Are Skin Diseases Systemic Ones?

5

Clinics in Dermatology: Are Skin Diseases Systemic Ones?

VOLUME 32 NUMBER 3 MAY/JUNE 2014

Vol. 32 No. 3 May/June 2014

Are Skin Diseases Systemic Ones? Guest Editors: Nikolai Tsankov MD, PhD, MSc, Jana Kazandjieva MD, PhD, and Razvigor Darlenski MD, PhD

Pages 341–456

Official Publication of

THE INTERNATIONAL ACADEMY OF COSMETIC DERMATOLOGY

Elsevier

Editor-in-Chief Lawrence Charles Parish, MD Philadelphia, Pennsylvania USA Deputy Editors Larry E. Millikan, MD Meridian, Mississippi USA

Joseph A. Witkowski, MD Philadelphia, Pennsylvania USA

Managing Editor Hirak Behari Routh, MBBS Philadelphia, Pennsylvania USA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt Klaus Ejner Andersen, MD Odense, Denmark Lucio Andreassi, MD Siena, Italy Jean Bolognia, MD New Haven, Connecticut USA Sarah Brenner, MD Tel-Aviv, Israel Philip R. Cohen, MD Bellaire, Texas USA Timothy C. Flynn, MD Cary, North Carolina USA Mauricio Goihman-Yahr, MD Caracas, Venezuela Robin A.C. Graham-Brown, FRCP Leicester, United Kingdom Jane M. Grant-Kels, MD Farmington, Connecticut USA Andrzej Grzybowski, MD, PhD, MBA Poznan´, Poland Aditya K. Gupta, MD London, Ontario, Canada Andreas Katsambas, MD, PhD Athens, Greece Sidney N. Klaus, MD Lebanon, New Hampshire USA

Mark Lebwohl, MD New York, New York USA Antonio Ledo, MD Madrid, Spain Jasna Lipozencˇi´c, MD, PhD Zagreb, Croatia Jean Paul Ortonne, MD Nice, France Oumeish Y. Oumeish, MD, FRCP Amman, Jordan Joseph Pace, MD, FRCP Naxxar, Malta Daniel H. Parish, MD, JD Bala-Cynwyd, Pennsylvania USA Yoon-Kee Park, MD Seoul, Korea Marcia Ramos-e-Silva, MD Rio de Janeiro, Brazil Joo-Young Roh, MD, PhD Incheon, Korea Diane Roseeuw, MD Brussels, Belgium Marti Jill Rothe, MD Farmington, Connecticut USA Noah Scheinfeld, MD, JD New York, New York USA Virendra N. Sehgal, MD New Delhi, India

Nanette B. Silverberg, MD New York, New York USA Rodney Sinclair, MBBS Melbourne, Australia Stephen P. Stone, MD Springfield, Illinois USA Nikolai K. Tsankov, MD Sofia, Bulgaria Maria Tsoukas, MD, PhD Chicago, Illinois USA Yalçin Tüzün, MD Istanbul, Turkey Guy F. Webster, MD, PhD Hockessin, Delaware USA Oliverio Welsh, MD Monterrey, Mexico John E. Wolf, Jr., MD Houston, Texas USA Ronni Wolf, MD Tel-Aviv, Israel Uwe Wollina, MD Dresden, Germany Chu-Kwan Wong, MD Tokyo, Japan Jim E. Zeegelaar, MD, PhD Almere, The Netherlands Xue-Jun Zhu, MD Beijing, China

Volume 32, Number 3, May/June 2014

Guest Editors: Nikolai Tsankov MD, PhD, MSc Jana Kazandjieva MD, PhD Razvigor Darlenski MD, PhD

Elsevier

Clinics in Dermatology is cited in Index Medicus, Current Contents, and EM-BASE/Excerpta Medica. Publication Information. Clinics in Dermatology (ISSN 0738-081X) is published bi-monthly by Elsevier, 360 Park Avenue South, New York, NY 10010-1710. Periodicals postage paid at New York, NY and additional mailing offices. USA POSTMASTER: Send address changes to Clinics in Dermatology, Elsevier Customer Service Department, 3251 Riverport Lane, Maryland Heights, MO 63043, USA. Annual Subscription Rates. Domestic Individual: $297.00; Domestic Student/Resident: $100.00; International Individual: $338; International Student/Resident: $139.00. To receive student/resident rate, orders must be accompanied by name of affiliated institution, date of term, and the signature of program/ residency coordinator on institution letterhead. Orders will be billed at individual rate until proof of status is received. Advertising information. 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VOLUME 32, NUMBER 3, MAY/JUNE 2014

CONTENTS Commentary: Are skin diseases systemic ones? Nikolai Tsankov, Jana Kazandjieva, and Razvigor Darlenski

341

Psoriasis as a systemic disease Ivan Grozdev, Neil Korman, and Nikolai Tsankov

343

Sarcoidosis as a systemic disease Virendra N. Sehgal, Najeeba Riyaz, Kingshuk Chatterjee, Pradeep Venkatash, and Sonal Sharma

351

Autoimmune blistering dermatoses as systemic diseases Snejina Vassileva, Kossara Drenovska, and Karen Manuelyan

364

Neutrophilic dermatoses as systemic diseases Lola Prat, Jean-David Bouaziz, Daniel Wallach, Marie-Dominique Vignon-Pennamen, and Martine Bagot

376

Acne as a chronic systemic disease Christos C. Zouboulis

389

Hidradenitis suppurrativa (acne inversa) as a systemic disease Clio Dessinioti, Andreas Katsambas, and Christina Antoniou

397

Contents Cont’d Atopic dermatitis as a systemic disease Razvigor Darlenski, Jana Kazandjieva, Evgeniya Hristakieva, and Joachim W. Fluhr

409

Contact dermatitis as a systemic disease Aleksandra Kulberg, Sibylle Schliemann, and Peter Elsner

414

Chronic urticaria as a systemic disease Razvigor Darlenski, Jana Kazandjieva, Torsten Zuberbier, and Nikolai Tsankov

420

Herpes zoster as a systemic disease Ivan Staikov, Neyko Neykov, Branka Marinovic, Jasna Lipozencic, and Nikolai Tsankov

424

Vitiligo as a systemic disease Torello Lotti and Angelo Massimiliano D’Erme

430

Behçet’s disease as a systemic disease M. Cem Mat, Ays¸egül Sevim, I˙zzet Fresko, and Yalçın Tüzün

435

CONTEMPORARY DERMATOLOGY Dermatologic Disquisitions And Other Essays Improving patients’ satisfaction with care

444

Caretaker Of The Skin Robert Koch (1843–1910) and dermatology on his 171st birthday

448

Erratum Erratum to “Adjuvant drugs in autoimmune bullous diseases, efficacy versus safety: facts and controversies” [Clin Dermatol 2010; 28:337–343]

451

IACD Officers page

452

Dermatology Around the World

453

IACD Membership Application

455

Clinics in Dermatology (2014) 32, 341–342

Commentary

Are skin diseases systemic ones? “Nothing is more profound than that which appears superficial” —Georg Wilhelm Friedrich Hegel

Within the first 14 years of the twenty-first century, psoriasis has been transformed from a cutaneous entity into one with significant systemic manifestations. The association of psoriasis with the metabolic syndrome, as well as other cardiovascular and gastrointestinal disease, had suggested similarities between the inflammatory processes in the skin and other internal organs and tissues.

Questions of concern Such a growing body of evidence poses several questions: • Is the skin a screen on which the changes in the internal homeostasis are projected? • Are skin diseases only superficial ones and only the integument is involved? • Are the skin and the internal organs involved in a common pathophysiologic process that is only visible at the skin surface? • Are atopic dermatitis, other dermatitides, and acne simply skin disease or can they be regarded as systemic inflammatory disorders with skin manifestations? • What stands for the autoimmune connective tissue and blistering disease? We present a concept that is not widely accepted in the general medical community, not even by dermatologists. Only those fragments of the etiopathogenesis eventually related to the systemic involvement of the focused skin diseases will be revealed. The relationship between skin changes and internal organ pathology will be discussed.

The issue In this issue, we focus on acne, atopic dermatitis, Beçhet disease, contact dermatitis, herpes zoster, hidradenitis suppurativa, neutrophilic dermatoses, pemphigus, psoriasis, 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.013

urticaria, and vitiligo, each as a systemic disease. The multisystemic involvement in these diseases is without doubt and will be discussed in this issue of Clinics in Dermatology. The similarities in the inflammatory process and the spectrum of associated diseases, as well as in the response to certain types of treatment, have enabled psoriasis to be classified as one of the “immune-mediated inflammatory diseases.” The goal of the authors (Grozdev, Tsankov, and Korman) of this contribution is to provide an overview, supporting the concept of understanding psoriasis as a systemic disease. The team of Sehgal provides evidence in support of sarcoidosis as a systemic disease. They show that sarcoid granuloma formation is a result of the abnormal localized collections of chronic inflammatory cells that form nodule(s) in the tissue of any organ of the body, particularly the lungs, with lymph node involvement being common. The paper on autoimmune blistering diseases (AIBD) reveals that AIBD are examples of skin specific autoimmune disorders, which can sometimes represent the cutaneous manifestation of a multiorgan disease. For example, in paraneoplastic pemphigus the internal organs (particularly the lungs) are affected by autoimmune injury. Dermatitis herpetiformis is currently regarded as the skin manifestation of gluten sensitivity. The authors provide clinical and laboratory data in support of the concept of AIBD as systemic illnesses. A French team discusses the group of neutrophilic dermatoses, which are often idiopathic but may be associated with myeloid hematologic malignancies, inflammatory bowel disease, rheumatoid arthritis, and monoclonal gammopathies. The possible infiltration of internal organs with neutrophils during the setting of neutrophilic dermatoses underlies the concept of a neutrophilic systemic disease. In his contribution, understanding acne as a chronic, systemic disease, Zouboulis points out that acne is the most common skin disorder. Interestingly, it is also a cardinal component of many systemic diseases or syndromes, such as congenital adrenal hyperplasia, seborrhea-acne-hirsutismandrogenic alopecia syndrome, polycystic ovarian syndrome, hyperandrogenism-insulin resistance-acanthosis nigricans syndrome, Apert syndrome, synovitis-acne-

342 pustulosis-hyperostosis-osteitis syndrome, and pyogenic arthritis-pyoderma gangrenosum-acne syndrome. Dessinioti, Katsambas, and Antoniou debate whether hidradenitis suppurrativa (HS) may be considered as a systemic disease, relying on the presence of accompanying systemic manifestations. There are several reports in the literature of the coexistence of HS with other diseases, including pyoderma gangrenosum, Adamantiades-Behçet disease, Crohn’s disease, SAPHO, pachyonychia congenita, and other syndromes. We know for certain that the atopic march is a classic example for the multiorgan involvement in atopy. Atopic dermatitis can be accompanied by a variety of systemic diseases, such as autoimmune disorders, ophthalmologic involvement, eosinophilic gastroenteritis, inflammatory bowel disease, nephritic syndrome, and metabolic diseases. The paper by Darlenski, Kazandjieva, Hristakieva, and Fluhr reviews these associations and focuses on the possible common underlying mechanisms of AD and these associated syndromes. Systemic contact dermatitis (SCD) is a well-known condition, occurring in previously sensitized individuals after systemic reexposure to the same or cross-reacting substance. Elsner and his team from Jena concentrate their work on the most common allergens (nickel, aminoglycoside antibiotics, corticosteroids, balsam of Peru, and plants) and the most typical presentations of SCD, including the baboon syndrome. Chronic urticaria is a complex disease with different etiopathologic mechanisms and evoking factors. In this paper, the authors describe the associations between chronic urticaria and a variety of disorders, such as autoimmune diseases, atopy, infections, metabolic disease, and neoplastic disorders. Beyond the mechanistic association, the possible common underlying mechanisms, such as systemic immunological processes, are discussed. With the advancement of medicine, more and more case reports have started to emerge showing the different incidences of herpes zoster, whose clinical presentations and complications break the well-known fact that “herpes zoster affects the skin and nervous system.” Together with the common complications, the authors review the otorinolaryngologic, ophthalmologic, gastrointestinal, nephrologic, and urologic involvements

Commentary The view of Lotti and his coauthors reflects that vitiligo most visibly affects not only the skin, but it can also involve melanocytes in different organs and systems. In addition, some types of vitiligo (nonsegmental vitiligo) may also be associated with several, but distinct, diseases, mainly with autoimmune pathogenesis. For these reasons, it is important to face a patient with vitiligo always as a patient affected by a systemic disease. Tuzun and his coauthors present the concept that Behçet’s disease is a multiorgan systemic disease. Behçet’s disease usually begins with cutaneous manifestations, but eye involvement, leading to loss of vision, as well as vascular, articular, and central nervous system involvement, is possible and more commonly observed among men.

Raisôn d’etre The current issue is not only attempting to present a theory but also trying to reveal facts. The continuous discussion of these ideas may result in building a hypothesis on the link between skin and internal pathologies. Basing it on the law of Hegel, which postulates passage of quantitative changes into qualitative changes, it could be assigned to skin diseases. One day this could be the ground for a new understanding and concept of cutaneous disorders. Nikolai Tsankov MD, PhD, MSc Department of Dermatology and Venereology Tokuda Hospital-Sofia 51B Nikola Vaptsarov blvd, 1407 Sofia, Bulgaria E-mail address: [email protected] Jana Kazandjieva MD, PhD Department of Dermatology and Venereology Medical Faculty Medical University-Sofia 1 St. Georgi Sofiiski str., 1431 Sofia, Bulgaria Razvigor Darlenski MD, PhD Department of Dermatology and Venereology Tokuda Hospital-Sofia 51B Nikola Vaptsarov blvd, 1407 Sofia, Bulgaria

Clinics in Dermatology (2014) 32, 343–350

Psoriasis as a systemic disease Ivan Grozdev, MD, PhD a,⁎, Neil Korman, MD b , Nikolai Tsankov, MD, PhD c a

Department of Dermatology and Venereology, Medical Faculty, Medical University-Sofia, 1 Georgi Sofiiski Boulevard, 1431 Sofia, Bulgaria b Murdough Family Center for Psoriasis, University Hospitals Case Medical Center, Cleveland, Ohio c Department of Dermatology and Venereology, Tokuda Hospital-Sofia, Sofia, Bulgaria

Abstract Psoriasis is an inflammatory immune-mediated disease that affects the skin and has pathogenic effects with systemic impact. The relationship between psoriasis and comorbidities remains controversial. The hypothesis of a causative role of psoriasis in its cardiovascular and metabolic comorbidities is based on pathophysiologic concepts establishing a link between chronic inflammation in psoriasis, endothelial dysfunction, formation of atherosclerotic plaques, and the different compounds of metabolic syndrome. Psoriasis management has to be multidisciplinary. It implicates identification and treatment of psychological disorders, addictions, and associated cardiovascular and metabolic diseases, together with improvement of quality of life of patients. © 2014 Elsevier Inc. All rights reserved.

Psoriasis, a recalcitrant disease of chronic and systemic inflammation, affects approximately 2% to 3% of the population.1–3 The cutaneous manifestations of this disease, often the most renowned, typically wax and wane throughout the progression of this lifelong disease. Similarities in the inflammatory process and the spectrum of associated diseases, as well as in the response to certain types of treatment, have enabled psoriasis to be classified as one of the “immunemediated inflammatory diseases,” a group that also includes rheumatoid arthritis, Crohn disease (CD), and other conditions.4 The goal of this contribution is to provide an overview supporting the concept of understanding psoriasis as a systemic disease.

is significantly increased in psoriasis.5 One report divides comorbidities into two groups.6 The first group includes diseases that are pathogenetically associated with psoriasis, such as psoriatic arthritis, CD, and pustular dermatoses. The second group includes diseases such as metabolic syndrome and cardiovascular diseases (CVD) that are associated with psoriasis through its severe chronic course. It has been suggested that comorbidities are secondary manifestations of a disease that can occur at different times and in one or more organs.7 Although they are secondary conditions, comorbidities can sometimes have an even greater social health impact than primary conditions. Table 1 provides a suggested classification of comorbidities in psoriasis.

Epidemiologic data It has been observed epidemiologically that the frequency of some noncutaneous diseases and conditions ⁎ Corresponding author. Tel.: +359 888 233 123. E-mail address: [email protected] (I. Grozdev). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.001

Psoriasis and psoriatic arthritis The prevalence rate of psoriatic arthritis in general population is estimated to 0.25%,8 although it is reported to be between 5% and 48% among patients with psoriasis.9–11 These results demonstrate that the prevalence rate of arthritis

344 Table 1

I. Grozdev et al. Classification of psoriasis comorbidities

Common diseases Psoriatic arthritis Crohn disease Persistent activation of cutaneous T cells Cutaneous T-cell lymphoma Chronic/Systemic skin inflammation Metabolic syndrome Atherogenic dyslipidemia Hypertension Abdominal obesity Diabetes and insulin resistance Predisposition to thrombosis Nonalcoholic hepatic steatosis Comorbidities related to impaired quality of life Anxiety, depression Smoking, alcoholism Comorbidities related to treatment Nephrotoxicity, hepatotoxicity, dyslipidemia, skin cancer Adapted from Puig-Sanz et al.7

in patients with psoriasis may actually be higher than the previously accepted rate of 7%.12

Psoriasis and CD Prevalence of psoriasis among patients with CD is higher than in the general population. Results from five independent case–control studies reveal that 9% of patients with CD have psoriasis versus 1.4% of the control subjects.13 In addition, families with psoriasis or CD have an increased risk for development of the other disease. Another study shows that 10% of patients with CD have a first-degree relative with psoriasis compared with 3% of the control subjects.14 Psoriasis and CD also have a genetic link through the Human Leukocyte Antigen (HLA) system. The most important susceptibility locus for psoriasis is on chromosome 6 p21, also known as PSORS-1.15 A chromosome locus 6 p23, also known as IBD-3, is partially responsible for the genetic susceptibility for CD.16 The gene, encoding tumor necrosis factor (TNF)-α, is situated close to PSOR-1 and IBD-3, supporting the genetic importance of TNF-α for both diseases. Further studies are needed to elucidate whether different TNF-α gene mutations could lead to an increased risk for psoriasis and CD.

Psoriasis and metabolic syndrome Metabolic syndrome has been identified as a clustering of metabolic abnormalities in individuals and is associated with an increased risk for type 2 diabetes and CVD.17 The most recent definition of metabolic syndrome requires central

obesity (body mass index N 30 kg/m2) and any two of the following abnormalities: elevated plasma triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and raised fasting plasma glucose.18 In a study comparing 625 hospitalized patients with psoriasis and 1044 surgically treated patients, it was shown that hyperlipidemia, hypertension, coronary artery disease, type 2 diabetes, and increased body mass index are increased in patients with psoriasis compared with control subjects.19 The presence of these conditions in a single patient, defined as metabolic syndrome, was two times more frequent if the patient suffered from psoriasis. A case– control study revealed elevated triglycerides and abdominal obesity are more frequent in 338 adult patients with plaque psoriasis than in 334 control subjects with other skin diseases.20 The association of psoriasis with metabolic syndrome and its components has been confirmed in other large epidemiologic studies.21–24 One report found that this association is more significant in patients older than 50 years.25

Psoriasis and CVD It has been more than 35 years since McDonald et al.26 reported that rates of occlusive vascular diseases such as thrombophlebitis, myocardial infarction, pulmonary embolism, and cerebrovascular incidents were significantly higher in patients with psoriasis than in those without psoriasis. Since then, substantial data have been accumulating on the association between psoriasis and CVD.27–29 Psoriasis has been found to be an independent risk factor for myocardial infarction, stroke, coronary artery, cerebrovascular, peripheral vascular diseases, and CV mortality.30–33 The data of a 10-year prospective study of a cohort of 1376 patients enrolled in a photochemotherapy follow-up study did not support the hypothesis that severe psoriasis is an independent risk factor for CVD.34

Impact of psoriasis onset and severity A cohort study among 8991 hospitalized patients with psoriasis and 19,757 ambulatory patients with psoriasis was conducted.35 The authors found a 50% increased risk for CV mortality in hospitalized patients. The risk was positively associated with the number of hospitalizations and the earlier age of first hospitalization. In their large, population-based study among patients of the General Practice Research Database in the United Kingdom, investigators also demonstrated that young and severe psoriasis patients were more likely to have myocardial infarction.30 Diabetes, obesity, and other CV risk factors are also more prevalent in severe than in mild psoriasis.36 In a prospective study, however, the authors

Psoriasis concluded that very severe psoriasis is associated with increased noncardiovascular mortality, but not with increased cardiovascular (CV) risk.34

Psoriasis, alcohol, and smoking Alcoholism and liver cirrhosis are reportedly more common in psoriasis, with a reported prevalence rate of alcoholism of 18% among patients with psoriasis compared with 2% in other dermatologic control patients.37 Alcohol consumption is positively correlated with psoriasis severity.38,39 It is higher before psoriasis onset than it is before other skin disease onset and the increased alcohol consumption is sustained throughout the psoriasis course.40 Among hospitalized dermatologic patients, alcoholism is more prevalent in psoriasis than in other skin diseases.41 A case–control study revealed that the risk for psoriasis was greater in ex-smokers and current smokers than in those who never smoked, and smoking was strongly associated with the occurrence of pustular lesions.23 Within the General Practice Research Database in the United Kingdom, smoking is more prevalent in psoriasis patients than in control subjects.30 In a cross-sectional study, patients with psoriasis, enrolled in the prospective Utah Psoriasis Initiative, had a significantly higher prevalence of obesity and smoking than the general population of Utah. The prevalence of obese smokers was significantly higher.42 Both alcohol and smoking may cause increased mortality in patients with moderate-to-severe psoriasis.43

345 depression, and the treatment of depression may reduce the pruritus.49 An association between psoriasis and stressful life events in the year preceding diagnosis has been reported, suggesting that psychological stress may have a role in the pathogenesis of psoriasis.23 Psoriasis-related stress can play a role in the exacerbation of psoriasis, and greater stress reactivity has been associated with onset of psoriasis at an earlier age.45

Pathogenic mechanisms shared between psoriasis and comorbidities Although epidemiologic studies have demonstrated an increased risk for adverse cardiac events among patients with psoriasis, they do not provide insight to the cause of this increased risk. The term march of psoriasis was first introduced by Boehncke et al.49 to describe the causal link that may exist between psoriasis and CVD (Figure 1). The concept is that systemic inflammation associated with psoriasis enhances insulin resistance, causing endothelial dysfunction, subsequent atherosclerosis, and ultimately coronary events. Patients with psoriasis have significant in-

Psoriasis and psychiatric/psychological diseases The first reports on the impaired psychosomatic health of psoriasis patients date back to the 1960s of last century.44 The association between psoriasis and high depression scores, anxiety, obsessiveness, and difficulty in verbalizing emotions (especially anger) is well-known45; furthermore, an association has been reported between severe psoriasis and clinical depression and suicide ideation in 7.2% of hospitalized patients.46 This association was found in only 2.5% of outpatients, which is comparable with that found in general medical patients (2.4%-3.3%). Psychological comorbidity in psoriasis probably contributes to a sedentary lifestyle, alcoholism, and smoking, and all these increase the risk for other comorbidities in these patients. In the study among patients enrolled in the General Practice Research Database in the United Kingdom, it was demonstrated that annually, 10,400 cases of depression, 7100 cases of anxiety, and 350 cases of suicide could be related to concomitant psoriasis.47 Depression is more prevalent in psoriasis patients who are young, male, and suffer from a severe disease.48 The severity of depression correlates with pruritus. Alleviation of the itch may improve the course of the

Fig. 1

Common pathways of psoriasis and atherosclerosis.49

346 flammation not only in the skin, but also subclinical inflammation in the liver, joints, tendons, and vascular tree even after adjusting for traditional CV risk factors, suggesting that psoriasis itself predisposes to proinflammation pathways independent of traditional risk factors.50 The concept of “psoriasis march” was not supported by the results of a detailed population-based study with a follow-up of more than 10 years.51 By using standardized measures of atherosclerosis, it was demonstrated that patients with psoriasis of a cohort with predominantly mild disease are as likely to experience development of atherosclerosis and CV events as subjects without psoriasis.

Common inflammatory molecules and pathways between psoriasis and CVD T helper cells type 1 (Th1) and type 17 (Th17), and regulatory T cells (Treg) play integral roles in psoriasis and atherosclerosis pathogenesis. In psoriasis, the disease cycle is perpetuated through Th1 cytokines (interferon [IFN]-γ, interleukin [IL]-2, and TNF-α), stimulated keratinocytes, as well as the production of more cytokines (TNF-α, IL-1, and IL-6) and chemokines. 52,53 The recruitment and localization of T cells to the dermis and epidermis are mediated through various adhesion molecules and integrins. Psoriasis involves upregulation of adhesion molecules such as E-selectin and intracellular adhesion molecule-1.54,55 In atherosclerotic plaques, there is the same cytokine milieu of TNF-α, IL-6, IL-8, and IL-17 as that found in the gut of a patient with CD, in a psoriatic plaque, or in an arthritic joint. The rupture of the plaque is triggered by the same factors of infection and emotional stress that cause flares in these diseases.56 Endothelial dysfunction in atherosclerosis is associated with an increased level of TNF-α and other cytokines.57 Dendritic cells within the plaques are activated to express IL-12 in higher quantities, initiating transcription of IFN-γ.58 Increased IFN-γ transcription factors exist in T cells of patients with acute coronary syndrome.59 The initiation and perpetuation of these Th1 responses known in psoriasis and atherosclerotic plaques demonstrates a link between these two conditions.52 Th17 cells, stimulated by IL-23, produce IL-17 and IL-22, which activate keratinocyte proliferation and release of other inflammatory proteins.53,60 IL-17 is the mechanistic link between T-cell activation and inflammation. It is known to induce the key psoriatic cytokines of TNF-α, and IL-1, IL-6, and IL-8, among a cascade of inflammatory mediators. Its key role in driving epidermal activation in psoriatic plaques is evidenced by the mechanism of certain therapies. IL-17 is increased in patients with psoriasis. Its levels correlate positively with lesion area and decrease with therapy,61,62 whereas the correlation with disease severity is controversial.63 IL-17 is also seen at higher levels, along with IL6, IL-8, and C-reactive protein, in the plasma of patients who

I. Grozdev et al. have suffered unstable angina and acute myocardial infarction.64,65 Endothelial cell injury leads to cytokine release and Th17 differentiation. Similar to psoriasis, TNF-α and IL-17 synergistically upregulate further cytokine transcription.66 IL-17 and IFN-γ levels are undetectable in healthy volunteers but are elevated in patients with coronary artery disease. The utility of measuring IL-17 levels in patients with psoriasis to identify those at a higher risk for myocardial infarction is under investigation.52 Angiogenesis is a recognized feature common to psoriasis and atherosclerosis, and vascular endothelial growth factor (VEGF) is a potent proangiogenic factor that has been reported to be upregulated in both conditions, and thus may be a link between the two diseases.67,68 VEGF is produced by human keratinocytes in response to stimulation with cytokines (IL-17, IL-8, TNF-α) involved in psoriasis pathogenesis. Tregs inhibit T-cell activation and proliferation through IL-10, transforming growth factor (TGF), and cell–cell interaction.69–71 The inhibitory function of Tregs may be reduced in patients with psoriasis.72 Increased levels of TGF exist in the serum and epidermis of patients with psoriasis, correlating with psoriasis disease severity.73,74 A decrease in TGF receptors in psoriatic epidermis may indicate a reduced activity of TGF.69–71,75 In atherosclerosis, TGF and IL-10 may inhibit plaque formation.76,77 Several lines of evidence suggest that psoriasis and coronary artery disease have reductions in the inhibitory function of Tregs.52 Chronic inflammation and proinflammatory cytokines play significant roles in the pathogenesis of both psoriasis and vascular disease. Evidence suggests that psoriasis and CVD share common pathogenic features78,79 including immunologic processes, inflammatory cytokine profiles, and the presence of local and systemic inflammatory markers.49,78,79 Activation of these inflammatory cells (dendritic cells, macrophages, and T cells) together with the release of proinflammatory cytokines (eg, TNF-α, IFN-γ, IL-12) contribute to the development of psoriatic lesions and play a major role in the development and vulnerability of atherosclerotic plaque.57,80,81 The question whether psoriasis has the capacity to directly cause vascular inflammation and thrombosis remains unknown. An attempt to elucidate this question is the use of a murine model of psoriasis that recapitulates many aspects of the disease but without having the standard CVD risk factors.82 Using this model, investigators have identified that sustained skin inflammation is sufficient to promote vascular inflammation and thrombosis.83

Common inflammatory molecules and pathways between psoriasis and obesity Adipose tissue is an active endocrine organ with many secretory products. Leptin, an adipokine secreted by

Psoriasis adipocytes, has been shown to participate in the pathogenesis of immune-mediated inflammatory diseases such as type 1 diabetes, RA, inflammatory bowel disease, and psoriasis.84 High levels of leptin in obese patients are associated with increased proinflammatory mediators that may lead to development of psoriasis.85 Adiponectin, another adipocyte-specific protein, was shown to inhibit TNF-α production.86 It also inhibits the biological activity of TNF-α.87 In endothelial cells, adiponectin downregulates the expression of adhesion molecules, intracellular adhesion molecule-1, and vascular cell adhesion molecule 1, thus contrasting the effect of TNF-α. Plasma levels of adiponectin are decreased in obesity and in psoriasis compared with healthy control subjects.88

Common inflammatory molecules and pathways between psoriasis and diabetes Chronic inflammation in psoriasis leads to increased insulin-like growth factor II in the skin and blood of patients with psoriasis.89 Insulin-like growth factor II promotes epidermal proliferation and is also implicated in promoting atherosclerosis, in modulating body fat mass and lipid metabolism in mice, and is linked to diabetes and hyperlipidemia in animal and human models.90 Immunocytes and keratinocytes in psoriatic skin produce angiogenic factors, such as VEGF, which promote angiogenesis and endothelial cell activation. VEGF is also increased in hyperinsulinemic states such as the metabolic syndrome, in which adipocytes are its primary source.91 Hyperinsulinemic states such as obesity and the metabolic syndrome, therefore, might promote susceptibility to psoriasis or exacerbate existing psoriasis not only through their role in promoting and facilitating inflammation, but also through increased and sustained levels of circulating VEGF.

Common inflammatory molecules and pathways between psoriasis and hypercoagulation In psoriasis, thrombotic events could be triggered through established platelet activation.92 Activated platelets may exert a role in psoriasis pathogenesis by favoring leukocyte rolling in the skin microvasculature.93 In patients with psoriasis, there is a homeostatic misbalance toward a prothrombotic state, which might be sustained by platelet hyperactivity.94 Inflammatory markers in psoriasis, such as TNF-α, IL-1, and IL-6, can induce synthesis and release of acute-phase proteins, that is, C-reactive protein and serum amyloid A, by the liver. They also can increase the expression of cellular adhesion molecule on endothelial cells (eg, intracellular adhesion molecule-1, vascular cell adhesion molecule),

347 which is required for the migration of leukocytes out of the circulation into the inflamed tissue, and potentially modulate prothrombic factors, thus increasing plasminogen activator inhibitor-1 and decreasing tissue plasminogen activator.95

Common inflammatory molecules and pathways between psoriasis and hypertension Angiotensinogen is the precursor of Angiotensin I, which, after conversion to Angiotensin II, has a major role in blood pressure regulation. It was shown that upon Angiotensin II stimulation, peripheral blood T cells are activated to produce TNF-α and IFN-γ, and to express tissue-homing receptors.96 Blocking TNF-α by etanercept normalized the blood pressure and vascular O2– production in Angiotensin II–infused animals.

Treatment data Because there is strong evidence that psoriasis is an independent risk factor for the development of metabolic and CV comorbidities, the most important question is whether longterm control of psoriasis could prevent, reverse, or attenuate its comorbidities. An investigation into the effect of continuous systemic therapy found that patients who responded to therapy had significant correlations between psoriasis area severity index and high-sensitivity C-reactive protein, VEGF, and the adipokines, resistin and adiponectin.97 The metabolic state of patients improved with inflammatory control.

Cholesterol-lowering agents A pilot study evaluated the effectiveness of simvastatin, which is a cholesterol-lowering statin, on serum lipoprotein levels and dermatitis in patients with severe psoriasis.98 The authors found increased high-density lipoprotein cholesterol levels and diminished psoriasis area severity index during the therapy, concluding that statins can correct lipid metabolism and reduce cutaneous lesions in psoriasis. A decreased risk for psoriasis associated with statin intake has been reported.99 Oral statins also enhance the therapeutic effect of topical steroids against psoriasis.100

Thiazolidinediones Researchers studied the effect of pioglitazone in psoriasis.101 In 70 patients with moderate-to-severe disease, the psoriasis area severity index scores improved significantly in treated versus placebo patients with greater benefit being noted in those receiving higher doses of pioglitazone.101

348

I. Grozdev et al.

Traditional systemic therapies for psoriasis 2.

Traditional systemic therapies for psoriasis using methotrexate and cyclosporine may reduce the risk for CVD by decreasing inflammation.102 Treatment with methotrexate has been shown to be associated with decreased risk for CVD.103 The traditional treatments, however, are limited by the potential for adverse effects such as hypertension, dyslipidemia, hyperhomocysteinemia, and renal and hepatic toxicity.

3. 4. 5. 6. 7.

Biologic agents

8.

Novel investigations have focused on how biologics, used in psoriasis or RA, may affect patients’ CV risk factors and adverse cardiac outcomes. In a retrospective cohort, it was shown that the risk for diabetes was lower in patients with psoriasis starting a TNF-α blocker or hydroxychloroquine compared with those initiated on other disease-modifying antirheumatic drugs.104 Methotrexate initiation was not associated with any significant diabetes risk reduction. Compared with placebo, there was no significant difference in the rate of major adverse cardiovascular events in patients receiving either anti–IL-12⁄23 or anti–TNF-α agents.105 The phase 3 REVEAL trial indicated that adalimumab was well tolerated and significantly improved outcomes in patients with psoriasis and comorbidities compared with patients in the placebo group.106 When TNF inhibitors were compared with nonbiological disease-modifying antirheumatic drugs on the effect of adverse cardiac outcomes in RA patients, the patients using TNF-α blockers experienced a reduced hazard of adverse cardiac outcomes including nonfatal myocardial infarction, transient ischemic attack, stroke, and CV death compared with the nonbiological disease-modifying antirheumatic drugs.107

9.

Conclusions

10.

11.

12.

13.

14.

15.

16.

17. 18.

Psoriasis is now considered a chronic, immune-mediated inflammatory disease presenting with skin lesions and development of comorbidities. Further investigation of the epidemiologic link between psoriasis and comorbidities should take into account various confounding factors. The proposed common pathways between psoriasis and comorbidities highlight the importance of treating psoriasis as a multifaceted disease and the need of regular screening of patients with psoriasis for CV risk factors.

19.

20.

21.

22.

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23.

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Clinics in Dermatology (2014) 32, 351–363

Sarcoidosis as a systemic disease Virendra N. Sehgal, MD a,⁎, Najeeba Riyaz, MD, FRCP(Glasg) b , Kingshuk Chatterjee, DNB c , Pradeep Venkatash, MD d , Sonal Sharma, MD e a

Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033, India Department of Dermatology Govt Medical College, Calicut c Department of Dermatology, Bankura Sammilani Medical College, West Bengal d Dr R.P. Center for Opthalmic Sciences AIIMS, New Delhi e Department of Pathology, University College of Medical Sciences, and associated Guru Teg Bahadur Hospital, Shahdara Delhi b

Abstract Sarcoidosis is a systemic disease, where for the abnormal localized collections of chronic inflammatory cells, the granuloma is cardinal, which may result in the formation of nodule(s) in the tissue of any organ of the body, with lungs and lymph nodes involvement being the most common. The granulomas are nonnecrotizing. The disease may either be asymptomatic or chronic. Its onset is gradual and may improve or clear up spontaneously. Clinical features of specific and nonspecific cutaneous lesions are described, emphasizing their role as a prelude to its systemic manifestations, afflicting respiratory, liver, spleen, musculoskeletal, ocular, cardiac, and neurologic systems. The salient briefs of diagnostic procedures are outlined, in addition to historical background and etiopathogenesis. Several currently available treatment modalities are outlined for instant reference. © 2014 Elsevier Inc. All rights reserved.

Eponymy/nomenclature

Historical landmarks/background

Sarcoidosis has a captivating nomenclature, derived from sarc, which means “flesh,” -oid, “like,” and -osis, “diseased/ abnormal condition.”1 It is also known by Besnier–Boeck disease or Besnier–Boeck–Schaumann disease. For abnormal collections of chronic inflammatory cells, the granuloma is cardinal, which may result in formation of nodule(s) in the tissue of any organ of the body, with lungs and lymph nodes involvement being the most common.2,3 Essentially, the granulomas are of the nonnecrotizing variety. It may either be asymptomatic or chronic. Its onset is gradual and may improve or clear up spontaneously. A few of those patients who suffer for a long time may experience lung scarring or infection leading to respiratory failure.

A total recall of the historical background of sarcoidosis is profusely studded with a peculiar nostalgia, which focused on the incredible Sir Jonathan Hutchinson of London, who for the first time described the skin lesions, sending a clear and loud message about an advent of a new entity, the reverberation of which went far and wide across the globe. It set in motion a proactive search for the components to ultimately evolve the entity. Several galaxies of distinguished practitioners in the field of medicine of yesteryears participated in the process. The exercise indeed was intriguing to form a focus on the natural history of the disease (Table 1).1,4-18,19 The exercise came into being in the year 1868 and continued relentlessly until 1958, spread over 90 years. The perceptive outcome of these arduous endeavors culminated into the First International Conference on Sarcoidosis in London to take stock of the various facets

⁎ Corresponding author. E-mail address: [email protected] (V.N. Sehgal). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.002

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to consolidate and comprehend the entity in its entirety. The perpetuation of the innovations resulted in yet another conference, the first in Washington, DC; furthermore, an exclusive issue on “Sarcoidosis and Respiratory Disorders” was a noticeable breakthrough. It was a commemorative publication, in honor of Louis E. Siltzbach,2 recognizing his contribution to the subject. A journal of sarcoidosis, now called Sarcoidosis, Vasculitis and Diffuse Lung Diseases, was consequently launched by Rizzato in 1984. He also had the privilege to found the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG). In the sojourn, D.G. James was elected the first president. A commemorative publication subsequently dedicated to him was brought out on sarcoidosis.3 Sarcoidosis currently occupies a pride of place, and its multisystemic orientation is now well-documented. Of course, skin affliction provides a substantive clue to the systemic involvement.

Clinical aspects Cutaneous manifestations of sarcoidosis are variable and manifest either as specific or nonspecific.

Table 1

Specific Specific cutaneous manifestations of sarcoidosis are identified usually by the presence of papules or plaques. The papules are of smaller size resembling millet. The color of the papules may vary according to the skin type.20 They may be flesh colored, red, yellow, purple, or brown in types I-IV, whereas in darker races, types V-VI, they are hypopigmented (Figures 1 to 4). Their distribution on the head, around the eyes, on the neck, and in the nasolabial folds is classic. Some of the papules are umbilicated. Lichenoid eruptions may also be a feature. Papules may coalesce to form well-demarcated, indurated, ring-shaped plaque. They are often located on the face and have color similar to those of papules. They are slow growing and are recalcitrant. A few lesions may have a prominent telangiectasia, the angiolupoid resembling true pernio, red to purple plaques, termed lupus pernio, simulating frostbite. They affect ears, nose, cheeks, and fingers. Lupus pernio is often associated with upper respiratory tract disease and bone cysts in the phalanges and tends to run a chronic course.21 It has a nasal, laryngeal, and pharyngeal mucosal involvement, which may result in ulceration of the mucous membrane, perforation of the nasal septum, and/or nasal obstruction.

Historical landmarks

Authors’ accreditation 4

Year

Hutchinson : First account of skin lesion(s) 1868 Besnier5: Coined the term Lupus pernio de la face: Synovites fongueuses symétriques des extrémités supérieures 1888-1889 Boeck6: Multiple benign sarcoid of the skin 1899 Tenneson7: Lupus pernio. defined histology 1892 Hutchinson8: Mortimer malady (a form of lupus) 1898 Boeck6: Described skin lesions in a policeman 1897 Kienbock, Kreibich, Jungling9: Portrayed bone changes 1902 Darier–Roussy10: Recounted subcutaneous nodules in sarcoidosis, the Darier–Roussy syndrome 1906 Heerfordt11: Über eine Febrid Uveo-Parotidea Subchronica und der Glandula Parotis under Uvea des Auges lokalisiert und 1909 häufi g mit paresen cerebrospinaler Nerven kompliziert Schumacher, Heerfordt, Bering11: Recognized sarcoidosis responsible for causing uveitis 1909-1910 Schaumann12: Multisystemic disorder, emphasized for the first time 1915 Kusnitsky, Bittord13: Boecksches Sarkoid mit Beteiligung innerer Organe 1915 Kuznitsky8: Classified skin lesions 1915 Bittorf: Described lung lesions 1915 Schaumann12: Etude sur le lupus pernio et ses rapports avec les sarcoïdes et la tuberculose 1917 Jungling9: Osteitis tuberculosa multiplex cystica 1920-1921 Bruins-Slot, Pautrier, Longcope, Pierson, Costa Waldenstrom J: Described uveoparotid fever 1937 Kveim14: Introduced Kveim test S 1941 Löfgren15: Described Löfgren syndrome 1941 Kerley16: The significance of the radiologic manifestations of erythema nodosum 1942 Leitner17: Der Morbus Besnier–Boeck–Schaumann 1949 Wurm K: First proposal for radiographic staging 1958 Reynolds, Hunninghake, Crystal: Bronchoalveolar lavage 1967-1981 Commemorative publication dedicated to Siltzbach18: Mount Sinai Journal of Medicine, New York 1976 Scadding1: The eponymy of sarcoidosis 1981 Epstein19: “Multiple benign sarkoid of the skin” by Boeck, December 1899. Commentary: What begot Boeck? 1982

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Fig. 3 Cutaneous sarcoidosis depicting papule, nodule, and/or plaques over the face.

Nonspecific

Fig. 1 Cutaneous sarcoidosis depicting papule, nodule, and/or plaques over the dorsa of the forearms.

Subcutaneous nodules (Darier–Roussy type) sarcoidosis are characterized by multiple subcutaneous nodules on the trunk and extremities. Psoriasiform plaques and erythrodermic, ulcerative verrucous, ichthyotic, and rarely pustular, are its other cutaneous manifestations with a specific histology.22 Nail involvement with pterygium development is rare.23 Dystrophy of the nail, 20-nail dystrophy as well, may be a striking feature of chronic sarcoidosis associated with lung involvement, yet another cause of the condition.24 Scarring alopecia also is not that infrequent. Scars produced by radiation, mechanical trauma, or infection may reveal cutaneous changes like that of sarcoidosis.

Erythema nodosum is a preeminent, nonspecific lesion of sarcoidosis seen in 17% of the patients.25 It is characterized by tender, red, subcutaneous nodules that are most often found on the shin. Septal panniculitis is its cardinal histopathology. Its association with bilateral hilar adenopathy, fever, migrating arthritis, and uveitis is characteristic enough that biopsy confirmation is unnecessary.15

Associated syndromes Specific and nonspecific lesions of sarcoidosis may be associated with multisystem involvement, recognized as syndromes. This section outlines their nomenclature, as well as the components of the syndromes.

Löfgren syndrome Löfgren syndrome has the following characteristics: • Enlargement of the lymph nodes near the inner border of the lungs, the bilateral hilar lymphadenopathy, depicted by the radiograph of the chest

Fig. 2 Cutaneous sarcoidosis depicting papule, nodule, and/or plaques over the dorsa of the forearms.

Fig. 4 Cutaneous sarcoidosis depicting papule, nodule, and/or plaques over the face.

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• Erythema nodosum typically occupy the shins, predominantly in women • Accompanied by arthritis or arthralgia, more prominent in men and with fever; the arthritis is often acute and involves the lower extremities26 • Associated with human leukocyte antigen (HLA)DRB1*0327 • Good prognosis, with resolution after several months28

Heerfordt–Waldenström syndrome Fig. 6 uveitis.

Heerfordt–Waldenström syndrome consists of: • • • • •

Fever, Parotid enlargement Anterior uveitis (Figures 5, 6) Facial nerve palsy Familial

Mikulicz syndrome Mikulicz syndrome consists of bilateral sarcoidosis of the parotid, submandibular, sublingual, and lacrimal glands.

Etiopathogenesis and pathology It is customary to consider the etiopathogenesis of sarcoidosis as infective, noninfective, and genetic predisposition.

