug, and in the urine as metabolites. Renal metabolism is negligible. There is no deep compartment storage in fatty tissue, as is the case with etretinate. Isotretinoin crosses the placenta.

7.2.4.4 Mutagenicity No mutagenic effects have been seen in various systems, including the Ames test using bacterial strains Salmonella typhimurium, the gene mutation test with hamster cells, and the mouse micronucleus test. A dose-dependent increase in sister chromatid exchanges was induced by isotretinoin in human diploid fibroblast cultures, but this is not thought to pose a clinical hazard. 7.2.4.5 Mode of Action: Apoptosis-Mediated Sebum Suppression One of the stunning effects is the dramatic decrease in sebum production in every patient. The decrease is unequaled by any other drug such as estrogen, estrogen-progestin combinations, or antiandrogens. It is of rapid onset within the first 2 weeks and is dose-dependent. Quantitative studies have revealed a dose-dependent suppression of about 30% with 0.1 mg, 40% with 0.5 mg, and 70% with 1.0 mg/kg/day, reaching almost 90% with the latter dose after 3 months of therapy. Histopathological and electron microscopic studies showed an astonishing reduction of the population of sebocytes. The large cauliflower-like sebaceous lobules regress to barely discernible miniature buds of undifferentiated epithelial cells. Qualitative analysis of the skin surface lipids reveals significant alterations. Following the cutoff of sebum, there is an increase in the amount of epidermal-derived cholesterol, with a decrease of wax esters and squalenes. This reflects the pattern seen in childhood, before IGF-1 and androgens stimulate the sebaceous glands. What is left on the surface is mainly the contribution from epidermal lipids. Normally about 95% of the skin surface lipids are of sebaceous origin. Following discontinuation of therapy, sebum production begins to increase within 2–3 weeks and slowly

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returns to nearly normal levels by 10–12 months. In some patients, sebum production never reaches its original value. The clinical benefits of sebum suppression are particularly noteworthy. Even the worst cases of seborrhea improve; the skin looks and feels dry. Likewise, seborrhea of the scalp, common in acne patients, completely vanishes. Instead of shampooing the greasy scalp and hair daily, this is reduced to intervals of 3–7 days. Isotretinoin’s apoptotic effect on human Meibomian gland epithelial cells explains longstanding dry eye symptoms after isotretinoin treatment. Orally administered isotretinoin shows significant reductions in the number of P. acnes on the skin, including resistant isolates potentially acquired from previous treatments with antibiotics. To appreciate the sebum-suppressive effect of isotretinoin, it is necessary to understand isotretinoin’s pro-apoptotic effects leading to sebocyte and Meibomian cell apoptosis. Acne is a survival disease of sebaceous follicles associated with increased IGF-1-PI3K-AKT signaling. Isotretinoin treatment of acne patients decreases serum IGF-1 levels. Decreased activation (phosphorylation) of AKT has been reported in Meibomian cells during isotretinoin treatment. AKT-mediated phosphorylation activates the ubiquitin ligase mouse double minute 2 (MDM2). MDM2 via ubiquitination and proteasomal degradation inactivates the key transcription factor p53, which induces cell cycle arrest and apoptosis. Thus, IGF-1-mediated suppression of p53 is antagonized by isotretinoin treatment. After intracellular isomerization of isotretinoin to ATRA, this active compound is intracellularly transported via cellular retinoic acid-binding protein-2 (CRABP-2) to the nucleus. CRABP-2, an intracellular lipid-binding protein for ATRA, is strongly expressed in sebocytes compared to the epidermis in the isotretinoin-treated patients, promoting a preferential transport of ATRA to retinoic acid receptors (RARs) in sebocytes. Isotretinoin does not have its own specific receptors but is a prodrug of ATRA that binds and activates RARs leading to transcriptional activation of ATRA-regulated primary target genes. An important target gene of ATRA is the transcription factor p53, the guardian of the genome. Sebocyte apoptosis is the major mechanism that explains isotretinoin’s sebum-suppressive effect. The induction of sebocyte death, which histologically corresponds to the involution of sebaceous glands during isotretinoin treatment, explains the pioneering histological and planimetrical studies that demonstrated a marked decrease of size of sebaceous glands of up to 90% of the pretreatment values observed after 12 weeks of treatment. The labeling index of sebocytes regressed significantly under isotretinoin therapy pointing to sebocyte cell cycle arrest. Isotretinoin induces the expression of cell cycle inhibitor p21, the first characterized p53 target gene. Sebocyte apoptosis can be explained

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by isotretinoin-mediated apoptosis of basal sebocytes and sebocyte progenitors. Another ATRA-induced target gene is p14 (ARF), which binds and thereby inactivates MDM2, thereby attenuating p53 proteasomal degradation (Fig. 7.1). Apoptotic pathways are controlled by p53. It induces the expression of the pro-apoptotic effector tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Upregulated expression of TRAIL has been observed in basal and suprabasal layers of sebaceous glands of isotretinoin-treated acne patients. p53 stimulates the expression of the transcription factors FoxO1 and FoxO3, which as well promote the expression of TRAIL. p53 also suppresses mTORC1 activity and SREBP1c, which are increased in acne skin. Basal sebocytes are predominant targets of isotretinoin-mediated apoptosis exhibiting upregulated expression of TRAIL. TRAIL-activated caspases inactivate p63, a critical transcription factor required for the basal/ progenitor sebocytes (Fig. 7.1). IGF-1

Isotretinoin

IGF1R

AR p53

Isomerization ATRA CRABP2

PI3K

ATRA RAR

PTEN ARF

TP53

Nucleus

p14 BLIMP1 AKT

FoxO1

MDM2

p53

FoxO3

c-Myc

FoxO1 TRAIL mTORC1 SREBP1

S6K1

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Caspase 3

SEBOCYTE APOPTOSIS

Fig. 7.1 Sebocyte apoptosis explains the sebum-suppressive effect of systemic isotretinoin. In the sebocyte, isotretinoin is isomerized to alltrans retinoic acid (ATRA), which is transported to the nucleus via cellular retinoic acid-binding protein 2 (CRABP2). In the nucleus, ATRA binds to retinoic acid receptor (RAR) that activates the RAR-responsive target genes TP53 promoting the expression of p53 and of ARF promoting the expression of p14. p14 is a negative regulator of mouse double minute 2 (MDM2), the key inhibitor of p53. Increased IGF-1 signaling is attenuated by p53 via suppression of IGF-1 receptor (IGF1R) and upregulation of phosphatase and tensin homolog (PTEN) suppressing the activity of the kinase AKT. p53 induces the expression of BLIMP1, FoxO1, and FoxO3, known suppressors of c-Myc. p53, FoxO1, and FoxO3 activate the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which activates caspase 3 leading to sebocyte apoptosis. BLIMP1 B lymphocyte-induced maturation protein 1, FoxO forkhead box class O, mTORC1 mechanistic target of rapamycin complex 1, PI3K phosphoinositide-3 kinase, S6K1 ribosomal protein S6 kinase, SREBP1 sterol regulatory element-binding protein 1. Published with kind permission of © Bodo Melnik 2019. All Rights Reserved

7.2.4.6 Comedolytic and Anti-comedogenic Effects Comedones result from a proliferation-retention hyperkeratosis of infundibular keratinocytes building a follicular filament, from which a microcomedo and finally open and closed comedo arise. Unlike any other drug given orally, isotretinoin prevents the development of new comedones, stopping the disease at its inception. Comedones are loosened and uprooted, literally popping out of the follicle. Follicular filaments (follicular casts) and microcomedones are likewise eliminated. It is not unusual to observe fingerlike protrusions of oil-soaked casts from prominent facial pores. The diameters of facial pores, which are wide and spacious in acne patients, are reduced to a third or a fifth of their original size. Histopathologically, one can readily appreciate the elimination of excess corneocyte material retained in comedones, follicular filaments, and normal sebaceous follicles. The number of corneocyte layers in a normal sebaceous filament is about 30–60, which is reduced after isotretinoin treatment to 5–10. Much less sebum is available for colonization by P. acnes, and no cavernous lacunae are maintained in the follicular filaments. The tiny vellus hair comes into close contact with the follicular epithelium. Several biochemical alterations may lead to the enhanced dehiscence of keratinocytes. In vitro studies show that isotretinoin changes the pattern of keratinization. It inhibits the expression of cytokeratin 1/10 and 14, filaggrin, and matrix metalloproteinase-3 (MMP-3) but enhances cytokeratin 7, 13, and 19, lamin B1, as well as IL-1 in normal human epidermal keratinocytes. Isotretinoin impairs the formation of corneodesmosomes, which bind corneocytes together, analogous to desmosomes of the follicular layers, into which tonofilaments insert. ATRA compromises desmosome expression in human epidermis. There is evidence that isotretinoin modifies the composition of intercorneocyte lipids, the mortar-like domain which is responsible for the barrier function of the stratum corneum. We showed that isotretinoin treatment significantly increased the total amounts of ceramides in comedones. Barrier-active long-chain ceramides and hydrolytic enzymes are predominantly transported in lamellar bodies (Odland bodies) which are extruded into the intercorneocyte space. In an experimentally induced comedo model, ATRA treatment enhanced the formation of lamellar bodies, which are believed to contribute to normal desquamation. Lamellar body-mediated enzymatic attacks of intercorneocyte proteins and lipids play a key role for the disintegration of corneodesmosomes and complex lipids which maintain stratum corneum cohesion. ATRA as well upregulated the levels of ceramides in a reconstructed human epidermal keratinization culture model. Ceramide homeostasis plays a key role for epidermal keratinization