Infective Despite sarcoidosis being a multisystem disease, its etiopathogenesis is largely elusive. Initially, Mycobacterium tuberculosis, as an infective organism, was considered. It was due to similarities between the granuloma of

Fig. 5

Large granuloma in the anterior chamber, the anterior

tuberculosis and sarcoidosis. The occasional occurrence of tuberculosis before, during, or after the identification of sarcoidosis was circumstantial evidence 29-32 ; however, failure to isolate bacteria, fungi, Mytoplasma, and/or acidfast organisms from the patients with sarcoidosis proved counterproductive.33 Sarcoidosis, a hypersensitive reaction to atypical mycobacteriosis, was also considered.34 Replication of the results was a major impediment. There seems hardly any similarity between sarcoidosis and tuberculosis due to the vast epidemiologic, clinical, radiologic, and immunologic differences.35,36 The current consensus, therefore, revolves around that the sarcoidosis is neither tuberculosis nor a mycobacteriophage. Known viruses, such as that of mumps, influenza, Newcastle, and some uncommon viruses, have also been implicated.37-40 The demonstration of ovoid bodies within the mitochondria and linear densities in the membranes of dilated cistermac, resembling the partial express of indigenous organism(s), were favorable. It was supplemented by cultured biopsy specimens of sarcoid-involved lymph nodes, postulating that the abnormal growth of the fibroblasts is indicative of the presence of viral agent.41 Mycoplasma orale, Nocardia, or a similar organism has also been incriminated.42,43

Sarcoid granulomas in both eyes.

Sarcoidosis

Noninfective Many noninfective causes of sarcoidosis including beryllium44-46 were proposed but renounced due to wideranging clinical expression of chronic berylliosis. Pine pollen, a casual cause of the disease, came into being because of the epithelioid cell granulomas induced by its inhaling in tuberculin-sensitive guinea pigs.47,48 In addition, peanut dust, hair sprays, eating clay, zirconium exposure, mineral oil, talc powder, and the use of phenylbutazone, sulfonamide, or methotrexate have been incriminated.

355 dynamic relationship between the various components of the granuloma. Its center is composed of macrophage-derived cells and OK T4 helper lymphocytes, whereas the periphery of the granuloma has a large number of antigen-presenting interdigitating macrophages and OK T8 suppressor lymphocytes. The lymphokines from the inflammatory cells recruit blood-borne monocytes, prevent macrophage migration, and keep the chronic inflammatory reaction alive and efficient. It is probable that this arrangement of interdigitating OK T8 cells in the periphery and the epithelioid cell-OK T4 pattern in the center does indeed provide an efficient response to a persistent antigenemia.59,60

Genetic predisposition The prevalence of sarcoidosis across the globe is variable. It is highest among blacks in New York, plus Irish and West Indians in London, pointing to an unrecognized genetic and environmental predisposition.49,50 Likewise, a considerable variation in HLA marker has been used to define genetic predisposition. Interestingly, an increase in HLA-DR TM2 and HLD-Bw6 in sarcoidosis and HLA-B8 in erythema nodosum and early sarcoidosis was found in Japanese.51 There was an increase in HLA-B27 in Swedish patients with advanced sarcoidosis. These findings seem exclusive, for they could not be duplicated elsewhere. 52-57 Other environmental factors, such as smoking, may influence the occurrence of sarcoidosis, especially in young black women.

Histopathology It is necessary to take a biopsy of the representative lesion and preserve it in 10% formaldehyde to confirm the diagnosis of sarcoidosis. The paraffin-embedded tissue is subjected to serial sections. The hematoxylin and eosin– stained section(s) may reveal a well-defined round and/or oval granuloma composed of compact, radially arranged epithelioid cells a modified macrophage. Their nuclei are pale staining, for the growth of the chromatin does not keep pace with the growth of the cytoplasm. Langhans-type and foreign body-type multinucleated giant cells are an important constituent of granuloma. Its nuclei are arranged in an arc or a circular pattern around a central granular zone. Only sparse infiltrate of lymphocytes and plasma may be found within the granuloma, the “naked granuloma” (Figures 7 to 10). The lymphocytes are usually seen at its periphery. Caseation necrosis is conspicuous by its absence. Occasionally, fibrinoid necrosis may be seen. It is prominent in areas where several granulomas have coalesced. It may be distinguished from caseation by the presence of a fine reticulin pattern on silver stain.58 The recent advent of monoclonal antibody and indirect immunofluorescence techniques has added dimensions in the understanding of

Diagnosis 61 Sarcoidosis is a systemic, noncaseating granulomatous disorder of unknown origin. Its clinical polymorphism is intriguing and looms large. Its diagnosis has to be suspected in light of specific and nonspecific cutaneous manifestations (Table 2), warranting exclusion of several disorders simulating sarcoidosis; hence it is a contentious issue, and its differential diagnosis (Table 3) forms an unequivocal link. Sarcoidosis, being a multisystem disease, should be considered in the right perspective (Table 4).62

Treatment For treatment purpose, sarcoidosis can be classified into three broad and partially overlapping groups: Acute disease—resolves within 2 to 5 years of diagnosis Chronic disease—persists beyond 5 years after diagnosis Refractory disease—chronic disease that worsens despite adequate systemic therapy

Fig. 7 Hematoxylin and eosin stain depicting granuloma(s). Original magnification × 4.

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Fig. 8 Hematoxylin and eosin stain depicting granuloma(s). Original magnification × 10.

Sarcoidosis has been treated in the past with modalities such as multivitamins, heavy metals (bismuth and gold), antituberculous drugs, BCG vaccine, and infrared rays, but without much benefit.96

Treatment strategy for sarcoidosis Recently, an evidence-based approach for treatment of sarcoidosis has been commended.97 Topical therapy is useful only in cutaneous sarcoidosis, where high-potency fluorinated corticosteroids are effective in localized lesions.98,99 In refractory skin lesions, topical steroids under occlusion100 or intralesional steroids have been found to be beneficial.99 Tacrolimus (FK506),100,101 a topical immunomodulator, in the form of 0.03% to 0.1% ointment, is rapidly effective and safe both in pediatric and in adult patients. The successful treatment of lupus pernio with t flashlamp pulsed dye laser102 has also been reported. For patients with severe single/multiorgan disease or those who

V.N. Sehgal et al.

Fig. 10 Hematoxylin and eosin stain depicting granuloma(s). Original magnification × 40.

do not respond to topical therapy, systemic corticosteroids are indicated.97 In the event of relapse, while tapering steroids, or if the signs persist with steroids alone, steroidsparing/cytotoxic agents should be instituted. Thalidomide and biologicals are often given for chronic or refractory sarcoidosis, or both. Corticosteroids The supremacy of corticosteroids in the treatment of sarcoidosis is well-known, ever since their inception.103 Their systemic administration is absolute in chronic, extensive, disfiguring, and ulcerative skin lesions, persistent hypercalciuria, and hypercalcemia; however, their dosage and duration in cutaneous sarcoidosis has not been well determined.96,97 The recommended starting dose of prednisolone is 20 to 40 mg daily for a period of 1 to 2 months, after which it is gradually reduced to a minimum maintenance dose, which keeps the disease under control and avoids the occurrence of adverse effects. The duration of treatment is variable; erythema nodosum requires only short-term treatment for less than 6 months,104 whereas lupus pernio,105 a chronic lesion, may need prolonged treatment.

Table 2

Fig. 9 Hematoxylin and eosin stain depicting granuloma(s). Original magnification × 40.

Sarcoidosis: Cutaneous lesions61

Specific lesions

Nonspecific lesions

1. Maculopapule (most common) 2. Nodule 3. Plaque 4. Subcutaneous nodule 5. Infiltrative scar 6. Lupus pernio (most characteristic)

1. Erythema nodosum 2. Calcifications 3. Prurigo 4. Erythema multiforme 5. Nonspecific nail changes (clubbing, subungual hyperkeratosis, onycholysis)

Sarcoidosis Table 3

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Sarcoidosis: Differential diagnosis

Diagnosis

Clinical

Pathologic

Others

Diseases of transmissible nature Cutaneous tuberculosis63-65 1. Lichen scrofulosorum66 Groups of minute, keratotic, discrete papules, surmounted by a tiny pustule/thin scale; mostly affecting children; active TB at a different site

2. Papulonecrotic tuberculid

3. Erythema induratum

4. Miliary tuberculosis

5. Lupus vulgaris

Tuberculin test is always positive. Noncaseating, tuberculoid granulomas, below the epidermis, between and surrounding hair follicles; tubercle bacilli not seen in tissue sections; nor can they be cultured Epidermal ulceration, large zone of PCR may detect mycobacterial Successive crops of firm, dermal necrosis, fibrinoid necrosis of DNA in up to half of cases. inflammatory papules, and/or papulonecrotic pustules occupying the vessel wall, and occlusion of the extremities, face, ears, glans penis; vessels by thrombi; positive Mantoux tuberculin skin test PPD test healing by varioliform scarring; evidence of TB elsewhere; may appear in scrofuloderma Tender, erythematous/violaceous Lobular panniculitis with fat Mantoux TST is positive subcutaneous nodules, with or necrosis; noncaseating granuloma without ulceration over posterior in 1/3 calf in women; heal by scarring Polymorphic eruptions in setting of Tuberculoid granuloma(s) with or Negative tuberculin reaction. fulminant TB of lung/meninges in without caseous necrosis Strongly positive PCR-DNA; debilitated patient positive ZN staining Mantoux TST is positive; ZN Nodular lesions with “apple-jelly” Tuberculoid granuloma, occasional caseous reactions staining negative appearance on diascopy; developing away from the primary focus of infection

Leprosy 1. Lepromatous leprosy67,68 Disseminated plaques, and nodules Epidermal atrophy, clear typical gloves and stocking anesthesia subepidermal zone (Grenz zone) and foamy histiocytes, laden with and trophic ulcerations, callosities lepra bacilli, forming loose granulomas 2. Tuberculoid leprosy67,69 Well-defined erythematous Well-defined nest of epithelioid plaques with raised and clear-cut cell granulomas, often surrounded edges sloping inward, saucer the by a dense mantle of lymphocytes; scanty Langhans type of giant right way up, thickening and/or cells, the granuloma(s) replace tenderness of the nerves dermal nerves completely 3. Histoid leprosy70,71 Grenz zone seen circumscribed Firm, reddish to skin colored, pseudocapsule numerous spindledome shaped, and/or oval shaped histiocytes form interlacing papulonodules with shiny and bands, whorls, and cuticles; bacilli stretched overlying skin are present in groups along the long axis of these cells 4. Lucio’s leprosy72-74 Epidermal necrosis with Slowly, progressive, diffuse periadnexal histiocytic and infiltrations marked by multiple neutrophilic infiltrate and fibrinoid painful ulceration vasculitis Late syphilis75,76 Perivascular lymphocytic and plasma Disseminated secondary papular syphilids and papulonecrotic forms cell infiltrate, and prominent endothelial proliferation are seen of lues maligna Cutaneous leishmaniasis 1. Localized leishmaniasis Seen in endemic areas; slowly Ulcer with a heavy infiltrate of cutis77 growing nodulo-ulcerative lesions histiocytes, lymphocytes, plasma or localized ulcerations with cells, and polymorphonuclear infiltrated border leukocytes; parasitized histiocytes

Strongly positive ZN and FF stain; negative lepromin test

Lepromin test is strongly positive; presence of bacilli in ZN and FF stain are rare

Negative lepromin test; abundance of bacilli in lesional skin

Treponema pallidum DNA detection by PCR in lesional skin; 19S-FTA abs IgM testing of serum Positive Giemsa staining high to average high serum antibody titers; culture in specialized media, eg, NNN media (continued on next page)

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Table 3 (continued) Diagnosis

Clinical

Pathologic

Others

form tuberculoid granulomas in the dermis; the organisms within histiocytes often line up at the periphery of a vacuole, like the bulbs surrounding a movie marquee 2. Post Kala-azar dermal Lewy dementia bodies may be May appear during or shortly after Diffuse infiltration with leishmaniasis78 macrophages, filled with present in blood of individuals; treatment (up to 10 years); amastigotes is characteristic positive IFAT and ELISA test. depigmented macules or warty papular eruptions are the features Allergic and immunologic disorders ASO titers may be raised 1. Erythema annulare Circinate, small papular and large Dense, superficial, and deep centrifugum79 dermal, perivascular infiltrate plaquelike disseminated lesions; (sometimes described as “coatmainly associated with various sleeved”) comprised mainly of malignancies and infections lymphocytes but also including macrophages (histiocytes) and occasional eosinophils 2. Perniosis80 Fibrosing inflammation in the The determination of antithrombin Functional peripheral vascular disease; erythema and induration over dermis, vascular dilation, necrosis III, protein C, factor V Leiden tips of fingers and toes; bullous and and/or subepidermal blistering, and mutation, antiphospholipid infiltrates composed of antibodies with their respective ulcerative forms may be seen lymphocytes and macrophages subfractions (anticardiolipin and antiphospholipid), lupus anticoagulant, cryoglobulins, cryofibrinogen, and paraproteins is indispensable 3. Discoid lupus Erythematosquamous plaques with Hyperkeratosis, variable epidermal Leukopenia, raised ESR, presence erythematosus81 of ANA, RA factor, anti-Sm, antiatrophy; often localized to facial atrophy, thickened basement Ro/SSA, anti-La/SSB antibodies area, but may also be disseminated membrane and chronic inflammatory infiltrate in perivascular and periappendageal spaces; dermal mucin deposition Other granulomatous disorders Necrobiosis (degeneration of Peripheral blood smear, chest 1. Classical granuloma Papules coalesce into annular annulare82 plaques with central clearing, over collagen), palisaded arrangements radiograph and ultrasonography to of macrophages (histiocytes) and rule out malignancies extremities perivascular lymphocytic infiltrates 2. Necrobiosis lipoidica83 Localized plaques and ulcerations Prominent necrobiosis, associated Elevated blood glucose levels; glycosylated hemoglobin level over pretibial area with palisaded arrangement of histiocytic infiltrate and giant cells raised in the dermis 3. Rheumatoid nodules Skin-colored firm, mobile, Discrete granulomata at different Raised ANA, RA factor + subcutaneous nodules, occurring in stages of development separated by middle aged men over juxtascar tissue, containing small articular areas84 vascular islands of lymphocytes, plasma cells, and histiocytes85 86 Grouped shiny lichenoid papules Lymphohistiocytic infiltrates and 4. Lichen nitidus giant cells, often encircled by dermal papillae (claw clutching the ball) Presence of monoclonal IgG with 5. Necrobiotic Ulcerated plaques and nodules in Pronounced necrobiosis with abnormal marrow profile; xanthogranuloma87 adult patients epithelioid and foam cells, characteristic presence of Touton histiocytes negative for S100 stain and foreign body giant cells with lipid vacuoles ANA, antinuclear antibody; ASO, ; ELISA, enzyme-linked immunosorbent assay; ESR, erythrocyte sedimentation rate; FF, ; NNN, ; IFAT, ; PCR, polymerase chain reaction; PPD, ; RA, rheumatoid arthritis; TB, tuberculosis; TST, tuberculin skin test; ZN.

Sarcoidosis Table 4

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Sarcoidosis: Systemic ramifications

Systemic organ/ granuloma(s)

Frequency Symptoms

Signs

Investigations

Lung88-90 affecting interstitial tissue (alveoli, blood vessels, bronchioles) Liver, spleen91

90%

Dry rales/rhonchi, restricted lung expansion, abnormal gas exchange

Radiographic, stage I: bilateral, hilar/ paratracheal adenopathy; stage II: adenopathy with pulmonary infiltrate; stage III: pulmonary infiltrates only; stage IV: pulmonary fibrosis Liver function tests, elevated alkaline phosphatase

Musculoskeletal92

Ocular93

Cardiac manifestations94

Neurologic sarcoidosis95

Dyspnea, cough, chest pain, hemoptysis

50%-80% Asymptomatic, Hepatosplenomegaly but may cause obstructive jaundice 39% Weakness, Tenderness, and erythema, bone cysts and pain osteolytic lesions, chronic myopathy, muscle nodules, tumorlike lesions, arthralgias, arthritis, and tenosynovitis 30%-50% Blurred vision, Posterior uveitis, conjunctival nodules, Slit-lamp examination photophobia, scleral plaques, lacrimal gland excessive enlargement, and iritis lacrimation 5% Sudden cardiac Electrocardiographic abnormalities, death complete heart block and other arrhythmia; papillary muscle dysfunction, infiltrative cardiomyopathy with congestive heart failure, and pericarditis 5%-10% Self-limiting VII nerve facial palsy, aseptic meningitis, Magnetic resonance imaging sudden hearing loss, seizure, psychiatric changes, spaceoccupying masses, peripheral neuropathy

Corticosteroids act by suppressing bone marrow, subsequently resulting in reduction in blood monocyte and the serum levels of inflammatory mediators and angiotensinconverting enzyme. Their withdrawal can lead to relapse of sarcoidosis, whereas prolong use may cause well-known adverse effects. Osteoporosis is a frequent adverse effect of chronic steroid therapy. 106,107 Because sarcoidosis is associated with direct bone lesions, hypercalcemia, and increased vitamin D levels, the mechanism of action seems multifactorial.108 The institution of steroid-sparing medication is indicated, either while tapering steroids or their inability to control the disease. Methotrexate,109,110 azathioprine,111 mycophenolate mofetil,112 cyclophosphamide, and leflunomide113,114 are the available drugs. Hydroxychloroquine115 is sometimes useful. Methotrexate Methotrexate is the most widely used nonsteroidal drug. In adults, its average starting dose is 10 to 15 mg/week. Monitoring of the patient for neutropenia is imperative to adjust its dose. It may cause nausea and vomiting due to gastrointestinal intolerance, hepatitis, myelosuppression, mucositis, teratogenesis, lymphoma, and interstitial pneumonitis. Occasionally, it may be the cause of an unexplained cough.116

Azathioprine Azathioprine has been a widely used steroid-sparing agent. It is a purine analogue, inactive until it is metabolized to mercaptopurine by the liver and erythrocytes. Hypoxanthine phosphoribosyl transferase metabolizes mercaptopurine to thioinosinic acid, which, in turn, suppresses the synthesis of adenine and guanine, interfering with DNA synthesis. Its plasma half-life is approximately 75 minutes. Its dosage is 50 to 200 mg daily. The kidneys are the major route of excretion. Azathioprine crosses the placenta. Toxicity to the gastrointestinal tract (oral ulcers, nausea, vomiting, diarrhea, epigastric pain) is common. Hepatotoxicity is rare and consists of mild elevation of transaminases and cholestatic jaundice. It may also cause interstitial pneumonitis, pancreatitis, and maculopapular rash. Dose-related toxicity to the bone marrow results in leukopenia and, less commonly, thrombocytopenia and anemia. Leflunomide Leflunomide is an immunomodulatory agent that inhibits de novo pyrimidine synthesis by inhibiting the enzyme dihydro-orotate dehydrogenase. Its dosage is 20 mg/day. The major adverse effect is an increase in liver enzymes that occurs in 5% of patients receiving leflunomide alone, and in more than 50% of those taking leflunomide and

360 methotrexate. Leflunomide has been shown to be synergistic with methotrexate in treating sarcoidosis.113 Mycophenolate mofetil (CellCept) Mycophenolate mofetil (CellCept) is a prodrug of mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase. This is the rate-limiting enzyme in the de novo synthesis of guanosine nucleotides. Initially, it was used with great success in patients with solid organ transplants, and has also been found to be effective in cutaneous sarcoidosis.112 Its dosage is 500 to 3000 mg/week. It may cause leukopenia, anemia, thrombocytopenia, hyperglycemia, hypercholesterolemia, hypomagnesemia, hypocalcemia, hyperkalemia, and an increase in blood urea nitrogen. Rarely, melanoma and lymphoma in addition to gastrointestinal bleeding and pulmonary fibrosis may be encountered.117 Cyclophosphamide (Cytoxan) Cyclophosphamide (Cytoxan) has been reported to be effective in refractory neurosarcoidosis.118 It is administered in the dosage of 500 to 2000 mg by slow intravenous infusion every 2 to 4 weeks. Major complications include neutropenia, nausea, hemorrhagic cystitis, and increased risk for malignancy. Combinations of cytotoxic agents require monitoring for cumulative toxicity, including gastrointestinal, hematologic, and hepatic adverse effects.

Antimalarial agents Chloroquine (Aralen) and hydroxychloroquine (Plaquenil) have widely been used in chronic cutaneous sarcoidosis.118,115 Ocular toxicity,119 in particular, may limit the prolong use of chloroquine.

Minocycline and doxycycline Minocycline is effective because it has an antibacterial effect against Propionibacterium acnes, a putative agent for sarcoidosis,120 and the anti-inflammatory effect.121,122 Its dosage is 200 mg daily. In a report123 comprising 12 cases of chronic cutaneous sarcoidosis, 8 had excellent response and 2 had partial response. Nausea, skin eruption, autoimmune hemolytic anemia, and autoimmune hepatitis are a few of its adverse effects. Doxycycline,124 a less toxic agent, is a good alternative. Thalidomide Thalidomide is effective in a variety of immune-mediated disorders including sarcoidosis. It has an ability to block tumor necrosis factor (TNF),125,126 in addition to T helper 1 cell mediators comprising interferon-γ, interleukin-2, and interleukin-12. It also induces and enhances interleukin-4 and interleukin-5 production, indicating a therapeutic switching from Th1 to Th2 activation. Its dosages of 50 to more than 400 mg/day have limited albeit promising

V.N. Sehgal et al. supporting data,127 whereas its dose for long-term maintenance is 50 mg/15 days to 100 mg every other day. Most of the patients had a good to variable response. 127-135 Somnolence, constipation, and peripheral neuropathy are its dose-dependent toxicity, in addition to teratogenicity. Biologic agents Biologic agents that block TNF-α, such as infliximab136-140 and adalimumab,141 are found to be effective in refractory sarcoidosis. They are monoclonal antibodies directed against TNF-α; however, etanercept, a TNF receptor antagonist, has not been as effective in the treatment of sarcoidosis.142 Infliximab (Remicade) Infliximab (Remicade) is a chimeric IgG1 anti–TNF-α antibody (inhibitor). Unlike etanercept, it binds not only to soluble TNF-α but also to membrane-bound TNF-α, leading to both antibody-dependent and complement-dependent cytotoxicity. It is, therefore, more efficacious in sarcoidosis, a granulomatous inflammatory disorder. Its dosage is 3 to 5 mg/kg intravenously initially every 2 weeks, later every 1 to 2 months. Infection remains the major concern with it. Many more cases of tuberculosis have been reported in patients treated with infliximab than in those treated with etanercept, probably due to the destabilization of previously formed granulomata. Histoplasmosis, coccidioidomycosis, and listeriosis are the other reported infections. Adalimumab (HUMARA) Adalimumab (HUMARA) is a humanized monoclonal antibody against TNF-α. It is given subcutaneously in the dosage of 40 mg every 1 to 2 weeks. Only a few case reports and one case series have thus far been reported. The drug seems to have some efficacy, but the response rate was not as high as that seen with infliximab. The toxicity is similar to that reported with infliximab, except that there seems to be a lower risk for tuberculosis and other opportunistic infections.

Miscellaneous agents Fumaric acid esters have been used successfully to treat refractory sarcoidosis.143,144 Radiation and Q-switched Ruby Laser145,146 have been tried with some effect in refractory lesions.

References 1. Scadding JG. The eponymy of sarcoidosis. J R Soc Med. 1981;74: 147-157. 2. Sarcoidosis at Merck Manual of Diagnosis and Therapy Home Edition. 3. http://en.wikipedia.org/wiki/Sarcoidosis-cite_ref-Harrison_2-03. Harrison’s Practice, Sarcoidosis. 4. Hutchinson J. Illustrations of Clinical Surgery. London: J and A Churchill. 1875.

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Clinics in Dermatology (2014) 32, 364–375

Autoimmune blistering dermatoses as systemic diseases Snejina Vassileva, MD, PhD ⁎, Kossara Drenovska, MD, PhD, Karen Manuelyan, MD Department of Dermatology and Venereology, University of Medicine, Sofia, 1 G. Sofiiski Street, 1431 Sofia, Bulgaria

Abstract Autoimmune blistering dermatoses are examples of skin-specific autoimmune disorders that can sometimes represent the cutaneous manifestation of a multiorgan disease due to potential common pathogenic mechanisms. As soon as a distinct autoimmune blistering dermatosis is diagnosed, it is imperative to consider its potential systemic involvement, as well as the autoimmune and inflammatory conditions that are frequently associated with it. In paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome, the internal organs (particularly the lungs) are affected by the autoimmune injury. Pemphigus erythematosus may manifest with overlapping serologic and immunohistologic features of lupus erythematosus. In patients with bullous pemphigoid, there is a greater prevalence of neurologic disease, possibly caused by cross-reactivity of the autoantibodies with isoforms of bullous pemphigoid antigens expressed in the skin and brain. Anti-laminin 332 pemphigoid shows an increased risk for adenocarcinomas. Patients with anti-p200 pemphigoid often suffer from psoriasis. A rare form of pemphigoid with antibodies against the α5 chain of type IV collagen is characterized by underlying nephropathia. Particularly interesting is the association of linear IgA disease or epidermolysis bullosa acquisita with inflammatory bowel disease. Dermatitis herpetiformis is currently regarded as the skin manifestation of gluten sensitivity. Bullous systemic lupus erythematosus is part of the clinical spectrum of systemic lupus erythematosus, a prototypic autoimmune disease with multisystem involvement. © 2014 Elsevier Inc. All rights reserved.

Introduction Autoimmune blistering dermatoses (AIBDs) represent a heterogeneous group of rare organ-specific autoimmune diseases characterized by blistering of the skin and mucous membranes. They are associated with tissue-bound and circulating autoantibodies to structural components of the skin. AIBDs are divided into two main categories depending on whether the cleavage plane is intraepidermal, as in pemphigus, or at the basement membrane zone (BMZ), as in the group of subepidermal blistering diseases. These disorders, particularly the pemphigus group, are important for the morbidity associated with the involvement of skin and mucous membranes, especially if left untreated. Rupture of blisters leads to painful erosions that cause significant loss of fluid, electrolytes, and proteins, mainly in cases of extensive ⁎ Corresponding author. Tel.: +359 2 9230379; fax: +359 2 8518779. E-mail address: [email protected] (S. Vassileva). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.003

body surface involvement. If the oral mucosa, pharynx, and esophagus are involved, the patient may not be able to tolerate adequate intake of food and medication. These changes lead to immunosuppression, which along with the lack of epidermis secondary to erosions predispose patients to life-threatening infections and sepsis. Although the primary problem in AIBDs is in the skin and/or mucous membranes, they are associated with secondary systemic complications that may be potentially fatal. Immunobullous diseases provide another challenge, because their treatment warrants the use of high doses of systemic corticosteroids and immunosuppressive drugs associated with various adverse side effects and high risk for serious systemic complications. The latter have been extensively discussed in the literature and will not be considered in this review. It has been well documented that both organ-specific and systemic autoimmune diseases may coexist in the same patient, either sequentially or concurrently, sustained by the presence of autoantibodies directed against the corresponding

AIBDs as systemic diseases

365 autoantigens. This is illustrated by the association of the organ-specific AIBDs with other organ-specific or systemic autoimmune disorders. Multiple factors, including those of immunologic, genetic, endocrine, and environmental origin, contribute to this coexistence.1 In addition, several reports have focused on the association of bullous dermatoses with many differing internal conditions. Most of these associations have been already reviewed previously.2,3 There is a growing body of evidence, however, that some of the bullous disorders may represent the cutaneous manifestation of a multiorgan disease because of potential common pathogenic mechanisms. In this contribution, the AIBDs that warrant further investigation for occult underlying systemic disease will be discussed. Table 1 summarizes blistering diseases and their well-documented systemic associations.

Table 1 Autoimmune blistering diseases with potential systemic involvement Disease

Potential systemic involvement

Pemphigus erythematosus Endemic pemphigus (Columbia) Paraneoplastic pemphigus Bullous pemphigoid Anti-laminin 332 pemphigoid Anti-p200 (laminin γ1) pemphigoid α5 chain of type IV collagen blistering disease Pemphigoid gestationis

Systemic lupus erythematosus Systemic lupus erythematosus

Linear IgA dermatosis Dermatitis herpetiformis Epidermolysis bullosa acquisita Bullous systemic lupus erythematosus

Table 2

Hematologic malignancies Neurologic diseases Adenocarcinoma Psoriasis Nephropathy Pregnancy or trophoblastic tumors Inflammatory bowel disease Celiac disease Inflammatory bowel disease (Crohn’s disease) Systemic lupus erythematosus

Pemphigus Pemphigus is a group of rare autoimmune blistering diseases, characterized by the occurrence of autoantibodies against desmosomal structure proteins (Table 2). Deposition

Target antigens and immunofluorescence findings in pemphigus

Diagnosis

Autoantigen

DIF

IIF

Pemphigus vulgaris

Dsg 3, Dsg 1 (Dsg 4) Acetylcholine receptor Dsc 1-3 Dsg 3 Dsg 1 Dsc 3 Dsg 1 (Dsg 4) Plakoglobin

Intercellular IgG and C3 in the epidermis/epithelium

Intercellular IgG antibodies on monkey esophagus

See pemphigus vulgaris

See pemphigus vulgaris

Intercellular IgG and C3 in the epidermis

Intercellular IgG antibodies on monkey esophagus or guinea pig lip/tongue Intercellular IgG antibodies on monkey esophagus; ANA on monkey esophagus or Hep-2 Intercellular IgG antibodies on monkey esophagus

Pemphigus vegetans

PF

PE

Endemic pemphigus

Dsg 1

Northern Colombia Pemphigus herpetiformis

Dsg 1 (Dsg 3)

Paraneoplastic pemphigus

Drug-induced pemphigus

IgA pemphigus

Dsg 3, Dsg 1 Desmoplakin 1 and 2 Envoplakin, Periplakin, A2ML1 (170-kDa protein) Plektin, Dsc 1–3, BP230 Dsg 1 (Dsg 3)

Dsg 3 Dsg 1 Dsc 1 (IgA)

Intercellular IgG and C3 in the epidermis; lupus band (IgG and C3) at the BMZ See PF See PE Intercellular IgG and C3 in the epidermis Intercellular IgG and C3 in the epidermis; linear IgG and/or C3 along the DEJ Intercellular IgG and C3 in the epidermis; sometimes linear IgG or C3 Intercellular IgA and C3 in the epidermis

Intercellular IgG antibodies on monkey esophagus Intercellular IgG antibodies on monkey esophagus and on plakin rich substrate (rat urinary bladder)

Intercellular IgG antibodies on monkey esophagus Intercellular IgA antibodies on monkey esophagus

A2ML1, α2 macroglobulin-like 1; ANA, antinuclear antibodies; BMZ, basement membrane zone; BP, bullous pemphigoid; DEJ, dermal–epidermal junction; DIF, direct immunofluorescence; Dsc, desmocollin; Dsg, desmoglein; IIF, indirect immunofluorescence; PE, pemphigus erythematosus; PF, pemphigus foliaceus.

366 of autoantibodies to their target antigens causes loss of cell– cell adhesion between keratinocytes and intraepithelial blister formation called acantholysis. Pemphigus is classically divided into two main subtypes, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), that differ in their clinical, histologic, and immunologic features and prognosis. A third subtype of the disease, paraneoplastic pemphigus (PNP), was described in 1990 as atypical pemphigus, occurring in patients with associated neoplasia, most commonly of lymphoproliferative origin.4 Besides, several other subtypes of pemphigus exist, including pemphigus vegetans, pemphigus erythematosus (PE), endemic PF, pemphigus herpetiformis, drug-induced pemphigus, and IgA pemphigus. The diagnosis in all these variants is confirmed by histology, direct (DIF) and indirect immunofluorescence (IIF) microscopy, and immune serology (Table 2). Classic pemphigus variants, such as PV and PF, are believed not to affect internal organs and other body systems. At the same time, pemphigus often demonstrates a severe clinical course, physical impairment, significant impact on the quality of life (QOL), and life-threatening potential. All these negative characteristics of the disease are likely to be related to other, more complex mechanisms besides isolated skin and mucous membrane involvement. In the literature, there are innumerable reports on the associations of pemphigus with other autoimmune, inflammatory, or neoplastic disorders, affecting the organism in its integrity.5 Being itself an autoimmune disorder, pemphigus is very likely to be associated with other disturbances of autoimmune nature, both organ-specific and systemic ones. The tendency to develop another disease occurs in about 25% of the patients.6 Inflammatory and infectious conditions, malignancies, endocrinopathies, and hormonal changes during pregnancy, food and drug intake, smoking, exposure to trauma, radiation, or pesticides may all be related to triggering or exacerbation of pemphigus. This is the reason for many authors to regard such cutaneous disorders as pemphigus, psoriasis, or urticaria as systemic ones. PNP is the only form of pemphigus in which internal organs can be affected by autoimmune injury. PNP is mostly associated with lymphoproliferative neoplasms, such as, non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman disease, and less commonly thymoma and retroperitoneal sarcomas.7 Patients with PNP present with painful mucosal erosions that appear erythema multiformelike or Stevens-Johnson-like (Figure 1A), and polymorphic skin lesions showing a wide variation in morphology. Since its original description, the spectrum of PNP subsequently expanded to include many clinical forms, including lichenoid eruptions,8 which may not necessarily comprise bullae, erosions, or both.9 There has also been growing evidence of involvement of internal organs, such as lungs, thyroid, kidney, smooth muscles, and gastrointestinal tract.10 The constellation of clinical, histopathologic, and immunologic features has prompted several revisions of the diagnostic criteria for this subtype of pemphigus.11–13

S. Vassileva et al.

Fig. 1 A, Severe mucositis in a patient with paraneoplastic pemphigus and B-cell lymphoma. B, Periungual blistering lesions in the same patient with paraneoplastic pemphigus.

The additional recognition of systemic involvement and clinical heterogeneity in PNP resulted in its broader classification under the heading of paraneoplastic autoimmune multiorgan syndrome (PAMS).14 This term has been adopted as more appropriate to encompass the full spectrum of signs and symptoms associated with this challenging paraneoplastic process. In addition, some authors have suggested that the former term PNP describes only the classic epithelial manifestations of PNP/PAMS, and it may lead to overlooking the multiorgan nature of this syndrome in cases presenting without blistering lesions.15 PNP/PAMS fundamentally differs from classic pemphigus variants in several ways. It is a rare disease with approximately 450 patients reported in the literature to date.15 Most cases occur between 45 and 70 years of age, but children and adolescents may also be affected.16 Men are more frequently involved than women,17 in contrast with PV, which shows a female predominance.18 An association of PNP with HLA class II DRB1*03 allele has been reported in contrast with PV that is associated with HLA-DRB1*14 and -DRB1*04:02.19 A key distinction between clinical features of PNP/PAMS and classic pemphigus is that PNP/PAMS may present with inflammatory skin lesions over the trunk and extremities. Lesions in PNP/PAMS often arise on the palms and soles, and in the periungual areas (Figure 1B), which is not a common location for the blisters in PV. Nikolsky sign is positive in PV,

AIBDs as systemic diseases but negative in PNP/PAMS. The latter is characterized by a diffuse intractable stomatitis, whereas in PV, mucosal erosions are usually more discrete and isolated. Cicatrizing conjunctivitis is particularly common in PAMS but is not observed in PV. PAMS can manifest with several clinical phenotypes (at least five): Pemphigus-like, bullous pemphigoid (BP)-like, erythema multiforme-like, graft-versus-host disease-like, and lichen planus-like. Pemphigus vegetans-like,20 psoriasiform, and pustular forms21 have been additionally described. Autoantibodies can be directed against an antigen complex comprising all the plakin family members (Table 2). In addition to the humoral response, the pathophysiology of PNP/ PAMS also incorporates a cellular autoimmunity response, mediated by CD8+ cytotoxic T lymphocytes, CD56+ natural killer cells, and CD68+ monocytes and macrophages.15 PV rarely, if ever, affects other organs, except for the esophageal mucous membranes, whereas PNP/PAMS commonly affects the respiratory mucous membranes.15 Rapidly progressive respiratory failure, caused by pulmonary involvement, constitutes the terminal event in approximately 30% of these patients. This complication first manifests itself as obstructive disease affecting both large and small airways. It is due to deposition of PAMS autoantibodies in bronchial epithelia that leads to dyskeratosis and acantholysis of bronchial epithelial cells that detach from the lamina propria and neighboring cells. The lumen of the affected bronchioles becomes severely stenotic, and patients develop a functional pattern of obstructive or restrictive bronchiolitis. As a result, autoantibody-mediated injury takes an important role in the pathogenesis of bronchiolitis obliterans in PNP/PAMS, and is the cause of rapidly progressive and often fatal respiratory failure. Histologic study of a lung biopsy will demonstrate dense lymphohistiocytic infiltration, as well as fibrosis around bronchioles. Patients have a dry cough and severe dyspnea, associated with decreased blood pO2. Chest radiography and computed tomography are often negative. With pulmonary function testing, however, marked obstructive patterns with limitation in diffusion capacity are diagnostic.21 Pulmonary injury has appeared to account for the very high mortality rates observed among children and adolescent patients (10/14 patients in the largest reported series).16 The results of a multicenter study recently carried out in France showed that the presence of erythema multiforme-like skin lesions in association with histologic keratinocyte necrosis is a poor prognostic factor in patients with PNP who are likely to have a more severe and rapid fatal outcome, and should be managed very carefully.22 PNP/PAMS is traditionally difficult to treat. Often patients are resistant to all conventional therapies. Prednisone, combined with immunosuppressive agents, including immunoablative cyclophosphamide, cyclosporine A, plasmapheresis, immunoapheresis, rituximab, and, most recently, alemtuzumab are recommended.15 Early detection and complete resection of the tumor are of paramount importance and prerequisites for a better outcome.21 Prognosis depends on the nature of the underlying malignancy and the

367 development of severe respiratory failure. The distinction of PNP/PAMS from the other subtypes of pemphigus is of critical importance, because PAMS has a poor prognosis and is rapidly fatal. Unfortunately, because the inciting malignancy and the paraneoplastic syndrome do not always follow the same evolution, patients with PNP/PAMS may often progress to recalcitrant mucosal or pulmonary disease even in cases when the malignancy has been treated and is in remission. Another variant of pemphigus that may display systemic involvement is PE, also known as Senear–Usher syndrome. It was initially described nearly a century ago by Francis Senear and Barney Usher in Chicago in 11 patients with pemphigus who shared clinical features of lupus erythematosus (LE) and whose biopsies revealed acantholysis.23 PE is currently recognized as a variant of PF with overlapping clinical, serologic, and immunohistologic features of LE.24 PE clinically presents with erythematous, scaly, and superficially eroded lesions with a seborrheic distribution. The involvement of sun-exposed areas, namely, the face, scalp, and upper part of the chest and back, suggests induction of the lesions by sunlight. On the face, the skin changes often exhibit the “butterfly” distribution of LE. PE shares common histopathology and immunofluorescence findings with PF.25 They differ in that PE typically has positive circulating antinuclear antibodies and a positive lesional lupus band test in addition to intercellular staining on DIF. When tested by IIF on epithelial cell substrate, serum samples from patients with PE produce the typical pemphigus network epithelial cell-surface fluorescence, often combined with staining of the keratinocyte nuclei (Figure 2). Patients with PE may also have other signs of systemic involvement, such as anemia, lymphopenia, thrombocytopenia, renal abnormalities, proteinuria, or positive rheumatoid factor. In addition to an association with LE, the concurrence of PE and myasthenia gravis has been described.24 Most of these patients had a thymoma and presented with antibodies to the cross striations of skeletal muscle in addition to immunologic evidence of pemphigus and LE. A variety of other immunologic diseases may be seen in patients with PE, a phenomenon that justifies considering this form of pemphigus as a distinct variant of the disease.26 Interestingly, PE was the predominant clinical phenotype among the patients in a recently described outbreak of endemic PF in Northern Colombia.27 Colombian cases of endemic pemphigus differ from those in other endemic foci, such as Brazil (Brazilian PF, fogo selvagem) and other South America countries.28 It differs from nonendemic forms in its geographic distribution, high familial incidence, younger age of onset, and poor general state.29 Clinically, most of the patients with Colombian endemic pemphigus showed keratotic follicular skin lesions resembling discoid LE, with a high degree of photosensitivity as in Senear–Usher syndrome, along with a lupus band-like deposition of immunoglobulins and complement at the BMZ. In addition, some hospitalized

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Fig. 2 Indirect immunofluorescence findings in pemphigus erythematosus: combined intercellular and nuclear staining on human esophagus substrate.

patients had proteinuria, hypoalbuminemia, generalized edema, hematuria, leukocyturia, and a frank nephrotic syndrome indicating possible renal failure. Pemphigus is a chronic disease with a sometimes severe clinical picture, relapses, and prolonged immunosuppressive treatment that impairs both physical and psychosocial aspects of QOL. There is a growing interest in QOL of such patients, and recent studies have demonstrated that QOL was worse in patients with nasal and pharynx involvement, positive Nikolsky sign, and severe skin lesions with intensive pruritus.30 PV was found to be responsible for great alteration in QOL, especially in its severe forms. High probability of anxiety and depression in patients with PV was also observed.31 These data lead to the conclusion that the management of pemphigus patients should take into account both their physical and their emotional condition at the start of the treatment.32

Pemphigoid group The pemphigoid group of AIBDs is characterized by the production of autoantibodies that target adhesion molecules which are part of the hemidesmosomes at the dermal– epidermal junction (DEJ). Their immunohistologic hallmark is the formation of a subepidermal blister and deposits of immunoreactants, usually IgG and complement, at the DEJ.