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and ordered desquamation. Isotretinoin treatment via sebocyte apoptosis decreases sebum free fatty acids (oleic and sapienic acid) that modify the production of acylceramides by replacing barrier-active linoleic acid. Isotretinoin not only corrects the corneocyte retention but also modifies keratinocyte proliferation. This was originally demonstrated histologically and electron microscopically with isotope labeling. The proliferation marker Ki-67 is overexpressed in acne skin. ATRA, the effector compound of isotretinoin, activates RAR-dependent induction of G1/S cell cycle arrest via upregulation of the cyclindependent kinase inhibitor p21. The p21 gene (CDKN1A) is a key p53 target gene. Upregulated expression of p21 has also been observed in SEB-1 sebocytes during isotretinoin treatment. Isotretinoin-mediated overexpression of p53p21 signaling induces keratinocyte cell cycle arrest and thereby normalizes acroinfundibular follicular hyperproliferation. p21 mRNA increased with calcium-induced differentiation in a time-dependent manner, suggesting that activated p53 signaling contributes to keratinocyte differentiation.

7.2.4.7 Anti-inflammatory Action The term anti-inflammatory is loosely used to describe the rather rapid resolution of inflammatory lesions: papules, pustules, persisting nodules, and inflammatory components of smoldering scars all respond to isotretinoin. This was initially shown by serial biopsies using histology and electron microscopy also in patients with rosacea receiving oral isotretinoin. Anti-inflammatory effects in acne vulgaris are either indirectly mediated by isotretinoin-induced sebocyte apoptosis or directly induced by isotretinoin-mediated suppression of inflammatory mediators such as interleukin-1β (IL-1β), interleukin-17 (IL-17), and Toll-like receptor 2 (TLR2) in lesional skin of acne patients. IGF-1-stimulated cultured human sebocytes in a PI3K/AKT-dependent manner enhance gene expression of nuclear factor κB (NF-κB) promoting the synthesis and secretion of proinflammatory cytokines including IL-1β, IL-6, IL-8, and TNF-α. Increased PI3K/AKT-mTORC1 signaling also positively regulates Th17 cell differentiation and expression of its signature cytokine IL-17. In acne lesions, NF-κB and activator protein-1 (AP-1) are activated with consequent elevated expression of their target gene products, inflammatory cytokines, and matrix-degrading metalloproteinases (MMPs), respectively. Isotretinoin-induced reduction in MMP-9 and MMP-13 may contribute to the therapeutic effects of the agent in acne. Isotretinoin-mediated sebocyte apoptosis reduces the total pool of viable sebocytes that in an IGF-1-dependent fashion produce proinflammatory cytokines. Sebum suppression also reduces the number of P. acnes that stimulate TLR2 and induce a mixed Th1/Th17 response.

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7.2.4.8 Dosage Isotretinoin was registered in the United States as Accutane® in 1982 and as Roaccutan® or Roaccutane® in Europe in 1985. The drug is available in capsules containing 5, 10, 20, and 40 mg. Capsules of 5 mg are available in Germany and Switzerland. The dose ranges from 0.1 to 2.0 mg/kg/day for 16–20 weeks or 16–24 weeks for lower dose. The high dose of 2.0 mg/kg/day was originally promoted, but worldwide this is hardly used anymore. We do not recommend this high dose anymore. Isotretinoin should be divided into two daily doses if the dose is greater than 40 mg daily. Dosage is dependent on a number of variables. Moderately severe inflammatory acne generally responds well to 0.5 mg/kg/day. We include persistent acne papulopustulosa as an indication for isotretinoin. A dose as low as 0.1 mg/kg/day is surprisingly effective in many cases. The acute effect in clearing the moderate acne seems less dependent on the daily dose. Women usually respond better and quicker than men and need a lower daily dose. Resolution is slower and the relapse rate higher. Low dosage is recommended for anxious patients, for those living in cold, dry, wintry climates, or for those with Celtic skin type I. Physicians less experienced with isotretinoin are well advised to start with 0.2–0.3 mg/kg/day or less and to adjust the dose according to the clinical response. 7.2.4.9 Duration of Treatment A course of 15–20 weeks is recommended by the manufacturer, and this was also the duration in early trials. Experience suggests that longer periods, 24–32 weeks, may be necessary to achieve complete healing in severe cases with deep nodules. Treatment programs should be individualized. Some patients require less than 15 weeks, and others more than 32 weeks. It is a common observation that the disease continues to improve after the drug is discontinued. Another tactic which seems promising in moderately severe inflammatory acne is to start with 0.1 mg/kg/day and to maintain this for 5–6 months. High doses are associated with faster response, complete instead of incomplete clearing, and lower recurrence rates. The inevitable price are troublesome adverse effects. 7.2.4.10 Relapse Rate and Retreatment Recurrences, though milder than the original presentation, are fairly common, less so when high doses are given. The relapse rate is indirectly proportional to the therapeutic cumulative dose. Six months after withdrawal of the drug, only 5% of patients receiving 1.0 mg/kg/day relapsed, but 26% of the cohort receiving 0.2 mg/kg/day. This rises to about 50% with 0.1 mg/kg/day but can be kept to less than 25% by adding topical retinoids, during and after oral dosing. In general, post-therapy relapse is minimized by treatment courses that amount to a total of at least 120 mg/kg. There is no reason to recommend not to exceed the total

7.2 Systemic Therapy

cumulative dose of 120 mg/kg. Typically, this total dose can be achieved in 4–6 months at 0.5–1.0 mg/kg/day. As the current trend is to use lower daily dose (0.3 mg/kg/day or lower), a longer duration of treatment is to be expected, which is usually difficult to follow after 6 months of treatment. The benefits of different modifications in administration such as “alternated day” or “1 week within 4 weeks” remain to be determined. Long-term results about the relapse rates after isotretinoin treatment are limited and variable. A population-based cohort study of 17,351 first-time isotretinoin users between 1984 and 2003 showed a relapse rate at 41%. The incidence of recurrence after a course of at least 150 mg/kg of isotretinoin was estimated to be at 23%, with 80% of them within the first 2 years following the treatment completion. In a 10-year follow-up of patients with moderate to severe acne after isotretinoin treatment at doses of 0.5–1.0 mg/kg/day for 16 weeks, a relapse rate near 40% was observed, with 96% of them within 3 years of stopping treatment. There are patient groups showing a high rate of relapse with isotretinoin therapy. Preteens and young teenagers with acne conglobata respond to isotretinoin, but they have a high probability of relapse within 2 years and commonly require two to four courses of therapy before permanent remission occurs. The reasons for this difference in response remain unclear. By far the most common cause of failure to respond to therapy is the poor response of draining sinuses. Identification of these lesions before beginning isotretinoin therapy can help prepare a patient for the potential need for surgical removal if intralesional corticosteroids, systemic corticosteroids, and isotretinoin are not successful. A minority of patients can have acne as part of an androgen excess state due to congenital adrenal hyperplasia (CAH). These patients may respond to a course of isotretinoin, but very commonly will experience relapses within 6 months, or may not respond in a satisfactory way. The patients should be screened with endocrinology tests. Lowdose corticosteroids (2–4 mg/day) should be given with isotretinoin. We recommend to use oral isotretinoin at a lower daily dose of no more than 0.3 mg/kg/day with a lipid-rich meal to increase absorption. A cumulative dose of 120–150 mg/kg body weight is usually required to achieve long-term remission, but this varies individually. Higher cumulative doses can be justified as long as the general guidelines of drug administration are observed, especially in patients with risk factors for an unsatisfactory response. Retreatment is sometimes necessary and entirely feasible. Usually one waits a few months before starting a second or even third course. We prefer longer drug-free intervals. Severe relapse requires higher doses and, in rare cases, adjunctive therapy such as adrenal suppression with dexamethasone.

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7.2.4.11 Adverse Drug Effects Apoptosis explains isotretinoin’s desired (sebocyte death) as well as undesired drug effects. Generally, they are reversible and dose related. Most side effects are predictable and do not interfere with the patient’s management. They are tolerated by modification of the dose and/or additional symptomatic therapy. The following side effects are frequent when the dose is 0.5 mg/kg/ day or more. Also a few rare or even questionable side effects are discussed, as they are presented in the package insert and therefore noticed by the patients or their parents and brought to the attention of the physician. The most serious adverse effect of isotretinoin treatment is teratogenicity (Table 7.4). 7.2.4.12 Teratogenicity Isotretinoin is embryotoxic and teratogenic when administered at susceptible stages of pregnancy. Despite warnings on Table 7.4 Adverse effects of isotretinoin Cutaneous Cheilitis, nasal vestibulitis Dry skin (xerosis) Desquamation, peeling Pruritus Initial exacerbation of acne lesions (during initial treatment) Exuberant granulation tissue Increased susceptibility to sunburn (photosensitivity) Hair loss (anecdotal reports, not substantiated by our findings) Mucous membranes Eye irritation, dryness Conjunctivitis Rhinitis, dryness of oral, pharyngeal, genitourinary tract mucous membranes Epistaxis, subconjunctival hemorrhage Musculoskeletal Bone, joint, and muscle pain or stiffness Neurological Headaches Benign intracranial hypertension (aggravated by concomitant administration of tetracyclines) Gastrointestinal Nausea, vomiting Acute pancreatitis (anecdotal, hypertriglyceridemia-induced) Respiratory system Exercise-induced bronchoconstriction Eosinophilic pleural effusion Psychiatric Depression rare, in a predisposed subgroup of patients Loss of self-esteem, anxiety Teratogenicity Malformations usually involving the craniofacial, cardiovascular, thymic, and central nervous system Laboratory parameters Hypertriglyceridemia increased very low-density lipoproteins Decreased high-density lipoprotein Increased cholesterol Abnormalities of liver-function tests Decreased counts of white and red blood cells