Bullous pemphigoid Bullous pemphigoid (BP) is the most common autoimmune blistering disease in Western European countries, typically affecting elderly individuals older than 60 years. Clinically, BP is characterized by a polymorphic eruption

S. Vassileva et al. consisting of large, tense blisters on inflamed or normalappearing skin, and urticaria-like and eczematous papules and plaques. BP is a prototypical organ-specific disease, mediated by antibodies against structural components of the cutaneous BMZ, namely, a 230-kDa protein called BP antigen 1 (BPAG1) and a 180-kDa transmembrane protein known as BPAG2 (Table 3). The pathogenic role of anti-BPAG2 antibodies has been widely accepted, and their serum levels have been found to parallel disease activity in patients with BP. The role of anti-BPAG1 antibodies in the pathogenesis of BP remains controversial, but their examination may be useful in a limited number of patients with BP and mucosal lesions or with negative anti-BPAG2 antibodies.33 Because target antigens are located within the cutaneous BMZ structures, other organs and systems are believed not to be primarily affected by the autoimmune process in BP. Over the past decade, however, there has been growing evidence of a higher prevalence of neurologic diseases in patients with BP, possibly caused by cross-reactivity between the BP180 and BP230 isoforms expressed in the skin and brain. The reported associations include not only dementia, cerebrovascular disease, or multiple sclerosis, but also Parkinson disease, gonadotropic adenoma, trembling, dyskinesia, and lumbar spinal stenosis.34 A significant increase in the odds of development of BP has been found in people with neurologic diseases.35,36 Dementia, Parkinson disease, and unipolar or bipolar disorder are independent risk factors for BP.37 An English study of 90 consecutive patients with BP and 141 control subjects showed that patients with BP had greater than 6-fold increased odds of any neurologic disease and a nearly 8-fold increased likelihood of dementia.38 In 72% of the patients with known onset of neurologic disease, BP developed later and was diagnosed after a median of 5.5 years. Common autoimmune mechanisms may be involved, as isoforms of BPAG1 (BP230) are expressed in the central and peripheral nervous systems.39 It has been shown that serum of patients who have both BP and neurologic disease recognizes BPAG1 in the human brain. In a study from China, a 230-kDa protein of human epidermal extract and a 230-kDa protein of human brain extract were recognized by serum samples from elderly patients with BP and concomitant neurologic disease in а significantly higher percentage compared with serum samples from patients with BP only, neurologic disease only, or control subjects.40 The authors conclude that both human skin and brain contain immunogenic BPAG1 in patients with BP and neurologic disease. The pathologic changes in elderly patients with neurologic disorders could expose the neural isoforms of BPAG1 or other BP antigens. In certain cases, autoantibodies, initially directed against neuronal isoforms of BP230, may cross-react with isoforms in the skin, causing the delayed development of BP after the onset of the neurologic symptoms.38 It has been speculated that neuroautoimmunity associated with the aging process or neurologic disorder may be involved in pemphigoid

AIBDs as systemic diseases Table 3

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Target antigens and immunofluorescence findings in acquired subepidermal bullous diseases

Disease

Target antigens

Bullous pemphigoid

BP180 NC16A BP230 LAD-1 Mucous membrane pemphigoid BP180 NC16A, BP230, α6β4 Laminin 311 Anti-laminin 332 (antiepiligrin) Laminin 332 pemphigoid Anti-p200/Laminin γ1 Laminin γ1 pemphigoid α5 chain of type IV collagen α5(IV)NC1 blistering disease Linear IgA bullous dermatosis

LAD-1 Type VII collagen

Ultrastructural location

DIF

IIF/split skin substrate

Hemidesmosomes Linear deposits of IgG and/or C3 at the BMZ

Circulating IgG anti-BMZ antibodies—epidermal pattern

Lamina lucida

Linear deposits of IgG and C3 at the BMZ

Lower lamina lucida Lower lamina lucida Lamina densa

Linear deposits of IgG and C3 at the BMZ Linear deposits of IgG and C3 at the BMZ Linear deposits of IgG and C3 at the skin BMZ

Lamina lucida

Linear deposits of IgA and C3 at the BMZ (rarely IgG or IgM) Linear deposits of IgG and C3 at the BMZ, rarely IgA and IgM Linear or granular deposits of IgG and C3 at the BMZ; rarely IgA and IgM Granular deposits of IgA and C3 along the BMZ, more intensive at the tips of the dermal papillae

Circulating IgG anti-BMZ antibodies—epidermal or mixed pattern Circulating IgG anti-BMZ antibodies—dermal pattern Circulating IgG anti-BMZ antibodies—dermal pattern Circulating IgG anti-BMZ (and anti-GBM) antibodies—dermal pattern Circulating IgA anti-BMZ antibodies—epidermal, dermal, or mixed pattern Circulating IgG anti-BMZ antibodies—dermal pattern

Epidermolysis bullosa acquisita Type VII collagen

Anchoring fibrils

Bullous systemic lupus erythematosus

Type VII collagen

Anchoring fibrils

Dermatitis herpetiformis

Epidermal transglutaminase

Papillary dermis

Circulating IgA anti-BMZ antibodies—epidermal, dermal, or mixed pattern IgA anti-endomysial antibodies on monkey esophagus substrate

α5(IV), α5 chain of type IV collagen; BMZ, basement membrane zone; DIF, direct immunofluorescence; GBM, glomerular basement membrane; IIF, indirect immunofluorescence; LAD, linear IgA dermatosis.

development via autoimmune response against dystonin, a cytoplasmic protein present in different compartments of a mature neuron (dendrites, axon, cell body) that shares homology with BPAG1.35 The homologous region of BPAG1 is the one recognized by autoantibodies in BP, which suggests that BP may be a marker of neuroimmune response and neurodegeneration. From a different perspective, circulating antibodies against epithelial isoforms of BP230 may recognize common sequences in neural isoforms and contribute to the neurologic manifestations. Causal associations, including age-related risk factors, immobility, and factors related to the management of the neurologic disease, have also been discussed.36 Historically, BP has been thought to have a better prognosis than pemphigus.41 Over the past decade several large European studies have demonstrated that even with treatment, patients with BP have a prognosis as grim as a diagnosis of end-stage heart disease, with more than 40% of patients dying within 12 months.42–44 Much of the mortality may be related to the age and the general condition of patients or secondary to treatment with corticosteroids and other immunosuppressive agents. In a retrospective study from Scotland, 48% of patients with BP died within 2 years of diagnosis, particularly from respiratory diseases.45 For

this reason, there is now a tendency to treat patients with less aggressive regimens. It has been suggested that patients with circulating antibodies to BPAG2 tend to have a poorer prognosis because of a more severe disease requiring higher doses of systemic steroids.46,47 BP has also been found in association with certain dermatoses, such as psoriasis and lichen planus. The inflammatory process near and within the DEJ, sometimes in combination with irritating therapy, for instance, tar or ultraviolet therapy, can lead to exposure of previously “hidden” antigens and subsequent autoimmune response. After the initial tissue damage, additional antigen epitopes may be targeted by antibodies in a process called epitope spreading, which is hypothesized to play a role in disease progression and chronicity,48 and cause development from one unrelated immunologic disorder to another.49 The coexistence of lichen planus and BP is referred to as lichen planus pemphigoides. Fortuitous associations of BP with various autoimmune, endocrine, and inflammatory disorders have been subject to isolated case reports or small series.5 In some cases, BP has been thought to be induced by physical injury (burn, radiotherapy, ultraviolet irradiation),50 or by numerous systemic or topical medications, or both.51

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Mucous membrane pemphigoid Mucous membrane pemphigoid (MMP), previously known as cicatricial pemphigoid, is a rare but well-defined variant of pemphigoid, characterized by erosive, scarring, subepidermal blistering lesions of mucosal surfaces, particularly of the oral and ocular mucosa (Figure 3), and less often, the skin. Depending on the mucosal surface that is mainly affected, patients with MMP may first present to the ophthalmologist, dermatologist, dentist, gastroenterologist, gynecologist, otolaryngologist, or primary care physician. Even though MMP is not a systemic disease by definition, mucosal involvement may interfere with the function of the digestive, respiratory, and reproductive systems, as well as disrupt normal vision and speech. The oral mucosa is almost always affected, followed by other mucosae (ocular, nasal, pharyngeal, laryngeal, esophageal, genital, and anal) and rarely the skin. Bullae quickly rupture, leaving slowly healing erosions, followed by scarring and adhesions between the various structures of the oral cavity. Laryngeal involvement may lead to a sore throat, hoarseness, and possible loss of speech. Supraglottic stenosis secondary to erosions, scarring, and edema may necessitate a tracheostomy, as the airway is further compromised. Esophageal erosions and scarring may result in the formation of strictures, with dysphagia, odynophagia, and weight loss. Ocular cicatricial pemphigoid is characterized by progressive subconjunctival cicatrization that leads to decreased vision, photosensitivity, scarring, and fibrosis that can eventually cause blindness. A rare variant of MMP with antibodies against laminin 332 is known as anti-laminin MMP (previously called antiepiligrin or anti-laminin 5 pemphigoid). It constitutes between 5% and 20% of all cases of MMP and is clinically indistinguishable from other forms of cicatricial pemphigoid.52 Anti-laminin MMP is associated with an increased relative risk for solid cancer, compared with the general population and similar to that for adults with dermatomyositis.53 Most patients have adenocarcinomas involving the gastrointestinal, gynecologic, and pulmonary systems, but non-Hodgkin and cutaneous T-cell lymphomas have been

Fig. 3 Mucous membrane pemphigoid: eye involvement with scarring.

S. Vassileva et al. also associated. Laminin-332 is essential for epithelial cell adhesion to the basement membrane but is also highly expressed in different cancer cells, promoting tumor growth, metastatic behavior, and invasion.54 Malignant tumors may show an aberrant synthesis of laminin-332, with subsequent induction of a secondary autoimmune response.55,56

Pemphigoid gestationis Pemphigoid gestationis (PG), previously known as “herpes gestationis,” is a rare pregnancy-specific form of pemphigoid. PG usually develops in the second or third trimester and clinically presents with severely pruritic urticarial lesions that progress to large tense bullae (Figure 4). The placenta has been suggested as the initiating organ, because the disease is not only associated with pregnancy, but also with hydatiform mole and choriocarcinoma,57 which should be considered in cases of persistence of PG for several months or onset of the disease more than 2 weeks after delivery. Blistering and early PG onset (first or second trimester) may lead to adverse pregnancy outcomes, including decreased gestational age at delivery, preterm birth, and low-birth-weight infants. Such pregnancies should be considered high risk and appropriate obstetric care should be provided.58

Anti-p200 (laminin γ1) pemphigoid Anti-p200 pemphigoid is a new subepidermal AIBD first described in 1996.59 It is characterized by circulating

Fig. 4 Pemphigoid gestationis: urticarial lesions and grouped vesicles on erythematous basis in the periumbilical area.

AIBDs as systemic diseases autoantibodies that bind to the dermal side of NaClseparated human skin and recognize a 200-kDa protein of the DEJ that was recently identified as the laminin γ1 chain.60 Although laminin γ1 is widely expressed in different basement mebranes, anti-laminin γ1 autoantibodies from patients with anti-p200 pemphigoid are associated only with skin blisters and show no pathology in other organs; however, patients with anti-p200 pemphigoid are often suffering from preexisting psoriasis. They tend to be of younger age than those with BP and present with a pruritic vesiculobullous eruption, mimicking BP. Rarely, dermatitis herpetiformis-like grouped papulovesicles and oral mucosal lesions can be observed.61 Several lines have suggested that expression of integrins is modified in the BMZ of psoriatic skin. Changes in integrin expression in basal keratinocytes may affect the laminin– integrin interaction, as well as the molecular kinetics and metabolism of laminins in the BMZ. These changes may be involved in anti-laminin autoantibody production. Pathogenic interaction between anti-laminin γ1 pemphigoid and psoriasis, which is currently recognized as a systemic disease, should be further elucidated.

A novel disease with autoantibodies against the α5 chain of type IV collagen In addition to the subepidermal AIBDs listed earlier, few patients have been described with a pemphigoid disease, characterized by renal insufficiency and autoantibodies against the α5 chain of type IV collagen [α5(IV) chain] of lamina densa.62,63 α5(IV) chain is present at the DEJ, as well as in the glomerular basement membrane. Patients respectively suffered from a blistering skin eruption and nephropathy leading progressively to uremia. Kidney biopsy was consistent with crescentic glomerulonephritis, whereas skin perilesional biopsy revealed a subepidermal blister with marked polymorphonuclear infiltrate. In vivo deposited and circulating IgA and IgG antibodies reacting with the skin BMZ and the glomerular basement membrane were found on immunofluorescence testing (Table 3).63 This is in contrast with BP, linear IgA disease, and epidermolysis bullosa acquisita (EBA) autoantibodies that fail to react with the glomerular basement membrane. Despite the small number of patients with this novel blistering disease reported, it is of great interest because it represents the second primary human disease caused by autoimmunity to type IV collagen along with Goodpasture syndrome. The latter, however, is mediated by IgG antibodies to α3 chain of type IV collagen chain, which is present only in the renal glomerular basement membrane. This novel disease expands the repertoire of AIBDs and provides an explanation for the association of anti-type IV collagen autoantibodies and glomerulonephritis with subepidermal blisters.

371

Linear IgA dermatosis Linear IgA dermatosis (LAD) is a rare chronic autoimmune bullous disease associated with IgA anti-BMZ antibodies. Although LAD was historically confused with DH, it is now well recognized that these two IgA-mediated diseases are distinct entities. In contrast to DH, LAD shows no association with gluten-sensitive enteropathy, and the gluten-free diet is ineffective. LAD is mediated by IgA autoantibodies directed against heterogeneous antigen targets in the cutaneous BMZ (Table 3), which ultrastructurally localize to lamina lucida, anchoring fibrils, or lamina densa.64 LAD can occur at any age, but there are two peaks of onset: in adult individuals usually at 40 to 60 years of age and in children of preschool age. Most case series show a slight female predominance. 65 Improvement of LAD during pregnancy has been reported and reducing or stopping the medication if possible during pregnancy has been recommended, although postpartum relapses are likely.66 The clinical features of LAD can be heterogeneous. The cutaneous eruption is polymorphic and consists of pruritic urticarial papules, plaques, tense vesicles, and blisters, often in annular and polycyclic arrangement, appearing on the buttocks and perineum, as well as on the trunk and extremities. The annular pattern of the lesions is characteristically described as the “string of pearls” sign or “cluster of jewels” sign. Lesions are usually generalized, with some tendency to grouping, but in contrast with DH, no symmetry is present. Pruritus may be severe or entirely absent. Mucous membrane involvement is reported in 60% to 80% of patients ranging in severity from mild to severe oral or conjunctival lesions67; rarely mucosal involvement can be the sole clinical manifestation. LAD is “idiopathic” in most of the cases, and being an autoimmune disease itself, associations with other disorders of autoimmune and other origin are likely.5 There is a welldocumented association of LAD with inflammatory bowel disease (IBD), Crohn disease, and ulcerative colitis,68 as well as pancreatic lipase deficiency, chronic hepatitis,69 and even celiac disease (gluten-sensitive enteropathy),70 although by definition LAD is not associated with gluten enteropathy. Other associations of LAD include malignancies, which are to be found in about 5% of patients with LAD, presenting as both lymphoid and nonlymphoid malignant diseases. Several other triggers have been implicated in disease onset, including skin trauma,71 ultraviolet exposure, infections, and a wide range of drugs. The significance of these associations remains uncertain.

Dermatitis herpetiformis Dermatitis herpetiformis, also known as Duhring’s disease, is an uncommon subepidermal blistering disease characterized by an intensely pruritic cutaneous eruption, associated with a

372 gluten-sensitive enteropathy. Several clinical and immunofluorescence features, typical for DH and not found in other immunobullous diseases, were identified that led to the current concept of DH as a distinct entity, strongly related to celiac disease in the spectrum of the gluten-sensitive diseases.72,73 Alternatively, it can be regarded as a skin manifestation of gluten sensitivity, a systemic disorder capable of affecting multiple organs. This notion is supported by demonstrated IgA autoantibodies in extraintestinal tissues such as the liver, muscle, and lymph nodes in patients with celiac disease.74 Similar IgA deposits were observed around the brain vessels in a patient with gluten ataxia.75,76 DH and celiac disease have a common immunogenetic background, sharing a strong association with certain major histocompatibility complex antigens, such as HLA-B8, HLA-DR3, and HLA-DQw2. First-degree relatives of patients with DH frequently experience development of celiac disease. Recently, it has been found that epidermal and tissue transglutaminases, cytosolic enzymes involved in cell envelope formation during keratinocyte differentiation, are the major autoantigens recognized in the skin lesions of DH and targeted by the circulating IgA antiendomysium (intermyofibril substance of smooth muscle) antibodies found in the serum of patients with DH and celiac disease.77 Clinically, DH presents with an intensely itchy polymorphic cutaneous eruption involving symmetrically the extensor surfaces, including elbows, knees, shoulders, sacrum, and buttocks. Morbidity is mainly related to the intense pruritus, scratching, discomfort, and insomnia, as well as to the risk for superimposed bacterial or viral infections. Systemic complications consist mainly of the symptoms of the associated gluten-sensitive enteropathy, which is now accepted to be present in practically all patients with DH, despite most of them having only subclinical gastrointestinal disease. Symptoms related to the gluten-sensitive enteropathy are milder than those seen in patients with celiac disease without skin findings, although up to 40% of children with DH have a history of chronic or relapsing diarrhea before the diagnosis of DH.78 Other clinical signs include malnutrition, weight loss, abdominal pain and dyspepsia, sometimes even mimicking peptic ulcer disease, and perforation. All patients with DH have evidence of gluten sensitivity in the small intestine, although only two thirds of them would show villous atrophy on a single biopsy. Patients with DH, similar to those with celiac disease, have a higher incidence of associated autoimmune conditions, especially thyroid problems, atrophic gastritis, type 1 diabetes, pernicious anemia, Addison disease, vitiligo, and various connective tissue disorders. Patients with DH, like patients with celiac disease, are at an increased risk for development of the so-called enteropathy-associated T-cell lymphomas.79 Once DH is diagnosed, examinations for possible signs and symptoms of such accompanying problems are necessary.80 DH and celiac disease have been described in association with such neurologic diseases as ataxia, dementia, and epilepsy. About 10% of patients with celiac disease experience

S. Vassileva et al. neurologic disorders.81 It has been postulated that the central and peripheral nervous systems are susceptible to immunemediated damage caused by gluten, although no convincing evidence for immune-mediated neurologic injury in DH has been confirmed.82 A study of 305 patients in Finland found no significant association between DH and neurologic disease.83 A cohort of 35 patients with DH had low prevalence of neurologic abnormalities, but the unexpected presence of a novel antispinal antibody was found in more than 50% of these patients, requiring further investigation.82

Epidermolysis bullosa acquisita Epidermolysis bullosa acquisita (EBA) is a rare subepidermal blistering disease, characterized by chronic course, resistance to therapy, and often debilitating sequelae. It is mediated by autoantibodies against type VII collagen of the BMZ in stratified squamous epithelia. Recently, type VII collagen was also found in the BMZ of the colon and in the intestinal epithelium.84 The two main clinical presentations of EBA include the mechanobullous or “classical” and the inflammatory phenotype. Classical EBA shows features reminiscent of hereditary dystrophic epidermolysis bullosa, with skin fragility, blisters, scarring, and milia formation limited to the trauma-prone skin surfaces. Alternatively, the inflammatory phenotype manifests with a widespread inflammatory blistering eruption similar to BP or LAD. In a subset of patients with predominant mucous membrane involvement, the disease manifests with blisters and scarring in the oral, ocular, vaginal, and other mucous membranes, leading to significant dysfunction, such as visual function loss, dysphagia, malnutrition, or even death. This clinical phenotype is indistinguishable from MMP. Similar to other immunobullous disorders, EBA has been related to a number of systemic diseases, including autoimmune disorders, malignancies, hematologic, infectious, and endocrine conditions.5 IBD, in particular, Crohn disease and less often, ulcerative colitis, seems to be most frequently associated with EBA to an extent that EBA is currently recognized as one of the extraintestinal manifestations of IBD. Crohn disease has been described in up to 30% of patients with EBA, although many of these observations were made before modern diagnostic criteria for EBA had been established. A recently published review of all previously described cases of EBA and IBD identified 42 reports of coexistence of both diseases in the literature: 35 cases of Crohn disease and 7 with ulcerative colitis.85 In the majority of cases, the onset of the gastrointestinal symptoms preceded or occurred simultaneously with the skin blistering disease. It has been hypothesized that chronic, but occasionally subclinical, inflammation of the gut can precede the development of EBA in all patients.86 The pathogenesis of IBD is not yet completely understood, but it has been proposed that autoimmune mechanisms

AIBDs as systemic diseases may also be responsible. It has been demonstrated that up to 68% of patients with Crohn disease have circulating antibodies against type VII collagen. 87 Anti-type VII collagen antibodies have been detected in patients with ulcerative colitis as well, although with a lower frequency than for Crohn disease. Apart from antibodies to type VII collagen, a number of other autoantibodies to different targets, including intestinal epithelial antigens, pancreatic proteins, cardiolipin, cytoskeletal proteins, Saccharomyces cerevisiae, and tropomyosin, as well as peripheral antineutrophil cytoplasmic antibodies, have been described in patients with IBD, but there is still no evidence for their direct pathogenic role. The exact significance of autoimmunity to type VII collagen in IBD pathogenesis and its relationship to EBA is not yet clarified. It has been proposed that autoimmunity to type VII collagen, which exists in both gut and skin, may explain why patients with EBA frequently have IBD. The presence of type VII collagen antibodies in patients with Crohn disease may be an epitope spreading phenomenon whereby inflammation originally invoked by Crohn disease could perturb the intestinal epithelial BMZ and cause alteration of BMZ components resulting in an ongoing autoimmunity to type VII collagen.87 Another possibility is that the epitopes of type VII collagen targeted by autoantibodies in EBA and IBD may differ, which could further explain the presence of EBA in some patients and the absence of skin blistering in the majority of patients with IBD. Based on all these data, a classification of EBA as manifestation (ie, involvement of the skin with blistering caused by primary IBD processes) or complication (skin blistering caused by secondary processes associated with IBD), including chronic inflammation or side effects of therapy of IBD, has been addressed; however, because production of blister-inducing autoantibodies against type VII collagen occurs only in some patients with IBD later in the course of their gastrointestinal disorder, the second possibility seems to be more likely.

Bullous systemic lupus erythematosus Another autoimmune blistering disease closely related to EBA and autoimmunity to type VII collagen is bullous systemic lupus erythematosus (BSLE). Over the years, BSLE has been recognized as a separate entity with distinct diagnostic criteria: (1) a diagnosis of systemic lupus erythematosus (SLE) by American Rheumatism Association criteria, (2) vesicles and bullae arising on but not limited to sun-exposed skin, (3) histopathology compatible with DH, (4) negative or positive IIF for BMZ autoantibodies, and (5) positive DIF at the BMZ.88 By definition, BSLE is a part of the clinical spectrum of SLE, a prototypic autoimmune disease with multisystem clinical manifestations in association with autoantibody production.

373 BSLE usually affects young adults in the second or third decade of life and is characterized by a rapid development of a widespread, symmetric, nonscarring vesiculobullous eruption showing predilection for the sun-exposed areas, but also for the chest, back, neck, and axillae.89 Depending on the predominance of inflammatory lesions and the distribution of the eruption, it may mimic BP, LAD, as well as both the inflammatory or “classical” variant of EBA.90 The onset and course of cutaneous lesions does not necessarily parallel the activity of the systemic involvement, but antinuclear antibody test results are generally positive. Other laboratory abnormalities related to SLE can include low levels of complement (C3, C4, CH50), anemia, leukopenia, thrombocytopenia, proteinuria or cellular casts on urinalysis, and an elevated erythrocyte sedimentation rate.91 An important clinical feature of BSLE that further differentiates it from EBA is its striking therapeutic response to dapsone. Systemic corticosteroids and immunosuppressors applied to control the visceral manifestations of SLE, in contrast, may be often ineffective to the eruption, and a combination of corticosteroids and dapsone is then indicated. Both BSLE and EBA have an increased incidence of HLA-DR2 haplotype that has been associated with hyperimmunity.92 It is possible that this genetic predisposition is responsible for an increased risk for development of autoimmunity to BMZ antigens. Overproduction of diverse autoantibodies by hyperreactive B cells as a result of depressed T suppressor activity is a protean feature of SLE. It has been hypothesized that antibodies to type VII collagen in BSLE are part of the autoantibody repertoire of SLE.93

Conclusions AIBDs are examples of a skin-specific autoimmune response, in which there are autoantibodies against adhesion molecules in the epidermis and the BMZ that are presumed to be pathogenic and to cause the blistering in the skin. Their diagnosis is based on the clinical findings, histology, and DIF and IIF, as well as identification of antigenic targets through other more specific and sensitive diagnostic laboratory methods. As soon as a distinct immunobullous disease is diagnosed, it is imperative to consider its potential systemic complications, as well as the potential autoimmune or inflammatory conditions that are frequently associated with it.

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Clinics in Dermatology (2014) 32, 376–388

Neutrophilic dermatoses as systemic diseases Lola Prat, MD, Jean-David Bouaziz, MD, PhD ⁎, Daniel Wallach, MD, Marie-Dominique Vignon-Pennamen, MD, Martine Bagot, MD, PhD Université Paris Diderot, Sorbonne Paris Cité; AP-HP, Paris, France Service de Dermatologie et Service d’Anatomo-Pathologie, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France

Abstract Neutrophilic dermatoses (ND) are inflammatory skin conditions characterized by a sterile infiltrate of normal polymorphonuclear leukocytes. The main clinical forms of ND include Sweet syndrome, pyoderma gangrenosum, erythema elevatum diutinum, subcorneal pustular dermatosis, and their atypical or transitional forms. ND are often idiopathic, but they may be associated with myeloid hematologic malignancies (Sweet syndrome), inflammatory bowel disease or rheumatoid arthritis (pyoderma gangrenosum), and monoclonal gammopathies (erythema elevatum diutinum, subcorneal pustular dermatosis). The possible infiltration of internal organs with neutrophils during the setting of ND underlies the concept of a neutrophilic systemic disease. ND may be seen as a polygenic autoinflammatory syndrome due to their frequent association with other autoinflammatory disorders (monogenic or polygenic) and the recent published efficacy of interleukin-1 blocking therapies in their management. © 2014 Elsevier Inc. All rights reserved.

The neutrophilic dermatoses (ND) are a group of disorders characterized by skin lesions for which histologic examination reveals intense inflammatory infiltrates composed primarily of neutrophils with no evidence of infection. ND mainly include Sweet syndrome (SS), pyoderma gangrenosum (PG), subcorneal pustular dermatosis (SPD), other well-defined entities, and their atypical or transitional forms. The concept of ND relies on four premises: 1. The existence of transitional and overlap forms 2. A similar histopathologic feature characterized by an infiltrate of normal polymorphonuclear leukocytes 3. The possible occurrence of extracutaneous neutrophilic symptoms (the neutrophilic disease) 4. A frequent association with multisystemic diseases1

⁎ Corresponding author. Tel.: +33142494680; fax: +33142494620. E-mail address: [email protected] (J.-D. Bouaziz). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.004

The diagnosis of extracutaneous neutrophilic manifestations of ND is often difficult because it requires intensive investigations to rule out an infectious or neoplastic process. ND may be associated with a variety of systemic disorders including especially myeloproliferative disorders, monoclonal gammopathies (mainly IgA type), inflammatory bowel disease, and rheumatoid arthritis (RA).2,3 The classical sterile infiltration of the skin that occurs in ND may also be observed in many organs including the lungs, bones, joints, digestive tract, liver, spleen, pancreas, central nervous system, heart, and blood vessels4; furthermore, some patients may suffer from aseptic systemic abscesses without cutaneous involvement.5 In 2006, researchers proposed a clinical and histologic classification according to the localization of the neutrophilic infiltrate and divided ND in three groups: ND “en plaques” characterized by a dermal neutrophilic infiltrate (SS, erythema elevatum diutinum [EED]), superficial ND characterized by an epidermal neutrophilic infiltrate (SPD), and deep ND characterized by

Neutrophilic dermatoses Table 1

377

Summary of neutrophilic dermatosis, extracutaneous involvement and associated diseases

Type of Neutrophilic Dermatosis Extracutaneous Involvement Dermal neutrophilic dermatosis AFND (Sweet syndrome) Arthralgias, myalgias, polyarthritis seronegative or seropositive, CRMO, myositis, recurrent encephalitis with ND (neuro-Sweet), meningitis, rarely peripheral neuropathy, abnormalities of hepatic enzymes, aseptic neutrophilic abscesses (liver, spleen, pancreas, digestive tract) BOOP, pleural effusion, lung nodular lesions, aneurysm of ascending aorta, myocardium infiltration Periorbital and orbital, inflammation, dacryoadenitis, conjunctivitis, episcleritis, scleritis, limbal nodules, peripheral ulcerative keratitis, iritis, glaucoma, and choroiditis Proteinuria, hematuria, renal insufficiency, rarely glomerulonephritis EED

Arthralgias Sclerosing glomerulonephritis

NEH Dermal and hypodermal neutrophilic dermatosis Pyoderma gangrenosum Nodular pulmonary lesions, with or without cavitation, noninfectious necrotizing tracheitis, CRMO, polyarthritis seronegative or seropositive, “colitis arthritis” Abnormalities of hepatic enzymes and digestive aseptic neutrophilic abscesses Myositis, cardiac involvement, keratitis, episcleritis, rapidly progressive renal failure, sclerosing glomerulonephritis, pyosalpinx

Associated Diseases AML, lymphomas, myelodysplastic syndromes, chronic leukemias, myelomas G-CSF, bortezomib Solid tumors, IBD (CD N UC), RA, Behçet disease, relapsing polychondritis, thyroid diseases

IgA gammopathy, hepatitis B, streptococcal infections, HIV, polycythemia vera, myelodysplastic syndrome, hairy cell leukemia, mixed cryoglobulinemia Induction chemotherapy in AML++, CML, Hodgkin lymphoma, various solid tumors

IBD (UC N CD) RA, ankylosing spondylitis, relapsing polychondritis, AML, polycythemia vera, monoclonal gammopathy, Waldenström macroglobulinemia, large granular lymphocytic leukemia, myelofibrosis, and non-Hodgkin lymphoma G-CSF, IFN-α2b

Neutrophilic panniculitis

Melanoma treated with vemurafenib, Crohn's disease, myelodysplastic syndrome treated by azacitidine, CML treated by imatinib, RA

Skin aseptic abscesses

Crohn's disease

Epidermal neutrophilic dermatosis SPD Arthritis, abnormalities of hepatic enzyme and digestive aseptic neutrophilic abscesses, sclerosing glomerulonephritis

IgA pemphigus

Monoclonal gammopathies (IgA type), lymphomas, multiple myelomas, aplastic anemia, CML Solid tumors (metastatic thymoma, epidermoid carcinoma of the lung) G-CSF Mycoplasma pneumoniae respiratory infection RA, IBD, autoimmune disorders (Sjögren syndrome, SLE), thyroid disease, SAPHO Monoclonal gammopathy, typically of the IgA class, B cell lymphomas, myeloma, and CD30+ anaplastic large cell lymphoma Cryoprecipitate IgG, CD, gluten-sensitive enteropathy

378

L. Prat et al.

Table 1 (continued) Type of Neutrophilic Dermatosis Extracutaneous Involvement Dermatosis arthritis syndrome

Arthritis, erythema nodosum

Associated Diseases Ileojejunal bypass, inflammatory bowel diseases

AFND, acute febrile neutrophilic dermatosis; AML, acute myelogenous leukemia; BOOP, bronchiolitis obliterans organizing pneumonia; CD, Crohn's disease; CML, chronic myelogenous leukemia; CRMO, chronic recurrent multifocal osteomyelitis; EED, erythema elevatum diutinum; G-CSF, granulocyte colony-stimulating factor; IBD, inflammatory bowel disease; IFN, interferon; ND, neutrophilic dermatosis; NEH, neutrophilic eccrine hidradenitis; RA, rheumatoid arthritis; SAPHO, synovitis, acne, pustulosis, hyperostosis, osteitis; SLE, systemic lupus erythematous; SPD, subcorneal pustular dermatosis; UC, ulcerative colitis.

a dermal and hypodermal infiltrate (PG).1 The purpose of this contribution is to describe the ND clinical spectrum, the neutrophilic systemic disease, and the most frequent diseases associated with the ND (see Table 1 for a summary).

The neutrophilic dermatoses: Cutaneous clinical features Acute febrile neutrophilic dermatosis or SS, the prototype of the neutrophilic dermatoses en plaques (dermal ND) Sweet syndrome Acute febrile neutrophilic dermatosis was described by Robert Douglas Sweet in 1964 and soon came to be known as SS.6 It is characterized by fever; neutrophilia (with blood polymorphonuclear leukocyte level greater than 10,000/ mm3); painful, erythematous 0.5 to 12 cm papules or plaques (Figure 1) on the extremities, face, and neck; and a dense dermal neutrophilic infiltrate.6 Additional criteria for SS include absence of infection and responsiveness to corticosteroid.6 Microscopic examination reveals a dense dermal infiltrate of mature neutrophils with edema. The infiltrate is usually localized to the upper portion of the dermis but may extend into the subcutaneous tissue as recently reported in association with myeloid disorders (neutrophilic panniculitis or subcutaneous SS).7 Other typical histologic features may include a mixture of lymphocytes and eosinophils, vascular endothelial swelling, and erythrocyte extravasation. Changes of a primary leukocytoclastic vasculitis are typically absent

Fig. 1

Clinical picture of idiopathic Sweet syndrome.

but may be observed as an epiphenomenon in old lesions or in some localizations.8,9 Most cases are considered to be idiopathic,10 but SS can be associated with different disorders. The association between malignancy and SS was first recognized in the early 1970s. Ten to 20% of SS cases occur in the setting of an underlying malignancy, most commonly myelogenous acute leukemia,11 but also lymphomas, myelodysplastic syndromes, chronic leukemias, myelomas, and other myeloproliferative disorders. In addition, SS can occur after treatment with granulocyte colony-stimulating factor (G-CSF) in patients with hematologic disorders. An association with solid tumors is rare but has been reported. SS has also a bonafide association with inflammatory bowel disease (both Crohn's disease and ulcerative colitis), Behçet disease, relapsing polychondritis, RA, and thyroid disease (both Graves disease and Hashimoto thyroiditis). Most cases occur between 30 and 60 years of age. A prior upper respiratory tract infection is frequently associated with idiopathic SS, but a prodrome is not typically seen in malignancy-associated SS. The cutaneous lesions in patients with underlying malignancies frequently have atypical features including pustular, vesicular, bullous, and even ulcerating lesions, as well as the more typical plaques and nodules.11 Generalized pustular lesions may occur in association with chronic myeloid leukemia.12 Oral mucosal lesions are rare and occur more frequently in malignancy-associated SS.13 The frequency of SS extracutaneous manifestations varies, but they may occur in more than 50% of the cases associated with an underlying hematologic malignancy.11 The most common systemic symptoms are arthralgias and myalgias, but SS can involve many organs including the lung.14 Massive swelling of the tongue15 and cutaneous pathergy have been reported in patients with underlying hematologic disorders.16 Erythema elevatum diutinum In 1894, Henry Radcliffe-Crocker and investigators coined the name “erythema elevatum diutinum” (EED), a chronic inflammatory dermatosis characterized by brownish red, elevated lesions occurring symmetrically over extensor surfaces of the interphalangeal joints, elbows, ankles, and knees.17 A predominantly acral distribution with truncal sparing is characteristic. Most cases begin in the middle age, but the age at onset can vary from 6 months to 75 years. There is no sex predilection or familial association.17

Neutrophilic dermatoses The pathologic findings in EED correlate with the age of the lesion at the time of biopsy.18 The cause of EED is unknown, but the dermatopathologic process begins with a leukocytoclastic angiitis. Leukocytoclastic vasculitis may be accompanied by bullae formed secondary to epidermal necrosis. Later lesions show nodules with vasculitis, dermal aggregates of neutrophils, and granulation tissue formation.19 The final stage of EED is a nodule with fibrosis and infiltration by histiocytes and macrophages. The disease may be associated with a variety of underlying processes, including hepatitis B, streptococcal infections, ulcerative colitis, Crohn's disease, RA, recurrent bacterial infection, collagen vascular diseases, polycythemia vera, myelodysplastic syndrome, hairy cell leukemia, mixed cryoglobulinemia, and HIV infection, but IgA gammopathy is by far the most frequent disease associated with EED.10,20 Other ND en plaques Other ND en plaque include: 1. The neutrophilic eccrine hidradenitis, which is clinically very similar to SS. It commonly occurs in patients receiving chemotherapy for acute myelogenous leukemia, and the distinction with SS is usually made by the histologic examination that reveals neutrophils in and around the eccrine coil.21 2. The neutrophilic rheumatoid dermatitis that occurs in patients with severe, seropositive RA.22 Clinical symptoms are erythematous plaques and periarticular nodules. 3. The granulomatous PG, which is a rare variant of PG characterized by a vegetating, unique plaque that slowly extends and that may be hollowed out by a very superficial ulceration.23

PG, the prototype of the deep ND (dermal and hypodermal ND) Pyoderma Gangrenosum PG was first described in 1930.24 Active lesions are characterized by chronic evolutive ulcerations with violaceous, undermined borders (Figure 2). Five clinical variants are currently recognized: classic (ulcerative), bullous,

Fig. 2 Pyoderma gangrenosum in a patient with relapsing polychondritis.

379 pustular, vegetative, and peristomal cases.25 The diagnosis of PG is generally made clinically because the histologic findings are not diagnostic, and appropriate cultures should be taken and infection should be ruled out. Characteristically, PG presents with pustules or nodules that progress to ulcers with central necrosis. The lesions have undermined, dusky borders and are surrounded by violaceous, erythematous haloes.24 The lesions are exquisitely tender and heal with cribriform scarring. There is a female predominance in nonmalignancy-associated PG.26 Men are more commonly affected in malignancy-associated PG and have a worse prognosis.27 The average age of onset of the disease is 40 years, and only 4% of patients are younger than 15 years.3 The histology is determined by the type of lesion for which a biopsy was taken (ulcerative, vegetative), the stage of the lesion, and the portion of the lesion sampled. More than 50% of patients with PG have an associated systemic disease,28 including ulcerative colitis, Crohn's disease, RA, relapsing polychondritis, and hematologic malignancies.28 Inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, are the systemic diseases most frequently reported in association with PG. This association was seen in up to 41% of PG cases published in the last three decades.25 In a recent prospective study of 2402 French patients with inflammatory bowel diseases, 0.75% of patients had PG, without any association between the severity of inflammatory bowel diseases and the presence of PG.29 PG is also frequently associated with various arthritis forms, most commonly seronegative arthritis of a single, large joint,30 but classical forms of RA and ankylosing spondylitis are also commonly associated.28 The clinical severity of the arthritis is unrelated to PG activity.31 PG has also been reported after the administration of interferon-α2b in a patient with chronic granulocytic leukemia32 and after the administration of G-CSF in a patient with myelodysplastic syndrome (MDS).33 Approximately 7% of patients with PG have an associated hematologic malignancy, most commonly acute myelogenous leukemia (AML).34 Overlaps between PG and SS are typically found in patients with a myeloproliferative disorder.35 Other associated hematologic disorders include monoclonal gammopathy (usually IgA subtype), Waldenstrom macroglobulinemia, large granular lymphocytic leukemia, myelofibrosis, and non-Hodgkin lymphoma.10 Systemic involvement of PG affecting the liver, lungs, meninges, and kidneys (rapidly progressive renal failure associated with monoclonal gammopathies) has been reported.36 Primary PG of the lung preceding cutaneous PG has been described in two patients.37,38 Other deep ND Other deep ND include the neutrophilic panniculitis, characterized by painful, inflammatory subcutaneous masses,39 and skin aseptic abscesses characterized by nodules or subcutaneous masses that fluctuate and from which spontaneous sterile pus may drain.40

380 Neutrophilic panniculitis has been reported to be associated with RA,39,41,42 with Crohn's disease,43 MDS,44 and MDS treated by G-CSF or azacitidine,45 with CML treated by imatinib,46 and with metastatic melanoma treated by vemurafenib.47,48 In a recent review, extracutaneous aseptic abscesses were well described in 29 French patients involving abdominal lymph nodes, liver, lung, pancreas, and brain. Only 20% of the patients in this cohort had an associated “skin” ND.5

SPD (Sneddon-Wilkinson disease), the prototype of the superficial ND (epidermal ND) Subcorneal pustular dermatosis SPD is a rare and chronic condition, described for the first time in 1956 by Sneddon and Wilkinson.49 Criteria for the diagnosis of SPD include a new onset of pustular eruptions without systemic symptoms, absence of existing psoriasis, subcorneal neutrophilic pustules without spongiosis, and responsiveness to dapsone.50 It is characterized by a symmetric pustular eruption that involves intertriginous areas (such as the axillae, groin, and submammary), and also the flexural sites of the trunk and extremities51-53 (Figure 3). New waves of pustules spread in an annular or gyrate pattern, leaving a ring-shaped scale. Classically, SPD occurs in women between the ages of 40 to 70 years.54 A subcorneal accumulation of neutrophils with the absence of spongiosis or acantholysis is the salient histologic feature of the condition. There is a superficial split between the stratum corneum and the layers of epidermis beneath, and a minimal distortion of the epidermis and dermis underlying the blister. In addition to neutrophils, occasional eosinophils may be present in the blister. In the superficial dermis, a mixed inflammatory infiltrate may be present, with perivascular infiltrate.53 SPD may be associated with many systemic disorders, including monoclonal gammopathies, lymphomas, and multiple myelomas. The paraprotein in SPD is usually of the IgA type.50 IgG-cryoglobulinemia, IgA myeloma, and IgG myeloma have also been described with SPD.55 Also, SPD

L. Prat et al. has been reported to occur in association with aplastic anemia.56 In addition to monoclonal gammopathies, SPD is associated with other hematologic malignancies such as chronic lymphocytic leukemia, solid tumors such as metastatic thymoma, and epidermoid carcinoma of the lung. SPD has also been associated with Mycoplasma pneumoniae respiratory infection, RA, thyroid disease, inflammatory bowel disease, autoimmune disorders (such as systemic lupus erythematosus and Sjögren syndrome), and other conditions such as multiple sclerosis, apudoma syndrome (an endocrine tumor that arises from the amine precursor uptake and decarboxylation cells), and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome.53 IgA pemphigus In 1979, the case of a patient with a condition similar to SPD, but with epidermal IgA deposits in a “pemphigus-like” pattern, was reported.57 Other cases of the condition were named intraepidermal neutrophilic IgA dermatosis,58 “intraepidermal IgA pustulosis,”59 or more commonly, IgA pemphigus. IgA pemphigus includes two subgroups, intraepidermal and subcorneal, with different target autoantigens. A monoclonal IgA is often associated (as in the initial case) and dapsone is often efficient, as in SPD. IgA pemphigus is considered as a continuum between the ND and autoimmune bullous skin diseases. Cases of IgA pemphigus have been recently reviewed.60 Other superficial ND Deep pustules on an inflammatory basis may represent the initial lesions of ulcerative PG or the superficial component of pustular-bullous PG or atypical SS. Isolated pustules, sometimes with an erythematous or violaceous component, have been described as pustular vasculitis and are part of the “dermatosis arthritis syndrome” (pustulosis, erythema nodosum, and arthritis) in patients with an ileojejunal bypass or with inflammatory bowel diseases.61 Bullous forms of PG and sometimes bullous forms of SS can occur and are mainly associated with myeloproliferative disorders. One report described three new cases and summarized previously published cases of a recently described entity called “amicrobial pustulosis of skin folds.” 62 Patients with autoimmune diseases, especially lupus erythematosus, experienced recurrent attacks of aseptic pustules in major and minor skin folds.

Extracutaneous neutrophilic involvement: The neutrophilic disease Lung

Fig. 3 Erythema and aseptic pustules in the setting of subcorneal pustular dermatosis (Sneddon-Wilkinson disease).

Culture-negative pulmonary lesions in patients with ND have been reported in patients with SS, PG, and SPD. Most patients had fever, and pulmonary symptoms were

Neutrophilic dermatoses characterized by cough, dyspnea, or chest pain. One patient had aseptic abscesses in many organs, especially the lung, without skin lesions, which underlines the possibility of a neutrophilic systemic disease without skin ND.63 The most recent review of the literature about SS with lung involvement, in 2006, reported 23 cases.64 In SS, skin and pulmonary lesions were generally concomitant, but in some cases, skin lesions appeared before pulmonary involvement of SS. Chest radiograph was always abnormal, disclosing patchy infiltrates, homogenous opacity in one segment or lobe, or bilateral interstitial pneumonia. Some patients had pleural effusion preceding or accompanying lung involvement. Open-lung biopsy or transbronchial biopsy when performed disclosed massive neutrophilic infiltrates that formed a suppurative exudate in the alveoli. Analysis of fluid obtained by bronchoalveolar lavage from six patients showed a predominance of neutrophils. Cases of bronchiolitis obliterans organizing pneumonia associated with SS have been reported.65 None of the patients who had biopsy-proven bronchiolitis obliterans organizing pneumonia were found to have an underlying malignancy. In one case, SS with pulmonary and muscle involvement appeared a few days after the initiation of all-trans retinoic acid for the treatment of promyelocytic leukemia.66 Pulmonary involvement in SS may occur more frequently, because many steroid-responsive lung infiltrates are not examined.65 SS with pulmonary involvement were more frequently associated with hematologic malignancy (12/23 patients in one review64). A total of 32 cases of PG with pulmonary involvement have been reported in a recent review.67 The most frequent lung alterations were nodular lesions with or without cavitation. Hematologic malignancies were reported in 13 cases (myelodysplastic syndrome or monoclonal gammopathy). In one case, PG was associated with a noninfectious necrotizing tracheitis.68 Patients with ND and lung involvement were treated with systemic corticosteroids after empirical antimicrobial or antifungal therapy had failed. Both the cutaneous and pulmonary lesions rapidly improved. Many patients died of respiratory failure, septicemia, toxic shock syndrome, or intracerebral hemorrhage.69

Bone A 1972 contribution reported a syndrome of acquired, culture-negative, multifocal osteomyelitis in children and named it “subacute and chronic symmetric osteomyelitis.”70 In 1986, the association between ND and multifocal, aseptic bone lesions in children was termed chronic recurrent multifocal osteomyelitis (CRMO).71 Fever, arthralgias, and myalgias were often present. The diagnosis of CRMO was made in conjunction with bone pain, tenderness, and swelling around a joint at one or multiple sites and lasting between 1 and 2 weeks, mild periosteal reaction, sometimes radiolucent metaphyseal lesions, and an increased uptake at the metaphyseal ends of the involved bones. This disease

381 predominantly affects the metaphyses of long bones, with only rare reports of epiphysis or apophysis involvement.72 Other sites reported include the mandible sternum, clavicle, vertebrae, and the frontal and sphenoid bones. In most cases, bone biopsies showed acute inflammation or chronic inflammatory changes, fibrosis, and excessive resorption of bony trabeculae. Slightly elevated ESRs and sometimes increased white blood cell count are noted. Skin ND lesions associated with CRMO include psoriasis, palmoplantar pustulosis, PG, and SS.73 Many authors have suggested that CRMO and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome belong to the same clinical spectrum, with CRMO being the pediatric form of SAPHO.73 The two syndromes share numerous characteristics, including osteitis, a unifocal or multifocal presentation, hyperostosis, and pustulosis, which all occur in a generally healthy individual. Skin DN lesions associated with SAPHO include palmoplantar pustulosis, nonpalmoplantar pustulosis, psoriasis vulgaris, acne, PG, SS, and SPD.73 Patients are refractory to antibiotic therapy but dramatically respond to systemic steroids and may need to be maintained on lowdose steroids to prevent relapses.