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the use of retinoids during pregnancy and the need for adequate contraception in women of childbearing potential and other strict guidelines on their use, intrauterine exposure to retinoids has still occurred, though with regional differences. The manufacturer has prepared an elaborate educational program to reduce the risk of teratogenicity. The number of annual cases of congenital abnormalities has been decreasing steadily. Nonetheless, physicians are responsible for explaining the potential side effects of the drug and to make sure that the patient understands the full implication of teratogenicity. An abortion is an option that should be discussed beforehand, in case of noncompliance or contraceptive failure. The risk of malformation appears to be high at all therapeutic doses of isotretinoin, even when the duration of exposure is short. The majority of malformations induced by isotretinoin treatment during pregnancy primarily affect neural crest cells (NCCs) which explains the predominance of craniofacial dysmorphic features of isotretinoin embryopathy. Many of the craniofacial dysmorphic features in infants of isotretinoin-exposed mothers have been observed in pigtail monkeys exposed to ATRA during gestation. The most frequent findings were cleft palate, malformed ears, hypertelorism, exophthalmos, hypoplasia of the bone of the mid-face and mandible, a curvature of the inferior border of the mandible, retrognathia, and distortion of the cranium (Table 7.5). During embryogenesis, NCC homeostasis is tightly controlled and requires the appropriate magnitude of apoptosis to allow normal development of NCC-derived tissues. Malformations observed in CHARGE syndrome (including inner and outer ear malformations, heart outflow tract defects, Table 7.5 Retinoid embryopathy presents with multiple neural crest cell-derived abnormalities Central nervous system abnormalities Cerebellar malformation Cerebral abnormalities Cranial nerve deficit Hydrocephalus Microcephaly Cardiovascular defects Septum defect Aorta anomalies Tetralogies Skull abnormalities External ear abnormalities Anotia Auditory canal defect Micropinna Eye abnormalities Microphthalmia Facial dysmorphia Cleft palate Thymus gland abnormality Low IQ (detected in infancy)

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and craniofacial defects) resemble isotretinoin embryopathy. The majority of patients with CHARGE syndrome exhibit loss-of-function gene mutations of CHD7, a protein that negatively regulates the p53 promoter. CHD7 loss in mouse NCCs or samples from patients with CHARGE syndrome results in p53 activation. Abnormal bone specimens in ATRAinduced embryopathy of pigtail monkeys resembled the Treacher Collins syndrome in humans and were related to defective NCC migration in the first and second branchial arches. Unscheduled activation of p53 is responsible for perturbations in tissue homeostasis that causes the development of Treacher Collins syndrome. Increased p53 signaling associated with increased NCC apoptosis has been related to fetal alcohol spectrum disorders, which as well exhibit craniofacial dysplasia. p53-mediated NCC apoptosis promotes dysmorphic craniofacial syndromes including retinoid embryopathy.

7.2.4.13 Contraindication and Warning Isotretinoin must not be used by women who are pregnant, who may become pregnant while undergoing therapy and 1 month thereafter, or who may not use reliable contraception for 1 month before treatment, during treatment, and 1 month after treatment. Even the metabolite with the longest terminal elimination half-life (4-oxo-isotretinoin) returns to endogenous concentrations within 2 weeks after the end of oral isotretinoin treatment. Therefore, a 1-month post-therapy contraceptive period provides an adequate safety margin for isotretinoin. More fetal abnormalities were seen in the United States than in Europe. This has all changed. Exhaustive information is now provided by the manufacturer. It is well summarized in the advertisement: “Start right, or don’t start.” We notice and worry about the trend that oral isotretinoin is increasingly sought by demanding patients merely with mild acne and loosely prescribed, even without reassurance of adequate and reliable contraception. The iPLEDGE program is the latest in a series of FDA-mandated isotretinoin risk management programs designed to prevent pregnancies in patients of childbearing potential (Table 7.6). Table 7.6 Treatment rules for women of childbearing age Women of childbearing age must have a sensitive urine or serum pregnancy test done to exclude pregnancy before taking isotretinoin. A prescription should not be filled until a recent report of a negative pregnancy test has been obtained Do not start isotretinoin until the third day of the menstrual period Effective contraceptive measures must be used 1 month before, during, and after cessation of isotretinoin Some countries, e.g., the United States, provide a special form to register for a confidential follow-up survey A special consent form, written in easily understandable language, is provided. The patient, parent, or guardian signs it, and the prescribing dermatologist countersigns it. This record is kept by the physician

7.2 Systemic Therapy

7.2.4.14 Mucocutaneous Side Effects Isotretinoin treatment consistently induces mucocutaneous side effects such as cheilitis and nasal vestibulitis. The incidence of cheilitis or vestibulitis approaches almost 90% in patients treated with isotretinoin at 0.5 mg/kg/day or more. Frequent applications of bland emollients such as petrolatum and lip balm are helpful. Epistaxis occasionally is bothersome. Asteatotic dry skin with a compromised epidermal barrier involves the face, lateral aspects of upper arms, wrist, lower legs, and flanks and exacerbates particularly in the cold season with low humidity. Patients present with itching, scaling dermatitis of the craquelé or nummular-discoid type. Petrolatum, lanolin, and water-in-oil creams are usually beneficial. Palmoplantar exfoliation is observed in about 5% of patients complaining of a peculiar sticky feeling of their palms and soles. The thinned stratum corneum and abnormal barrier function resulting in increased transepidermal water loss and other structural changes probably accounts for this phenomenon. Epidermal aquaporin 3, a critical mediator of transepidermal water loss, is upregulated by oral isotretinoin and is a known p53 target gene. 7.2.4.15 Staphylococcus aureus Infection Isotretinoin treatment promotes the colonization by Staphylococcus aureus (S. aureus) in the nasal antrum. Therefore, impetiginization should be looked for. The infection may present as impetigo contagiosa anywhere on the body, manifesting as boils or furuncles, but mostly in the face with angular cheilitis. Other infections are impetiginized eczema, paronychia of the fingers or toes, meatal urethritis, otitis externa, scalp folliculitis, folliculitis barbae, and folliculitis elsewhere on the body. A short course of antibiotics quickly solves this problem, though it can recur. The prophylactic application of mupirocin or fusidic acid ointment or any other ointment base into the anterior nares could be helpful. Sebocytes are a significant source for the production of the antimicrobial protein cathelicidin and its active cleavage peptide LL-37. Sebum free fatty acids enhance the innate immune defense of human sebocytes by upregulating β-defensin-2 (HBD2) expression. Isotretinoin-/ p53-mediated sebocyte apoptosis reduces the number of sebocytes able to produce cathelicidin and further reduce the availability of sebum free fatty acids upregulating HBD2 expression. In the skin of isotretinoin-treated acne patients, decreased expression levels of cathelicidin and HBD2 have been reported. LL-37 is very potent and prompt in eliminating both extra- and intracellular S. aureus and was more effective than commonly used conventional antibiotics. LL-37 cleavage peptides exhibit anti-staphylococcal biofilm effects.

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7.2.4.16 Depression and Mood Disorders A small number of patients treated with isotretinoin have reported depression and psychosis, and, rarely, there have been suicide ideation, suicide attempts, and suicide. Patients complaining of depression reported that their depression subsided with discontinuation of therapy and recurred with reinstitution of therapy pointing to a real drug-related adverse effect. The relationship of depression with isotretinoin is problematic, since a depressed affect in patients with severe acne is fairly frequent. There is a small subgroup of susceptible patients that experience isotretinoin-induced mood disorders and depression. Clinically it is not easy to distinguish symptoms of acnerelated depression from isotretinoin-induced depression. Warning flags that should alert the physician include a previous history of altered mood or a history of taking antidepressive or psychotropic drugs or any suggestion of depression or psychotropic behavior developing during treatment. If any of these warning signs are detected, the possibility of an isotretinoininduced effect and the need for increased monitoring or discontinuation of isotretinoin treatment should be considered. The literature reviewed from 1960 to June 2010 by Bremner and coworkers is consistent with associations of isotretinoin administration with depression and with suicide in a subgroup of vulnerable individuals. The hippocampus is one of the brain regions where new neurons are constantly born, a phenomenon called neurogenesis. The pathogenesis of depression is related to decreased hippocampal and prefrontal cortex neurogenesis. In particular, the generation of new neurons within the hippocampus, a limbic region implicated in mood disorders, is compromised in animal models of depression. In contrast, antidepressant treatment such as lithium increases neurogenesis resulting in clinical improvement of the depression. During depression, the hippocampal volume is reduced. Isotretinoin treatment of mice decreased hippocampal neurogenesis and hippocampal volume, a potential effect of p53-mediated hippocampal cell apoptosis. In contrast, lithium, a known inducer of acneiform reactions, inhibits p53. Treatment of hypothalamic cells in mice with isotretinoin decreased cell growth and reduced the number of hypothalamic cells which has been associated with depression-related behaviors. The issue remains inconclusive, because there was marked heterogeneity in study design, outcome and exposure classification, and control for confounding factors, particularly comorbid mental and physical illness. Case reports, database studies, and biological evidence show a plausible association for a minor subgroup of patients, but most metaanalysis and prospective studies fail to support an increased risk. Before the initiation of treatment, all the patients should be inquired about the previous history of psychiatric disorders, and during the treatment this possible side effect should be regularly evaluated.