Joints Articular manifestations are frequently reported in the context of ND. They occur in approximately 50% of patients with SS and PG. They are less common in SPD and EED. Arthralgias reported in these diseases occur before, during, or after the onset of ND. They are characterized by episodic, pauciarticular, asymmetric, large joints, and lower extremity involvement. Radiographs are frequently normal or show soft-tissue swelling. In addition to the well-defined rheumatologic inflammatory disorders associated with ND (RA and ankylosing spondylitis), three main different dermatoarthritis syndromes can be individualized.74 The first pattern was mainly described by Holt et al75 and corresponds to a chronic, progressive, seronegative destructive polyarthritis with axial or peripheral involvement, or both. This polyarthritis has been observed mainly in PG and usually antedated the PG. Hidradenitis suppurativa or acne conglobate could also be observed. In all cases, the pattern was symmetric with small- and large-joint involvement. The clinical and radiologic pattern of joint disease was not typical of RA or ankylosing spondylitis. The course of the arthritis was progressive despite treatment of ND. The second pattern of arthritis reported in ND was a seronegative, nondestructive polyarthritis that paralleled the course of skin flares. A third group of patients had clinical characteristics of arthritis matching criteria that were fully established by Wright and Watkinson,76 who named it “colitis arthritis,” first recognized in patients with PG who had inflammatory bowel disease. In this condition, a recurrent acute synovitis occurred usually in a monoarticular distribution. The attacks were of short duration and almost never associated with residual joint deformity or radiologic change.

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Central nervous system In 1983, the case of a patient with SS, neurologic signs, and psychiatric symptoms was reported; however, the cerebrospinal fluid analysis was normal, and the link between SS and neurologic abnormalities was not clearly established. The term benign recurrent encephalitis or neuroSweet disease with ND (NSD) was introduced in 1999 by Hisanaga et al,77 who described patients with erythematous plaques of SS and encephalitis. The most common neurologic diseases in SS were encephalitis and meningitis (disturbance of consciousness, headache), and rarely peripheral neuropathy. The initial episodes of neurologic symptoms usually followed SS skin symptoms; but in a few cases, the neurologic findings preceded the onset of dermatologic involvement.78 Abnormal signal intensities on MRI were demonstrated in various central nervous systems regions. The differential diagnosis between NSD and neuro-Behçet disease may be difficult because the two diseases may share common clinical features. In 2006, in a large, retrospective study, diagnostic criteria of NSD and criteria to allow the distinction between NSD and neuro-Behçet disease were established.78 In brief, NSD is characterized by its age of onset (30-60 years of age in NSD vs 20-30 in neuro-Behçet disease), the absence of central nervous system site predilection involvement (basal ganglion and brainstem in neuro-Behçet disease), highly systemic glucocorticoid responsiveness and infrequent neurologic sequelae (frequent in neuro-Behçet disease), classical sign of skin SS without vasculitis (vasculitis is frequent in skin lesions of Behçet disease), specific ocular findings (episcleritis and conjunctivitis in NSD vs uveitis in Behçet disease), specific human leukocyte antigen association (CW1 vs B54 in Behçet disease), and absence of other specific signs of Behçet disease, mainly thrombosis.78 Pituitary involvement has been reported in a patient with PG who was treated with prednisone, which produced a dramatic improvement of the pituitary pseudotumor.79

Intra-abdominal viscera Hepatic involvement has been frequently suggested in SS. Reviews have reported increased levels of alkaline phosphatase (50% of cases) and transient increased levels of aspartate transaminase and gamma glutamyl transferase.80 Abnormalities of hepatic enzymes returned to normal when steroids were started. Aseptic neutrophilic abscesses have been reported in lymph nodes, spleen, pancreas, liver, and digestive tract. 81 The patients had SS, PG, SPD, or subcutaneous abscesses. Fever and acute abdominal pain leading to surgical procedure was observed. In a few cases, the diagnosis could be performed by percutaneous aspiration of mesenteric lymph nodes, endoscopic retrograde cholangiopancreatography, or by rectal and liver biopsies. The pancreatic involvement was suggested by enzymatic abnor-

L. Prat et al. malities and/or echography disclosing pancreas defects.82 Biopsies showed neutrophilic infiltration without vasculitis. Associated diseases were monoclonal gammopathy, Fanconi anemia, acute myelogenous leukemia, and Crohn's disease.74 The disease was usually severe and was controlled by steroids. Some patients required immunosuppressive therapy. In one case, thalidomide was used with a good result.83

Muscle Muscle involvement is usually considered to be an uncommon manifestation of ND. In a series of 136 patients with ND, fewer than 10% of patients had myalgias.84 One patient had PG with lung involvement (bilateral infiltrates), liver involvement, and a severe sterile neutrophilic myositis as the first manifestation of an acute myelogenous leukemia.85 Patients with a true myositis and SS have also been reported.66,86 Most patients had SS that followed induction of chemotherapy for an acute myelogenous leukemia. Muscle involvement was characterized by a marked swelling and pain, an increase of serum creatine phosphokinase,86 and signs of myositis and fasciitis on magnetic resonance imaging.66 Biopsy of the deltoid muscle performed in one case showed scant degenerated and necrobiotic muscle cells, which were separated from one another by a heavy, partly leukocytoclastic neutrophilic infiltrate.86 Muscular involvement and cutaneous lesions resolved when corticosteroid therapy was introduced.86

Heart and blood vessels Aneurysm of ascending aorta was described, with probably a rupture, revealing at autopsy a neutrophilic infiltrate within the aortic wall.87 In one patient with SS and myositis, autopsy was performed after he died of myocardial infarction. It revealed segmental neutrophilic infiltrates in the media of the abdominal aorta.86 There has also been a report of a myocardial neutrophilic infiltration in a patient with SS and a MDS.88 Cardiac involvement has been demonstrated at autopsy in one case of bullous PG associated with a MDS that evolved to an acute myelogenous leukemia.89

Eye Ocular manifestations of 20 patients with SS were reviewed in 2008.90 Ocular SS manifestations included periorbital and orbital inflammation, dacryoadenitis, conjunctivitis, episcleritis, scleritis, limbal nodules, peripheral ulcerative keratitis, iritis, glaucoma, and choroiditis. Of the 20 cases, half were bilateral and 7 cases happened in malignancy-associated SS. Biopsies of ocular tissue were infrequent, but in the seven cases when ocular tissue was analyzed, the histopathology was similar to that of the cutaneous lesions. Oral prednisone was the mainstay

Neutrophilic dermatoses treatment in half of the cases and was efficient even if relapses occurred. Nine of the 20 patients analyzed had extracutaneous manifestations, primarily arthralgia, but also polyneuropathy, pulmonary involvement, and sterile infiltrates including pharyngitis, laryngitis, otitis media, and mastoiditis. A 60-year-old woman with RA, PG, and SS, who had a peripheral ulcerative keratitis and episcleritis successfully treated with oral cyclosporine was reported.91

Kidney Renal involvement in ND is rarely reported, presenting mostly as proteinuria,92-94 hematuria,95 renal insufficiency,96 and more rarely as glomerulonephritis or even death from renal failure.97 Most of the reported cases in the literature were SS, whereas only 3 cases linked PG with renal failure. The first case was a child with three types of ND (EED, SPD, and PG) who experienced development of sclerosing glomerulonephritis.98 The second case was a patient with PG and pulmonary involvement, who also had aseptic leukocyturia, and cystoscopy demonstrated intravesical purulent debris that disappeared with steroid therapy.99 The third case was a patient with vulvar and renal neutrophilic involvement.93

Fallopian tube The case of a 28-year-old woman with abdominal pain during pregnancy revealed a right pyosalpinx with histologic features consistent with PG (neutrophilic infiltrate with moderate vasculitis).100 Although cases of skin PG have already been reported during pregnancy, this is the only case reported with fallopian tube localization.

Systemic diseases frequently associated with ND Hematologic disorders Acute myelogenous leukemia AML may be associated with ND (more frequently SS, but sometimes PG), and ND may reveal an AML. Recently, the same cytogenetic anomaly in the neutrophils infiltrating the skin and in the bone marrow in myeloid malignancies has been demonstrated, and hence is indicative of a clonal neutrophilic dermatosis.101 A case of SS with folliculitis and neutrophilic panniculitis after remission of an AML with an increased level of endogenous G-CSF has been reported.102 Neutrophilic dermatosis of the dorsum of the hands, a subtype of SS, has been described in patients undergoing chemotherapy for AML.103 SS, in the setting of AML, may also occur after treatment with all trans retinoic acid104 or with cytosine arabinoside. Neutrophilic eccrine dermatosis,

383 an eccrine variant of SS, is associated with AML after the induction of chemotherapy, but it can also be rarely associated with AML before the treatment.105 Leukemia, other The association between ND and other forms of leukemia is relatively rare. Acute lymphoblastic leukemia may be rarely associated with PG,106 with neutrophilic eccrine hidradenitis after chemotherapy107 and with SS.10 Chronic leukemias (chronic myelogenous leukemia and chronic lymphoblastic leukemia) may be associated with SS or neutrophilic eccrine hidradenitis.10 Lymphoma Although rare, both Hodgkin and non-Hodgkin lymphomas (more than 30 cases) were reported in association with SS,10,108 sometimes with an atypical histiocytoid histologic feature.109 Cases of bortezomib-induced SS for the treatment of lymphomas have also been reported.110 Monoclonal gammopathies and multiple myeloma Benign IgA monoclonal gammopathies are strongly associated with PG, EED, and SPD, and overlapping forms of these DN may exist in this setting.111 Multiple myeloma is known to be associated with SS, predominantly in patients secreting an IgG paraprotein and after G-CSF administration.112 A patient with Sjögren syndrome with an IgG of undetermined significance that later became a multiple myeloma had initially an SS. In this patient, skin lesions relapsed after G-CSF treatment.113 There is an association between the administration of bortezomib, a proteasome inhibitor, and lenalidomide (both used for the treatment of multiple myeloma) with the development of ND, in particular, SS.114,115 Myelodysplastic syndrome Relationships between MDS and SS,116 and a case of SS after azacitidine treatment for MDS have been described.117 A case of SS of the oral cavity with neutrophilic infiltrate revealed the same chromosomal 20q deletion in the neutrophilic infiltrate than in the bone marrow.118

Inflammatory bowel diseases and neutrophilic dermatosis Inflammatory bowel disease is frequently associated with PG (1%-3%), which is often pustular, and most rarely with SS.119,120 PG is more frequent in ulcerative colitis (5%-12%) than in Crohn's disease (1%-2%), and the cutaneous lesions are often more severe and resistant to therapy, requiring more aggressive treatment than in PG not associated with inflammatory bowel disease.121,122 Peristomal PG is a rare variant of PG and is usually seen in patients with ulcerative colitis or Crohn's disease. Effective treatment is important because peristomal PG is

384 extremely painful, may interfere with adhesion of the stomal appliance, and may potentially cause loss of the stoma. Systemic corticosteroids are the most common therapy, and several case reports have shown successful treatment with infliximab. Recently, the efficacy of monoclonal antibodies targeting the interleukin (IL)-12/IL-23 has been reported for the treatment of peristomal PG.123 SS is more frequent in patients with Crohn's disease than in patients with ulcerative colitis, and they are gladly pustular with palmoplantar pustulosis.124 Aseptic abscesses syndrome is characterized by deep abscesses with a predilection for the spleen, accompanied by fever, abdominal pain, and a raised leukocyte count. Aseptic abscesses are associated with inflammatory bowel disease in 66% of cases, in particular Crohn's disease. Twenty percent of patients with aseptic abscesses have ND skin lesions primarily PG and SS.125

Rheumatoid disorders Rheumatoid arthritis The recruitment of a large number of activated neutrophils plays an important role in chronic inflammation in RA; thus, neutrophilic disorders with neutrophilic activation are often associated with RA,126 which include PG, EED, SS, pustular panniculitis, and SPD. IL-8, which is able to attract neutrophils and lymphocytes, is elevated in the serum of patients with RA and may play a role in the induction of these neutrophilic conditions. There is no prevalence of seronegative (no circulating rheumatoid factor) or seropositive polyarthritis in the development of PG127: Seropositive RA has been associated with PG, averaging a 12% occurrence (ranging from 4% to 50%) in report series about PG. In the same series, 15% revealed an association with seronegative polyarthritis.26,27,75,128,129 The ulcerative form of PG has been associated with RA and a seronegative polyarthritis.31 One author theorized that PG represents an independent disease and not a cutaneous manifestation of an underlying disease, such as RA.27 This theory is based on the observation that episodes of PG occur during times of stability or remission of such underlying diseases. RA (seropositive or seronegative) is also associated with an entity described for the first time in 1987: rheumatoid neutrophilic dermatosis, characterized by nontender erythematous, urticaria-like papules, plaques, or nodules with lesions often symmetric.130 Vesicular formation may be observed, as well as tense blister formations.131 Finally, there is an association between RA treated by adalimumab (a TNF-α blocker) and palisaded neutrophilic and granulomatous dermatitis.132 Ankylosing spondylitis Ankylosing spondylitis is known to be associated with SS.133 One patient had Crohn's disease and ankylosing spondylitis with skin lesions of SS with a psoriasiform aspect.134 A case of anterior chest wall arthritis and

L. Prat et al. clavicular osteomyelitis associated with SPD showed that ND skin lesions in ankylosing spondylitis may be involved in a broad spectrum of lesions including the so-called SAPHO syndrome.135

Pathophysiology, perspectives, and conclusion Currently, the pathophysiology of ND is poorly understood, but the current knowledge of ND suggests that they should be categorized within the spectrum of “polygenic” autoinflammatory diseases. The exact term autoinflammatory disease encompasses an enlarging group of inflammatory disorders defined as Mendelian genetic diseases (monogenic diseases) of the innate immune system that involves mutations in molecular platforms called inflammasomes, resulting in an excessive inflammatory cytokine production by the innate immune cells (in particular, IL-1) in response to danger signals. The neutrophilic disease shares many clinical features of monogenic inflammatory disorders including fever, arthralgias, and neutrophilic infiltration of the skin and visceral organs. Several monogenic inflammatory diseases have clinical features that include DN skin lesions or aseptic neutrophilic visceral involvement. The PAPA syndrome (pyogenic sterile arthritis, PG, acne) is an autosomal dominant autoinflammatory disorder due to a mutation in the PSTPIP1 gene and presents with typical PG lesions.136 The acronym PASH syndrome was recently proposed in patients with a clinical triad of PG, acne, and suppurative hidradenitis.137 This syndrome belongs to the group of autoinflammatory diseases, although no specific mutation of a gene involved in the innate immune system was found in these patients. The presence of an autosomal recessive form of CRMO with SS lesions, the Majeed syndrome, caused by mutations in the LPIN2 gene, is in favor of SS and CRMO belonging to the spectrum of polygenic autoinflammatory diseases.138 Inflammatory diseases in which selective mutations of genes implicated in the innate immune system increases the risk for development of the disease were called polygenic autoinflammatory diseases. The best example is Crohn's disease, in which selective mutations of the NOD2/CARD15 gene (a gene mutated in a monogenic inflammatory disease called Blau syndrome) increased by far the disease susceptibility.139,140 DN are frequently associated with Crohn's disease. The extreme efficacy of IL-1 blocking therapies in some autoinflammatory monogenic diseases (cryopirin associated periodic syndrome, deficiency of IL-1 receptor antagonist syndrome) suggests that the efficacy of IL-1 blocking therapies may be a diagnostic criterion for an autoinflammatory disease). Although corticosteroids remain the mainstay treatment for most ND, the efficacy of IL-1 blocking agents (anakinra) in neutrophilic panniculitis141 and in SS142 has been recently published. If DN has no hallmark of an autoimmune disorder (absence of detectable autoantibodies

Neutrophilic dermatoses and absence of an antigen-specific T cell response), some recent findings may, however, also implicate the adaptive immune system in its pathogenesis. For example, cytokines implicated in T cell polarization such as IL-17 have been found overexpressed in ND skin lesions,143 and a recent contribution reported the possible efficacy of anti–IL-12/ IL-23 antibodies in refractory cases of ND,144 reflecting the possible complexity of ND mechanism. We could also speculate that IL-6 may also be a potential target for the treatment of ND. IL-6145 indeed is a key cytokine for the development of myeloma, and IL-6 blocking agents (tocilizumab) have been approved for the treatment of RA, and these two diseases may be associated with ND. In conclusion, the clinician should be aware that ND may be important clinical signs of an underlying systemic disorder and that the systemic symptoms that occur in the setting of a well-proven ND may reveal neutrophil infiltration of a “systemic” organ.

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multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet. 2005;42:551-557. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599-603. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411: 603-606. Lipsker D, Perrigouard C, Foubert A, et al. Anakinra for difficult-totreat neutrophilic panniculitis: IL-1 blockade as a promising treatment option for neutrophil-mediated inflammatory skin disease. Dermatology (Basel). 2010;220:264-267. Kluger N, Gil-Bistes D, Guillot B, et al. Efficacy of anti-interleukin-1 receptor antagonist anakinra (Kineret®) in a case of refractory Sweet’s syndrome. Dermatology (Basel). 2011;222:123-127. Marzano AV, Cugno M, Trevisan V, et al. Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases. Clin Exp Immunol. 2010;162:100-107. Guenova E, Teske A, Fehrenbacher B, et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab. Arch Dermatol. 2011;147:1203-1205. Hitzler JK, Martinez-Valdez H, Bergsagel DB, et al. Role of interleukin-6 in the proliferation of human multiple myeloma cell lines OCI-My 1 to 7 established from patients with advanced stage of the disease. Blood. 1991;78:1996-2004.

Clinics in Dermatology (2014) 32, 389–396

Acne as a chronic systemic disease Christos C. Zouboulis, MD, PhD ⁎ Departments of Dermatology, Venereology, Allergology, and Immunology, Dessau Medical Center, Auenweg 38, 06847 Dessau, Germany

Abstract Acne is the most common skin disorder. In the majority of cases, acne is a disease that changes its skin distribution and severity over time; moreover, it can be a physically (scar development) and psychologically damaging condition that lasts for years. According to its clinical characteristics, it can be defined as a chronic disease according to the World Health Organization criteria. Acne is also a cardinal component of many systemic diseases or syndromes, such as congenital adrenal hyperplasia, seborrhea-acne-hirsutism-androgenetic alopecia syndrome, polycystic ovarian syndrome, hyperandrogenism-insulin resistance-acanthosis nigricans syndrome, Apert syndrome, synovitis-acne-pustulosishyperostosis-osteitis syndrome, and pyogenic arthritis-pyoderma gangrenosum-acne syndrome. Recent studies on the Ache hunter gatherers of Paraguay detected the lack of acne in association with markedly lower rates of obesity, diabetes mellitus, hyperlipidemia, and cardiovascular diseases, a finding that indicates either a nutritional or a genetic background of this impressive concomitance. © 2014 Elsevier Inc. All rights reserved.

Introduction Acne is the most common skin disease and also the lead diagnosis in medicine1; however, it is widely considered to be a simple, self-limited disorder of adolescents. The majority of lay people, as well as many physicians, believe that treatment of acne is only required in extreme cases. Unfortunately, not only successful acne treatment can become difficult but acne, itself, can be a devastating disease for the patient, both because it manifests on visible body parts of children and adolescents, who are vulnerable both socially and psychologically, but also because it can heal with considerable scar sequelae.1 The pathogenesis of acne is dominated by up-regulation of inflammatory signaling in skin epithelial cells, leading to excessive sebum production and hyperproliferation/hyperkeratosis of the infrainfundibulum of the sebaceous follicles.2–5 Hypercolonization of the sebaceous follicles with ⁎ Corresponding author. Tel.: + 49 340 5014000; fax: + 49 340 5014025. E-mail address: [email protected]. 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.005

Propionibacterium acnes, a commensal bacterium, has been considered as an additional pathogenetic factor.6 Several cellular or animal models are used for acne research6–15; nevertheless, there is no single cellular or animal model that encompasses all the pathogenic factors and their interactions in acne formation, which is a genuine human disease.

Acne is a chronic disease In most cases, acne is not an acute disease but rather a condition that continuously changes in its distribution and severity.1 Treatment of acne is usually necessary for months to, sometimes, years, and mostly, acne may cause scarring and associated negative psychological effects despite treatment. It is important for dermatologists to educate other clinicians and patients that acne is a chronic disease1,16 and not just a self-limited disorder of teenagers. For many patients, acne has characteristics that the World Health Organization (WHO) has used to define chronicity of diseases: A prolonged course, a pattern of recurrence or

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Fig. 1 WHO criteria for classifying acne as a chronic disease (after Gollnick et al.).1 Comparison of acne and atopic dermatitis, a widely accepted chronic disease, reveals striking similarities.

relapse, manifestation as acute outbreaks or slow onset, and a psychological and social impact that affects the individual’s quality of life16,17 (Figure 1). There is wide evidence that acne can be a physically (scar development) and psychologically damaging condition that lasts for years,18–24 even, if there is not always correlation with the clinician’s assessment of severity at one point in time.1,25 In addition, there is evidence that acne can persist into adult years in as many as 50% of individuals.19,26–29

Acne as a manifestation of systemic diseases Acne is an essential component of many systemic diseases or syndromes, 30 among them (1) congenital adrenal hyperplasia (CAH), (2) seborrhea-acne-hirsutismandrogenetic alopecia (SAHA) syndrome, (3) polycystic

ovarian syndrome (PCOS), (4) hyperandrogenism-insulin resistance-acanthosis nigricans (HAIR-AN) syndrome, (5) synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome, (6) pyogenic arthritis-pyoderma gangrenosumacne (PAPA) syndrome, and (7) Apert syndrome.

CAH CAH (OMIM 201910) represents a heterogeneous group of autosomal inherited enzymatic defects in the biosynthetic pathway of cortisol and/or aldosterone.31 21-hydroxylase (21-OH) deficiency due to mutations in the 21-hydroxylase gene (CYP21, 6p21.3) is the most common defect (95%).32 Cortisol deficiency results in oversecretion of adrenocorticotropic hormone (ACTH), and overstimulation and hyperplasia of the adrenals, via the impaired cortisol-mediated

Fig. 2 A female patient with acne due to nonclassical CAH before (A) and after treatment with prednisolone 5 mg/d orally over 6 months (B) (after Zouboulis and Piquro-Martin).38

Acne as a systemic disease negative feedback control of ACTH secretion from the anterior pituitary. Androgen excess affects the pilosebaceous units, resulting in androgenic alopecia, hirsutism, and acne. Classic CAH (complete loss of enzyme function), presenting in the neonatal period, occurs in 1/15,000 births, while late onset nonclassic CAH is more frequent, affecting 1% of the general population.33 Acne and hirsutism are the major skin manifestations of CAH and usually develop during adolescence. Classic CAH clinical manifestations, such as virilization, impaired fertility, short stature, early appearance of facial/axillary/pubic hair, and acne, are more severe. 31,34 Nonclassic CAH is also associated with hyperandrogenic manifestations, such as severe acne refractory to treatment, hirsutism, androgenic alopecia or seborrhea, but also with irregular menses and polycystic ovaries.35–37 The determination of 17-hydroxyprogesterone, the immediate substrate for 21-OH, is used for biochemical diagnosis.35 For mild nonclassical CAH with normal basal adrenal steroids, the ACTH stimulation test is recommended. Oral glucocorticoids and/or fludrocortisone reduce increased androgen production in CAH.33 The treatment of nonclassical CAH is symptom-associated. Low-dose prednisolone (2.5-5 mg/day; Figure 2) or low-dose dexamethasone (0.250.75 mg) can be administered orally at bedtime.31,38

SAHA syndrome The association of seborrhea and acne with hirsutism and/ or androgenetic alopecia in women was defined in 1982 as SAHA syndrome.39 It includes the dermatologic manifestations of androgen excess in women, either on the basis of high circulating androgen levels (hyperandrogenemia) or due to the capacity of the pilosebaceous apparatus to respond with increased sensitivity to normal circulating androgen levels (hyperandrogenism).40,41 The SAHA syndrome is classified into idiopathic, ovarian, adrenal, and hyperprolactinemic types,40 and can be associated with polycystic ovaries, cystic mastitis,

Fig. 3

391 obesity, insulin resistance (IR), and infertility.42 All four major signs of SAHA syndrome are present in approximately 20% of the patients; seborrhea is always present, acne occurs in 10% of the patients, androgenetic alopecia in 21%, and hirsutism in 6% of the patients (Figure 3).40,42,43 Androgen excess in women is one of the most frequent endocrine disorders considered to affect 5% to 10% of them in reproductive age. It can be caused by elevated androgen synthesis in adrenals and ovaries, disturbed peripheral metabolism of androgens or induction of metabolism and activation of androgens in the skin.41 The sebaceous gland is an important organ of active androgen formation, expressing all the necessary enzymes for the de novo biosynthesis of testosterone.2,44 Local androgen excess induces shortening of the follicular anagen phase and progressive conversion of terminal hair to intermediate ones, leading to androgenic alopecia45; moreover, up to 50% of the total circulating testosterone in women is produced in the skin and in other peripheral organs. The diagnosis of SAHA syndrome requires a complete history, physical examination with emphasis on evidence of androgen excess and—in the presence of hyperandrogenemiaassociated signs—laboratory investigations, including dehydroepiandrosterone sulphate, testosterone, prolactin, and 17-OH-progesterone to exclude hyperandrogenemia.3,40 Treatments for the dermatologic conditions of hyperandrogenism include lifestyle modification, oral contraceptives, hormonal antiandrogens, and insulin-sensitizing medications.46

PCOS The PCOS (OMIM 184700) is a complex endocrine disorder affecting 5% to 20% of women depending on their ethnical background. It is characterized by clinical and/or biochemical evidence of hyperandrogenism with oligo- and/ or anovulation and polycystic ovaries.47 Hyperandrogenemia and altered gonadotropin secretion, as well as IR, are involved in its pathogenesis. There is accumulating evidence for a strong genetic background of PCOS.48,49 A clear

SAHA syndrome with acne and hirsutism, signs of hyperandrogenism, without hyperandrogenemia.

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relationship with obesity-associated genes has recently been shown.50 Women with PCOS frequently suffer from infertility, acne, hirsutism, and alopecia.42 Acne is detected in about 23% to 35% of patients with PCOS, while the prevalence of PCOS in the acne group was estimated to be 27% or even higher. Women with severe acne, late onset acne, persistent acne, and acne resistant to conventional therapies are likely to have PCOS. Clinical examination hormonal examinations are mandatory for making the diagnosis.47 Gynecological examination routinely includes ovarian ultrasound, ovulation tests, and the validation of a menses calendar. Lifestyle intervention, insulin sensitizers (metformin), and oral contraceptives are the most common therapeutic approaches for the management of PCOS. In case that family planning is not an issue for the patients, oral contraceptives with an established antiandrogen efficacy can help to control both androgen levels and skin symptoms and hirsutism.46,47

The primary abnormality in patients with this syndrome is supposed to be IR with a compensatory elevation in insulin levels, which may have a direct short-term effect on the regulation of steroidogenesis in ovaries, leading to a subsequent overproduction of androgens.52 Hyperinsulinemia and hyperandrogenemia together stimulate epithelial proliferation and melanin accumulation and result in the cutaneous manifestation of AN. The binding of insulin to insulin receptors and insulinlike growth factor (IGF)-receptors on keratinocytes and fibroblasts leads to epidermal thickness, which probably induces formation of the AN lesions.53 The enhanced lipogenesis of the sebaceous gland caused by IGF-1 may indirectly lead to oily skin and acne formation in patients with HAIR-AN syndrome. A mutation in the fibroblast growth factor receptor 3 was recently reported to be associated with AN, hyperinsulinemia, and skeletal dysplasia.54 Current management of HAIR-AN syndrome resembles that of SAHA and PCOS.51,52

HAIR-AN syndrome

SAPHO syndrome

HAIR-AN is the acronym for hyperandrogenism, IR, and acanthosis nigricans (AN). HAIR-AN syndrome can be considered as a unique subtype of PCOS in women.51 Patients with the disorder usually present with clinical signs of hypandrogenemia, such as seborrhea, acne, hirsutism, menstrual irregularities, androgenic alopecia, deepening of voice, clitoromegaly, and changes in muscle mass, plus IR with diabetic symptoms, as well as AN (Figure 4). Five percent of women with hyperandrogenemia, are considered to have this condition.52 Generally, these patients have markedly elevated insulin levels, elevated or high-normal levels of testosterone and androstenedione, but normal levels of luteinizing hormone and prolactin. Adrenal function is normal.

The acronym SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) defines a syndrome, which was first described in 1987.55 It is a rare, probably underrecognized, disease with an estimated prevalence probably no greater than 1/10,000.30 It primarily affects children and young adults. 56 Three diagnostic criteria for this syndrome have been proposed: (1) chronic recurrent multifocal osteomyelitis with or without skin manifestations; (2) acute or chronic sterile arthritis associated with either pustular psoriasis or palmoplantar pustulosis or severe acne; and (3) sterile osteitis in the presence of one of the skin manifestations. Any of these three presentations is sufficient for diagnosis of this syndrome.57

Fig. 4

HAIR-AN syndrome presenting with papulopustular acne and hirsutism on the face, indicating a manifesting hyperandrogenemia.

Acne as a systemic disease SAPHO syndrome is characterized by a rheumatoid factor-negative osteoarthropathy and various dermatologic manifestations, such as acne/hidradenitis suppurativa/dissecting folliculitis of the scalp, psoriasis/pustular psoriasis/ palmoplantar pustulosis, Sweet’s syndrome, SneddonWilkinson disease, and pyoderma gangrenosum. The clinical presentation of acne varies greatly, from mild to severe type, such as acne conglobata or acne fulminans. These dermatologic conditions may occur concomitantly but may also precede or follow bone involvement.58 A long-term followup study of 120 confirmed cases showed 55% of patients with palmoplantar pustulosis, 31% with psoriasis vulgaris, and 25% with severe acne, whereas 16% patients did not exhibit skin manifestations.58 Association with inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, has been reported. The pathogenesis of SAPHO syndrome remains poorly understood. Current results support the view that SAPHO syndrome may be triggered by an infectious state, leading to strong humoral and cellular inflammatory responses.59 Treatment experience of SAPHO syndrome is limited, mainly based on limited experiences in treating small groups of patients.60

PAPA syndrome The clinical triad of pyogenic sterile arthritis, pyoderma gangrenosum (PG), and acne conglobata was noted in several families and described with the acronym PAPA syndrome (OMIM 604416) in 1997.61 In 2002, the gene of CD2-binding protein 1 (CD2BP1; also called proline/ serine/threonine phosphatase-interacting protein 1, PSTPIP1) on chromosome 15q24–25.1 was identified as the responsible gene.62 PAPA syndrome belongs to the autoinflammatory diseases group, the CD2BP1 protein binds pyrin, which is an inhibitor of the inflammatory process. Because pyrin is expressed on neutrophils, but not on T or B cells, the decreased amount of unbound pyrin results in neutrophilic infiltration in arthritis, acne, PG, and other neutrophilic dermatoses.63 The manifestation of PAPA syndrome with its clinical triad varies in the affected family members. Arthritis is the most consistent sign, followed by acne and PG. Arthritis is the earliest sign occurring between ages 1 and 16 years.63 Being aseptic and seronegative, the pauci-articular, nonaxial arthritis of variable severity commonly affects knees, elbows, and ankles. At puberty, severe nodulocystic acne develops. PG occurs in adolescence or adulthood, usually after the appearance of acne. The transition of PAPA syndrome from inflammatory arthritis to cutaneous manifestations with acne and PG at puberty is notable. Of the triad, PG and acne may be present for decades. PAPA is responsive to systemic or locally administered glucocorticoids. Antimicrobial therapy is not effective. Dapsone can be helpful. Recombinant human interleukin

393 (IL)-1 receptor antagonists have shown efficacy in PAPA syndrome and other autoinflammatory diseases.64

Apert syndrome Apert syndrome (OMIM 101200), also known as acrocephalosyndactyly, was first described in 1906.65 Its prevalence is estimated to be 15/1,000,000, based on a recent population-based study, making up approximately 4% of all cases of craniosynostosis.66 Apert syndrome is inherited in an autosomal dominant manner and is characterized by synostoses of the extremities, vertebrae, and skull, with syndactyly of fingers and toes. Several Apert syndrome patients with acne have been described, having an unusual distribution with lesions extending to the surface areas of the forearms.67 Seborrhea and moderate to severe acne are the dermatologic hallmark of Apert syndrome, which often begins in early puberty.67 Histologic examination exhibits dilated follicular infundibula extending to mid-dermis, follicular abscesses in the upper and mid portions of the corium, and numerous larger sebaceous lobules. Plasma androgen levels and androgen receptor staining of sebaceous glands are normal.68 Two specific heterozygous missense germ-line mutations of the fibroblast growth factor receptor 2 gene (FGFR2) have been identified in patients with Apert syndrome.69 The two detected FGFR2 isoforms and their specific ligands are involved in mesenchymal-epithelial signaling, leading to downstream effects of activated FGFR2-signaling on follicular keratinocyte proliferation, sebaceous lipogenesis, and inflammatory cytokine response.70 In acne of Apert syndrome, FGFR2-mediated up-regulation of phosphoinositol-3 kinase (PI3K)/Akt may result in a nuclear deficiency of the transcription factor FoxO1, recently suggested to be a key transcription factor in the pathogenesis of acne vulgaris.71 The early onset of severe and persistent acne during puberty can be well explained by androgen-dependent up-regulation of fibroblast growth factor synthesis, which activates the mutated FGFR2 receptors; thus, overstimulating FGFR2-mediated downstream signal transduction, leading to a nuclear deficiency of FoxO1. Accumulating evidence supports the view that isotretinoin treatment restores decreased nuclear levels of FoxO1,72 which is in accordance with the excellent response of acne in Apert syndrome to oral isotretinoin treatment.

Dietary lipids and inflammatory process in acne Topically applied linoleic acid was shown to induce an almost 25% reduction in the overall size of microcomedones over a 1-month treatment period.73 Arachidonic acid, an essential, long-chain, proinflammatory ω-6 fatty acid, stimulates IL-8 and IL-6 synthesis in cultured human sebocytes74 and enhances synthesis of sebaceous lipids.75 Leukotriene B4 inhibition in vivo reduces concomitantly proinflammatory

394 sebaceous fatty acids and inflammatory acne lesions.76 The role of nutrition in acne still remains controversial. Inuit Eskimos, the inhabitants of the Okinawa Island, and the Chinese have been observed to develop acne with the changing of their nutrition habits.77 Westernized nutrition includes low amounts of ω-3-fatty acids and antioxidant vitamins and higher amounts of the proinflammatory ω-6 and trans-fatty acids.78 A current study reported that the Kitavan islanders of Papua New Guinea and the Ache hunter-gatherers of Paraguay do not have acne,79 but also present markedly lower rates of obesity, diabetes mellitus, hyperlipidemia, and cardiovascular diseases; however, other authors have suggested that these population studies may have detected a genetic background rather than a nutritional effect.80

Conclusions The manifestation and involvement of acne in different diseases/syndromes highlight the multifaceted nature of acne. In CAH, as well as SAHA, PCOS, and HAIR-AN syndromes, excessive hormones (in circulation or in situ) and/or exaggerated hormone response via aberrant hormone receptor expression/postbinding response induce the accelerated growth and differentiation of pilosebaceous units. The presence of acne in all syndromes reported above indicates the interplay of androgenic hormones in the pathogenesis.68 In daily medical practice, nonclassical CAH, PCOS, and SAHA syndrome should be excluded in patients with severe acne, acne tarda, acne associated with other signs (alopecia, hirsutism, or obesity), or acne recalcitrant to various therapies, especially in women. Acne accompanied by joint/bone involvement and/or other neutrophilic dermatoses, may be an early sign for SAPHO or PAPA syndrome, especially in a familial occurrence. The manifestation of acne in PAPA and SAPHO syndromes provides further evidence to the argument that acne is a genuine inflammatory disorder.2–5 The specific involvement of sebaceous gland in PAPA syndrome is unique among the so-called autoinflammatory diseases and raises the question of the targeted treatment against IL-1 may also benefit patients with acne.81

Acknowledgment The author thanks Dr. Razvigor Darlenski, Sofia, Bulgaria for his support in the arrangement of the manuscript.

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395 54. Blomberg M, Jeppesen EM, Skovby F, et al. FGFR3 mutations and the skin: report of a patient with a FGFR3 gene mutation, acanthosis nigricans, hypochondroplasia and hyperinsulinemia and review of the literature. Dermatology. 2010;220:297-305. 55. Chamot AM, Vion B, Gerster JC. Acute pseudoseptic arthritis and palmoplantar pustulosis. Clin Rheumatol. 1986;5:118-123. 56. Hayem G, Bouchaud-Chabot A, Benali K, et al. SAPHO syndrome: a long-term follow-up study of 120 cases. Semin Arthritis Rheum. 1999;29:159-171. 57. Kahn MF, Khan MA. The SAPHO syndrome. Baillieres Clin Rheumatol. 1994;8:333-362. 58. Kahn MF, Bouvier M, Palazzo E, et al. Sternoclavicular pustulotic osteitis (SAPHO). 20-year interval between skin and bone lesions. J Rheumatol. 1991;18:1104-1108. 59. Hurtado-Nedelec M, Chollet-Martin S, Nicaise-Roland P, et al. Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. Rheumatology (Oxford). 2008;47:1160-1167. 60. Olivieri I, Padula A, Palazzi C. Pharmacological management of SAPHO syndrome. Expert Opin Investig Drugs. 2006;15:1229-1233. 61. Lindor NM, Arsenault TM, Solomon H, et al. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc. 1997;72: 611-615. 62. 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 Molec Genet. 2002;11:961-969. 63. Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. J Dermatol. 2007;34:601-618. 64. Dierselhuis MP, Frenkel J, Wulffraat NM, et al. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology (Oxford). 2005;44:406-408. 65. Apert E. De l`a acrocéphalosyndactylie. Bull Soc Med Hop (Paris). 1906;23:1310-1330. 66. Boulet SL, Rasmussen SA, Honein MA. A population-based study of craniosynostosis in metropolitan Atlanta, 1989–2003. Am J Med Genet A. 2008;146A:984-991. 67. Solomon LM, Fretzin D, Pruzansky S. Pilosebaceous abnormalities in Apert's syndrome. Arch Dermatol. 1970;102:381-385. 68. 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;18:833-841. 69. Wilkie AO, Slaney SF, Oldridge M, et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995;9:165-172. 70. Melnik BC. Role of FGFR2-signaling in the pathogenesis of acne. Dermatoendocrinol. 2009;1:141-156. 71. Melnik BC. FoxO1-the key for the pathogenesis and therapy of acne? J Dtsch Dermatol Ges. 2010;8:105-114. 72. Melnik BC. Is nuclear deficiency of FoxO1 due to increased growth factor/PI3K/Akt-signalling in acne vulgaris reversed by isotretinoin treatment? Br J Dermatol. 2010;162:1398-1400. 73. Letawe C, Boone M, Pierard GE. Digital image analysis of the effect of topically applied linoleic acid on acne microcomedones. Clin Exp Dermatol. 1998;23:56-58. 74. Alestas T, Ganceviciene R, Fimmel S, et al. Enzymes involved in the biosynthesis of leukotriene B4 and prostaglandin E2 are active in sebaceous glands. J Mol Med (Berl). 2006;84:75-87. 75. Wrobel A, Seltmann H, Fimmel S, et al. Differentiation and apoptosis in human immortalized sebocytes. J Invest Dermatol. 2003;120:175-181. 76. Zouboulis CC, Nestoris S, Adler YD, et al. A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor. Arch Dermatol. 2003;139:668-670. 77. Steiner PE. Necropsies on Okinawans; anatomic and pathologic observations. Arch Pathol (Chic). 1946;42:359-380. 78. Simopoulos AP. Evolutionary aspects of diet and essential fatty acids. World Rev Nutr Diet. 2001;88:18-27.

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Clinics in Dermatology (2014) 32, 397–408

Hidradenitis suppurrativa (acne inversa) as a systemic disease Clio Dessinioti, MD ⁎, Andreas Katsambas, MD, Christina Antoniou, MD Department of Dermatology, A. Syggros Hospital, University of Athens, Athens, Greece

Abstract Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic follicular occlusive skin disorder characterized by recurrent abscesses, draining sinuses, and scarring, with a multifactorial pathogenesis. The answer to the question whether HS may be considered a systemic disease relies on the presence of accompanying systemic manifestations, on the proof of association with other diseases or conditions, and on the occurrence of systemic implications. We address these questions based on a systemic review of the existing literature. There are several reports in the literature of the coexistence of HS with other diseases, including pyoderma gangrenosum, PASH syndrome, Adamantiades-Behcet’s disease, spondylarthropathy, Crohn’s disease, SAPHO, pachyonychia congenita, Dowling-Degos disease, and the keratitis-ichthyosis-deafness (KID) syndrome. Case series exist only for Crohn’s disease, while most other reports are anecdotal, thus, not providing high-quality scientific evidence. Based on well-designed studies, HS has been associated with the metabolic syndrome and with excess body weight or obesity. The link between HS and systemic associations may be attributed to common genetic or environmental factors or shared inflammatory pathways. © 2014 Elsevier Inc. All rights reserved.

Introduction The term hidradenitis is derived from the Greek words hidros meaning sweat and adenas meaning gland. The German philosopher Karl Marx was thought to be affected by HS1. In 1839, the first clinical description of hidradenitis suppurativa (HS), as a distinct disease, was made by Velpeau, and in 1854, the French surgeon Verneuil coined the term hidradenitis suppurativa, relating the disease to the apocrine sweat glands. Apocrine sweat glands empty their content into the follicular canal, just above the sebaceous gland duct, in contrast to eccrine sweat glands that empty their ducts directly onto the skin surface. In 1989, Plewig and Steger proposed the term acne inversa.2 The term acne inversa is based on the infundibular ⁎ Corresponding author. Tel.: 00302107265259; fax: 00302107258476. E-mail address: [email protected] (C. Dessinioti). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.006

hyperkeratosis seen in terminal follicles in HS that parallels the infundibular hyperkeratosis of the pilosebaceous unit in acne vulgaris3; however, HS is not a type of acne. In HS, there are no closed comedones, as it is the deep and not the superficial part of the follicle that is affected.4 Also, hyperseborrhea and/or sebum lipid changes are not noted in HS, whereas they have prominent roles in the pathogenesis of acne. Similar frequency, density, and pattern of active sebaceous glands were found in HS patients and controls, and there was no significant facial, axillary, or genital seborrhea.5 Hidradenitis suppurativa (acne inversa) is a chronic inflammatory skin disorder characterized by recurrent, painful nodules, abscesses, and draining sinuses, with resultant scarring.6 Hidradenitis suppurativa mainly affects the intertriginous body areas including the axillae, the inguinal folds, the anogenital, the perineum, the inframammary regions, and the nape. Although HS was considered a rare disease in the past, its prevalence has

398 been estimated to be 1% to 4%.6 HS presents as a sporadic or familial form. It typically presents after puberty with an average age of onset in the second or third decade of life.5 The man:woman ratio is 1:2.7 to 1:3.3.7,8 A populationbased study in Omsted County, Minnesota, reported an overall annual age- and sex-adjusted incidence of HS of 6.0 per 100,000 person-years [95% confidence interval (CI): 5.2–6.7] during 1968–2008. The incidence was significantly higher among women than among men, with 8.2 per 100,000 (95% CI: 7.0–9.3) and 3.8 per 100,000 (95% CI: 3.0–4.7), respectively (P b .001).9 The answer to the question whether HS may be considered a systemic disease relies on the presence of accompanying systemic manifestations, on the proof of association with other diseases or conditions, and on the occurrence of systemic implications. We address these questions based on a critical appraisal of the existing literature. We have searched the English literature in MEDLINE, EMBASE, and Cochrane libraries for publications, from 1950 to May 2013, with the terms hidradenitis suppurativa and acne inversa in association with the following terms: comorbidities, systemic disease, Crohn’s disease, and inflammatory bowel disease. Based on existing literature, we included in our search the terms Fox-Fordyce disease, Adamantiades-Behcet disease, Complex regional pain syndrome type 1, pachyonychia congenita, SAPHO syndrome, PASH syndrome, spondyloarthropathy, follicular tetrad, Interstitial keratitis, KID syndrome, Dowling-Degos disease, and SCC, to search for updated reports for these possible associations. Results are discussed in the following sections.

Cutaneous characteristics The predilection of HS for hair-bearing skin sites and, especially, for body regions with apocrine sweat glands, as well as the histopathologic observation that the earliest involvement of HS occurs in and around of the distal hair follicle (HF) outer root sheath (ORS) have led to the suggestion that HS is a disease arising from the distal HF epithelium. 10 Histologically, HS is characterized by hyperkeratosis, follicular occlusion, perifolliculitis, apocrinitis and/or sinus tract formation, fibrosis, and a dense inflammatory cell infiltrate with neutrophils in the acute phase of the disease11; however, during the diagnostic approach of an HS patient, a biopsy and histology are not necessary, except for excluding another suspected disease. The diagnosis of HS is based exclusively on clinical grounds, and the following three criteria must all be met for establishing diagnosis: (1) the presence of typical lesions, including deep-seated painful nodules, and/or abscesses, and/or draining sinuses, and/or bridged scars; (2) typical topography, with predominant involvement of

C. Dessinioti et al.

Fig. 1 Hurley stage I: Single or multiple nodules/abscesses without sinus tracts or cicatrization. Characteristic pseudocomedones are noted in this patient.

the axillae and groin; and (3) chronic course with multiple recurrences.4,12 The primary HS lesions include painful nodules and/or abscesses (Figures 1-3). The secondary lesions include chronic sinus formation with intermittent release of serous, foul smelling (due to anaerobic colonization) discharge, hypertrophic scars, and open pseudocomedones. There are no closed comedones.13 The distribution pattern of HS corresponds with the “milk line” distribution of apocrinerelated mammary tissue in mammals.5 The disease severity is determined with the Hurley stage14 and/or the Sartorius score.15 There is no fever or significant associated laboratory findings.5 There is considerable clinical intrapatient heterogeneity as far as the predominant lesions or the sites of involvement are concerned and locations appear to have sexual predilection. Axillary, upper torso, groin, or thigh involvement is more common in women, while perianal or perineal disease is more frequent in men.9 The ratio of man:woman differs by body region, with women presenting most commonly having involvement of the axillary or inguinal areas (2:5) and the mammary area (1:14), while perianal HS is more common in

Fig. 2 Hurley stage II: Recurrent abscesses with tract formation and cicatrization. Widely separated lesions.

Hidradenitis suppurativa as a systemic disease

Fig. 3 Hurley stage III: Diffuse involvement, multiple interconnected tracts and abscesses across entire area.

men (5:1).16 A cross-sectional study of 618 patients with a median age of 31 years old, reported that the median age of HS onset was 20 years old and the median HS duration was 9 years. The majority of patients were smokers, either current (72.8%) or past smokers (10.4%). Patients were classified in three HS phenotypes (classes) with distinct characteristics. In particular, the axillary-mammary class was the more common type (48%) with high prevalence of breast and axillae involvement and of hypertrophic scars. The follicular class (26%) was characterized by all lesion types and mainly by follicular lesions, mainly epidermal cysts, pilonidal sinus, and by severe acne. The gluteal class was characterized by gluteal involvement, follicular papules, and folliculitis. In comparison with the axillary-mammary class, the follicular class was characterized by higher proportions of men

399 (OR:4.6, 95% CI: 3–7, P b .001), current/former smokers (OR:2.2, 95% CI:1.3–3.9, P = .005), greater disease severity (Sartorius and Hurley), earlier disease onset, and longer disease duration. The gluteal class was characterized by patients that were more often smokers, had lower body mass index (BMI) values and less severe disease despite a longer disease duration compared to the “axillary-mammary” class. The question remains whether these distinct phenotypes are associated with distinct biological, physiological, or genetic patterns.7 The frequency of disease appearing at specific anatomical sites might be likely to reflect the absolute number or density of apocrine sweat glands. Apocrine glands are densely located in the axilla, sparser in the groin and perineum, and least evident in perianal and mammary regions. The male predilection for perianal disease may be attributed to gender differences in the density of perianal apocrine glands, although other local factors may also be implicated.16

Pathophysiology and pathology of HS The pathogenesis of HS is complex and it remains unclear. Genetic factors, hormones, smoking, obesity, bacterial infection, and alteration of antimicrobial peptides (AMPs) that regulate cutaneous innate immunity, have been implicated in the multifactorial pathogenesis of HS (Figure 4).17 In HS, the primary event is increased outer root sheath (ORS) keratinocyte proliferation with subsequent

Fig. 4 Schematic pathophysiology of HS. KC, Keratinocyte; HF, Hair follicle; ASG, Apocrine sweat gland; hBD, Human b-defensin; dashed lines, Possible implication, still in hypothesis; solid line, Reported implication in published studies.

400 follicular occlusion and occlusion of the apocrine sweat gland.4,18 This is followed by rupture of the follicular canal and extrusion of contents, including corneocytes, bacteria, sebum, and hair follicles, into the surrounding connective tissue, and the development of an inflammatory infiltrate.17,10 In a total of 94 operative specimens from 60 patients with HS, hyperkeratosis of the terminal follicles was found in 82% (77⁄94) of the cases. Hyperplasia of follicular epithelium was evident in 77% (72⁄94), and pronounced perifolliculitis was observed in 68% (64⁄94) of the cases. Follicle ruptures, in contrast, were only found in 28% (26⁄94) of the tissue samples.3 The mechanism by which follicular plugging occurs in acne is not known; various candidates are genetic alterations in the γ-secretase/Notch pathway, and alterations of innate immunity. Decreased Notch signaling, due to loss-of-function mutations in the γ-secretase genes, is hypothesized to play a key role in the pathogenesis of familial and nonfamilial HS via aberrant trichilemmal keratinization. Familial HS [Online Mendelian Inheritance in Man (OMIM) 142690] is an autosomal dominant disease with genetic heterogeneity. An autosomal dominant inheritance in UK patients was first reported by Fitzsimmons et al, in 1985,19 a finding that was later confirmed by von der Werth et al.20 Thirty-four percent of first-degree relatives of probands also had HS.19 The genetic locus responsible for HS was located at chromosome 1p21.1-1q25.3 by genome-wide linkage scan in a fourgeneration Chinese family.21 This is a 73-Mb chromosome region containing nearly 900 genes. Mutations in the NCSTN gene (1q22-23) has been identified in Chinese families with HS, and familial HS in Japanese patients while it was not found in nonfamilial HS.6,22,10,23 NCSTN encodes Nicastrin, which is an essential subunit of γ-secretase complex. γSecretase is a transmembrane protease that mediates intramembranous cleavage of Notch. Notch is a highly conserved and ubiquitous signaling system that regulates cell fate determination and alterations in the Notch pathway lead to epidermal and follicular abnormalities in mouse skin that are histopathologically similar to those observed in human HS. A study of seven London families with HS that showed an autosomal dominant inheritance pattern failed to detect any pathogenic γ-secretase mutations in five of the seven families.24 It is still unclear whether the phenotype of familial cases differs from apparently sporadic cases of AI, some of which may be accounted for by incomplete penetrance. Among 48 UK HS patients, three variants in NCSTN were detected in three patients with nonfamilial HS. The authors proposed that germ line mutations of γsecretase are confined in a minority of patients and additional, and as yet unknown, genes may predispose to HS.25 Further research will investigate the genetics of HS in the European patient population and genotype–phenotype studies are important to associate disease phenotypes with potential mutations in the whole γ-secretase–Notch pathway.26

C. Dessinioti et al. The role of smoking was studied in a population-based case-control study (67 self-reported HS patients, 200 ageand sex-matched controls) and a clinic-based case-control study (302 HS patients, and 906 age- and sex-matched controls). Compared to controls, in self-reported patients and in multivariate analysis, current smoking remained significantly associated with HS (OR:4.16, 95% CI: 2.99-8.69). Compared to controls, in the medically assessed patients, HS was significantly associated with current smokers (OR:12.55, 95% CI:8.58-18.38).27 A total of 251 HS patients were included in the study and among them 99 patients with HS were clinically evaluated. Of the 249 patients who answered the question about smoking 173 (70%) were smokers, 37 (15%) former smokers, and 39 (16%) nonsmokers. Only one of 34 men was a nonsmoker compared with 38 of 215 women. On average, the patients were overweight, with a mean ± SD BMI of 28.3 ± 6.5 kg m- 2). There was more severe HS in smokers compared to nonsmokers (P = .032), as evaluated by the Hidradenitis Suppurativa Score.28 The effect of nicotine on the skin of HS patients compared to controls showed a significantly thicker epidermis in the presence of nicotine. This finding correlated with the production of nonneuronal acetylcholine in the skin, as suggested by an increased expression of acetylcholine receptors found around the follicular infundibulum in the epidermis of HS patients.10 Hormonal factors have been implicated in the pathogenesis of HS. One study found no difference in androgenism (acne, hirsutism, and irregular menstrual periods) between 70 woman HS patients and 100 healthy controls.29 It has been stated that the usual absence of clinical signs of virilism, the normal levels circulating androgens, the absence of hyperseborrhea, and the limited effect of antiandrogen treatments rule out a key role of hyperandrogenism.13 Although the verdict is still out, it has been proposed that bacteria play a secondary rather than a primary role in HS.5 The observation of many bacterial species, including Streptococcus viridans, Staphylococcus aureus, S milleri, anaerobes ( Peptostreptococcus species, Bacteroides melaninogenicus, and B corrodens), coryneform bacteria, and Gram-negative bacteria, such as Escherichia coli, Klebsiella, and Proteus, and no dominant single species, suggests that bacteria found on the surface of HS lesions are secondary colonizers rather than etiologic agents.5 A study involving an aspiration technique to sample deeper parts of early HS lesions clearly showed negative cultures in 51% of the cases, suggesting that HS is primarily a disease of the follicular epithelium that is secondarily colonized and infected by bacteria30; however, the persistence of bacteria frequently found in chronic and relapsing HS may contribute to flares of the disease.31 A disturbance of the cutaneous innate immune system has been implicated in the follicular occlusion and the inflammation of HS. Innate immunity provides the first line of defense against foreign microorganisms. AMPs exhibit antimicrobial and immunomodulatory functions, and they

Hidradenitis suppurativa as a systemic disease promote keratinocyte differentiation and/or proliferation.32 The majority of AMPs is expressed by epithelial cells, such as keratinocytes (human β–defensin [HBD]-3, ribonuclease [RNase] 7, and psoriasin) or by epithelial appendages, such as eccrine sweat glands (dermcidin), whereas α–defensins human neutrophil peptides 1 to 3 and human cathelicidin LL37 are contained within or secreted by circulating leukocytes.31 Innate immune markers were studied with immunohistochemistry in biopsies from 12 patients with HS, from both normal (uninvolved) skin and from inflammatory nodules. Skin biopsies from non-HS individuals were used as controls. The expression of TLR-2, -3, -4, -7, and -9, IL-6, TGF-β, α-MSH, β-defensin 2, β-defensin 4, and IGF-1, was suppressed in involved and uninvolved skin of HS patients compared to controls. Compared to control skin, TNF-α was suppressed in nonlesional HS skin (P b .001), while there was no difference in lesional HS skin (P = .08). Defensins also have antiinfectious properties, and a decrease in defensins may enable the development of bacteria. 18 Similarly, defective immune response was found in the blood of HS patients in another study. Monocytes isolated from healthy controls (n = 6) were more active for the secretion of TNF-α compared to those isolated from HS patients (n = 53).33 Contradictory results have reported significantly increased IL-1β, TNF-α, and IL-10 levels in lesional and perilesional HS skin compared with healthy control skin and psoriatic skin, suggesting that the inflammation is strong in HS skin and providing a rationale for anti-TNF therapy in HS patients.34 The in situ expression of proinflammatory cytokines TNF-α, IL-8, as well as, α-MSH, a potent antiinflammatory neuropeptide, and antimicrobial peptides, such as psoriasin, lysozyme, cathelicidin (LL-37), and hBD3, was studied with immunohistochemistry in biopsies from lesional skin from 18 HS patients compared to 12 controls. There was increased immunoreactivity for LL-37 in the apocrine sweat gland and distal ORS epithelium of inflammatory HS skin (P ≤ .01), psoriasin was increased in the epidermis and distal outer root sheath in inflammatory HS skin, hBD-3 was increased in the epidermis and the distal ORS in HS skin and α-MSH was significantly increased in the epidermis of inflammatory HS skin (P ≤ .01). Compared to controls, TNF-α was increased in the epidermis and the dermis of inflamed HS skin but decreased in the proximal ORS. IL-8 was increased in the epidermis and the ORS of inflamed HS skin.17 It is unclear if the up regulation of AMPs is a primary or a secondary event due to bacterial superinfection.17 The epidermis of HS patients shows signs of hyperplasia35 is well in line with the concept that excessive LL-37 secretion can lead to epithelial hyperproliferation. The observed up regulation of psoriasin and hBD-3 in HS epidermis may also be of relevance to stimulate keratinocyte proliferation and/or differentiation and could, thus, induce follicular hyperkeratinization and subsequent follicular occlusion. Psoriasin stimulates α-defensin and TNFα transcription.17 Up regula-

401 tion of IL-8 expression in HS skin may lead to a vicious circle that promotes neutrophil, mast- and T-cell chemotaxis, activation of NF-κB in neutrophils, macrophages, and neutrophils, are induced by IL-8 to produce more LL-37.17 Elevated levels of tumor necrosis factor (TNF-α) have been found in HS skin.17,34 The expression of AMPs, hBD-3, ribonuclease 7 (RNase 7), psoriasin, and dermcidin, were studied in skin biopsies in 33 patients with HS and in axillary or inguinal biopsy specimens from normal-appearing skin of 6 patients with melanoma undergoing lymphadenectomy. Immunohistochemistry showed increased immunoreactivity of HBD-3 in HS lesions compared to controls. Realtime reverse transcription-polymerase chain reaction (RTPCR) showed HBD-3 mRNA levels were increased in HS of lower severity (grades I and II) compared with controls (P = .046). Interestingly, lesional skin of patients with severe HS (Hurley grade III) clearly showed no significant induction of HBD-3 mRNA expression compared with healthy skin. Also, compared to controls, RNase 7 mRNA levels were significantly lower in HS skin, while there was no difference for psoriasin expression. The authors proposed that reduced HBD-3 inducibility may represent a predisposing factor for severe HS and, therefore, be present in these patients independent of the duration of the disease, or be the result of a secondary inhibition of AMP production due to longstanding disease.31 Another study also recently reported increased HBD-2 and HBD-3 in patients with HS (n = 7) compared with healthy control subjects (n = 8) (P b .0001 and P = .004, respectively)36; however, there were reports of an overexpression of psoriasin in lesional HS skin compared with normal-appearing skin of different locations, ie, of submammary origin or trunk.36,37 These conflicting findings may be explained in part by the fact that psoriasin secretion is dependent on the body location with highest levels secreted on head, hands, and axillae.31 It is tempting to speculate that the recently described deficiency of IL-22 in HS may explain the low psoriasin expression, because IL-22 strongly induces expression of cutaneous AMPs, including psoriasin in vivo.36

Is hidradenitis suppurativa a systemic disease? The answer to the question whether HS could be considered a systemic disease relies on the presence of accompanying systemic manifestations, on the association with other diseases or conditions, and on the occurrence of systemic implications. Not long ago, HS was a neglected, understudied disease. Identified reports on the association of HS with other diseases are summarized in Table 1. Most reports investigating HS rely on isolated case reports or involve a small number of patients providing only descriptive statistics, and

402 Table 1 Disease associated with HS

C. Dessinioti et al. Association of HS with other diseases or syndromes Type of study

Fox-Fordyce disease Case reports Complex regional Case report pain syndrome type 1 Pachyonychia congenita Case series Case report Crohn’s disease Case series Case report Case reports Interview-based pilot study SAPHO syndrome Multicenter study of 12 SAPHO patients Case report Case report PASH syndrome Case report PAPASH syndrome Case reports Pyoderma Case series gangrenosum Case series Interstitial keratitis Case series of 62 HS patients KID syndrome Case reports Dowling-Degos Case reports disease AdamantiadesCase reports BehcSet ́ disease

Number of patients with HS and associated disease 338 139

540 141 2445 246 347 2548 749

150 151 152 253,54 1155 656 457

258,59 860–63,42–44,64 565–69

without having analyzed results for statistical significance. As a result, there are a very small number of studies that may be used for drawing evidence-based conclusions.

Accompanying systemic manifestations Accompanying systemic manifestations that have been described in the context of HS include obesity and hormonal disturbances. Obesity has been associated with HS in more than 75% of cases, and it is considered to participate in the pathophysiology of the disease, as there is more friction and skin contact with adjacent skin surfaces in patients with excessive body weight.5,16 There were a population-based case-control study (67 self-reported HS patients, 200 age- and sexmatched controls) and a clinic-based case-control study (302 HS patients, and 906 age- and sex-matched controls). In selfreported patients, the association with BMI was nearly significant (OR 1.05 for every increase of 1 U of BMI). Compared to controls, in the medically assessed patients, HS

was significantly associated with each increase of 1 U of BMI (OR = 1.12 [1.08-1.15]). The multivariate OR was 2.08 (1.40-3.08) for being overweight and 4.42 (2.82-6.93) for obese.27 Obesity also has been associated with alterations in the hormonal milieu, such as changes in the production, metabolism, and biological activity of androgens and oestrogens.16 A hormonal dependence has been implicated in the pathogenesis of HS based on the observation of a female preponderance and of a HS decline following menopause, the association with polycistic ovary syndrome, and reported hormonal abnormalities.16,70 A disturbance of feedback signaling from peripheral hormones was reported in13 patients, with an exaggerated prolactin and TSH response to TRH71; however, the prevalence of acne, hirsutism, and irregular menses are not more common in HS patients compared to controls13 and most HS patients have normal hormone levels.16

Association of HS with other diseases or conditions There are several reports in the literature of the coexistence of HS with other diseases, including pyoderma gangrenosum, PASH syndrome, Adamantiades-BehcSet ́ disease, spondylarthropathy, Crohn’s disease, SAPHO, pachyonychia congenita, Dowling-Degos disease, and the keratitis-ichthyosis-deafness (KID) syndrome (Table 1)4; however, this does not establish that HS is characterized by systemic involvement, as they could be a serendipitous finding. Isolated case reports of patients with HS and another disease do not provide scientific-based evidence of a link between the two conditions. Association of HS with other diseases should be based on large studies including a large number of patients. Several case reports and studies have suggested an association between HS and CD.72–82,45,83,84,47,85,46 An interview-based study of 158 patients with inflammatory bowel disease (CD or UC), showed that 25 patients (16%) reported a history of “painful boils in the axillae and/or groin,” of whom 17 patients had CD and 8 patients had UC. The authors mentioned that this study was underpowered and so a higher prevalence of HS and IBD in these patients could not established.48 In the largest of these reports, 24 of 61 (39%) HS patients also had a CD diagnosis.45 In most of these cases, CD affected only the large bowel, and its diagnosis preceded that of HS, while diagnosis of HS preceding that of CD has also been reported.45,46 HS affected the perineal and perianal area in all patients and secondary sites in 83% of patients.45 Possible shared pathogenetic factors have been reported in HS and Crohn’s disease. Both are chronic diseases of epithelia, which are inhabited by commensal flora, and common key factors include genetic predisposition, smoking, fistula formation,

Hidradenitis suppurativa as a systemic disease

403

Fig. 5 Association of HS with Crohn’s disease. (A) Numerous fistulas in the inguinal folds in a patient with Crohn’s disease, (B) Hidradenitis suppurativa of the axilla with abscess, fistula, and hypertrophic scarring.

and clinical response to anti-TNF-α therapy.48 Decreased levels of intestinal hBD-2 have also been established as a risk factor for Crohn’s disease, and the protein expression of hBD-2 was significantly lower in the epidermis of HS lesions than in the control skin samples.37 It is important to differentially diagnose cutaneous Crohn’s disease from HS coexisting with Crohn’s disease, although diagnosis may be difficult in cases of HS affecting the perineal region. Additional involvement of the axilla favors a diagnosis of HS (Figure 5) as metastatic Crohn's disease of the skin usually affects the lower extremities. 46 When diagnosis is not certain, a colonoscopy should be performed even in the absence of overt digestive symptoms.13 Pyoderma gangrenosum (PG) has been reported in 17 patients with HS. The authors proposed that PG and HS may represent variant manifestations of cytokine dysregulation by the innate immune system with common etiology.55,56 PAPA syndrome (OMIM 604416) was first described in 1997 as the clinical triad of pyogenic sterile arthritis, pyoderma gangrenosum, and acne. Mutations in the gene of CD2-binding protein 1 (CD2BP1, also called proline-serine-threonine-phosphatase-interactive protein 1, PSTPIP1) (chromosome 15q24-q25.1), have been identified.86,87 Two unrelated patients have been reported with a symptom triad of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH syndrome)52, but with no identified mutations in the PSTPIP1 gene.52 Pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH syndrome) has been described54,53 and associated with a novel mutation of the PSTPIP1 gene.53

It has been proposed that HS belongs to the group of autoinflammatory diseases that are characterized by noninfectious recurrent inflammatory episodes, the absence of autoantibodies and antigen-specific T cells, and the presence of polymorphonuclear cell infiltrates. These disorders include Crohn’s disease (CD), pyoderma gangrenosum, acnelike syndromes, familial Mediterranean fever, tumor necrosis factor-receptor associated periodic syndrome, cryopyrin-associated periodic syndrome, pyogenic sterile arthritis, recurrent multifocal osteomyelitis, and Adaman5 tiades-BehcSet ́ disease. HS of the head and neck has been classified as a member of the follicular triad, together with acne conglobata and dissecting cellulitis of the scalp (perifolliculitis capitis). The follicular occlusion tetrad defines the aforementioned three diseases together with the pilonidal cyst.88 A given patient may have two or more disorders within the tetrad.89,90 Acne conglobata is a rare but severe form of acne comprised of multiple grouped comedones, inflammatory papules, tender, suppurative nodules that commonly coalesce to form sinus tracts on the trunk and arms. Perifolliculitis capitis is a chronic and progressive infection of the hair follicles of the scalp presenting with subcutaneous abscesses. At least eight reports have described the association of HS and Dowling-Degos disease that is a genetic syndrome characterized by acquired, reticulated, symmetric pigmentary macules of the flexural areas.60–63,42–44,64 Two case reports have reported an association of keratitis-icthyosisdeafness (KID) syndrome and HS.58,59 A single case series reported four patients with interstitial keratitis (IK)

404 among 62 HS patients. HS preceded IK by a mean of 7.2 years.57 The association of HS, spondyloarthropathy, and acne conglobata is well described.91–94,54,95–98 This association is seen predominantly in African American men and equally affects the axial and appendicular joints. It has a chronic course, with temporal concurrence between cutaneous and arthritic flare-ups.93 SAPHO syndrome is an acronym for synovitis, acne, pustulosis, hyperostosis, and osteitis. There are three proposed diagnostic criteria: (1) chronic recurrent multifocal noninfectious osteomyelitis with or without skin manifestations; (2) acute or chronic sterile arthritis associated with (a) pustular psoriasis or palmoplantar pustulosis, (b) acne, or (c) HS; (3) sterile osteitis in the presence of the aforementioned skin manifestations. Any of these three presentations is sufficient for diagnosis.87,49,99 In one study, 12 patients with SAPHO from three hospitals were analyzed, with seven having HS as part of the syndrome. Of the seven patients with HS six were African American, suggesting a possible predisposition in that population. HS in the presence of SAPHO may have more severe clinical manifestations compared to HS alone.49 Two additional case reports have been reported.50,51 An association between reflex sympathetic dystrophy or complex regional pain syndrome type 1 and HS has been reported in one patient.39 Five of six family members with Jackson-Lawler type pachyonychia congenita have reported to have a history of HS, with three of them having evidence of nodules, sinus tract formation, and scarring in the axillae. Pachyonychia congenita (PC) is a rare genodermatosis affecting ectodermal development. The Jackson-Lawler subtype is characterized by natal teeth presence, steatocystoma multiplex, and multiple epidermoid cysts on the trunk, axillae, neck, and scalp, in addition to pachyonychia. Palmar and plantar hyperkeratosis and blister development, hyperhidrosis and follicular hyperkeratosis, may also be present.40 A woman with PC and HS has been reported.41 Fox-Fordyce disease (FFD) is a rare pruritic disorder characterized by eruptions of small, discrete, flesh-colored papules located in the axillary, areolar, pubic, and sternal regions. Concurrent HS and FFD has been described in three African American women.38 The association of HS with inflammatory, peripheral oligoarthritis and seronegative spondyloarthropathy has been reported.93 It is hypothesized that the arthropathy may represent a reaction to chronic skin infection. There is a close association between flares of HS and exacerbation, as well as, severity of arthritis. Conversely, improvement of arthritis follows surgical therapy for HS.4 Isolated case reports of patients with Adamantiades65–69 BehcSet ́ disease and HS have been reported. The metabolic syndrome increases the risk of cardiovascular disorders, such as arteriosclerosis, coronary heart disease, myocardial infarction, and stroke. Its diagnosis

C. Dessinioti et al. is based on the presence of three or more of the following criteria, according to the United States National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III)100: (i) central obesity: Waist circumference ≥ 102 cm (men), ≥ 88 cm (women), (ii) hypo-HDL-cholesterolemia: Plasma HDL-cholesterol b 40 mg/dL (men), b 50 mg/dL (women), (iii) hypertriglyceridemia: Plasma triglyceride ≥ 1.695 mmol/l (≥ 150 mg/dL), (iv) hypertension: Blood pressure ≥ 130/85 mmHg or use of medication for hypertension, (v) hyperglycemia: Fasting plasma glucose ≥ 6.1 mmol/L (≥ 110 mg/dL) or use of medication for hyperglycemia. A hospital-based case-control study of 80 HS patients and 100 age- and sex-matched controls, showed that the average waist circumference, plasma TG levels, fasting plasma glucose levels, as well as the systolic and diastolic blood pressure were significantly higher in HS patients than in controls. The prevalence of central obesity (OR:5.88, 95% CI:2.93-11.91, P b .001), hypertriglyceridemia (OR:2.24, 95% CI: 1.11-4.54, P b .014), hypo-HDL-cholesterolemia (OR: 4.56, 95% CI: 2.21-9.46, P b .001), and hyperglycemia (OR:4.09, 95% CI: 1.59-10.84, P b .001) in HS patients were significantly higher than in controls. The metabolic syndrome was significantly more common in the patients than in controls (40.0% versus 13.0%, OR: 4.46, 95% CI: 2.02-9.96, P b .001).101 These results raise the question about the mechanisms underlying the increased frequency of the metabolic syndrome in HS patients. An hypothesis is that chronic inflammation promotes and enhances metabolic alterations; however, the severity and/or duration of disease were not associated with the metabolic parameters or metabolic syndrome in this study, suggesting that the magnitude of inflammation in HS is not associated with the metabolic syndrome. The authors proposed that the metabolic alterations might be the primary rather than a secondary pathologic event in these patients, ie, that they might trigger HS. In fact, the metabolic alterations can lead to poor blood circulation of respective skin areas. Hypoxia in turn induces IL-10 production in CD4 + T-cells, and IL-10 inhibits the production of IL-22, an important inducer of keratinocyte IL-20 production. Since IL-22 and IL-20 are major inducers of antibacterial proteins in epithelia, poor blood circulation would eventually lead to enhanced cutaneous bacterial persistence and the outbreak of AI.101 The link between HS and systemic associations may be attributed to common genetic or environmental factors, or shared inflammatory pathways.102 Having psoriasis, a wellstudied condition, as a paradigm, it has been reported that well established factors for cardiovascular disease (CVD) originate from inflammation in other tissues. Undeniably, inflammation is a risk factor for progressive development of atheroma and other vascular alterations. The profile of

Hidradenitis suppurativa as a systemic disease

405

cytokines in the skin of HS patients has not been well characterized, but there is evidence for overexpression of proinflammatory cytokines such as TNF-α17,34 and IL-8.17. The obesity of psoriasis has emerged as a key link with increased diabetes risk, with the metabolic syndrome, and increase cardiovascular risk. In addition to energy storage and lipid synthesis production, adipose tissue is an active endocrine organ with many secretory products, including adipocyte-derived hormones, adipokines (leptin, adiponectin), and a variety of proinflammatory cytokines, including IL-6 and TNF-α. Although the actions of TNF on adipocytes and monocytes are complex with respect to metabolic regulation, there is experimental evidence that TNF directly regulates insulin secretion and disrupts lipid synthesis, which are the central features of type 2 diabetes and obesity.102 The “obesity of HS” is yet to be unraveled, but the beneficial effect of anti-TNFα therapies in HS suggests an intriguing key role for TNFα in HS as well.

significant malignant associations included buccal cancer and primary liver cancer, but these findings were attributed to confounding by smoking and alcohol abuse.104 There are reports of 65 cases of SCC complicating HS.105 There is a need for studies with vigorous follow-up of HS patients for SCC development to provide data regarding the rate of SCC in these patients. HS has been shown to have a substantial negative impact on the patients’ quality of life and sexual health.106 An association of HS with an impact to the quality of life as assessed by the Dermatology Quality of Life Index (DLQI) has been reported. The basis for this association has been attributed to a combination of painful eruptions, malodorous discharge, stigma due to the location of lesions in intimate sites, and, until recently, the lack of medical care related to incorrect diagnosis or the hesitancy of patients to disclose the symptoms or signs of HS.107 Several studies have mentioned not only physical but also social and economic disabilities resulting from HS.5 One study found that patients with HS lost an average of 2.7 work days per year because of HS.108 A self-administered questionnaire study of 44 patients diagnosed with HS showed a significant impairment in sexual health compared to 41 age- and BMI-matched controls.106 A diagnosis of depression was found in 115 of 268 (42.9%) HS patients in a population-based U.S. study.9 A population-based study in Omsted County, Minnesota, investigated the potential association with other medical disorders. 268 confirmed HS patients were identified using the Rochester Epidemiology Project resources. The majority of these patients had mild HS, with 59.7% patients having Hurley stage I disease, 38.1% had Hurley stage II disease, and 2.2% had Hurley stage III disease. There were no significant associations identified between disease severity and BMI, depression, acne, or pilonidal disease. 9

Occurrence of systemic implications in HS

Conclusions

HS may have systemic implications on the physical, psychological, or sexual health of afflicted patients. There is a risk of serious infection depending on the location of lesions.5 It should be kept in mind that men with perineal fistula, bowel disease, scrotal or penile trauma, or past procedures are generally at increased risk for Fournier gangrene, a localized variant of necrotizing fasciitis caused by facultative and anaerobic organisms.103 Urethral fistulas and massive scrotal and vulvar lymphedema have also been reported in patients with HS.5 In addition, lymphedema of the pubis may develop (Figure 6). A large retrospective study with more than 2,000 subjects revealed that those with HS had a 50% increased risk in overall incidence of malignancy. A 4.6-fold increase in cutaneous SCC was observed in these patients. Other

The question if hidradenitis suppurativa could be considered as a systemic disease remains to be answered. The association of HS with other diseases is mostly based on isolated case reports or small case series failing to provide robust data for such an association. To quote Dr Roger Brinner, “the plural of anecdote is not data.” Based on welldesigned studies, HS has been associated with the metabolic syndrome and with excess body weight or obesity. The link between HS and systemic associations may be attributed to common genetic or environmental factors, or shared inflammatory pathways. HS has systemic implications, as it has been shown to have a substantial negative impact on the patients’ quality of life and sexual health.106 The answer to the question of whether HS is a systemic disease continues to elude us; however, it is a disease with

Fig. 6 Secondary lymphedema of the pubis in a patient with HS stage III.

406 considerable systemic implications for the afflicted patients. Further research in the context of well-designed, controlled studies in adequate number of HS patients is warranted to shed further light on this still understudied condition.

References 1. Shuster S. The nature and consequence of Karl Marx’s skin disease. Br J Dermatol. 2008;158:1-3. 2. Plewig G, Steger M. Acne inversa (alias acne triad, acne tetrad or hidradenitis suppurativa). In: Marks R, Plewig G, eds. Acne and related disorders. London: Martin Dunitz; 1989. p. 345-357. 3. Von Laffert M, Helmbold P, Wohlrab J, et al. Hidradenitis suppurativa (acne inversa): early inflammatory events at terminal follicles and interfollicular epidermis. Exp Dermatol. 2010;19:533537. 4. Fimmel S, Zouboulis CC. Comorbidites of hidradenitis suppurativa (acne inversa). Dermatol Endocrinol. 2010;2:9-16. 5. Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: a comprehensive review. J Am Acad Dermatol. 2009;60:539-561. 6. Liu Y, Gao M, Lv Y, et al. Confirmation by exome sequencing of the pathogenic role of NCSTN mutations in acne inversa (hidradenitis suppurativa). J Invest Dermatol. 2011;131:1570-1572. 7. Canoui-Poitrine F, Le Thuaut A, Revuz JE, et al. Identification of three hidradenitis suppurativa phenotypes: latent class analysis of a crosssectional study. J Invest Dermatol. 2013;133:1506-1511. 8. Revuz JE, Canoui-Poitrine F, Wolkenstein P, et al. Prevalence and factors associated with hidradenitis suppurativa: results from two casecontrol studies. J Am Acad Dermatol. 2008;5:596-601. 9. Vazquez BG, Alikhan A, Weaver AL, et al. Incidence of hidradenitis suppurativa and associated factors: a population-based study of Olmsted County Minnesota. J Invest Dermatol. 2013;133:97-103. 10. Kurzen H, Kurokawa I, Jemec GBE, et al. What causes hidradenitis suppurativa? Exp Dermatol. 2008;17:455-472. 11. Jemec GB, Hansen U. Histology of hidradenitis suppurativa. J Am Acad Dermatol. 1996;34:994-999. 12. Hidradentitis Suppurativa Foundation (HSF). Second International Conference on hidradenitis suppurativa, San Francisco, CA, March 5, 2009. Available from: www.hs-foundation.org. Accessed May 2, 2013. 13. Revuz J. Hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2009;23:985-998. 14. Hurley HJ. Axillary hyperhidrosis, apocrine bromhidrosis, hidradenitis suppurativa, and familial benign pemphigus: surgical approach. In: Roenigk RK, Roenigk HH, eds. Dermatologic Surgery. New York: Marcel Dekker; 1989. p. 729-739. 15. Sartorius K, Lapins J, Emtestam L, et al. Suggestions for uniform outcome variables when reporting treatment effects in hidradenitis suppurativa. Br J Dermatol. 2003;149:211-213. 16. Harrison BJ, Read GF, Hughes LE. Endocrine basis for the clinical presentation of hidradenitis suppurativa. Br J Surg. 1988;75: 972-975. 17. Emelianov VU, Bechara FG, Glaser R, et al. Immunohistological pointers to a possible role for excessive cathelicidin (LL-37) expression by apocrine sweat glands in the pathogenesis of hidradenitis suppurativa/acne inversa. Br J Dermatol. 2012;166: 1023-1034. 18. Dreno B, Khammari A, Brocard A, et al. Hidradenitis suppurativa. The role of deficient cutaneous innate immunity. Arch Dermatol. 2012;148:182-186. 19. Fitzsimmons JS, Guilbert PR, Fitzsimmons EM. Evidence of genetic factors in hidradenitis suppurativa. Br J Dermatol. 1985;113:1-8.

C. Dessinioti et al. 20. Von der Werth JM, Williams HC, Raeburn JA. The clinical genetics of hidradenitis suppurativa revisited. Br J Dermatol. 2000;142:947-953. 21. Gao M, Wang PG, Cui Y, et al. Inversa acne (hidradenitis suppurativa): a case report and identification of the locus at chromosome 1p21.1-1q25.3. J Invest Dermatol. 2006;126:13021306. 22. Wang B, Yang W, Wen W, et al. Gamma-secretase gene mutations in familial acne inversa. Science. 2010;330:1065. 23. Li CR, Jiang MJ, Shen DB, et al. Two novel mutations of the nicastrin gene in Chinese patients with acne inversa. Br J Dermatol. 2011;165: 415-418. 24. Pink AE, Simpson MA, Brice GW, et al. PSENEN and NCSTN mutations in familial hidradenitis suppurativa (acne inversa). J Invest Dermatol. 2011;131:1568-1570. 25. Pink AE, Simpson MA, Desai N, et al. Mutations in the γ-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa). J Invest Dermatol. 2012;132:2459-2461. 26. Ingram JR. The aetiology of acne inversa: an evolving story. Br J Dermatol. 2011;165:231-232. 27. Revuz JE, Canoui-Poitrine F, Wolkenstein P, et al. Prevalence and factors associated with hidradenitis suppurativa: results from two case-control studies. J Am Acad Dermatol. 2008;59: 596-601. 28. Sartorius K, Emtestam L, Jemec GBE, Lapins J. Objective scoring of hidradenitis suppurativa reflecting the role of tobacco smoking and obesity. Br J Dermatol. 2009;161:831-839. 29. Jemec GB. The symptomatology of hidradenitis suppurativa in women. Br J Dermatol. 1988;119:345-350. 30. Jemec GB, Faber M, Gutschik E, Wendelboe P. The bacteriology of hidradenitis suppurativa. Dermatology. 1996;193:203-206. 31. Hofmann SC, Saborowski V, Lange S, et al. Expression of innate defense antimicrobial peptides in hidradenitis suppurativa. J Am Acad Dermatol. 2012;66:966-974. 32. Scott MG, Davidson DJ, Gold MR, et al. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol. 2002;169:3883-3891. 33. Giamarellos-Bourboulis EJ, Antonopoulou A, Petropoulou C, et al. Altered innate and adaptive immune responses in patients with hidradenitis suppurativa. Br J Dermatol. 2007;156(1):51-56. 34. van der Zee HH, de Ruiter L, van den Broecke DG, et al. Elevated levels of tumour necrosis factor (TNF)–α, interleukin (IL)–1α and IL10 in hidradenitis suppurativa skin: a rationale for targeting TNF-α and IL-1α. Br J Dermatol. 2011;164(6):1292-1298. 35. von Laffert M, Stadie V, Wohlrab J, et al. Hidradenitis suppurativa/acne inversa: bilocated epithelial hyperplasia with very different sequelae. Br J Dermatol. 2010;164:367-371. 36. Wolk K, Warszawska K, Hoeflich C, Witte E, et al. Deficiency of IL22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa. J Immunol. 2011;186:1228-1239. 37. Schlapbach C, Yawalkar N, Hunger RE. Human beta-defensin-2 and psoriasin are overexpressed in lesions of acne inversa. J Am Acad Dermatol. 2009;61:58-65. 38. Spiller RF, Knox JM. Fox-Fordyce disease with hidradenitis suppurativa. J Invest Dermatol. 1958;31:127-135. 39. Moroz A, Lee MH, Clark J. Reflex sympathetic dystrophy with hidradenitis suppurativa exacerbation: a case report. Arch Phys Med Rehabil. 2001;82:412-414. 40. Todd P, Garioch J, Rademaker M, Susskind W, Gemell C, Thomson J. Pachyonychia congenita complicated by hidradenitis suppurativa: a family study. Br J Dermatol. 1990;123:663-666. 41. Pedraz J, Penas PF, Garcia-Diez A. Pachyonychia congenital and hidradenitis suppurativa: no response to infliximab therapy. J Eur Acad Dermatol. 2008;22:1500-1501. 42. Loo WJ, Rytina E, Todd PM. Hidradenitis suppurativa, DowlingDegos and multiple epidermal cysts: a new follicular occlusion triad. Clin Exp Dermatol. 2004;29:622-624.

Hidradenitis suppurativa as a systemic disease 43. Weber LA, Kantor GR, Bergfeld WF. Reticulate pigmented anomaly of the flexures (Dowling-Degos disease): a case report associated with hidradenitis suppurativa and squamous cell carcinoma. Cutis. 1990;45:446-450. 44. Fenske NA, Groover CE, Lober CW, Espinoza CG. Dowling-Degos disease, hidradenitis suppurativa, and multiple keratoacanthomas. A disorder that may be caused by a single underlying defect in pilosebaceous epithelial proliferation. J Am Acad Dermatol. 1991;24:888-892. 45. Church JM, Fazio VW, Lavery IC, et al. The differential diagnosis and comorbidity of hidradenitis suppurativa and perianal Crohn’s disease. Int J Colorectal Dis. 1993;8:117-119. 46. Burrows NP, Jones RR. Crohn’s disease in association with hidradenitis suppurativa. Br J Dermatol. 1992;126:523. 47. Ostlere LS, Langtry JA, Mortimer PS, Staughton RC. Hidradenitis suppurativa in Crohn’s disease. Br J Dermatol. 1991;125: 384-386. 48. Van der Zee HH, van der Woude CJ, Florencia EF, Prens EP. Hidradenitis suppurativa and inflammatory bowel disease: are they associated? Results of a pilot study. Br J Dermatol. 2010;162:195197. 49. Steinhoff JP, Cilursu A, Falasca GF, Guzman L, Reginato AJ. A study of musculoskeletal manifestations in 12 patients with SAPHO syndrome. J Clin Rheumatol. 2002;8:13-22. 50. Ozyemisci-Taskiran O, Bolukbasi N, Gogus F. A hidradenitis suppurativa related SAPHO case associated with features resembling spondylarthropathy and proteinuria. Clin Rheumatol. 2007;26:789791. 51. Legrand E, Audran M, Rousselet-Chapeau MC, et al. Iliac osteosarcoma in a patient with SAPHO syndrome. Rev Rhum Engl Ed. 1995;62:139-141. 52. Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)—a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. 2012;66:409-415. 53. Marzano AV, Trevisan V, Gattrno M, et al. Pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH): a new autoinflammatory syndrome associated with a novel mutation of the PSTPIP1 gene. JAMA Dermatol. 2013 http: //dx.doi.org/10.1001/jamadermatol.2013.2907. [Epub ahead of print]. 54. Shenefelt PD. Pyoderma gangrenosum associated with cystic acne nd hidradenitis suppurativa controlled by adding minocycline and sulfasalazine to the treatment regimen. Cutis. 1996;57: 315-319. 55. Hsiao JL, Antaya RJ, Antaya RJ, Berger T, et al. Hidradenitis suppurativa and concomitant pyoderma gangrenosum: A case series and literature review. Arch Dermatol. 2010;146:1265-1270. 56. Ah-Weng A, Langtry JA, Velangi S, et al. Pyoderma gangrenosum associated with hidradenitis suppurativa. Clin Exp Dermatol. 2005;30: 669-671. 57. Bergeron JR, Stone OJ. Interstitial keratitis associated with hidradenitis suppurativa. Arch Dermatol. 1967;95:473-475. 58. Maintz L, Betz RC, Allam JP, et al. Keratitis-ichthyosis-deafness syndrome in association with follicular occlusion triad. Eur J Dermatol. 2005;15:347-352. 59. Montgomery JR, White TW, Martin BL, Turner ML, Holland SM. A novel connexin gene mutation associated with features of the keratitisichthyosis-deafness syndrome and the follicular occlusion triad. J Am Acad Dermatol. 2004;51:377-382. 60. Lookingbill DP. Yield from a complete skin examination. Findings in 1157 new dermatology patients. J Am Acad Dermatol. 1988;18:31-37. 61. Dixit R, George R, Jacob M, Sudarsanam TD, Danda D. DowlingDegos disease, hidradenitis suppurativa and arthritis in mother and daughter. Clin Exp Dermatol. 2006;31:454-456. 62. Li M, Hunt MJ, Commens CA. Hidradenitis suppurativa, Dowling Degos disease and perianal squamous cell carcinoma. Australas J Dermatol. 1997;38:209-211.

407 63. Balus L, Fazio M, Amantea A, Menaguale G. Dowling-Degos disease and Verneuil disease [in French]. Ann Dermatol Venereol. 1993;120:705-708. 64. Bedlow AJ, Mortimer PS. Dowling-Degos disease associated with hidradenitis suppurativa. Clin Exp Dermatol. 1996;21:305-306. 65. Sahin MT, Ozturkcan S, Turel-Ermertcan A, Yurtman-Havlucu D, Bilac C. Behcet’s disease associated with hidradenitis suppurativa. J Eur Acad Dermatol. 2007;21:428-429. 66. Alpsoy E, Zouboulis CC, Ehrlich GE. Mucocutaneous lesions of Behçet’s disease. Yonsei Med J. 2007;48:573-585. 67. Nijsten TE, Meuleman L, Lambert J. Chronic pruritic neutrophilic eccrine hidradenitis in a patient with Behçet’s disease. Br J Dermatol. 2002;47:797-800. 68. Mercader-García P, Vilata-Corell JJ, Pardo-Sanchez J, Fortea-Baixauli JM. Neutrophilic eccrine hidradenitis in a patient with Behçet’s disease. Acta Derm Venereol. 2003;83:395-396. 69. Bilic M, Mutasim DF. Neutrophilic eccrine hidradenitis in a patient with Behçet’s disease. Cutis. 2001;68:107-111. 70. Barth H, Layton AM, Cunliffe WJ. Endocrine factors in pre- and postmenopausal women with hidradenitis suppurativa. Br J Dermatol. 1996;134:1057-1059. 71. Harrison BJ, Kumar S, Read GF, et al. Hidradenitis suppurativa: evidence for an endocrine abnormality. Br J Surg. 1985;72:1002-1004. 72. Williams GT, Carey PD. Probable association between hidradenitis suppurativa and Crohn’s disease: significance of epithelioid granuloma. Br J Surg. 1997;84:375-376. 73. Scheinfeld N. Treatment of coincident seronegative arthritis and hidradentis supprativa with adalimumab. J Am Acad Dermatol. 2006;55:163-164. 74. Bleiziffer O, Dragu A, Kneser U, Horch RE. Solving acne inversa (hidradenitis suppurativa) in Crohn disease with buried chip skin grafts. J Cutan Med Surg. 2009;13:164-168. 75. Goertz RS, Konturek PC, Naegel A, et al. Experiences with a longterm treatment of a massive gluteal acne inversa with infliximab in Crohn’s disease. Med Sci Monit. 2009;15:14-18. 76. Goischke HK, Ochsendorf FR. Acne inversa in Crohn’s disease. Z Gastroenterol. 2001;39:96553-96559. 77. Moschella SL. Is there a role for infliximab in the current therapy of hidradenitis suppurativa? A report of three treated cases. Int J Dermatol. 2007;46:1287-1291. 78. Martinez F, Nos P, Benlloch S, Ponce J. Hidradenitis suppurativa and Crohn’s disease: Response to treatment with infliximab. Inflamm Bowel Dis. 2001;7:323-326. 79. Katsanos KH, Chistodoulou DK, Tsianos E. Axillary hidradentis suppurativa treated with infliximab in a Crohn’s disease patient. Am J Gastroenterol. 2002;97:2155-2156. 80. Roussomoustakaki M, Dimoulios P, Chatzicostas C, et al. Hidradenitis suppurativa associated with Crohn’s disease and spondyloarthropathy: Response to anti-TNF therapy. J Gastroenterol. 2003;38: 1000-1004. 81. Rosi YL, Lowe L, Kang S. Treatment of hidradenitis suppurativa with infliximab in a patient with Crohn’s disease. J Dermatol Treat. 2005;16:58-61. 82. Tsianos EV, Dalekos GN, Tzermias C, et al. Hidradenitis suppurativa in Crohn’s disease. A further support to this association. J Clin Gastroenterol. 1995;20:151-153. 83. Gheorghe C, Cotruta B, Trifu V, et al. Perineal abscesses and fistulas —always a mark of Crohn’s disease? J Gastrointestin Liver Dis. 2007;16:307-308. 84. Lebwohl B, Sapadin AN. Infliximab for the treatment of hidradenitis suppurativa. J Am Acad Dermatol. 2003;49:275-276. 85. Wiltz O, Schoetz Jr DJ, Murray JJ, Roberts PL, Coller JA, Veidenheimer MC. Perianal hidradenitis suppurativa. The Lahey Clinic experience. Dis Colon Rectum. 1990;33:731-734. 86. Lindor NM, Arsenault TM, Solomon H, Seidman CD, McEvoy MT. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc. 1997;72:611-615.