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7.2.4.17 Pseudotumor Cerebri The most frequent neurological adverse effect associated with oral isotretinoin is headache, either as an independent symptom or as part of pseudotumor cerebri syndrome. Pseudotumor cerebri syndrome refers to a benign intracranial hypertension without detectable neurological abnormalities. It affects primarily obese women of childbearing age but may be caused by a variety of drugs, including tetracyclines and vitamin A derivatives. Patients report such symptoms as headaches, nausea, impaired or blurred vision, alterations in color sense, emotional instability, paresthesia, and drowsiness. The diagnosis is suspected clinically and easily made by fundoscopy and confirmed with papilledema. When the drug is discontinued, symptoms disappear within a few days. It is possible to start over again, usually with a much lower dose. Oral tetracyclines and isotretinoin must not be given together, as pseudotumor cerebri is common with this combination. The washout period after oral tetracycline (doxycycline and minocycline) and before oral isotretinoin for patients with normal liver and renal function takes 7 days to adequately avoid pseudotumor cerebri. For patients with past history of pseudotumor cerebri, a neurologic/ophthalmic check should be considered. Disturbed p53-regulated aquaporin expression in the choroid plexus has been implicated to play a role in the pathophysiology of intracranial hypertension. 7.2.4.18 Telogen Effluvium Long-term use of isotretinoin in higher doses used for disorders of keratinization affects hair growth and is associated with increased hair loss and telogen effluvium in susceptible individuals. Hair loss is not a common problem of isotretinoin treatment of acne. Hair follicles undergo repetitive stages of cell proliferation and programmed cell death. The catagen stage of physiological apoptosis is connected with dynamic changes in morphology and alterations in gene expression. ATRA induces premature hair follicle regression and induces a catagen-like stage in human hair follicles. Hair shaft elongation declined significantly already after 2 days in the ATRA-treated group, and approximately 80% of the ATRA-treated hair follicles had prematurely entered catagen-like stage at day 6, compared with 30% in the control group. This corresponded to an upregulation of apoptotic cells in ATRA-treated hair follicles. It has been demonstrated in murine hair follicles that p53 is strongly expressed and co-localized with apoptotic markers in the regressing hair follicle compartments during catagen. Isotretinoin-mediated upregulation of p53 explains the apoptotic basis of isotretinoin-induced hair loss. Hair loss is a well-known side effect of retinoids and was earlier reported following ingestion of high doses of vitamin A. This is seen especially with etretinate and acitretin. Some clinicians think this occurs with oral isotretinoin, but the data are inconclusive. Hair loss is mentioned in the package

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insert. We have studied trichograms in a series of patients before and during isotretinoin therapy and were unable to demonstrate telogen effluvium (loss of club hairs). Discoloration of hair, e.g., temporary lightening of the natural hair color, has also been reported.