408 87. Chen W, Obermayer-Pietsch B, Hong J-B, et al. Acne-associated syndromes: models for better understanding of acne pathogenesis. J Eur Acad Dermatol. 2011;25:637-646. 88. Plewig G, Kligman AM. Acne: Morphogenesis and Treatment. Berlin: Springer-Verlag. 1975. p. 192-193. 89. Chicarilli ZN. Follicular occlusion triad: hidradenitis suppurativa, acne conglobata, and dissecting cellulitis of the scalp. Ann Plast Surg. 1987;18:230-237. 90. Scheinfeld NS. A case of dissecting cellulitis and a review of the literature. Dermatol Online J. 2003;9:8. 91. Bhalla R, Sequeira W. Arthritis associated with hidradenitis suppurativa. Ann Rheum Dis. 1994;53:64-66. 92. Rosner IA, Burg CG, Wisnieski JJ, Schacter BZ, Richter DE. The clinical spectrum of the arthropathy associated with hidradenitis suppurativa and acne conglobata. J Rheumatol. 1993;20:684-687. 93. Leybishkis B, Fasseas P, Ryan KF, Roy R. Hidradenitis suppurativa and acne conglobata associated with spondyloarthropathy. Am J Med Sci. 2001;321:195-197. 94. Vasey FB, Fenske NA, Clement GB, Bridgeford PH, Germain BF, Espinoza LR. Immunological studies of the arthritis of acne conglobata and hidradenitis suppurativa. Clin Exp Rheumatol. 1984;2:309-311. 95. Libow LF, Friar DA. Arthropathy associated with cystic acne, hidradenitis suppurativa, and perifolliculitis capitis abscedens et suffodiens: treatment with isotretinoin. Cutis. 1999;64:87-90. 96. Ellis BI, Shier CK, Leisen JJ, Kastan DJ, McGoey JW. Acne associated spondylarthropathy: radiographic features. Radiology. 1987;162:541-545. 97. Rosner IA, Richter DE, Huettner TL, Kuffner GH, Wisnieski JJ, Burg CG. Spondyloarthropathy associated with hidradenitis suppurative and acne conglobata. Ann Intern Med. 1982;97:520-525.

C. Dessinioti et al. 98. Thein M, Hogarth MB, Acland K. Seronegative arthritis associated with the follicular occlusion triad. Clin Exp Dermatol. 2004;29:550-552. 99. Kahn MF, Chamot AM. SAPHO syndrome. Rheum Dis Clin North Am. 1992;18:225-246. 100. Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497. 101. Sabat R, Chanwangpong A, Schneider-Burrus S, et al. Increased prevalence of metabolic syndrome in patients with acne inversa. PLOS ONE. 2012;7:e31810. 102. Davidovici BB, Sattar N, Jorg PC, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010;130: 1785-1796. 103. Weinberg AN, Swartz MN, Tsao H, Johnson RA. Soft-tissue infections: erysipelas, cellulitis, gangrenous cellulitis, and myonecrosis. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, eds. Fitzpatrick’s Dermatology in General Medicine, 6th edition, Vol II. New York: McGraw-Hill; 2003. p. 1883-1895. 104. Lapins J, Ye W, Nyren O, Emtestam L. Incidence of cancer among patients with hidradenitis suppurativa. Arch Dermatol. 2001;137:730-734. 105. Lavogiez C, Delaporte E, Darras-Vercambre S, et al. Clinicopathological study of 13 cases of squamous cell carcinoma complicating hidradenitis suppurativa. Dermatology. 2010;220:147-163. 106. Kurek A, Peters EMJ, Chanwangpong A, et al. Disturbances of sexual health in patients with acne inversa. J Am Acad Dermatol. 2012;67: 422-428. 107. von der Werth JM, Jemec GB. Morbidity in patients with hidradenitis suppurativa. Br J Dermatol. 2001;144:809-813. 108. Jemec GB, Heidenheim M, Nielsen NH. Hidradenitis suppurativa— characteristics and consequences. Clin Exp Dermatol. 1996;21:419-423.

Clinics in Dermatology (2014) 32, 409–413

Atopic dermatitis as a systemic disease Razvigor Darlenski, MD, PhD a,⁎, Jana Kazandjieva, MD b , Evgeniya Hristakieva, MD c , Joachim W. Fluhr, MD d a

Department of Dermatology and Venereology, Tokuda Hospital-Sofia, 51B Nikola Vaptsarov blvd, 1407 Sofia, Bulgaria Department of Dermatology and Venereology, Medical Faculty, Medical University-Sofia, 1 St. Georgi Sofiiski str., 1431 Sofia, Bulgaria c Department of Dermatology and Venereology, Medical Faculty, Trakia University, 11 Armeiska str., 6000 Stara Zagora, Bulgaria d Department of Dermatology, Charité University Clinic, Charitéplatz 1, 10117 Berlin, Germany b

Abstract Atopic dermatitis (AD) is a chronic inflammatory disease that seriously affects the quality of life of these patients. Both immune deviations and epidermal barrier deficiency have been defined as pathophysiologic mechanisms in the disease development. The atopic march, or the natural progression form atopic dermatitis in infancy to asthma and allergic rhinitis, is a classic example for the multiorgan involvement in atopy. It has been hypothesized that epidermal barrier impairment is the primary pathologic condition responsible for the atopic march. In recent decades, a growing body of evidence has accumulated that AD can be accompanied by a variety of systemic diseases, such as autoimmune disorders, ophthalmologic involvement, eosinophilic gastroenteritis, inflammatory bowel disease, nephritic syndrome, and metabolic diseases. This contribution reviews these associations and focuses on the possible common underlying mechanisms of AD and the associated syndromes. We present a concept on AD as a multiorgan systemic disease. © 2014 Elsevier Inc. All rights reserved.

Introduction

Historical perspective

Atopic dermatitis (AD), also known as atopic eczema, is a chronic, inflammatory, clinically defined disease with predominant affection of the skin that seriously disturbs the quality of life of these patients.1,2 It affects around 20% of the pediatric population and up to 3% of the adults in western societies. 3 Beyond affection of the individual due to the chronic pruritus, insomnia, attention concentration disturbances, and absence from work, the economic burden of AD has tremendously increased in the past decades.3

Although descriptions of chronic pruritic skin conditions exist in ancient and Hippocrates’s texts, the first known AD mentioned in the literature was made by Suetonus for the case of the Emperor Augustus suffering from an itchy skin condition together with seasonal respiratory complaints.4 In the medical literature, AD was mentioned first in the De morbis cutaneis (1572) by Girolamo Mercurialis, the first textbook of dermatology.5 Willan and Bateman were the first describing the morphologic basis of eczema/ dermatitis, and their approach was dominant for almost two centuries until the work of Hebra, who showed that the disease can be dominated by different lesions in its different stages, and then Besnier, who focused on the subjective manifestations of AD.4 Systemic involvement in AD was disclosed in the classic descriptions of Hebra, who stated that axillary and inguinal lymphadenopathy

⁎ Corresponding author. Tel.: +359 890 545599. E-mail address: [email protected] (R. Darlenski). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.007

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were present and that in children urticarial lesions were often observed. The term “atopy” was coined by the allergists Arthur Coca and Robert Cooke in 1923 for abnormal hypersensitivity against environmental triggers that tended to occur within families and required obvious prior sensitization.6 The term “atopic dermatitis” was introduced by Fred Wise and Marion Sulzberger the 1930s to describe the classic flexural skin involvement of the disease.

Pathophysiology in the light of systemic involvement Immune disturbances

Fig. 2 Schematic overview on the approximate incidence of the disease from the atopic spectrum throughout life.

In its classic description, AD is only part of the so-called atopic complex or atopic syndrome that comprises beyond skin changes allergic rhinoconjunctivitis and asthma and is accompanied by typical psychologic trait. One of the key hypotheses for the disease pathogenesis is that all diseases in this group are organ-specific manifestations of a systemic disorder. In consistency, peripheral eosinophilia and elevated IgE are often observed in these conditions.3 Immune dysregulation is one of the key components in AD pathogenesis (Figures 1 and 2), ie, inside-out concept. According to it, AD is a systemic immunologic disorder with increased propensity toward inflammatory response. Certain genetic predisposition to such phenotypes has been witnessed.7 Antigen stimulation of Langerhans cells (LC), mast cells, and keratinocytes results in increased populations of eospinophils and inflammatory dendritic epidermal cells, which in turn are capable of switching to the predominant Th2-response in chronic AD.8 IgE is responsible for the antigen presentation. There is evidence that in both lesional and nonlesional skin of AD patients overexpress IgE receptor is on the surface of LC in comparison to healthy subjects.9 Subclinical inflammation in nonlesional AD skin is also characterized by Th2- infiltrates and increased Th2-orginating cytokines, such as interleukin (IL)-4

and IL-13.2,10 Both elevated IgE and Th2-cytokine profile have been witnessed in patients with asthma and allergic rhinitis.11

Genetic background

Epidermal barrier defect

Epidermal barrier defects The outside-in concept focuses on epidermal barrier dysfunction as the milestone in AD pathogenesis. A decrease in all three major extracellular stratum corneum (SC) lipids, especially ceramides, was disclosed in both lesional and nonlesional skin of AD patients.12,13 Epidermal barrier impediment is witnessed even in uninvolved skin of AD patients, characterized by decreased SC hydration, increased transepidermal water loss (TEWL), and specific structural deficits.8 Mutations in the gene encoding for filaggrin, a structural protein of the cornified envelope of the SC, are found in 15% to 50% (severe cases) of AD.14 In addition, the impeded degradation of filaggrin to the major constituents of the natural moisturizing factor results in diffusely xerotic skin of AD patients. Filaggrin mutations have been associated with asthma, food allergies, nickel sensitization, and allergic rhinitis.15-18 This mutation was not prevalent in asthma without dermatitis, however, suggesting the role of epidermal barrier impairment for the penetration of allergens through the skin.17,18 These findings confirm the role of the skin for the development of lifetime prevalent systemic inflammatory disease; however, not all AD patients and not all severe AD cases show the filaggrin mutation indicating that other relevant mechanisms, as yet undiscovered, play a major role in the development of AD.

Immunologic dysregulation

Clinical evidence for systemic involvement in AD The atopic march Environmental factors

Fig. 1

Ethiopathogenetic factors in atopic dermatitis.

The most explicit evidence that AD can be regarded as a systemic disease is the so-called “atopic march.” It is defined

Atopic dermatitis as the progression through the atopic individual’s life-form atopic dermatitis in infancy to asthma and allergic rhinitis in childhood. There is a growing body of evidence that dermatitis precedes the sensitization to aeroallergens.19 Up to 50% of AD patients will develop asthma and even more are prone to get allergic rhinitis later in life according to different studies (reviewed in Ref 3). Probably, the risk is overestimated, as the majority of studies recruit inpatients hospitalized at specialized clinics, favoring severe disease forms. Indisputably, the atopic, also called the allergic march, can be detected in many AD patients, suggesting the complex systematic nature of AD.

Disease associations Skin disorders The list of commonly associated skin diseases with AD is long, and some nosology associations have been addressed by multiple studies. Table 1 summarizes the dermatologic diseases (in alphabetic order) reported to be associated with AD. Some of them are barrier driven; others are more related to known immunological factors. Eye involvement Ocular involvement is seen in many AD patients. The most common eye disorder is allergic belpharoconjunctivitis. Atopic or vernal keratoconjunctivitis is a distinct, selflimited disease with seasonal exacerbation and is more prevalent in climatic hot regions. 20 Findings include stinging, lacrimation, and mild photophobia. Keratoconus, characterized by conical transformation of the cornea, is common in AD patients. A multivariate analysis disclosed atopy as a risk factor for keratoconus development.21 The disease is characterized by vision distortion (multiple

Table 1 Associations of atopic dermatitis and other skin disorders Allergic and irritant contact dermatitis Alopecia areata Cutaneous amyloidosis Cutaneous lymphomas Dermatitis herpetiformis Exfolliative erythroderma Lichen sclerosus et atrophicus Netherton’s syndrome Palmo-plantar keratoderma of Thost-Unna Pityriasis rosea Psoriasis (especially inverted) Skin infections - Bacterial (Staphylococci and Streptococci) - Fungal (Dermatophytes, Candida, Malassezia) - Viral (Molluscum contagiosum, Herpes simplex, HPV) - Parasitic (Sarcoptes scabiei) Urticaria Vitiligo

411 images) and exaggerated phosensitivity. Posterior and anterior subcapsular cataracts have been described in AD. Although posterior forms are more common, anterior subcapsular cataract is more specific to AD.22 A decreased inducibility of superoxide dismutase was registered in the disease, suggesting oxidative damage of the lens related to chronic inflammation in AD.22 Gastrointestinal involvement Involvement of the digestive system is known in AD patients. The most specific one is eosinophilic gastroenteritis —a relatively rare condition characterized by prominent eosinophilic infiltration of the stomach or small intestine.23 Clinical findings vary with abdominal pain, nausea, vomiting, diarrhea, weight loss, malabsorption, protein-losing enteropathy, anemia, and nutritional deficiencies being the most common. Atopy was found to be highly prevalent in inflammatory bowel disease by most of the studies.24 A potential sharing of Th2 cytokine-related pathways in the pathogenesis of these two disorders of barrier dysfunction was suggested.25 Renal involvement Approximately 48% of pediatric patients with idiopathic nephritic syndrome have a history of atopy and/or elevated serum IgE, and 40% had clinical sign of an atopic disease.26 Steroid-responsive nephrotic syndrome can be exacerbated by reaction to aero and food allergens and atopy is highly prevalent in this disease.27,28 Autoimmunity and AD A connection between atopy and autoimmunity has been suspected. An increased incidence of autoimmune disorders was observed in atopic children, especially in those with gastrointestinal symptoms after milk ingestion.29 More recently, atopy was disclosed as risk factor for thyroid autoimmunity in children.30 A review of epidemiologic data on rheumatoid arthritis, multiple sclerosis, and type I diabetes mellitus suggested that Th1- mediated inflammation can protect against atopy, and atopy could reduce the severity but not necessarily the onset of autoimmunity.31 It has been shown that AD patients exhibit IgE autoreactivity to human proteins in a variety of cell and tissue types.32 The level of IgE autoantibodies are associated with severity of disease. These findings suggest autoimmunity as a mechanism in the pathogenesis in AD. Metabolic syndrome Obesity was linked to asthma; however, no association between insulin resistance and atopy was witnessed.33 A possible explanation for this phenomenon is the secretion of proinflammatory mediators from the adipose tissue and their effects on mast cells.34 Greater maternal adiposity is associated with transient wheeze in offsprings but not asthma or atopy.35 A significant positive association between total and low-density lipoprotein cholesterol levels and atopy

412 was found suggesting a link between atopy and hyperlipidemia in schoolchildren.36 Psychological profile of AD patients and psychiatric comorbidities: AD can be regarded as a psychosomatic disease Psychological factors are considered serious eliciting factors in AD. In past decades, a great number of studies showed that AD patients have impaired quality of life, accompanied by coping problems, sleep disturbance, and impeded interpartner relationships.37,38 Hostility, neuroticism, and problems in dealing with anger are typical for the psychological profile of the patients.39,40 Personality features of AD patients include temperaments of depression, feelings of inferiority, nervousness, and lack of objectivity in a Japanese cohort.41 The most common psychiatric comorbidities of atopy patients are anxiety and depression.42 Having both asthma and rhinitis strengthens the association with anxiety in comparison to having either disease alone. Attention deficit hyperactivity disorder is observed in AD children.43 The same study found increased risk for depression, anxiety, conduct disorder, and autism among the pediatric AD patients. Restless legs syndrome, characterized by an unpleasant sensation in the legs, which produces an urge to frequently move the legs, was more common in AD than in psoriasis patients and healthy controls.44 A recent study linked schizophrenia to atopic diseases and asthma in particular suggesting common immunologic mechanisms.45 Stress is considered as a major eliciting factor in AD. Psychologic stress has the potential to induce systemic inflammation and enhancement of dendritic cell migration from the skin and recruitment of CD8+Т lymphocytes upon antigen stimulation.46 In addition, psychologic stress may interfere with epidermal barrier permeability and homeostasis, a key pathomechanism in AD.47 Other disorder A variety of systemic diseases have been reported to be associated with AD among which are cystic fibrosis, endometriosis, hypoproteinaemia, Down syndrome, hearing loss, insect venom allergy, and drug hypersensitivity, which are beyond the scope of this paper, and the reader is referred to the extensive review by Vieluf et al for further details.48

Unifying concept We are practicing in the era of evidence-based medicine. It is recognized as the process of acquiring and applying into practice the best available research findings in a defined field.49 In this paper, we have tried to summarize the knowledge on AD not simply as a skin condition but as a disorder affecting the whole organism with its multiple organs and systems. Evidence exists that epidermal barrier

R. Darlenski et al. impairment is a major driver for the subsequent sensitization and respiratory symptoms.19 Systemic inflammation in AD can be witnessed by the so-called subclinical inflammatory changes of clinically uninvolved skin. Finally, the numerous associations of AD with multiple disorders can be accepted as coincidence, but we think that they are intimately linked. The plethora of clinical findings and comorbidity along with discovering distinct altered pathways will lead to a diagnostic stratification of AD and subsequently to more specific treatments. The near future will disclose the intimate mechanism of systemic involvement in AD.

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Atopic dermatitis 19. Hogan MB, Peele K, Wilson NW. Skin barrier function and its importance at the start of the atopic march. J Allergy (Cairo). 2012;2012:901-940. 20. De Smedt S, Wildner G, Kestelyn P. Vernal keratoconjunctivitis: an update. Br J Ophthalmol. 2013;97:9-14. 21. Bawazeer AM, Hodge WG, Lorimer B. Atopy and keratoconus: a multivariate analysis. Br J Ophthalmol. 2000;84:834-836. 22. Bair B, Dodd J, Heidelberg K, et al. Cataracts in atopic dermatitis: a case presentation and review of the literature. Arch Dermatol. 2011;147:585-588. 23. Khan S, Orenstein SR. Eosinophilic gastroenteritis. Gastroenterol Clin North Am. 2008;37:333-348, v. 24. Tzanakis NE, Tsiligianni IG, Siafakas NM. Pulmonary involvement and allergic disorders in inflammatory bowel disease. World J Gastroenterol. 2010;16:299-305. 25. Niwa Y, Sumi H, Akamatsu H. An association between ulcerative colitis and atopic dermatitis, diseases of impaired superficial barriers. J Invest Dermatol. 2004;123:999-1000. 26. Salsano ME, Graziano L, Luongo I, et al. Atopy in childhood idiopathic nephrotic syndrome. Acta Paediatr. 2007;96:561-566. 27. Cheung W, Wei CL, Seah CC, et al. Atopy, serum IgE, and interleukin13 in steroid-responsive nephrotic syndrome. Pediatr Nephrol. 2004;19:627-632. 28. Yap HK, Yip WC, Lee BW, et al. The incidence of atopy in steroidresponsive nephrotic syndrome: clinical and immunological parameters. Ann Allergy. 1983;51:590-594. 29. Kokkonen J, Niinimaki A. Increased incidence of autoimmune disorders as a late complication in children with early onset dermatitis and/or milk allergy. J Autoimmun. 2004;22:341-344. 30. Pedulla M, Miraglia Del Giudice M, Fierro V, et al. Atopy as a risk factor for thyroid autoimmunity in children. J Biol Regul Homeost Agents. 2012;26:S9-S14. 31. Rabin RL, Levinson AI. The nexus between atopic disease and autoimmunity: a review of the epidemiological and mechanistic literature. Clin Exp Immunol. 2008;153:19-30. 32. Mittermann I, Aichberger KJ, Bunder R, et al. Autoimmunity and atopic dermatitis. Curr Opin Allergy Clin Immunol. 2004;4:367-371. 33. Ma J, Xiao L, Knowles SB. Obesity, insulin resistance and the prevalence of atopy and asthma in US adults. Allergy. 2010;65: 1455-1463. 34. Sismanopoulos N, Delivanis DA, Mavrommati D, et al. Do mast cells link obesity and asthma? Allergy. 2013;68:8-15.

413 35. Pike KC, Inskip HM, Robinson SM, et al. The relationship between maternal adiposity and infant weight gain, and childhood wheeze and atopy. Thorax. 2013;68:372-379. 36. Kusunoki T, Morimoto T, Sakuma M, et al. Total and low-density lipoprotein cholesterol levels are associated with atopy in schoolchildren. J Pediatr. 2011;158:334-336. 37. Chernyshov PV. Gender differences in health-related and family quality of life in young children with atopic dermatitis. Int J Dermatol. 2012;51:290-294. 38. Misery L, Finlay AY, Martin N, et al. Atopic dermatitis: impact on the quality of life of patients and their partners. Dermatology. 2007;215: 123-129. 39. White A, Horne DJ, Varigos GA. Psychological profile of the atopic eczema patient. Australas J Dermatol. 1990;31:13-16. 40. Gieler U, Ehlers A, Höhler T, et al. Die psychosoziale Situation der Patientenmit endogenem Ekzem. Hautarzt. 1990;41:416-423. 41. Takahashi H, Tsuji H, Honma M, et al. Japanese patients with psoriasis and atopic dermatitis show distinct personality profiles. J Dermatol. 2013;40:370-373. 42. Slattery MJ, Essex MJ. Specificity in the association of anxiety, depression, and atopic disorders in a community sample of adolescents. J Psychiatr Res. 2011;45:788-795. 43. Yaghmaie P, Koudelka CW, Simpson EL. Mental health comorbidity in patients with atopic dermatitis. J Allergy Clin Immunol. 2013;131: 428-433. 44. Cicek D, Halisdemir N, Dertioglu SB, et al. Increased frequency of restless legs syndrome in atopic dermatitis. Clin Exp Dermatol. 2012;37:469-476. 45. Pedersen MS, Benros ME, Agerbo E, et al. Schizophrenia in patients with atopic disorders with particular emphasis on asthma: a Danish population-based study. Schizophr Res. 2012;138:58-62. 46. Saint-Mezard P, Chavagnac C, Bosset S, et al. Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo. J Immunol. 2003;171:4073-4080. 47. Choi EH, Brown BE, Crumrine D, et al. Mechanisms by which psychologic stress alters cutaneous permeability barrier homeostasis and stratum corneum integrity. J Invest Dermatol. 2005;124:587-595. 48. Vieluf D, Rieker J, Ruzicka T. Complications and diseases associated with atopic eczema. In: Ring J, Przybilla B, Ruzicka T, eds. Handbook of Atopic Eczema. Berlin, Heidelberg: Springer; 2006. p. 115-143. 49. Darlenski RB, Neykov NV, Vlahov VD, et al. Evidence-based medicine: facts and controversies. Clin Dermatol. 2010;28:553-557.

Clinics in Dermatology (2014) 32, 414–419

Contact dermatitis as a systemic disease Aleksandra Kulberg, MD, Sibylle Schliemann, MD, Peter Elsner, MD ⁎ Department of Dermatology, University Hospital Jena, Erfurter Strasse 35, D-07743 Jena, Germany

Abstract Systemic contact dermatitis (SCD) is a condition occurring in previously sensitized individuals after systemic re-exposure to the same or cross-reacting substance. Systemic route of administration means uptake of an allergen via percutaneous, transmucosal, oral, intravenous, intramuscular, and inhalational routes, as well as through implants. The intimate mechanisms behind SCD are not yet fully understood, but it is thought to be a T-cell mediated delayed type hypersensitivity reaction. The most common allergens recognized to date are nickel, aminoglycoside antibiotics, corticosteroids, balsam of Peru, and plants from the Anacardiacae and Compositae families. The most typical presentation of SCD, known as baboon syndrome, includes diffuse erythema of the buttocks, the upper inner surface of the thighs, and the axillary folds. Cases with the classical baboon pattern of distribution elicited by systemically introduced drugs without previous sensitization are encompassed by the acronym SDRIFE (Symmetric Drug-related Intertriginous and Flexural Exanthema). Interestingly, corticosteroids, although widely applied for anaphylaxis and other allergic conditions, can produce sensitization, and they are commonly mentioned as triggers of SCD. © 2014 Elsevier Inc. All rights reserved.

Introduction

Definition

Systemic contact dermatitis (SCD) is a condition occurring in previously sensitized individuals after systemic re-exposure to the same or cross-reacting substance. Systemic route of administration means uptake of an allergen via percutaneous, transmucosal, oral, intravenous, intramuscular, and inhalational routes, as well as through implants.1-3 The intimate mechanisms behind SCD are not yet fully understood, but it is thought to be a T-cell mediated delayed type hypersensitivity reaction.4 The most common allergens recognized so far are nickel, aminoglycoside antibiotics, corticosteroids, balsam of Peru, and plants from the Anacardiacae and Compositae families. The most typical presentation of SCD includes diffuse erythema of the buttocks, the upper inner surface of the thighs and the axillary folds, also known as baboon syndrome.

Contact dermatitis by definition is an inflammatory skin reaction, caused either by allergens (allergic contact dermatitis; ACD) or irritants (irritant contact dermatitis; ICD). The mechanism behind ACD is a delayed, cell-mediated hypersensitivity reaction induced by exposure to an allergen to which the patient has already been previously sensitized. The clinical picture of ACD varies according to the severity, location, and duration of the inflammation. In the acute form, the exudative lesions predominate, consisting of welldemarcated erythema, on which closely grouped vesicles and/or papules are situated. In the subacute and chronic forms, scaling and lichenification predominate. ICD, on the other hand, is a toxic phenomenon, characterized by a nonspecific inflammatory response of the skin to direct chemical damage. It can be subdivided into two forms. The acute form occurs after a single exposure to the offending substance; it is concentration dependent and develops in every exposed individual. Lesions may vary in severity, ranging from mild erythema

⁎ Corresponding author. Tel.: +49 3641 937 350; fax: +49 3641 937 418. E-mail address: [email protected] (P. Elsner). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.008

Systemic contact dermatitis and vesiculaton, to caustic burns and necrosis. The chronic form is triggered by repeated cumulative exposure to mild irritants and is often accompanied by disturbance of the barrier function of the skin manifested clinically by dryness, hyperkeratosis and scaling, fissures, and crusting on a mildly erythematous base. In severe cases of ACD, the pathological process is no longer confined to a single skin area but can encompass large body surfaces leading to erythroderma/exfoliative dermatitis. The usual route of administration of the allergen, in patients with ACD, is through the skin; however, there are cases in which the allergen or a cross-reacting molecule may enter the organism via the bloodstream of previously sensitized individuals, thus reaching the skin and producing varying skin changes. Such alterations include a flare of eczema and/or a patch test reaction, vasculitis-like lesions, pompholyx or a generalized eruption, and also a specific exanthema, consisting of an acute eruptions, localized in the major flexures and the anogenital area with the catchy name baboon syndrome (BS). Systemic routes of administration mentioned in the literature include oral, transmucosal (including transrectal), intravenous, intramuscular, inhalational, and implants.5 There are many terms applied for this condition, among which are internal-external contact-type hypersensitivity,6 mercury exanthema,7 baboon sydrome,8 nonpigmenting fixed drug eruption (Comment: A proposed term for cutaneous eruptions related to or imitating the baboon syndrome. We think they mean a distinct entity and not fixed drug eruption, although the terms seem similar),9 drug-induced intertrigo,10 systemic contact dermatitis (SCD), 2 paraptic eczema,11 symmetric ptychotropic and nonpigmenting fixed drug eruption,12 flexural drug eruption,13 and symmetric drugrelated intertriginous and flexural exanthema.14 In 1983, researchers described 15 cases of an exanthema developing after inhalation of mercury vapor from crushed thermometers in previously sensitized individuals, the socalled “mercury exanthema.”7 A paper from 1984 described three different cases with ampicillin, nickel, and mercury as allergens and introduced the term baboon syndrome (BS), due to the characteristic clinical presentation resembling the gluteal region of a baboon and in an attempt to make the entity memorable.8 Ten years later, the umbrella term systemic contact dermatitis (SCD) was introduced, which included BS and other types of dermatitis from systemically administered substances with or without previous topical exposure.2 Later, the term ACDS (allergic contact dermatitis syndrome) was proposed for patients with prior cutaneous sensitization to distinguish them from other cutaneous allergic dermatitis reactions without the background of a previous skin sensitization.15 Other researchers introduced a new acronym, SDRIFE (Symmetric Drug-related Intertriginous and Flexural Exanthema). According to them, since the first description of the BS, about 100 cases have been published in the literature, in which systemic drugs have been recognized as the causative

415 agents of the skin changes; however, for most of these medications, previous cutaneous or cross-sensitization has not been discovered. As a result, these researchers proposed that cases with the classical baboon pattern of distribution elicited by systemically introduced drugs without previous sensitization be encompassed by the more politically correct term SDRIFE.14 In this paper, we shall use the term SCD, which we find is a broad enough and contemporary designation to encompass the variety of triggers and patterns of reaction in previously sensitized individuals, who are systemically exposed to the same contact allergen or a cross-reacting molecule. From our point of view, SDRIFE should be reserved for cases elicited by systemically administered drugs without prior sensitization and with the characteristic distribution pattern. SDRIFE should supersede the colorful term baboon syndrome. The most common triggers of SCD can be divided into three major groups: metals, drugs, and plant products.1-3

Metals Metals are ubiquitous in our environment, especially after the industrialization of modern society, thus making skin and systemic exposure easy and inconspicuous. Higher exposure levels lead to an increase in the percentage of allergies towards metals. Metal ions are haptens, which need to be bonded to protein molecules to form antigenic complexes that can be further recognized by dendritic cells that allow sensitization to occur. The most common metals reported in the literature that elicit ACD and SCD are nickel, mercury, cobalt, chromium, zinc, and gold. Nickel, by far, is the most common contact allergen. Nickel sensitization is observed in up to 17% of women and 3% of men. The higher percentage among women can be explained with the specific consumer demands. Many alloys, foods, jewelry, and everyday items contain nickel, thus the route of exposure varies significantly, including surgical implants.16,17 The clinical manifestation can vary dramatically. In previously sensitized individuals, nickel can elicit pompholyx after oral provocation.18 Recently, a case of SCD to nickel occurred in a 14-year-old boy after intake of cocoa19 and also another challenging case of a patient with longstanding therapy resistant pruritus ani turned out to be an allergy case due to ingestion of peanut butter, which has high nickel content.20 The previous recommendation of a nickelfree diet for nickel-sensitized individuals is of decreasing popularity and controversial among dermatologists.21 Cobalt and chromium (more specifically hexavalent chromium) sensitization is estimated to be 1% to 3% in the general population.4 Cobalt is used in the production of paints, jewelry, prosthetics, and various everyday objects. Concomitant allergy between cobalt and nickel has been researched and proves to be on the basis of cosensitization, rather than due to cross-reactivity.22

416

A. Kulberg et al. arthritis patient was described in 1988.34 Since then, a growing number of cases on the subject have been published.35-38 An interesting case of SCD induced by gold was reported in a patient using a homeopathic drug containing the metal. The patient had been previously exposed to it through her gold earrings and a dental gold crown.39

Drugs Fig. 1 Systemic contact dermatitis 24 hrs after an oral provocation test with hydrocortisone with confluent macular papular erythema. The patient had a history of ACD due to a prednisolone-containing topical eye ointment. The patch test reaction to prednisolone 1.0%/pet. was ? at 48 hrs and + at 72 hrs.

Chromium is an important alloying material for the production of steel (stainless steel) due to its corrosion resistant properties. It is also used in the dye and pigment industry, as a wood preservative, in the tanning of leather, the production of polyethylene, and in environments like blast furnaces, cement kilns, molds for the firing of bricks, and as foundry sands for the casting of metals. Chromium can be found in water, soil, and foods. This availability of the element makes it easy for individuals to be sensitized to it or to be reexposed. There are cases in the literature describing dermatitis associated with chromium after knee arthroplasty,23 dermatitis to a chromium dental plate,24 and SCD due to ingestion of multivitamin tablets or different types of food supplements, containing the element.25,26 Mercury and its compounds have been used in medicine in dental amalgams, as a preservative in vaccines, and in antiseptic preparations for topical use. Because light was shed on its toxic properties, its use has significantly declined, but mercury is still used in some parts of the world. This element is also used for the production of chlorine and caustic soda, in thermometers, fluorescent lamps, in make-up products (such as mascara), and also some foods that have higher mercury content (seafood). SCD to mercury has been reported in a patient using a skin-lightening cream,27 in metal workers,7,28 in a patient with a dental amalgam,29 and after exposure to mercury vapor.30 Zinc is an essential element in many physiologic processes. It is also used for dental restoration, as an anticorrosion agent, in batteries, alloys, in paints, and for other industrial purposes. A case of a severe SCD due to zinc allergy has been reported.31 Two other cases have been found in the literature in patients who developed SCD due to dental fillings with zinc.32,33 Gold has been used since ancient times for the production of jewelry and coins, as well as in medicine and dentistry. It can also be found in some foods and beverages. The first proven case of contact allergy to gold induced after systemic administration of sodium aurothiomalate in a rheumatoid

The second most common group causing SCD is drugs. Medications can be applied both topically and systemically, which increases the risk of developing allergic reactions. In the past, local application of antibiotics was a popular treatment modality that nowadays is avoided in part due to the high sensitization potential of some drugs, such as neomycin and bacitracin.40 In previously sensitized individuals to neomycin, the systemic application of gentamycin may induce SCD.41 There is a case of SCD in a patient who underwent knee replacement with an implant containing gentamycin.42 Research shows that half of patients allergic to neomycin will react to gentamycin.41 There is also a case of SCD to ampicillin due to systemic absorption of the drug. Interestingly, corticosteroids, although widely applied for anaphylaxis and other allergic conditions, can produce sensitization, and they are commonly mentioned as triggers of SCD. Cross-reactivity is often present among them43-45 and might even occur between different classes of corticosteroids.46 Elaborate skin testing followed by subsequent provocational tests are essential in such cases in an attempt to differentiate cross-reacting from alternative compatible drugs (Figures 1 and 2). In our case, a SCD developed 24 hours after an oral provocation test with hydrocortisone with

Fig. 2 The same patient 24 hrs after oral provocation test with triamcinolone (group B), which belongs to a different group of corticosteroids than prednisone and hydrocortisone (group A) (Coopmann et al.46); however, the patch test to triamcinolone acetonide 0.1%/pet. was negative both at 48 and at 72 hrs. The patient finally tolerated dexamethasone (group C).

Systemic contact dermatitis a previous history of ACD to a prednisolon-containing topical eye ointment. The same patient developed SCD after an oral provocation test with triamcinolone, which belongs to a different group of corticosteroids; however, the patch test to triamcinolone acetonide 0,1% in petrolatum was negative both at 48 hours and 72 hours. Other medications that can induce SCD are anesthetics, antihistamines, aminophylline,47,48 5-aminosalicylic acid,49 and bufexamac (systemic absorption through anal application).50 The list of drugs that can elicit SDRIFE also includes a wide range of medications, amoxicillin being the most common, followed by mitomycin.14

Plants Plants are ubiquitous in our everyday life, being used as food, medications, and decoration. The most common adverse reaction caused by plants is ACD. Previous sensitization can easily occur, which also increases the risk for the development of SCD. This group includes Balsam of Peru (Myroxylon balsamum Pereira), garlic (diallyl disulfide), sesquieterpene lactones (Compositae/Asteracea family), and urushiol (Anacardiaceae).51-54 Balsam of Peru is an aromatic resin used in various fields, including medicine and pharmacy due to its excellent antiseptic properties, and in food and perfume industry due to its scent, reminiscent of vanilla and green olives. It is well known for its potential to elicit ACD. The chemical composition of Balsam of Peru consists of benzylcinnamate and benzyl benzoate, cinnamein; styrene, vanillin, and coumarin. Some of these are encountered in various foods and beverages, which facilitates their systemic administration; hence, the chance of provoking SCD.55,56 Another well-known contact allergen is propolis or “bee glue.” It consists of various resins, depending on the geographic area in which the beehive is situated, and is famous for its antiseptic properties. The main sensitizers identified in propolis are 3-methyl-2-butenyl caffeate and phenylethyl caffeate. Propolis can be found in cosmetic products, syrups, lozenges, tablets, etc; however, its growing use has led to an increase in ACD cases. In 2011 the first case of SCD due to propolis was reported.57

Diagnosis and management SCD has a vast spectrum of differential diagnoses, ranging form infections to bullous diseases. In pediatric patients viral exanthems, such as infectious exanthema,58 bacterial infections-impetigo, and perianal celullitis, should be excluded, and if there are systemic symptoms, staphylococcal scalded skin syndrome (SSSS) should be ruled out. Other dermatoses, which have similar localization, to be considered are Hailey-Hailey disease, pemphigus vegetans,

417 inverse psoriasis, candidosis, tinea cruris, acute generalized exanthematous pustulosis (AGEP), and SDRIFE, as well as common ICD and ACD. Flexural allergic and irritant contact dermatitis should be ruled out on the basis of the clinical presentation and patient’s history. Proving or excluding previous sensitization can be performed with the help of the epicutaneous patch test and exposure/provocation test. Patch testing is often necessary to differentiate between SCD and other drug induced eruptions without previous sensitization, especially, from the pattern specific entity SDRIFE.14 Epicutaneous patch testing can be performed with a standard series panel and/or with a customized one, depending on the suspected allergen. It is thought to be the gold standard in detecting contact allergy. The results obtained serve not only for elucidation of the triggering factor but also as a recommendation, showing which allergens and cross-reacting substances should be avoided in the future. It must be performed in a disease-free stage to prevent the so called “angry back” syndrome with false-positive reactions. Another diagnostic tool is the exposure/provocation test, which rechallenges the patient with the suspected allergen via systemic route of administration; however, it is not as safe as patch testing, leading in many instances to a flare-up of the previous eczematous condition. The most obvious way of treatment of any allergic condition, including SCD, is the avoidance of the causative allergen. Most of the substances causing SCD are ubiquitous, so this often proves to be a difficult or almost an impossible task. In professional settings, patients should be encouraged to seek requalification as means of allergen avoidance. In everyday life, an appropriate diet should be established to avoid or diminish allergen contact. Triggering medications and cross-reacting molecules should be avoided. Another management strategy, although yet at an experimental level, that may prove useful for patients with nickel allergy is oral hyposensitization.59 Depending on the severity of the skin inflammation, topical steroids with different potency can be applied. In severe cases, systemic use of corticosteroids or immunosuppressants may be necessary.

References 1. Jacob SE, Zapolanski T. Systemic contact dermatitis. Dermatitis. 2008;19:9-15. 2. Menne T, Veien NK, Maibach HL. Systemic contact dermatitis. Am J Contact Dermat. 1994;5:1-12. 3. Veien NK. Systemic contact dermatitis. Int J Dermatol. 2011;50:14451456. 4. Thyssen JP, Maibach HI. Drug-elicited systemic allergic (contact) dermatitis—update and possible pathomechanisms. Contact Dermatitis. 2008;59:195-202. 5. Winnicki M, Shear NH. A systematic approach to systemic contact dermatitis and symmetric drug-related intertriginous and flexural exanthema (SDRIFE): a closer look at these conditions and an approach to intertriginous eruptions. Am J Clin Dermatol. 2011;12: 171-180.

418 6. Ratner JH, Spencer SK, Grainge JM. Cashew nut dermatitis. An example of internal-external contact type hypersensitivity. Arch Dermatol. 1974;110:921-923. 7. Nakayama H, Niki F, Shono M, Hada S. Mercury exanthem. Contact Dermatitis. 1983;9:411-417. 8. Andersen KE, Hjorth N, Menne T. The baboon syndrome: systemically-induced allergic contact dermatitis. Contact Dermatitis. 1984;10:97100. 9. Shelley WB, Shelley ED. Nonpigmenting fixed drug eruption as a distinctive reaction pattern: examples caused by sensitivity to pseudoephedrine hydrochloride and tetrahydrozoline. J Am Acad Dermatol. 1987;17:403-407. 10. Wolf R, Elman M, Brenner S. Drug-induced “intertrigo. Int J Dermatol. 1993;32:515-516. 11. Happle R. Paraptic eczema. Why a new name? Hautarzt. 1994;45:1-3. 12. Helmbold P, Hegemann B, Dickert C, Marsch WC. Symmetric ptychotropic and nonpigmenting fixed drug eruption due to cimetidine (so-called baboon syndrome). Dermatology. 1998;197:402-403. 13. Wakelin SH, Sidhu S, Orton DI, Chia Y, Shaw S. Amoxycillin-induced flexural exanthem. Clin Exp Dermatol. 1999;24:71-73. 14. Hausermann P, Harr T, Bircher AJ. Baboon syndrome resulting from systemic drugs: is there strife between SDRIFE and allergic contact dermatitis syndrome? Contact Dermatitis. 2004;51:297-310. 15. Lachapelle JM. The spectrum of diseases for which patch testing is recommended. Patients who should be investigated. In: Lachapelle JM, Maibach HI, eds. Patch Testing/Prick Testing. A practical Guide, Vol. 189. Berlin: Springer Verlag; 2003. 16. Basko-Plluska JL, Thyssen JP, Schalock PC. Cutaneous and systemic hypersensitivity reactions to metallic implants. Dermatitis. 2011;22:6579. 17. Benamran S, Votadoro A, Sleth JC. Acute systemic contact dermatitis in a patient with nickel hypersensitivity: contamination from an intravenous catheter? Acta Anaesthesiol Scand. 2007;51:647-648. 18. Gawkrodger DJ, Cook SW, Fell GS, Hunter JA. Nickel dermatitis: the reaction to oral nickel challenge. Br J Dermatol. 1986;115:33-38. 19. Krecisz B, Chomiczewska D, Kiec-Swierczynska M, Kaszuba A. Systemic contact dermatitis to nickel present in cocoa in 14-year-old boy. Pediatr Dermatol. 2011;28:335-336. 20. Silvestri DL, Barmettler S. Pruritus ani as a manifestation of systemic contact dermatitis: resolution with dietary nickel restriction. Dermatitis. 2011;22:50-55. 21. Pizzutelli S. Systemic nickel hypersensitivity and diet: myth or reality? Eur Ann Allergy Clin Immunol. 2012;43:5-18. 22. Wahlberg JE, Boman A. Sensitization and testing of guinea pigs with cobalt chloride. Contact Dermatitis. 1978;4:128-132. 23. Gao X, He RX, Yan SG, Wu LD. Dermatitis associated with chromium following total knee arthroplasty. J Arthroplasty. 2011;26:665 e613666. 24. Hubler Jr WR, Hubler Sr WR. Dermatitis from a chromium dental plate. Contact Dermatitis. 1983;9:377-383. 25. Fowler Jr JF. Systemic contact dermatitis caused by oral chromium picolinate. Cutis. 2000;65:116. 26. Ozkaya E, Topkarci Z, Ozarmagan G. Systemic allergic dermatitis from chromium in a multivitamin/multimineral tablet. Contact Dermatitis. 2010;62:184. 27. Ozkaya E, Mirzoyeva L, Otkur B. Mercury-induced systemic allergic dermatitis caused by “white precipitate” in a skin lightening cream. Contact Dermatitis. 2009;60:61-63. 28. Ozkaya E. An unusual case of mercurial baboon syndrome: lasting seasonal attacks in a retired metalworker. Contact Dermatitis. 2008;58: 107-108. 29. Pigatto PD, Zerboni R, Guzzi G. Local and systemic allergic contact dermatitis due to dental alloys. J Eur Acad Dermatol Venereol. 2008;22:124-126. 30. Zimmer J, Grange F, Straub P, Haegy JM, Guillaume JC. [Mercury erythema after accidental exposure to mercury vapor]. Ann. Med Interne (Paris). 1997;148:317-320.

A. Kulberg et al. 31. Yanagi T, Kodama K, Yoshihisa Y, Shimizu H, Shimizu T. Macrophage migration inhibitory factor in zinc-allergic systemic contact dermatitis. Cytokine. 2006;35:270-274. 32. Saito N, Yamane N, Matsumura W, et al. Generalized exacerbation of systemic allergic dermatitis due to zinc patch test and dental treatments. Contact Dermatitis. 2010;62:372-373. 33. Shimizu T, Kobayashi S, Tanaka M. Systemic contact dermatitis to zinc in dental fillings. Clin Exp Dermatol. 2003;28:675-676. 34. Wicks IP, Wong D, McCullagh RB, Fleming A. Contact allergy to gold after systemic administration of gold for rheumatoid arthritis. Ann Rheum Dis. 1988;47:421-422. 35. Hostynek JJ. Gold: an allergen of growing significance. Food Chem Toxicol. 1997;35:839-844. 36. Moller H. Contact allergy to gold as a model for clinical-experimental research. Contact Dermatitis. 2010;62:193-200. 37. Moller H, Ohlsson K, Linder C, Bjorkner B, Bruze M. Cytokines and acute phase reactants during flare-up of contact allergy to gold. Am J Contact Dermat. 1998;9:15-22. 38. Moller H, Ohlsson K, Linder C, Bjorkner B, Bruze M. The flare-up reactions after systemic provocation in contact allergy to nickel and gold. Contact Dermatitis. 1999;40:200-204. 39. Malinauskiene L, Isaksson M, Bruze M. Systemic contact dermatitis in a gold-allergic patient after treatment with an oral homeopathic drug. J Am Acad Dermatol. 2013;68:e58. 40. Spring S, Pratt M, Chaplin A. Contact dermatitis to topical medicaments: a retrospective chart review from the Ottawa hospital patch test clinic. Dermatitis. 2012;23:210-213. 41. Guin JD, Phillips D. Erythroderma from systemic contact dermatitis: a complication of systemic gentamicin in a patient with contact allergy to neomycin. Cutis. 1989;43:564-567. 42. Haeberle M, Wittner B. Is gentamicin-loaded bone cement a risk for developing systemic allergic dermatitis? Contact Dermatitis. 2009;60: 176-177. 43. Armingaud P, Martin L, Wierzbicka E, Esteve E. Baboon syndrome due to a polysensitization with corticosteroids. Ann Dermatol Venereol. 2005;132:675-677. 44. Baeck M, Goossens A. Systemic contact dermatitis to corticosteroids. Allergy. 2012;67:1580-1585. 45. Basedow S, Eigelshoven S, Homey B. Immediate and delayed hypersensitivity to corticosteroids. J Dtsch Dermatol Ges. 2011;9: 885-888. 46. Coopman S, Degreef H, Dooms-Goossens A. Identification of crossreaction patterns in allergic contact dermatitis from topical corticosteroids. Br J Dermatol. 1989;121:27-34. 47. Guin JD, Fields P, Thomas KL. Baboon syndrome from i.v. aminophylline in a patient allergic to ethylenediamine. Contact Dermatitis. 1999;40:170-171. 48. Isaksson M, Ljunggren B. Systemic contact dermatitis from ethylenediamine in an aminophylline preparation presenting as the baboon syndrome. Acta Derm Venereol. 2003;83:69-70. 49. Gallo R, Parodi A. Baboon syndrome from 5-aminosalicylic acid. Contact Dermatitis. 2002;46:110. 50. Proske S, Uter W, Schnuch A, Hartschuh W. Severe allergic contact dermatitis with generalized spread due to bufexamac presenting as the “baboon” syndrome. Dtsch Med Wochenschr. 2003;128:545-547. 51. Burden AD, Wilkinson SM, Beck MH, Chalmers RJ. Garlic-induced systemic contact dermatitis. Contact Dermatitis. 1994;30:299-300. 52. Mahajan VK, Sharma NL, Sharma RC. Parthenium dermatitis: is it a systemic contact dermatitis or an airborne contact dermatitis? Contact Dermatitis. 2004;51:231-234. 53. Oh SH, Haw CR, Lee MH. Clinical and immunologic features of systemic contact dermatitis from ingestion of Rhus (Toxicodendron). Contact Dermatitis. 2003;48:251-254. 54. Rodriguez-Serna M, Sanchez-Motilla JM, Ramon R, Aliaga A. Allergic and systemic contact dermatitis from Matricaria chamomilla tea. Contact Dermatitis. 1998;39:192-193.

Systemic contact dermatitis 55. Pfutzner W, Thomas P, Niedermeier A, Pfeiffer C, Sander C, Przybilla B. Systemic contact dermatitis elicited by oral intake of Balsam of Peru. Acta Derm Venereol. 2003;83:294-295. 56. Pfutzner W, Niedermeier A, Thomas P, Przybilla B. Systemic contact eczema against Balsam of Peru. J Dtsch Dermatol Ges. 2003;1:719-721. 57. Cho E, Lee JD, Cho SH. Systemic contact dermatitis from propolis ingestion. Ann Dermatol. 2011;23:85-88.

419 58. Dubois A, Thellier S, Wierzbicka-Hainaut E, Pierre F, Anyfantakis V, Guillet G. Two cases of baboon-like exanthema in primary parvovirus B19 infection. Ann Dermatol Venereol. 2010;137:709-712. 59. Minelli M, Schiavino D, Musca F, et al. Oral hyposensitization to nickel induces clinical improvement and a decrease in TH1 and TH2 cytokines in patients with systemic nickel allergy syndrome. Int J Immunopathol Pharmacol. 2010;23:193-201.

Clinics in Dermatology (2014) 32, 420–423

Chronic urticaria as a systemic disease Razvigor Darlenski, MD, PhD a,⁎, Jana Kazandjieva, MD b , Torsten Zuberbier, MD c , Nikolai Tsankov, MD, PhD a a

Department of Dermatology and Venereology, Tokuda Hospital-Sofia, 51B Nikola Vaptsarov Blvd., Bulgaria Department of Dermatology and Venereology, Medical Faculty, Medical University-Sofia, Bulgaria c Department of Dermatology, Venereology and Allergology, Charité University Clinic, Berlin, Germany b

Abstract Urticaria is one of the most common diseases seen in everyday dermatologic practice, characterized by the development of wheals, angioedema, or both. While acute urticaria is mostly related to allergic or pseudoallergic reaction to food, drugs, or infections, chronic urticaria is a more complex disease with different additional ethiopathologic mechanisms and evoking factors. While urticaria is an undisputed disease of the skin, growing evidence supports, like in other dermatologic diseases, the concept of urticaria as a systemic disease with clinical symptoms and signs predominantly presenting on the skin. In this review, we describe the evidence and association between chronic urticaria and a variety of disorders, such as autoimmune diseases, atopy, infections, metabolic conditions, and neoplastic disorders. Beyond the mechanistic association, the possible common underlying pathomechanisms, such as systemic immunologic processes, are discussed. © 2014 Elsevier Inc. All rights reserved.

Introduction A disease that affects a number of organs and tissues, or affects the body as a whole, can be regarded as a systemic one.1 Presuming this definition, a differentiation between disease association and true systemic involvement should be made. Urticaria, also known as hives, is an inflammatory disease, characterized by the development of wheals (hives), angioedema, or both.2 As different conditions, which may present with wheals or angioedema, eg, skin prick test, anaphylaxis, autoinflammatory syndromes, Muckle-Wells syndrome, Schnitzler’s syndrome, and Well’s syndrome, these are not the focus of this review and will not be addressed, herein. Chronic urticaria (CU) is defined as a duration of the disease for more than six weeks. The lifetime prevalence of ⁎ Corresponding author. Tel.: +359 890 545599. E-mail address: [email protected] (R. Darlenski). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.009

urticaria is 8.8% to 20% and 1.8% for CU in particular.3 CU seriously affects the quality of life of the patients and results in difficulties in relation to work, domestic activities, social life, home relationships, sexual life, hobbies, and holidays.4 It is the reason for sleep disturbances and impairs work and school productivity.5

Historical perspective Feng Yin Zheng is the name under which urticaria probably was first documented in the “The Yellow Emperor’s Inner Classic,” written about 1000 years B.C.E.6 As with many diseases, it was considered as an imbalance between Yin and Yang. Hippocrates suggested that ingesting some foods like milk, as well as contact with nettle and mosquito bites, can induce an itching skin rash, named knido.7 It is accepted that the modern name of the disease dates back to the old Latin term urtica for nettle (Urtica urens), although the first use of the term urticaria

Chronic urticaria was in the 18th century in the book Synopsia Nosalogiae Methodica. In subsequent years, different subtypes of urticaria have been described. The modern understanding of the disease is related to the works of one man who, in 1877, discovered the mastocytes and the works of several researchers on histamine. 8 Milestones in the study of urticaria include the revealing of the role of IgE and the classification of the disease as a type 1 reaction.8 The concept of CU, as a systemic disease crossing the frontiers of the skin, is not a new one. In the midtwentieth century, different loci of infection or other concomitant disease were revealed by many researchers. An autoimmune nature was first suspected by the Swedish dermatologist Rorsman, and supported by the findings of Leznoff on the association of CU with thyroid autoimmunity.9 Today, autoimmune urticaria is accepted as one of the possible underlying causes in CSU. In the beginning of this century, the concept of chronic urticaria (CU) as a systemic disease has further developed.

Pathophysiology in the light of systemic involvement Patients with CSU present spontaneous appearance of wheals, angioedema, or both in unpredictable places of the integument without external triggers. The mast cell is the key player, although not the only one, in the pathogenesis of urticaria. Degranulation of these cells results in the release of mediators, above all histamine, responsible for the inflammatory changes, sensory nerve activation, and the local increase in permeability of capillaries and venules. Beyond histamine, leukotrienes, serine proteases, heparin, tryptase, and proinflammatory cytokines are involved in the pathogenesis of the disease. Histamine can modulate systemic inflammatory response and posses certain effects on cellmediated immunity, eg, on monocytes. 10 Subclinical inflammation, as also observed in obesity, stimulates mast cell reactivity by the secretion of adipocytokines, such as interleukin-9 (IL-9), IL-33, and stress molecules, including corticotropin-releasing hormone and neurotensin.11 Biologic markers of inflammation, namely C-reactive protein (CRP) and procalcitonin, are elevated in the sera of CU patients, suggesting possible enrolment in urticarial inflammation.12 CU can be regarded as a disease with systemic vascular inflammation, even in sites uninvolved with lesions. In support of this hypothesis, an increase in the soluble P-selectin in CU (as well as in dermographic urticaria) compared to healthy controls and rhinitis subjects.13 P-selectin, a cell adhesion molecule on the surfaces of activated endothelial cells, was observed immunohistologically even in nonlesional skin, suggesting subclinical inflammation in clinically healthy areas. Coagulation factors may enhance vascular permeability or induce mast cell degranulation. Tissue factor, an initiator of

421 the extrinsic cascade of blood coagulation, has been linked to systemic inflammation. Its activation results in signaling from the coagulant mediators (factors VIIa, Xa, and IIa), as well as from the fibrin mediate diverse intracellular activation and the production of proinflammatory mediators, including cytokines, adhesion molecules, and growth factors.14 Such coagulation-dependent or noncoagulationmediated actions suggest the role of the so-called coagulation-inflammation-thrombosis circuit. CU is characterized by elevated blood coagulation potential with all parameters of a global coagulation test correlating to the urticaria severity.15 Fibrin degradation products, D-dimer and serum CRP levels decreased in serum of CU patients as their disease improved, while they rose during CU exacerbation.16 The role of concomitant infections is mainly focused in the pathogenesis of acute urticaria. Infections and microbial carriage have a potential role in CU, namely Helicobacter pylori, Streptococcus spp., Yersinia enterocolitica, and the hepatitis C virus.17 The most commonly affected systems include ear-nose-throat (ENT), gastro-intestinal tract (GI), and dental. The most widely studied microorganism is H pylori. The rate of remission of CU, when H pylori was eradicated, was 61.5% in comparison to 33.6% without eradication (remission rate among control subjects without H pylori infection was 29.7%).17 It is suggested that among other factors, screening for H pylori infection and its eradication is reasonable in patients with CU.17,18 ENT infections, such as tonsillitis and sinusitis, have been found in about half of the patients with CU.19 Nasal carriage of Staphylococcus aureus was found in 53.2% of patients with CU, while this percentage reached just 13.3% in healthy controls.20 Although the list of reports for the association between different infections and CU is increasing, the efficacy of systemic antimicrobial agents has not been challenged in prospective controlled studies.

Clinical evidence for systemic involvement CNS effects of urticaria The link between skin and the mind and the role of neuroendocrino-immunologic regulation in both psychiatric and skin diseases has been considered in recent decades. Psychological stress is accepted as one of the provoking factors in CU.21 In addition, CU patients show difficulties in dealing with emotion arousal, suggesting an association between CU and alexithymia.22 The psychological profile of CU patients includes a neurotic personality trait.23 Psychiatric comorbidities were registered in 60% of the CU adult population; depression was the most common diagnosis.24 Similar results were revealed in the pediatric population, where 70% of the patients with CU (versus 30% of the controls) presented with a psychiatric comorbidity.25

422 The most common diagnoses included social anxiety disorder, separation anxiety disorder, and specific phobias. The authors also disclosed depression, trait anxiety, internalizing problems, and somatic complaints as major issues in these patients. No correlation was found with the duration and the severity of CU. A recent study observed psychiatric problems in 48% of patients with chronic spontaneous urticaria.26 Among all anxiety disorders, mostly phobias, followed by depression, and somatoform disorders, were the most common. The role of treating psychiatric comorbidities in CU remains to be elucidated.

Association between CU and other diseases CU can often be associated with multiple systemic disorders. Some of the evidence shows that these associations are not simply mechanistic, but they also possibly involve common pathogenic mechanism.

Atopic diathesis A study among more than 4000 children up to 2 years of age found an association between atopic dermatitis (AD) and other manifestations from the atopic spectrum.27 Urticaria was one of the most common concomitant diseases with a ratio of proportions of 2.04 (CI 1.80-2.31). In another study, history of childhood dermatitis was strongly associated with urticaria (odds ratio, 2.50).28 In a large cohort, prick tests revealed sensitization of ≥ 1 for type 1 allergens in 39.1% of patients with urticaria.3 The results were related to comorbidities, such as allergic rhinitis or oral allergy syndrome, but were never the underlying cause of CU, as proven by doubleblind, placebo-controlled provocation tests. Allergic skin disorders, such as AD and urticarial, are frequently associated with comorbidities, including allergic rhinitis and chronic rhinosinusitis.29 In addition to the high prevalence and coincidence, probable common or similar pathomechanisms could be involved. In a study among almost 4000 schoolchildren urticaria was disclosed as a significant risk factor for the development of allergic rhinitis.30

Autoimmune diseases Chronic autoimmune urticaria (CAU) is caused by antiFcεRI, and less frequently, by anti-IgE autoantibodies that lead to mast cell activation. Autoimmunity is a systemic process not limited to the skin, in accordance with understanding of urticaria as a systemic disease. Confirmation comes from the numerous associations between CU and autoimmune diseases.31

R. Darlenski et al. Autoantibodies against the alpha subunit of the high-affinity IgE receptor have been witnessed in the sera of 35% to 55% of patients with CU, an entity that was later classified as autoimmune urticaria.32,33 The specificity of autoantibodies responsible for the activation of the basophils (CU index) was evaluated in different diseases, demonstrating positivity in 33% of the cases with CU, 23% in systemic lupus erythematosus, 3.7% of patients with rheumatoid arthritis, and 15% of controls.34 These results suggest that the functional autoantibodies are not specific, although highly prevalent in CU. Recent data from following nearly 13,000 patients with CU found that women had a significantly higher incidence of rheumatoid arthritis, Sjögren syndrome, celiac disease, type I diabetes mellitus, and systemic lupus erythematosus.31 Positive rheumatoid factor and antinuclear antibodies were significantly more prevalent in patients with CU. The diagnosis of the autoimmune disorder was made mostly in the 10 years after the patient was diagnosed with CU. CU was observed in 4.3 of the cases amongst 46 studied patients with systemic sclerosis.35 Antithyroid antibodies are detectable in up to 30% in patients with CU, although their presence is neither associated with hormonal dysfunction of the gland, nor with the severity and the course of urticaria.36,37

Miscellaneous The metabolic syndrome (MS) is associated with CU according to a recent report.38 MS was observed in 29.8% of patients with CU, significantly higher compared with 17.8% in a matched control group. Patients with coexistence of both disorders had a higher mean urticaria activity score and serum levels of eosinophil cationic protein, tumor necrosis factor-α, and complements, and showed a higher rate of negative autologous serum skin tests in comparison to those without metabolic syndrome. Lower serum vitamin D levels were found in patients with CU.39 In analogy to other diseases, supplementation of vitamin D in subjects with urticarial skin lesions resulted in improvement of the symptoms.40

Conclusions Until recently, extensive testing of urticaria patients was the rule. Currently, the evidence is clear that extensive testing is not economic and the guidelines strongly recommend focusing the diagnostic procedures based on patient history. A growing body of evidence suggests that CU is often accompanied, as well as modulated, by a plethora of systemic diseases. That may open a new debate on the clinical relevance of administering laboratory investigations for the active screening of concomitant disorders. The question of predicting markers and the role of treating these comorbidities remains to be addressed in future controlled clinical trials.

Chronic urticaria

References 1. Dorland WAN, Anderson DM. Dorland’s Illustrated Medical Dictionary. 28th ed. Philadelphia: Elsevier Health Sciences; 1994: 489, 1653. 2. Zuberbier T, Asero R, Bindslev-Jensen C, et al. EAACI/GA(2) LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. Allergy. 2009;64:1417-1426. 3. Zuberbier T, Balke M, Worm M, et al. Epidemiology of urticaria: a representative cross-sectional population survey. Clin Exp Dermatol. 2010;35:869-873. 4. O’Donnell BF, Lawlor F, Simpson J, et al. The impact of chronic urticaria on the quality of life. Br J Dermatol. 1997;136:197-201. 5. Zuberbier T. Pharmacological rationale for the treatment of chronic urticaria with second-generation non-sedating antihistamines at higherthan-standard doses. J Eur Acad Dermatol Venereol. 2012;26:9-18. 6. Veith I. The Yellow Emperor’s Classic of Internal Medicine. Malaysia: Pelanduk Publications. 1992. 7. Juhlin L. The History of Urticaria and Angioedema. ESHDV Special Annual Lecture: Geneva, Switzerland. 2000. 8. Greaves M. History of urticaria. In: Zuberbier T, Grattan CEH, Maurer M, eds. Urticaria and Angiodema. Heidelberg Dordrecht London New York: Springer-Verlag; 2010. p. 1-7. 9. Leznoff A, Sussman GL. Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients. J Allergy Clin Immunol. 1989;84:66-71. 10. Soga F, Katoh N, Kishimoto S. Histamine prevents apoptosis in human monocytes. Clin Exp Allergy. 2007;37:323-330. 11. Sismanopoulos N, Delivanis DA, Mavrommati D, et al. Do mast cells link obesity and asthma? Allergy. 2013;68:8-15. 12. Kasperska-Zajac A, Grzanka A, Machura E, et al. Analysis of procalcitonin and CRP concentrations in serum of patients with chronic spontaneous urticaria. Inflamm Res. 2013;62:309-312. 13. Zuberbier T, Schadendorf D, Haas N, et al. Enhanced P-selectin expression in chronic and dermographic urticaria. Int Arch Allergy Immunol. 1997;114:86-89. 14. Chu AJ. Tissue factor, blood coagulation, and beyond: an overview. Int J Inflam. 2011;367:284. 15. Takeda T, Sakurai Y, Takahagi S, et al. Increase of coagulation potential in chronic spontaneous urticaria. Allergy. 2011;66:428-433. 16. Takahagi S, Mihara S, Iwamoto K, et al. Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria. Allergy. 2010;65:649-656. 17. Wedi B, Raap U, Wieczorek D, et al. Urticaria and infections. Allergy Asthma Clin Immunol. 2009;5:10. 18. Federman DG, Kirsner RS, Moriarty JP, et al. The effect of antibiotic therapy for patients infected with Helicobacter pylori who have chronic urticaria. J Am Acad Dermatol. 2003;49:861-864. 19. Buss YA, Garrelfs UC, Sticherling M. Chronic urticaria—which clinical parameters are pathogenetically relevant? A retrospective investigation of 339 patients. J Dtsch Dermatol Ges. 2007;5:22-29. 20. Ertam I, Biyikli SE, Yazkan FA, et al. The frequency of nasal carriage in chronic urticaria patients. J Eur Acad Dermatol Venereol. 2007;21:777-780. 21. Gupta MA, Gupta AK. Chronic idiopathic urticaria and post-traumatic stress disorder (PTSD): an under-recognized comorbidity. Clin Dermatol. 2012;30:351-354.

423 22. Barbosa F, Freitas J, Barbosa A. Alexithymia in chronic urticaria patients. Psychol Health Med. 2011;16:215-224. 23. Chung MC, Symons C, Gilliam J, et al. The relationship between posttraumatic stress disorder, psychiatric comorbidity, and personality traits among patients with chronic idiopathic urticaria. Compr Psychiatry. 2010;51:55-63. 24. Ozkan M, Oflaz SB, Kocaman N, et al. Psychiatric morbidity and quality of life in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2007;99:29-33. 25. Herguner S, Kilic G, Karakoc S, et al. Levels of depression, anxiety and behavioural problems and frequency of psychiatric disorders in children with chronic idiopathic urticaria. Br J Dermatol. 2011;164: 1342-1347. 26. Staubach P, Dechene M, Metz M, et al. High prevalence of mental disorders and emotional distress in patients with chronic spontaneous urticaria. Acta Derm Venereol. 2011;91:557-561. 27. Bohme M, Lannero E, Wickman M, et al. Atopic dermatitis and concomitant disease patterns in children up to two years of age. Acta Derm Venereol. 2002;82:98-103. 28. Bingefors K, Svensson A, Isacson D, et al. Self-reported lifetime prevalence of atopic dermatitis and co-morbidity with asthma and eczema in adulthood: a population-based cross-sectional survey. Acta Derm Venereol. 2012;93:438-441. 29. Olze H, Zuberbier T. Comorbidities between nose and skin allergy. Curr Opin Allergy Clin Immunol. 2011;11:457-463. 30. Sultesz M, Katona G, Hirschberg A, et al. Prevalence and risk factors for allergic rhinitis in primary schoolchildren in Budapest. Int J Pediatr Otorhinolaryngol. 2010;74:503-509. 31. Confino-Cohen R, Chodick G, Shalev V, et al. Chronic urticaria and autoimmunity: associations found in a large population study. J Allergy Clin Immunol. 2012;129:1307-1313. 32. Tong LJ, Balakrishnan G, Kochan JP, et al. Assessment of autoimmunity in patients with chronic urticaria. J Allergy Clin Immunol. 1997;99:461-465. 33. Hide M, Francis DM, Grattan CE, et al. Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med. 1993;328:1599-1604. 34. Cho CB, Stutes SA, Altrich ML, et al. Autoantibodies in chronic idiopathic urticaria and nonurticarial systemic autoimmune disorders. Ann Allergy Asthma Immunol. 2013;110:29-33. 35. Ghosh SK, Bandyopadhyay D, Saha I, et al. Mucocutaneous and demographic features of systemic sclerosis: A profile of 46 patients from eastern India. Indian J Dermatol. 2012;57:201-205. 36. Wan KS, Wu CS. The essential role of anti-thyroid antibodies in chronic idiopathic urticaria. Endocr Res. 2013;38:85-88. 37. Nuzzo V, Tauchmanova L, Colasanti P, et al. Idiopathic chronic urticaria and thyroid autoimmunity: experience of a single center. Dermatoendocrinol. 2011;3:255-258. 38. Ye YM, Jin HJ, Hwang EK, et al. Co-existence of chronic urticaria and metabolic syndrome: clinical implications. Acta Derm Venereol. 2013;93:156-160. 39. Thorp WA, Goldner W, Meza J, et al. Reduced vitamin D levels in adult subjects with chronic urticaria. J Allergy Clin Immunol. 2010;126:413. [author reply 413-414]. 40. Goetz DW. Idiopathic itch, rash, and urticaria/angioedema merit serum vitamin D evaluation: a descriptive case series. W V Med J. 2011;107: 14-20.

Clinics in Dermatology (2014) 32, 424–429

Herpes zoster as a systemic disease Ivan Staikov, MD, PhD a,⁎, Neyko Neykov, MD a , Branka Marinovic, MD, PhD b , Jasna Lipozencic, MD, PhD b , Nikolai Tsankov, MD, PhD a a

Departments of Neurology and Dermatology, Tokuda Hospital Sofia, Bulgaria Department of Dermatology, Medical Faculty, Zagreb, Croatia

b

Abstract Herpes zoster (shingles, zona) is a viral infection commonly affliccting the skin and the nervous system with an overall occurring rate of 3 to 5 cases per 1000 persons per year, with higher rates in middle or later life. With the advancement of medicine, more and more case reports have started to emerge showing different incidences of VZV, some new localizations, clinical presentations, and complications, which break the well-known fact that “VZV affects the skin and nervous system.” Skin lesions are the most important ones for the early and exact diagnosis of herpes zoster (HZ), due to its visibility and well-defined clinical picture of lesions. The most frequent condition following the acute herpes zoster eruption is postherapeutic neuralgia (PHN). There have been other reports of the disease with otorinolaryngologic complications and ophthalmologic ones, such as ophthalmoparesis/ plegia. There have also been reports of delayed contralateral hemiparesis/hemiplegia following the infection, as a manifestation of vaculitis due to a direct VZV invasion of the cerebral arteries. Encephalitis and destructive myelitis is similarly rare, but a serious complication. Some authors found that patients with inflammatory bowel disease are at a significantly increased risk for herpes zoster. As a gastroenterologic complication, there have been several instances of HZV infection with symptoms resembling an acute abdomen. The diagnosis is hard to pinpoint, and a vast array of examinations are required to identify it, sometimes even posthumously. Nephrologic representations and complications have also been reported. With more and more skin diseases being acknowledged as systemic ones, this viral infection is a more likely candidate for the same title. © 2014 Elsevier Inc. All rights reserved.

Introduction Herpes zoster (shingles, zona) is a viral infection commonly afflicting the skin and the nervous system with an overall occurring rate of 3 to 5 cases per 1000 persons per year, with higher rates in middle or later life.1 Especially at risk are immunocompromised patients, the incidence in whom is about 20 times higher. Some historical features of herpes zoster show that the neurologic implications of the segmental distribution of the eruption were recognized in 1831. The first description of ⁎ Corresponding author. Tel.: +359 88 49 33 001; fax: +359 2 403 44 03. E-mail address: [email protected] (I. Staikov). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.010

the inflammatory changes in the ganglia and related portions of the spinal nerves were made in 1862. In 1909, the concept that varicella and zoster are caused by the same agent was introduced.1 The virus that causes herpes zoster is the varicella zoster virus (VZV), the causative agent of varicella.2 VZV is a large, double strained DNA-containing virus, enclosed in a protein envelope that is similar in structure to the virus of herpes simplex. 1,2 The infection is usually clinically characterized by a skin eruption preceded and followed by pain in the distribution of the affected root ganglia. Primary VZV infection, which usually occurs in childhood, results in chickenpox (varicella), after which the virus becomes latent in the cranial nerve ganglia, dorsal root ganglia, and

Herpes zoster autonomic ganglia along the entire neuraxis. Later, as cellmediated immunity to VZV declines with age or is caused by immunosuppression (such as in organ-transplant recipients or in patients with cancer or HIV), VZV can reactivate and cause zoster. With the advancement of medicine, more and more case reports have started to emerge, showing different incidences of VZV, some new localizations, clinical presentations, and complications that break the well-known fact that “VZV affects the skin and nervous system.” Skin lesions are the most important ones for the early and exact diagnosis of herpes zoster (HZ) due to its visibility and well-defined clinical picture of lesions. Varicella zoster virus (VZV) moves down the nerve axon and causes skin lesions in the corresponding dermatome. Basically, skin lesions are determined as a dermatome eruption with pain, but clinically they are characterized with different phases3: • Preeruptive phase • Acute eruptive phase • Chronic phase

Preeruptive phase (preherpetic neuralgia) This prodromal period is characterized by sensory nerves phenomena, including paresthesias, pain, burning, or itching in the affected area. Usually, this period lasts 48 to 72 hours but could be extended to a week. Pain may resemble headache, brachial neuritis, cardiac pain, appendicitis, etc. Malaise, myalgia, headache, photophobia, and fever can be present along with the main neurologic symptoms.

Acute eruptive phase

425 localized in the same area as the skin lesions. Pain can be mild to severe often with a burning sensation and can last for a long period after the eruption has disappeared. Pain is described as stinging, tingling, aching, or burning. Pruritus is usually mild.

Clinical forms Disseminated herpes zoster The eruption in disseminated herpes zoster is localized within the borders of one or more primarily affected dermatomes.4 These extradermatomal vesicles occur a week after the onset of classic dermatomal herpes zoster. Disseminated herpes zoster occurs in approximately 2% of the zoster cases. This clinical form often develops in patients with depressed cellmediated immunity, which can be caused by various underlying clinical situations, including malignancies, radiation therapy, cancer chemotherapy, organ transplants, and long-term use of systemic corticosteroids.

Recurrent herpes zoster In one study, the frequency of herpes zoster (HZ) recurrence in a community population was higher than previously reported.5 In this study, 1669 patients with a medically documented episode of HZ were investigated. Out of a total number of patients, 95 of them had 105 recurrences. The Kaplan-Meier estimate of the recurrence rate at 8 years was 6.2%. With a maximum follow-up of 12 years, the time between HZ episodes in the same person varied from 96 days to 10 years.

Zoster sine herpete After the prodromal period, typical skin lesions appear involving one or a few neighboring dermatomes. At first, erythematous macular, papular or urticarial-like lesions become visible on the skin, but they quickly turn to vesicles. The typical vesicles are grouped in a herpetiform pattern on the erythematous skin. The size of the vesicles is between 1 to 2 mm, but some of them can become confluent. Skin lesions are always distributed unilaterally in a stripe or beltlike pattern. They do not cross the midline. In the beginning, the vesicles are clear, filled with serous fluid. After 3 to 5 days, the vesicles become hemorrhagic and thereafter dry out with brownish crusts. A new eruption may appear over a period of 3 to 4 days. These new lesions appear in the same area and have the same evolutionary polymorphism. Patients are infectious until the vesicles convert to crusts. Enlarged regional lymph nodes can be observed. The eruption heals within two to four weeks. Scarring is rare, usually only if there is a superinfection. The subjective symptoms are usually pain, pruritus, and/or hyperesthesia

Patients with this clinical form represent the entire symptom characteristic for herpes zoster except the typical eruption. Patients experience pain and weakness in a dermatomal distribution, but they have no skin signs, or in rare cases only erythematous macules or plaques with no vesicles.

Herpes zoster and immunodeficiency HZ rates of 29.4 to 51.5 per 1000 person/year have been reported among adults infected with the human immunodeficiency virus. In this form, due to severe immunodeficiency, the eruption often crosses the midline (Figure 1). In addition, higher rates have also been reported in persons with systemic lupus erythematosus, rheumatoid arthritis, granulomatosis with polyangiitis (Wegener), and inflammatory bowel disease.6

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Herpes zoster and impetiginization of the lesions

Chronic phase (postherapeutic neuralgia)

This form is the result of a secondary bacterial infection at the site of the eruption (typically streptococcal or staphylococcal). Necrotizing fasciitis is a possible complication.

The most frequent condition following the acute herpes zoster eruption is postherapeutic neuralgia (PHN). PHN may affect cranial as well as peripheral nerves. The estimated incidence of PHN varies from country to country from 2.0 cases in 1000 people in the United States9 and 8.99/1000 in European countries, such as France.10 PHN is defined as pain at different time intervals after regression of the lesions of HZ in the affected dermatome. To confirm the diagnosis, there has to be daily pain that persists for 3 to 6 months after onset.11 PHN presents as chronic neuropathic pain in a dermatome with unpleasant sensations, such as “throbbing,” “shooting,” “stabbing,” etc. and a paroxysmal lancinating pain, which usually manifests every day and has a big impact on the patient’s quality of life.12 Current treatment involves opioids, tricyclic antidepressants, anticonvulsants, and lidocaine patches, which result only with partial pain relief, but the pain usually persists for months or years. The patient’s response to the treatment wildly varies, and the physician has to take into account and weigh out the possible various adverse effects of the medications for the pain relief and resulting quality of life.13 Any dermatome may be involved, but the most commonly involved are the thoracic dermatomes, particularly T5-T10, presenting in more than two-thirds of cases, followed by the craniocervical regions.1 Sometimes, a focal, asymmetric neurogenic weakness may occur in an extremity affected by cutaneous zoster. Such weakness is due to a lesion of the ventral nerve root, in close proximity to the inflammation in the initiating dorsal ganglion.14 Antiinflammatory treatment is usually administered together with antiviral treatment. Functional motor recovery appears in about 75% of cases within 1 to 2 years.

Wolf’s isotopic response (phenomenon) Inflammatory skin lesions following zoster infection can occur within the affected dermatome. Wolf's isotopic response may be explained as a special subtype of the Koebner phenomenon, in which one skin disease triggers another one.7

Herpes zoster after varicella-zoster vaccination 8 Varicella vaccine contains live attenuated VZV, which causes latent infection. The attenuated vaccine virus can reactivate the virus and cause herpes zoster. People who get vaccinated against varicella may develop herpes zoster later in life; however, their risk is lower than that of the people who were infected with the wild-type VZV. Vaccination also reduces the severity and duration of the disease, as well as its most common complication—postherapeutic neuralgia.

Neurologic and otorinolaryngological involvement

Fig. 1

Herpes zoster in HIV-positive patient.

A neurologic and otorinolaryngologic complication of VZV manifests as Ramsay Hunt syndrome (RHS). RHS is a peripheral facial nerve palsy, usually accompanied by a herpes zoster eruption in the external auditory canal, other parts of the cranial integument, and mucous membrane of the oropharynx, and affects the geniculate ganglion.15 Although similar to Bell’s palsy, its clinical symptoms are more heavily manifested, and there is a higher likelihood of multiple cranial nerve involvement.16 Compared with Bell’s palsy, patients with this syndrome often have more severe paralysis at the onset and are less likely to recover completely. Sometimes, due to the involvement of the vestibulocochlear nerve, RHS is accompanied by vertigo, tinnitus, and unilateral hearing loss,17 although there are reports of the involvement of other cranial nerves.18 Loss of taste over the anterior two-thirds of the tongue occurs in more than 50% of patients.2 There are several authors pinpointing VZV infection with RHS as a primarily

Herpes zoster otorinolaryngologic condition with a secondary dissemination toward the cranial nerves.19–21 Treatment involves usage of acyclovir and prednisone for a better outcome and prognosis.22

427 may cause asymmetric paraparesis, sensory lost, sphincter disturbances, and Brown-Sequard syndrome.1 Polyneuritis of the Guillain-Barre type has been also reported as a consequence of herpes zoster.2

Ophthalmologic involvement Gastrointestinal involvement There have been reports of ophthalmoparesis/plegia after herpes zoster ophthalmicus (HZO). Involvement of the trigeminal ganglion occurs in about 20% of patients and the first division—ophthalmic is the most frequently affected.2 Ophthalmoplegia as part of the sequela of HZO has typically been described as a late complication, often up to 2 months after the initial herpetic eruption.23 HZO involves not only the cranial nerve but also affects and impairs vision and causes damage to the eye bulbi and pupilae, as well as a pure ophthalmologic complication.24,25 Another complication of ophthalmic zoster is acute contralateral hemiplegia and ipsilateral hemisphere signs, such as aphasia, that can occur weeks or months later after HZO.2

Vasculopathy There have been reports of symptoms of delayed contralateral hemiparesis/hemiplegia following a VZV infection. This is a manifestation of vaculitis due to a direct VZV invasion of the cerebral arteries.26,27 This VZV vasculopathy affects both immunocompetent and immunocompromised patients, occurs after zoster or varicella, and can be either unifocal or multifocal. VZV vasculopathy among other conditions can cause ischemic stroke, potentiate a formation of an aneurysm, and sometimes indirectly cause subarachnoid and intraparenchimal cerebral hemorrhaging.28

Encephalitis Encephalitis is a rare but serious complication of herpes zoster. Although rare, it may occur in up to 5% of patients with HZ.29 A few studies have examined the brain changes and cognitive outcomes associated with herpes zoster encephalitis. They show variability in the brain regions affected, severity of neurologic damage, and cognitive deficit. Symptoms vary, the initial ones usually consist of headache, vomiting, fever, and altered sensory feel.30

Myelitis Destructive myelitis is similarly rare, but serious complication mainly of thoracic zoster. The signs of spinal cord involvement appear 15 to 21 days after the eruption and

Some authors have found that patients with inflammatory bowel disease are at a significantly increased risk for herpes zoster.31 They did a retrospective cohort and nested case– control study and analyzed more than 108,000 patients with inflammatory bowel disease and 430,000 matched controls. The overall annual incidence of herpes zoster per 100,000 person-years was 734 among inflammatory bowel disease patients, compared with 437 in noninflammatory bowel disease patients (incidence rate ratio = 1.68). This study gives evidences for an elevated risk for HZ in inflammatory bowel disease patients. According to the same paper, treatment with thiopurines, corticosteroids, and biologic antitumor necrosis factor–alpha (anti-TNF) agents was independently associated with an increased risk of herpes zoster. Some authors20,32,33 have reported several instances of HZV infection, appearing with symptoms resembling an acute abdomen. The diagnosis is hard to pinpoint, and a vast array of examinations were required to pose it, sometimes even posthumously. The patients’ symptoms usually only appear with a sudden sharp pain in the abdomen, without any skin lesions or characteristics of neuropathic pain. These cases have open or microinvasive surgery and sometimes reveal a disseminated infection, engaging various abdominal organs.20,21,34 The diagnosis is suggested as the condition visceral zoster. The dissemination of the VZV infection to the abdominal organs is majorly found in immunocompromised patients following transplantation surgeries, an HIV infection, systemic treatment with corticosteroids, postsepticemic conditions, and others. Although similar in case to case, the symptoms of the infection represent with gastroenterological signs, such as bleeding ulcers in the gastrointestinal tract, acute abdomen with the typical syndromological evolution, and reactive hepatitis with no prior HCV infection or patient history pointing out environmental factors.21–23,35,36 In the aforementioned there were no apparent typical neurologic or skin signs.

Nephrologic and urologic involvement Nephrologic representations and complications have also been reported.37 At first, the clinical signs only manifest with direct imaging diagnostic and paraclinical signs of renal impairment or failure and no typical skin or neurologic condition to pinpoint. Some authors even suggest that the high overall incidence of HZV infection in the general

428 populace increases the morbidity rate of renally transplanted patients by as high as 30%.38 Urologic complications have also been reported, although usually these are secondary to a skin or neurologic representation of the VZV infection, the virus has started to be associated with the incidence of bladder cancer39 and acute urinary retention, with or without an apparent primary affect of the disease.40–42

HZ and immunocompromised patients The incidence of HZ complications is common in immunocompromised patients, and it is even higher in those with bone marrow transplantation. Diagnosis is difficult due to the fact that it can coexist together with a visceral dissemination. When this viral infection is discovered late, it is associated with high morbidity and mortality usually caused by acute respiratory distress, liver failure, pancreatitis, and others.43

Conclusions VZV infection has been recognized for more than a century as a skin or neurologic disease, but as science progresses, more basic evidence has emerged that this might not be the case. With more and more skin diseases being acknowledged as systemic ones, this viral infection is a more and more likely candidate for the same title.

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I. Staikov et al. 10. Mick G, Gallais JL, Simon F, et al. Burden of herpes zoster and postherpetic neuralgia: incidence, proportion, and associated costs in the French population aged 50 or over. Rev Epidemiol Sante Publique. 2010:393-401. 11. Thyregod HG, Rowbotham MC, Peters M, et al. Natural history of pain following herpes zoster. Pain. 2007;128:148-156. 12. Niv D, Maltsman-Tseikhin A. Postherpetic neuralgia: the never-ending challenge. Pain Pract. 2005;5(4):327-340. 13. Hempenstall K, Nurmikko TJ, Johnson RW, et al. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med. 2005;2:e164. 14. Merchut MP, Review Gruener G. Segmental zoster paresis of limbs. Electromyogr Clin Neurophysiol. 1996;36:369-375. 15. Ropper AH, Samuels MA. Diseases of the cranial nerves. Adams and Victors’s Principles of Neurology, 9th ed. New York: McGraw-Hill, Inc; 2009. p. 1326-1340. 16. Sweeney CJD, Gilden H. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry. 2001;71:149-154. 17. Iwasaki H, Toda N, Takahashi M, et al. Vestibular and cochlear neuritis in patients with Ramsay Hunt syndrome: a Gd-enhanced MRI study. Acta Otolaryngol. 2013;4:373-377. 18. Babtain FA, Bhatia HS, Assiri AH. Ramsay Hunt syndrome with multiple cranial neuropathies in a liver transplant recipient. Neurosciences (Riyadh). 2012;17:262-264. 19. Heymans F, Lacroix JS, Terzic A, Landis BN. Gustatory dysfunction after mandibular zoster. Neurol Sci. 2011;32:461-464. 20. Lin YY, Kao CH, Wang CH. Varicella zoster virus infection of the pharynx and larynx with multiple cranial neuropathies. Laryngoscope. 2011;121:1627-1630. 21. Chen PS, Lin YY, Huang BR. Pharyngolaryngeal zoster: a case report. Arch Otolaryngol Head Neck Surg. 2012;138:592-595. 22. Uscatequi T, Dorée C, Chamberlain IJ, Burton MJ. Antiviral therapy for Ramsay Hunt syndrome (herpes zoster oticus with facial palsy) in adults. Cochrane Database Syst Rev. 2008:CD006851. 23. Chang-Godinich A, Lee AG, Brazis PW, Liesegang TJ, Jones DB. Review. Complete ophthalmoplegia after zoster ophthalmicus. J Neuroophthalmol 17(4):262–265. 24. Czyz CN, Bacon TS, Petrie TP, Justice JD, Cahill KV. Isolated, complete paralytic mydriasis secondary to herpes zoster ophthalmicus. Pract Neurol. 2013;13:183-184. 25. Nithyanandam S, Joseph M, Stephen J. Ocular complications and loss of vision due to herpes zoster ophthalmicus in patients with HIV infection and a comparison with HIV-negative patients. Int J STD AIDS. 2013;24:106-109. 26. Hilt DC, Buchholz D, Drumholz A, Weiss H, Wolinsky JS. Herpes zoster ophthalmicus and delayed contralateral hemiparesis caused by cerebral angiitis: diagnosis and management approaches. Ann Neurol. 1983;14:543-553. 27. Melanson M, Chalk C, Georgevich L, et al. Varicella-zoster virus DNA in CSF and arteries in delayed contralateral hemiplegia. Evidence for viral invasion of cerebral arteries. Neurology. 1996;47:569-570. 28. Gilden D, Cohrs J, Mahalingam R, Nagel MA. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol. 2009;8:731. 29. Mazur MH, Dolin R. Herpes zoster at the NIH: a 20 year experience. Am J Med. 1978;65:738-744. 30. Bangen KJ, Delano-Wood L, Wierenga CE, et al. Dementia following herpes zoster encephalitis. Clin Neuropsychol. 2010;24:1193-1203. 31. Long MD, Martin C, Sandler RS, Kappelman MD. Increased risk of herpes zoster among 108,604 patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2013;37(4):420-429. 32. O’Loughlin CJ. Visceral varicella zoster after bone marrow transplantation. An obscure cause of an “acute abdomen. Dig Dis Sci. 1964;47:1962-1964. 33. Verdonck LF, Cornelissen JJ, Dekker AW, Rozenberg-Arska M. Acute abdominal pain as a presenting symptom of varicella-zoster virus infection in recipients of bone marrow transplants. Clin Infect Dis. 1993;16:190-191.