7.2.4.19 Inflammatory Bowel Disease Although the great majority of patients treated with isotretinoin do not experience the development or aggravation of inflammatory bowel disease (IBD), an increased risk of IBD in a subgroup of patients cannot be excluded. Results from case-control, cohort, and meta-analysis studies fail to show a consistent causal association. Close follow-up is warranted for a potential exacerbation of preexisting inflammatory bowel diseases during systemic isotretinoin treatment. Excessive death of intestinal epithelial cells (IEC) in the ileal and colonic epithelium has been suggested to represent a major pathogenetic feature of IBD. It is conceivable that in a subgroup of predisposed patients prone to develop IBD, isotretinoin further promotes IEC apoptosis inducing or aggravating IBD. The p53 gene (TP53) plays a predominant role in the development of IBD. TP53 codon 72 Arg/Arg genotype has been associated with increased risk for IBD. The 72Arg allele predisposes individuals to IBD development and is associated with increased colonic mucosa cell apoptosis. Patients with selected TP53 polymorphisms may be more susceptible for the development of isotretinoinrelated IBD. 7.2.4.20 Hepatotoxicity Mildly to moderately elevated serum concentrations of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are measured in about 15% of patients. These are usually asymptomatic and reverse quickly after discontinuation. Apart from steatosis hepatis, isotretinoin has not been associated with significant hepatotoxicity, which is related to p53-/TRAIL-induced hepatocyte apoptosis. Patients should avoid excessive alcohol consumption during treatment. 7.2.4.21 Hypertriglyceridemia A population-based analysis showed that the cumulative incidence of new abnormalities in patients with normal baseline values was 44% for the level of triglyceride, 31% for total cholesterol, and 11% for transaminase, while hematological test results were mostly unremarkable. All these lipid abnormalities occur early during treatment and are usually reversible within a few weeks after discontinuation. Isotretinoin treatment can induce moderate to severe hypertriglyceridemia especially in predisposed individuals, usually dose-dependent. Increased serum triglycerides are found primarily in the very low-density lipoprotein (VLDL) frac-

7.2 Systemic Therapy

tion of the plasma and occur during both the fasted and fed state. Isotretinoin-induced hypertriglyceridemia is caused by increased hepatic VLDL secretion. The critical factor that determines the rate of hepatic VLDL production is the availability of apolipoprotein B-100 (Apo-B100). A p53 response element has been identified in gene encoding ApoB-100, which promotes ApoB-100 and subsequent VLDL synthesis. Triglyceride loading to ApoB-100 is facilitated by microsomal triglyceride transfer protein (MTP), which is activated by FoxO1, another p53 target gene, which is activated by isotretinoin and suppressed by increased insulin/IGF-1 signaling. Upregulation of p53 and hepatic ApoB-100 is a most attractive explanation for isotretinoin-induced hypertriglyceridemia. When serum triglyceride concentrations exceed 400 mg/dL the isotretinoin dose should be reduced. In rare instances, genetically predisposed patients may exhibit severe hypertriglyceridemia leading to acute pancreatitis. A case crossover study fails to show any statistically significant association between oral isotretinoin and acute myocardial infarction, phlebitis/thrombophlebitis, pulmonary embolism, thrombosis, or stroke.

7.2.4.22 Musculoskeletal Symptoms In about 15% of patients, minor to major forms of arthralgia occur, sometimes severe enough to require discontinuation of isotretinoin. It is observed mainly in the morning when they get out of bed or follow strenuous exercise and intensive physical activity. Isotretinoin-associated arthritis, in particular sacroiliitis, is occasionally reported. Myalgia or elevated creatine phosphokinase (CPK), particularly of the isoenzyme fraction MM (skeletal musculature, myopathy), has been reported in 16–51% of patients on isotretinoin. The vast majority shows a benign course; even remarkable CPK values above 5000 IU/l return to normal within 2 weeks after completing treatment. Lethal cases due to rhabdomyolysis are exceptional. Patients performing vigorous physical exercise should be informed about this potential risk before the start of the treatment. The musculoskeletal symptoms are usually dose-dependent and rarely seen on low-dose treatment. In a prospective observational study, spondyloarthropathy findings were identified in 23.1% of the patients on a daily dose of 0.8–1 mg/ kg/day for a total dose of 120–150 mg/kg within 4–6 months. CPK has been found to be elevated, occasionally by up to 100 times the normal value particularly in those patients undergoing vigorous physical exercise. Increased TRAIL expression was detected in myositis muscle fibers. TRAIL induced NF-κB activation and IκB degradation in cultured muscle cells that are resistant to TRAIL-induced apoptosis but that undergo autophagic cell death. It is thus conceivable that isotretinoin-induced myalgia is related to TRAILmediated muscle cell apoptosis.

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7.2.4.23 Fertility and Sexual Functions Isotretinoin poses no hazard to the male reproductive system or fertility. Teratogenicity cannot be transferred via the ejaculate or sperm to the woman. No adverse effects of oral isotretinoin on fertility in female acne patients given a total dose of 120 mg/kg over a period of 6 months were found. In humans, long-term adverse effects of systemic isotretinoin treatment on female fertility in humans have been excluded. There is also no concern about adverse effects of isotretinoin on male fertility. There is evidence that treatment of severe acne with oral isotretinoin at a dose of 0.5–0.75 mg/kg/day can significantly lower the serum level of total testosterone, more prominently in women (Table 7.7). 7.2.4.24 Increased Susceptibility to Sunburn The stratum corneum becomes thinner, and keratinocytes do not accumulate as much melanin owing to increased turnover. This means a poorer shield against ultraviolet radiation. Isotretinoin-induced photosensitivity is negligible at low dose (