Herpes zoster 34. Yagi T, Karasuno T, Hasegawa T, et al. Acute abdomen without cutaneous signs of varicella zoster virus infection as a late complication of allogenic bone marrow transplantation: importance of empiric therapy with acyclovir. Bone Marrow Transplant. 2000;25:1003-1005. 35. Rogers SY, Irving W, Harris A, Russell NH. Visceral varicella zoster infection after bone marrow transplantation without skin involvement and the use of PCR for diagnosis. Bone Marrow Transplant. 1995: 15805-15807. 36. Krones E, Petritsch W, Valentin T, et al. Visceral dissemination of herpes zoster with multiple ulcers in the upper gastrointestinal tract of an apparently immunocompetent patient. Endoscopy. 2012;44 Suppl 2 UCTN:E302-3. doi: 10.1055/s-0032-1309926. [Epub 2012 Aug 29]. 37. Peritz DC, Duncan C, Kurek K, Perez-Atayde AR, Lehmann LE. Visceral varicella zoster virus (VZV) after allogeneic hematopoietic stem cell transplant (HSCT) in pediatric patients with chronic graft-versus-host disease (cGVHD). J Pediatr Hematol Oncol. 2008;30:931-934.

429 38. Jantsch J, Schmidt B, Bardutzky J, Bogdan C, Eckardt KU, Raff U. Lethal varicella-zoster virus reactivation without skin lesions following renal transplantation. Nephrol Dial Transplant. 2011;26:365-368. 39. Rommelaere M, Maréchal C, Yombi JC, Goffin E, Kanaan N. Disseminated varicella zoster virus infection in adult renal transplant recipients: outcome and risk factors. Transplant Proc. 2012;44: 2814-2817. 40. Panagiotakis GI, Papadogianni D, Chatziioannou MN, Lasithiotaki I, Delakas D, Spandidos DA. Association of human herpes, papilloma and polyoma virus families with bladder cancer. Tumour Biol. 2013;34:71-79. 41. Julia JJ, Cholhan HJ. Herpes zoster-associated acute urinary retention: a case report. Int Urogynecol J Pelvic Floor Dysfunct. 2007;18:103-104. 42. Chan JE, Kapoor A. Herpes zoster infection: a rare cause of acute urinary retention. Can J Urol. 2003;10:1912-1913. 43. Chen PH, Hsueh HF, Hong CZ. Herpes zoster-associated voiding dysfunction: a retrospective study and literature review. Arch Phys Med Rehabil. 2002;83:1624-1628.

Clinics in Dermatology (2014) 32, 430–434

Vitiligo as a systemic disease Torello Lotti, MD a , Angelo Massimiliano D'Erme, MD b,⁎ Chair of Dermatology and Venereology, University of Rome “G. Marconi,” Rome, Italy Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Viale Michelangiolo 41, 50100 Florence, Italy a

b

Abstract Vitiligo is an acquired depigmentary skin disorder of unknown etiology. Vitiligo is not only a disease of melanocytes of the skin. Human melanocytes are derived from the neural crest and are located on various parts of the body. The involvement of skin melanocytes is the most visible one, but a systemic involvement of melanocytes can be observed. Some types of vitiligo (nonsegmental vitiligo) may also be associated with various diseases, mainly with autoimmune pathogenesis. Vitiligo represents a spectrum of many different disorders with different etiologies and pathogeneses, causing a common phenotype: the loss of melanocytes and/or their products. This phenotype is always consistent with a systemic involvement. © 2014 Elsevier Inc. All rights reserved.

Introduction Vitiligo is an acquired depigmentary skin disorder of unknown etiology. It is characterized by white macules and patches, often symmetric, whose size increase during time, relating to the loss of functioning melanocytes. Approximately, 0.5% to 1% of the European and American population is affected with no racial or sex differences.1-3 The prevalence ranges from less than 0.1% to more than 8% worldwide. Vitiligo can appear at any time, and it significantly impairs the patients' quality of life.1,3 It is usually asymptomatic. This disease does not target merely the skin: it seems to have a potential to trigger the development of generalized syndromes, mainly linked with the immune system. The first report of vitiligo in association with other diseases was published by Thomas Addison in 1855, in which he described the association of adrenal insufficiency and vitiligo.2,4,5 From then, several systemic diseases, mainly with autoimmune pathogenesis, have been described to be significantly associated with vitiligo. ⁎ Corresponding author. Tel.: +393498451303. E-mail address: [email protected] (A.M. D'Erme). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.011

The clinical observation that 10% to 15% of patients with vitiligo develop autoimmune disease in comparison with the prevalence of 1% to 2% of autoimmune diseases in the general population and the presence of autoantibodies against melanocytes support the autoimmune etiopathogenesis of the disease and characterize a part of the systemic involvement.2,6

Clinical manifestation White macules or patches, surrounded by normal skin, usually involve areas that are normally hyperpigmented, such as the face, hand, periorificial area, nipples, and axillae Leukotrichia often follows a depigmentation of surrounding epidermis. Occasionally, mucosae and internal organs containing melanocytes may be affected. The diagnosis is made clinically. Recently, vitiligo has been classified into localized (focal, unilateral/segmental, and mucosal), generalized (vulgaris, acrofacialis, and mixed), and universal (including also special forms such as trichrome vitiligo, quadrichrome vitiligo, and inflammatory vitiligo) according to the extension of the involved areas.7

Vitiligo, a systemic disease Vitiligo can also be divided into segmental and nonsegmental. The first type matches totally or partially with a cutaneous segment (dermatomal distribution).1,8 It is characterized by white patches with rapid onset and involvement of the hair follicle pigmentary system. This form is related probably to a dysfunction of the sympathetic nerves.8 The second type of disease seems to more associated with systemic involvement.9,10

Systemic involvement The presence, morphology, distribution, and function of melanocytes and melanoblasts in the epidermis and in the hair bulb and buldge area are naturally and commonly investigated by dermatologists and skin biologists. Vitiligo is not only a disease of melanocytes of the skin. Human melanocytes are derived from the neural crest and are located spread on the body: skin, hair follicle, mucous membranes, leptomeninges, eye (uveal tract and retinal pigmented epithelium), inner ear (cochlea, vestibular system, utricle, ampullae), and adipocytes. Little information is presently available on melanocytes located in extra-cutaneous organs, even if the presence and functions of melanocytes have already been shown or hypothesized. The involvement of skin melanocytes is the most visible one but a systemic involvement of melanocytes can be observed. This requires a multidisciplinary diagnostic approach.2 Usually, abnormalities of the melanocytes at eyes or at ears do not bring any relevant sign to the patient and are not observed by physicians; however, their involvement in vitiligo provides a high theoretic and pathogenetic interest. Eye-uveal, well differentiated melanocytes (containing both eu- and pheomelanin) are present in the choroid, where they are responsible for constitutive eye pigmentation and for protection against UV radiation. These cells play important roles in the degradation of toxic derivates. Retinal pigment epithelium is formed by a distinct type of melanocytes specifically present as a single layer of cells behind the retina. These melanocytes are involved in the metabolism of retinoids and of rod outer segments, with major implication in vision. Vitiligo can be linked to pigmentary changes, mainly in the fundus, causing atrophic spot in the retinal pigmented epithelium or chorioretinal scars. It is worthy to underlie the involvement of the spectrum of wellknown ocular diseases associated with depigmented skin patches and the systemic symptoms with leptomeningeal or ear pigment cells. These phenomena may be present in different diseases, such as Vogt-Koyanagi-Harada, birdshot retinopathy, sympathetic ophthalmia and melanoma-associated vitiligo, and retinopathy.

431 Melanocytes can be also found in the inner ear, mainly in the vascular streak of the cochlea, where they are required for the generation of endolymph-mediated action potential necessary for normal hearing. In the inner ear, they have a well studied but partially still obscure role in balance. Audiologic studies among vitiligo patients provide contrasting results.2 The presence of hypoacusis due to alteration of melanocytes may be present in individuals affected by piebaldism. Melanocytes are also present in the brain and in the leptomeninges, possibly with different neuroendocrine functions. They are considered relevant in sleeping regulation and in the synthesis and release of central chemosensor(s) generating the respiratory rhythm. Melanocytes in the brain produce the neuromelanin, which seems involved in removing ROS and metals toxic for the neurons. Melanocytes are present in the heart, especially in valves and in septa and in the lungs. They are also present in the atrium and in the pulmonary veins, where they may contribute to the electrical signaling and to atrial arrhythmias. Vitiligo may also be associated with several and different diseases as shown in Table 1.3 Several reports have shown the close association between vitiligo and autoimmune disorders.3,11 A controlled study has clearly shown an increased incidence of autoantibodies in vitiligo patients: antinuclear (12.4%), antimicrosomal (7.1%), and antismooth muscle antibodies (25.7%).3,12 The association with autoimmune thyroid disease, either hypothyroidism or hyperthyroidism, Grave's disease and Hashimoto's disease, is the most well established. It is also a common finding in the sera of vitiligo patients thyroid autoantibodies (antithyroid, antithyroglobulin). Depending on the studies, thyroid dysfunction is variable in vitiligo patients. It ranges from 0.5% to 43%. Twenty-four percent of pediatric patients with vitiligo report thyroid disorders.13-16 One Italian study, performed on 15,126 vitiligo patients, reported an incidence of thyroid disease of 18.5%.17 All the studies agree with the higher prevalence of thyroid disease in vitiligo patients than in the general population, in which the prevalence of this disease is 1%.2,3,18,19 The course of vitiligo and autoimmune thyroid disease does not have any predictable relationship. The onset of these two diseases is often separated by more than a decade.20 Vitiligo is also associated with other endocrinologic disorders, such as polyglandular syndrome type I and type II, Addison's disease, hypoparathyroidism, and diabetes mellitus type I.2,3 Hematologic diseases(autoimmune hemolytic anemia, pernicious anemia, and hemolytic anemia) are reported to be associated with vitiligo. The incidence of their association is lower than with thyroid disease.2,3,21,22 An association with psychiatric diseases has been reported. Patients who present with emotional stress and low self-esteem tend to suffer more from anxiety and depression disorders.1-3,23 Their quality of life is severely compromised. There is a higher incidence of obsession and

432 Table 1 Disorders and syndromes possibly associated with vitiligo (in alphabetical order) (adapted from Alikhan et al.) 3 Less common associations: - Acrokeratosis paraneoplastica of Bazex - Alezzandrini syndrome - APECED syndrome (Autoimmune polyendocrinopathy candidiasis ectodermal dysplasia) - Asthma - Ataxia-telangiectasia - Deafness - Dermatitis herpetiform - DOPA-responsive dystonia - Dysgammaglobulinemia - Hepatitis C - HIV - Inflammatory bowel disease - Kabuki syndrome - Kaposi sarcoma - Lichen ruber planus - Myasthenia gravis More common associations: - Addison's disease - Alopecia areata - Atopic dermatitis - Atrophic gastritis - Autoimmune thyroid disease - Chronic urticaria - Diabetes mellitus - Halo nevi - Hemolytic anemia (autoimmune) - Hypoacusis - Hypoparathyroidism - Ichthyosis - Lymphoma - Melanoma - Metabolic syndrome - Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome - Morphea - Multiple sclerosis - Myasthenia gravis - Nail dystrophy - Nonmelanoma skin cancer - Ocular abnormalities - Pemphigus vulgaris - Pernicious anemia - Polyendocrinopathy - Psoriasis - Rheumatoid arthritis - Sarcoidosis - Schmidt syndrome - Systemic lupus erythematosus - Turner syndrome - Twenty-nail dystrophy - Vogt–Koyanagi–Harada syndrome

T. Lotti, A.M. D'Erme phobia among vitiligo patients, especially in those presenting markers of autoimmune diseases.23 Several additional skin diseases are associated with vitiligo. Some of them, such as alopecia areata, dermatitis herpetiformis, and morphea may be associated with vitiligo by a common pathogenic mechanism. On the contrary, atopic dermatitis, psoriasis, and lichen planus have been incidentally present in patients with vitiligo.2,3 There is an interesting association that appears between vitiligo and melanoma. The development of vitiligo in patients with metastatic melanoma can lead to a more favorable prognosis. Recent research has suggested that the immune system, responding to malignant pigmented cells, may also destroy the normal skin melanocytes. In patients with metastatic melanoma, antibodies to melanocytes have been shown.2,3,23-27 Recently, there is growing evidence that vitiligo can also be related to systemic inflammatory disorders, such as obesity and the metabolic syndrome. The last is characterized by a combination of abdominal obesity, glucose intolerance, diabetes mellitus, dyslipidemia, and hypertension.28-31 The association of vitiligo with glucose intolerance, insulin resistance, lipid abnormalities, and hyperhomocysteinemia, also characterizes the systemic involvement of the skin disease.30-32 Regarding the last association, Karadag et al.28,33 has revealed that the levels of homocysteinemia, known to inhibit tyrosinase that participates in melanine synthesis, are higher in the group of vitiligo patients in comparison with the controls; thus, hyperhomocysteine, involved in cardiovascular risks in patients with metabolic syndrome, may represent a risk for those with vitiligo. A recent study has shown that the presence of vitiligo is correlated with a family history of cardiovascular disease.33 Further studies need to clarify the vitiligo association with inflammatory systemic disorders, such as the metabolic syndrome,31 and also the role of melanin in obesity-related pathologies. A role for melanocytes has been recently identified in adipose tissue. Melanin biosynthesis takes place in the visceral adipose tissue of morbidly obese humans. With progression of obesity, adipocytes apparently become more exposed to endogenous apoptotic signals especially ROS-mediated. The melanocytes are believed to have a role in the antiinflammatory reactions and in the antioxidant protection as scavengers of free radicals and reactive oxygen species (ROS).34 Adipocytes may “activate” melanogenesis, thus neutralizing excess ROS levels and reducing oxidative damage. Adipocytic-related melanin production may down regulate the synthesis and the release of proinflammatory cytokines, thus impacting on the common metabolic syndrome. Fasting glucose levels correlate with the total and general output of the melanogenic pathway in the adipose tissue of obese subjects.32 The disturbance of their activity could have systemic consequences, worthy of study.

Vitiligo, a systemic disease

Pathophysiology and pathology of vitiligo as a systemic disease Despite new researches and progress, the pathogenesis of vitiligo is still enigmatic. One or more environmental, physiological, or other triggers might induce localized dysfunction or death of melanocytes in predisposed patients, and genetic studies are noncontributory at the moment.2,35,36 The evaluation of associating HLA antigens or genes in the different ethnic groups affected by vitiligo is not explanatory enough; hence, we have to determine the association between the genetic differences with the age of vitiligo onset and the presence of its comorbidities in several populations to better characterize the pathophysiologic mechanism of vitiligo. The involvement of genetic, immunologic, autoimmunologic, cytotoxic, neuronal, autocytotoxic, biochemical, oxidative, melanocyte, and inflammatory factors have supported by several intriguing but not always proven research. The autoimmune hypothesis remains one of the more interesting hypotheses.2,3,37-40 The proinflammatory cytokines (tumor necrosis factor, interleukin 1, and interleukin 6) and other inflammatory factors (eg, free radicals and reactive oxygen species) are known to be involved28,31 in vitiligo. Their systemic increase may be the result from an autoimmune process, as well as oxidative and cytotoxic activities. Because the etiology and pathogenesis of vitiligo are still unknown or uncertain, the question of whether vitiligo should be classified as a disease or a spectrum of disorders becomes central to its classification and management.3,35 Unfortunately, all vitiligo subjects can be included in one or more groups due to the lack of specific genetic markers or specific characteristics with predictive value for classification and differential diagnosis (Biomarkers).41 At the moment nonsegmental vitiligo represents a spectrum of many different disorders with different etiologies and pathogeneses causing a common phenotype: the loss of melanocytes and/or their products. This phenotype is always consistent with a systemic involvement. Some patients are affected (or present) only by vitiligo, some others suffer from multisystem organ dysfunction, the “vitiligo systemic syndromes.” Currently, no biomarker can allow us to distinguish the “cutaneous vitiligo” from the “vitiligo as a systemic syndrome.”1,7,38-40 The involvement of other organs (eg, eye and ear) are often asymptomatic at least in the beginning of the disease activity. For this reason, it is crucial to face a patient with vitiligo always as a patient affected by a systemic disease.

Conclusions Multiple research in the last decades has led to a changing view in the genomic, in the pathophysiology, and in the management of the vitiligo. Despite these remarkable

433 advances and high-content clinical and experimental research, there are still details and discrepancies in the understanding of vitiligo.1,7,38-40 The study of the biology of melanocytes beyond the skin offers outstanding information to dermatologists and skin biologists for boosting the complex role of dermatology in general medicine and, more in general, offers unique chances for fertile collaborations with other specialists who may have less information about melanocytes and the biology of melanogenesis. The understanding of the interaction between skin and systemic diseases and the exploration of novel relevant interdependent pathomechanisms melanocytes-centered seem now mandatory.1,7,38-40 The classification of the phenotypic and systemic manifestation with many different clinical presentations, with unknown etiology, few genetic data, different and fragmented pathogenetic hypotheses is very frustrating for the researchers.7 There is an urgent and strong requirement for appropriate molecular markers.7,38-41 At the same time, there are always increasing data to classify vitiligo as a systemic disease.

References 1. Taieb A, Alomar A, Böhm M, et al. The writing group of the Vitiligo European Task Force (VETF) in cooperation with the European Academy of Dermatology and Venereology (EADV) and the Union Européenne desecins Spécialistes (UEMS). Guidelines for the management of vitiligo: The European Dermatology Forum consensus. Br J Dermatol. 2013 Jan;168:5-19. 2. Lotti T, Hautmann G, Hercogovà J. Vitiligo: disease or symptom? From the confusion of the past to current doubts. In: Lotti T, Hercogovà J, eds. Vitiligo. Problems and solutions. New York, NY: Basel: Marcel Dekker, Inc.; 2004. p. 1-14. 3. Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: a comprehensive overview Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol. 2011;65:473-491. 4. Nordlund J, Seung-Kyung H, eds. Vitiligo, A Monograph on the Basic and Clinical Science. Oxford: Blackwell Science; 2000. p. 89-96. 5. Zelissen PM, Bast EJ, Croughs RJ. Associated autoimmunity in Addison's disease. J Autoimmun. 1995;8:121-130. 6. Brostoff J. Autoantibodies in patients with vitiligo. Lancet. 1969;26: 2177-2178. 7. Hercogová J, Schwartz RA, Lotti TM. Classification of vitiligo: a challenging endeavor. Dermatol Ther. 2012;25(Suppl 1):S10-S16. 8. Hann SK, Lee HJ. Segmental vitiligo: clinical findings in 208 patients. J Am Acad Dermatol. 1996;35(5 Pt 1):671-674. 9. Zhang Z, Xu SX, Zhang FY, et al. The analysis of genetics and associated autoimmune diseases in Chinese vitiligo patients. Arch Dermatol Res. 2009;301:167-173. 10. Mazereeuw-Hautier J, Bezio S, Mahe E, et al, Groupe de Recherche Clinique en Dermatologie Pédiatrique (GRCDP). Segmental and nonsegmental childhood vitiligo has distinct clinical characteristics: a prospective observational study. J Am Acad Dermatol. 2010;62:945-949. 11. de Vijlder HC, Westerhof W, Schreuder GM, Claas FH. Difference in pathogenesis between vitiligo vulgaris and halo nevi associated with vitiligo is supported by an HLA association study. Pigment Cell Res. 2004;17:270-274.

434 12. Hann SK, Im S, Kim HI, Kim HS, Lee YJ, Park YK. Increased incidence of antismooth muscle antibody in Korean vitiligo patients. J Dermatol. 1993;20:679-683. 13. Handa S, Kaur I. Vitiligo: clinical findings in 1436 patients. J Dermatol. 1999;26:653-657. 14. Pagovich OE, Silverberg JI, Freilich E, Silverberg NB. Thyroid abnormalities in pediatric patients with vitiligo in New York City. Cutis. 2008;81:463-466. 15. Iacovelli P, Sinagra JL, Vidolin AP, et al. Relevance of thyroiditis and of other autoimmune diseases in children with vitiligo. Dermatology. 2005;210:26-30. 16. Kakourou T, Kanaka-Gantenbein C, Papadopoulou A, Kaloumenou E, Chrousos GP. Increased prevalence of chronic autoimmune (Hashimoto's) thyroiditis in children and adolescents with vitiligo. J Am Acad Dermatol. 2005;53:220-223. 17. Frati R, Frati C, Sassano PP, Antonaci A. Vitiligo, autoimmune thyroiditis: a rare thyroid cancer arising with bone metastates on maxillofacial area. J Exp Clin Cancer Res. 1999;18:85-87. 18. Barona MI, Arrunátegui A, Falabella R, Alzate A. An epidemiologic case-control study in a population with vitiligo. J Am Acad Dermatol. 1995;33:621-625. 19. Hegedüs L, Heidenheim M, Gervil M, Hjalgrim H, Høier-Madsen M. High frequency of thyroid dysfunction in patients with vitiligo. Acta Derm Venereol. 1994;74:120-123. 20. Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab. 2003;88:2983-2992. 21. Gould IM, Gray RS, Urbaniak SJ, Elton RA, Duncan LJ. Vitiligo in diabetes mellitus. Br J Dermatol. 1985 Aug;113:153-155. 22. Moretti S, Arunachalam M, Colucci R, et al. Autoimmune markers in vitiligo patients appear correlated with obsession and phobia. J Eur Acad Dermatol Venereol. 2012 Jul;26:861-867. 23. Grunnet I, Howitz J, Reymann F, Schwartz M. Vitiligo and pernicious anemia. Arch Dermatol. 1970;101:82-85. 24. Bystryn JC, Rigel D, Friedman RJ, Kopf A. Prognostic significante of hypopigmentation in malignant melanoma. Arch Dermatol. 1987;123: 1053-1055. 25. Lerner AB. Melanoma and vitiligo. Cancer Immunol Immunother. 1997 Aug;44:352-354. 26. Nordlund JJ, Kirkwood JM, Forget BM, Milton G, Albert DM, Lerner AB. Vitiligo in patients with metastatic melanoma: a good prognostic sign. J Am Acad Dermatol. 1983 Nov;9:689-696.

T. Lotti, A.M. D'Erme 27. Lindelöf B, Hedblad MA, Sigurgeirsson B. On the association between vitiligo and malignant melanoma. Acta Derm Venereol. 1998 Nov;78: 483-484. 28. Pietrzak A, Bartosińska J, Hercogová J, Lotti TM, Chodorowska G. Metabolic syndrome in vitiligo. Dermatol Ther. 2012;25(Suppl 1): S41-S43. 29. Reich K. The concept of psoriasis as a systemic inflammation: implications for disease management. J Eur Acad Dermatol Venereol. 2012;26(Suppl 2):3-11. 30. Karadag AS, Tutal E, Ertugrul DT. Insulin resistance is increased in patients with vitiligo. Acta Derm Venereol. 2011;91:541-544. 31. Pietrzak A, Lecewicz-Torun' B, Urban J. Comparison of serum lipid in girls affected with vitiligo and control group. Ann Univ Mariae Curie Sklodowska Med. 2000;55:269-274. 32. Rodríguez-Martín M, de Paz NM, Mehtani P, et al. Patients with vitiligo present fewer cardiovascular risk factors: results from a case-control study. J Eur Acad Dermatol Venereol. 2013;27: 124-125. 33. Arunachalam M, Dragoni F, Colucci R, et al. Non-segmental vitiligo and psoriasis comorbidity—a case-control study in Italian patients. J Eur Acad Dermatol Venereol. 2013;26. [Epub ahead of print]. 34. Karadag AS, Tutal E, Ertugrul DT, Akin KO, Bilgili SG. Serum holotranscobalamine, vitamin B12, folic acid and homocysteine levels in patients with vitiligo. Clin Exp Dermatol. 2012;37:62-64. 35. Huggins RH, Janusz CA, Schwartz RA. Vitiligo: a sign of systemic disease. Indian J Dermatol Venereol Leprol. 2006;72:68-71. 36. Majumder PA. Genetics and prevalence of vitiligo vulgaris. In: Hann SK, Nordlund JJ, eds. Vitiligo: A Monograph on the Basic and Clinical Science. Oxford: Blackwell Science Ltd; 2000. p. 18-20. 37. Ongenae K, Van Geel N, Naeyaert JM. Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res. 2003;16:90-100. 38. Lee BW, Schwartz RA, Hercogová J, Valle Y, Lotti TM. Vitiligo road map. Dermatol Ther. 2012;25(Suppl 1):S44-S56. 39. Lotti TM, Hercogová J, Schwartz RA, et al. Treatments of vitiligo: what's new at the horizon. Dermatol Ther. 2012;25(Suppl 1):S32-S40. 40. Valle Y, Lotti TM, Hercogova J, Schwartz RA, Korobko IV. Multidisciplinary approach to R&D in vitiligo, a neglected skin disease. Dermatol Ther. 2012;25(Suppl 1):S1-S9. 41. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89-95.

Clinics in Dermatology (2014) 32, 435–442

Behçet’s disease as a systemic disease M. Cem Mat, MD a , Ayşegül Sevim, MD a , İzzet Fresko, MD b , Yalçın Tüzün, MD a,⁎ a

Department of Dermatology, Cerrahpasa Medical Faculty, Istanbul University, 34098 Fatih, Istanbul, Turkey Department of Internal Medicine, Division of Rheumatology, Cerrahpasa Medical Faculty, Istanbul University, 34098 Fatih, Istanbul, Turkey b

Abstract Behçet’s disease usually begins with cutaneous manifestations, such as recurrent aphthous stomatitis, genital ulcers, erythema nodosum-like lesions, papulopustular findings, and pathergy phenomenon. Recurrent aphthous stomatitis is generally the first sign, and other findings may develop in the course of the disease. There is no specific diagnostic available for Behçet’s disease. It is most prevalent among patients along the ancient Silk Road. The high frequency of HLA-B51 among a wide range of ethnic populations favors the role of genetic factors. Behçet’s disease usually appears in the third to fourth decade of life, and is rarely seen in children and adults over 50 years of age. It affects both genders equally, but the course of the disease is more severe in men. Eye involvement leading to loss of vision, plus vascular, articular, and central nervous system involvement are more commonly observed among men. Behçet’s disease is a systemic inflammatory disorder. A complex genetic background, coupled with innate and adaptive immune system activation, causes the diverse clinical manifestations that characterize the clinical picture. © 2014 Elsevier Inc. All rights reserved.

Definition Behçet’s disease (BD) is a multisystemic vasculitis, characterized by cutaneous lesions such as aphthous stomatitis, genital ulcers, erythema nodosum-like lesions and papulopustular lesions, as well as uveitis, epididymitis, neurological symptoms, and involvement of vessels of all sizes, joints, and the gastrointestinal system.

hemoptysis, and thrombophlebitis.2 Today, there are many synonyms used for Behçet’s disease, including Behçet’s syndrome, Behçet’s triad, Trisymptom Behçet, La maladie de Behçet, Morbus Behçet, Adamantiades Behçet disease. “Behçet’s disease” is the most frequently used synonym, which is also approved by the International Society of Behçet’s Disease.3,4

Epidemiology History Behçet’s disease was first described by Hulusi Behçet in 1937, as a trisymptom complex, and today we still use these symptoms for diagnosis of the disease.1 Hulusi Behçet mentioned in his papers about patients having recurrent aphthous stomatitis, genital ulcers, and uveitis, together with erythema nodosum, papulopustular lesions, rheumatic pain, ⁎ Corresponding author. Tel.: 00902124143000. E-mail address: [email protected] (Y. Tüzün). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.012

There are sporadic cases of Behçet’s disease all around the world, but it is most frequently seen along the old Silk Road.5 According to epidemiological studies from different geographical regions of the world, the disease is most prevalent in the Middle East and the Far East regions. HLA-B5 and HLA-B51 genes are important in the pathogenesis of the disease, so this distribution may be attributed to the genetic background of these populations.6,7 According to the five large scale epidemiologic studies conducted among the Turkish population, prevalence of

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Behçet’s disease is about 20-421/100,000.8–10 Prevalence of the disease is relatively lower in the Thracian region, compared with Anatolia.11 It is also rarely seen in the pediatric population.12 Prevalence of Behçet’s disease in Istanbul is 42/10,000(10); however, among the Armenian population residing in Istanbul, Behçet’s disease is extremely rare. In addition to that, prevalence of the familial Mediterranean fever is much higher.13 In the light of these researches, genetic factors are thought to play a stronger role than environmental factors in the pathogenesis of the disease. Behçet’s disease is commonly observed in Iran, Israel, China, North Korea, and Japan, whereas in Europe and the United States the estimated prevalence of the disease is variable. Frequency of the diseases is higher in Southern Europe, compared with the Northern regions.5 In France, the total prevalence of the disease is higher among ethnic groups of Asian and North African origin.14 Patients with Behçet’s disease are usually in their third or fourth decades. It is very rare in children and adults over 50 years of age. The first sign is usually recurrent aphthous ulcers. The disease is diagnosed approximately 8.1 years after the presence of the first sign.15 Men and women are equally affected, but the course of the disease is more severe in men.16 Men have a greater tendency for eye involvement that may cause loss of vision, and for the central nervous system and pulmonary artery involvement.17

tional Study Group) for Behçet’s disease, aphthous lesions must recur more than three times a year.20 Incidental trauma, such as tooth brushing, gum chewing, or sharp and rough particles that can provoke the development of RAS.21 The application of a pathergy test to the oral mucosa showed a positivity rate of 47%, whereas 15% of the patients with a positive oral pathergy test develop aphthous lesions.22

Skin changes

Eryhema nodosum Erythema nodosum-like lesions are localized symmetrically on the lower extremities, as well as the thighs and sacral region. These painful nodules are about 1 to 5 cm in diameter. Women are more prone to develop erythema nodosum-like lesions. They usually heal in 1 to 6 weeks, with postlesional hyperpigmentation.18,19 Histology of the lesions shows characteristics of septal panniculitis. In some cases, lobular panniculitis with vasculitis can also be seen and is regarded as nodular vasculitis. Signs of vascular inflammation and infiltration of neutrophiles are common accompanying features. Granuloma formation is rarely seen.24

Mucocutaneous manifestations Recurrent aphthous stomatitis Recurrent aphthous stomatitis (RAS) is one of the most common clinical features of Behçet’s disease.2 In clinical practice, aphthous stomatitis is seen in approximately 97% to 100% of all Behçet patients.18,19 It usually presents as an initial sign of the disease, but it can also develop during the course of the disease, after the appearance of other signs and symptoms. In retrospective analysis, some signs of the disease become apparent many years after the development of aphthous stomatitis.15 Aphthae can be seen anywhere on the nonkeratinized mucosal membranes of the mouth, but the mucosal surface of the lips, the buccal mucosa, or on the lateral tongue are the most common locations. It begins as a painful papule and becomes rapidly ulcerated. White to yellowish pseudomembrane covers the surface of the ulcer and there is an erythematous halo surrounding the lesion. Minor aphthae with a diameter of less than 10 mm, are the most common type. They usually heal spontaneously within 7 to 10 days. Major aphthae consist of deep, painful ulcers, with diameter of more than 10 mm. They may cause scarring after the healing process. The third subgroup, herpetiform aphthae, are characterized by a convergence of multiple ulcers. According to the diagnostic criteria of ISG (Interna-

Genital ulcers Another cardinal sign of Behçet’s disease are genital ulcers. Men usually have ulcers on the scrotum, inguinal region, and penis, whereas women have femoro-inguinal and vulvar ulcers. The ulcer starts as a painful papule, pustule, or necrosis. It has a punched-out appearance with edematous borders and a fibrin layer on the floor. It usually resolves in 2 to 4 weeks. Prevalence of genital ulcer among Behçet’s patients is about 50% to 85 %.18,19 In Behçet patients, who are men 90% of ulcers larger than 1 cm in diameter heal with scar formation. Risk of scar tissue development in small ulcers is about 49%. In women, ulcers on the femoro-inguinal area and the major labia may leave scarring, whereas on the minor labia and vestibule no visible scar formation is seen.23 Vaginal and cervical ulcers are extremely rare.

Nodular lesions

Superficial thrombophlebitis Superficial thrombophlebitis migrans is another kind of nodular lesion seen in Behçet’s disease. They are more frequent in men. Dusky, red nodules are usually located on the medial side of the legs. Superficial thrombosis can present itself as palpable masses along the course of the veins. As old lesions heal with hyperpigmentation, new ones appear. Superficial thrombophlebitis migrans is also thought to be related to deep vein thrombosis.25 Histopathological examination is the gold standard method of differentiating superficial thrombophlebitis migrans lesions from erythema nodosum. High resolution ultrasound imaging is also helpful.

Behçet’s disease Hypoechoic nodules and the presence of thrombus in the lumen and negative compression are the cardinal findings of sonography in cases of superficial thrombophlebitis. Erythema nosodum lesions are hyperechogenic with regular contours.26

Papulopustular lesions Papulopustular lesions are one of the most common findings in Behçet’s disease. They are seen in 30% to 96% of patients with this disease. Acneiform lesions are polymorphous in nature. Inflammatory papules, pustules, and cysts can accompany noninflammatory lesions such as comedons. These acneiform lesions are mostly located on the back, chest, shoulder area, and, less commonly, on face. Acne vulgaris, on the other hand, is seen particularly on the facial area.27 According to ISG, postadolescent acne in patients who are not on systemic corticosteroid treatment, can be regarded as one of the diagnostic criteria; however, acne vulgaris can persist in 5% of men, and 20% of women who are over 25 years of age. Papulopustular lesions are mostly follicular. They were once regarded as noninfectious, sterile pustules, but recent studies have shown the colonization of coagulase negative staphylococcus and provotella species.28 Biopsy specimens of papulopustular lesions, obtained from 89 Behçet patients, were blindly analyzed. Eighty-seven percent of the specimens showed features of folliculitis and perfolliculitis, whereas 9% had vascular pathologies; thus, histological examination of papulopustular lesions are not diagnostic. Clinical differentiation of both follicular and nonfollicular lesions is also difficult.29 There are many studies that reveal a strong relationship between papulopustular skin lesions and arthritis.30,31

Other skin lesions Sweet syndrome can be seen during the course of the disease in Behçet patients, in approximately 4% of cases. Painful, erythematous nodules and papules emerge on the facial areas and extremities. Aphthous ulcers, arthritis, and uveitis can also be components of Sweet syndrome.32 Extragenital ulcers are very rare in Behçet’s disease, and they are located on the inframammarian folds, axillary region, and interdigital area of the feet.33 Patients with a history of deep vein thrombosis are more prone to develop ulcus cruris and vasculitis. Pathergy phenomenon The pathergy reaction is a nonspecific hyperreactivity to a needle prick, but it is indeed very specific in the diagnosis of Behçet’s disease.34 The test is applied to the hairless site of the forearm skin. After cleaning with alcohol, 20 G needles are inserted in an oblique or perpendicular angle. Forty-eight hours after insertion of the needles, a papule or pustule

437 formation on the area shows a positive result. We usually insert six needles at a time, three on one arm and three on the other, to increase the positivity rate. The frequency of pathergy positivity and intensity of the reaction is higher in men.35,36 Pathergy positivity is also one of the diagnostic criteria of ISG. Pathergy positivity rates show geographical variations. In the United Kingdom, pathergy positivity is rarely observed in Behçet patients,36 whereas the positivity rate among Japanese and Turkish Behçet patients is approximately 60% to 70%. Blunt tip needles, compared with disposable or sharp tip needles, cause more local injury to the area, which increases the positivity rate of the test.37

Systemic involvement Eye involvement Many organ systems may be affected by Behçet’s disease, but the most commonly involved organ is the eye. About half of the patients have eye involvement. The prevalence can be as high as 70% among young men, whereas in the older woman population, eye involvement is seen in about 30% of cases. In hospital-based studies, eye involvement begins within the first few years of the disease.17,38 Uveitis generally starts unilaterally, but eventually most patients develop bilateral uveitis. Among patients with uveitis, 80% of men and 64% of women have bilateral uveitis during their first visits.17 Ocular inflammation mostly presents itself as panuveitis or retinitis. Isolated anterior uveitis can be rarely seen but still most of them transform into panuveitis. When the anterior uveal tract is affected, the main symptom is photophobia. Depending on the extensity of the retinal vasculitis, scar formation on the vascular arch, and optic nerve damage may cause irreversible loss of vision. Topical treatments are used for anterior segment involvement, but frequent attacks may lead to the development of secondary glaucoma and cataract. In cases of posterior segment involvement, systemic treatment with corticosteroids or immunosuppressive agents is mandatory. Loss of vision is inevitable in some patients, despite intensive treatment.39

Joint involvement Up to 50% of Behçet patients have either arthritis or arthralgia. Arthritis of Behçet’s disease can be monoarticular or oligoarticular. Symptoms usually heal within a few weeks, without leaving a deformity. Knee, ankle, wrist, and elbow joints are the most frequently affected.40 Back pain and sacroiliac joint involvement is not seen.41 Examination of the synovial fluid reveals inflammatory findings and the formation of mucin clots. Histology of the synovial fluid shows features of nonspecific synovitis.40 Entesopathy usually accompanies arthritis. Acneiform lesions are also common findings of Behçet patients with

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arthritis. Papulopustular lesions and arthritis are together regarded as cluster of disease expression. This cluster is frequently found in familial cases. These observations lead to the hypothesis that coexistence papulopustular lesions and arthritis in Behçet’s disease may have a similar pathogenetic basis with acne-associated reactive arthritis.31

Vascular involvement Behçet’s disease involves both arteries and veins. According to the studies conducted in Turkey, more than 40% of Behçet patients have vascular involvement.17 The frequency of large-vessel involvement in Japan was 6% in a 412 patients series. Venous involvement was more common than arterial.42 Vascular involvement is more commonly seen in male patients with Behçet. The most frequent manifestation of vascular involvement is venous thrombosis in the lower extremities. These thrombotic symptoms become evident 2 to 3 years after the diagnosis of the disease.43 In the case of superficial thrombophlebitis, erythema nodosum-like lesions present on the medial side of the leg, along the course of the veins. These patients may have accompanying deep femoral vein thrombosis or inferior vena cava syndrome. Recurrent thrombosis may lead to chronic venous insufficiency and venous claudication (Figure 1).43 Vena cava thrombosis has variable clinical signs and symptoms, according to the level of obliteration. In cases of superior vena cava syndrome, there is an edema in the head and neck region, together with jugular venous distention, whereas inferior vena cava syndrome causes edema in the lower extremities, with stasis dermatitis and leg ulcers. The dilation of collateral veins in the abdominal area and thoracic wall is also another finding. Budd-Chiari syndrome is a rare, but a potentially fatal complication, of Behçet’s disease. Hepatic vein thrombosis results in ascite formation together with abdominal pain, edema of the lower extremities and scrotal area, and even

Fig. 1

Ulcers due to vasculitis and venous insufficiency.

Fig. 2

Chest X-ray unilateral hilar opacity.

hepatic failure in severe cases. Behçet’s disease is the single most frequent cause of Budd-Chiari syndrome.44 Arterial involvement can also be seen in forms of aneurysms, mostly on the pulmonary artery, peripheral arteries or abdominal aorta. A study of 101 patients with Behçet’s disease 45 found that arterial lesions develop approximately 4 years after the initial diagnosis, with an average age of 38 and a male predominance. Pulmonary artery involvement is rather rare (5%), presenting with either an aneurysm or thrombosis. Vasculitis causes endothelial injury, leading to formation of thrombosis. Main symptoms of pulmonary artery aneurysm are fever, chest pain, cough, dyspnea, and hemoptysis. On initial evaluation, unilateral or bilateral hilar opacities can be observed on a chest X-ray (Figures 2 and 3).46 Arterial aneurysms can also be observed in the peripheral arteries, such as the femoral, iliac, popliteal, or carotid artery, together with abdominal aorta. The rupture of these aneurysms is a major cause of mortality.43 Cardiac involvement is rare in Behçet patients. Intracardiac thrombosis is very rarely seen.47 Young male patients with a concomitant pulmonary artery involvement are candidates for intracardiac thrombosis. The thrombus is mostly located on the right ventricle, firmly attached to the underlying myocardium.48

Fig. 3

Right pulmonary artery aneurysm in CT scan.

Behçet’s disease

Gastrointestinal involvement Gastrointestinal involvement shows geographic variations. In Japan, almost half of the patients with Behçet’s disease have gastrointestinal involvement, whereas in the Mediterranean region it is relatively rare. Patients usually have mild symptoms, such as abdominal pain, diarrhea, nausea or vomiting. Gastrointestinal bleeding or inflammatory bowel disease-like symptoms are also rarely seen. Ulcers of the gastrointestinal tract are mostly located in the terminal ileum, cecum, and colon region, whereas the rectum is usually spared. Perianal ulcers are also rare. Esophageal involvement is more common in men, and ulcers are usually located at the midesophageal level. The main symptoms of these patients are substernal pain and dysphagia.49

Neurologic involvement According to large-scale studies, 5% to 10% of Behçet patients have central nervous system involvement. These patients are usually young men, with a mean age of 26 to 27. Neurologic manifestations are recognized approximately 5 years after the initial diagnosis. In 80% of neuro-Behçet patients, the brain parenchyma is affected. The second most common presentation is cerebral venous thrombosis, seen in about 20% of the patients. Both parenchymal disease and venous thrombosis can have accompanying vasculitis. The parenchymal form is characterized by small vessel involvement, with pyramidal symptoms, such as hemiparesis, cognitive changes, sphincter dysfunction, and impotence. In cases of cerebral venous thrombosis, the clinical picture is comprised of dural sinus thrombosis, severe headaches, papilledema, and motor or ocular nerve paralysis due to elevated intracranial pressure. Dural sinus thrombosis has a benign course. Neuropsycho-Behçet is an organic psychotic syndrome, and a rare variant of neuro-Behçet. Peripheric neuropathy is not seen in Behçet patients.50–52 In a large study of 728 patients, pediatric neuro-Behçet has a frequency of 3%, with a male predominance, and unlike adult patients, dural venous thrombosis is the most common presenting symptom.53

Pathophysiology Behçet’s disease is a systemic inflammatory disorder. A complex genetic background coupled to an innate and adaptive immune system activation causes the diverse clinical manifestations that characterizes the clinical picture. The presence of familial cases in around 10% of the patients, its geographic predilection (a high frequency along the so-called Silk Road from Japan to the Mediterranean basin), and the high frequency of HLA-B51 among a wide range of ethnic populations favors the role of genetic factors in the pathogenesis.6

439 HLA-B51 is a split antigen of HLA-B5. A recent metaanalysis has shown that the pooled odds ratio of HLA-B51/B5 carriers developing Behçet’s disease compared to noncarriers was 5,78 (95% CI 5.00 to 6.67). The risk was consistent across different populations with varying frequencies of Behçet’s disease.54 The role of HLA-B51 in the pathogenesis is not clear. The presentation of a specific peptide to CD 8 + T cells55 and interactions between KIR (killer immunoglobulin-like receptors) of natural killer (NK) cells, CD 8 + T cells and gamma delta T cells56 are possible mechanisms. The possibility of a linkage disequilibrium with HLAB51 has also been discussed. MICA 009 allele, and its transmembrane microsatellite polymorphism A6, was the main candidate; however, fine mapping among different ethnic groups showed that HLA-B51 still had the strongest association. The only exception to this was the HLA-A*26F*010101-G*010102 haplotype, which is associated with Behçet’s disease independently of HLA-B51.57 A recent meta-analysis explored the relationship of HLAB51 with different clinical manifestations of the disease in 72 studies representing 74 populations. The results showed that the main associations were between genital ulcers, eye and skin involvement, and with the male gender.58 Non-HLA genes also contribute to the pathogenesis of Behçet’s disease. Case control studies have shown various associations; however, these studies are usually carried out on a small number of patients and they lack statistical power. Two genome wide association studies (GWAS) have shown results with important functional consequences.59,60 The first was the reduced production of IL-10; an inhibitory cytokine that regulates both innate and adaptive immune responses. The second one concerned polymorphisms in the IL-23R gene, frequently associated with ankylosing spondylitis, inflammatory bowel disease, and psoriasis. Recent data presented in the 15th International Conference of Behçet’s disease, also reported associations with CCR1, STAT4, and KLRC4 encoding a chemokine receptor, a transcription factor implicated in IL-12 and IL-23 signaling and a natural killer receptor, and with ERAP1 that is an endoplasmic reticulum expressed aminopeptidase that trims peptides, and loads them on to MHC Class I. An epistatic interaction between HLA B51 and ERAP was demonstrated and MEVF, NOD2, and TLR4, and loci pertinent to innate immunity were also implicated.61 A Th1 predominance in the peripheral blood and tissue specimens of Behçet patients was reported in several studies.62 Recent evidence also showed the preponderance of Th17 cells in the pathogenetic process.63 A study that evaluated T cell profiles and their related cytokines in patients with neurologic involvement demonstrated that IL-21 induced IL-17 proliferation and a resultant suppression of regulatory T cells was prominent.64 Another study, which explored the roles of Th1, Th2, and Th17 cells in patients with Behçet’s disease, showed that peripheral blood Th17/Th1 ratio of Behçet patients was higher than those of the healthy controls, whereas the Th1/Th2 and Th17/Th2 ratios were

440 similar among the two groups. Patients with uveitis or folliculitis had higher Th17/Th1 ratios, compared with patients without these manifestations.65 Another study showed a predominance of Th1 cells compared to Th17 in patients with gastrointestinal manifestations. They also compared cytokine profiles of Behçet patients who have gastrointestinal involvement with those of ankylosing spondylitis, Crohn’s disease, and healthy controls. IL-23 MRNA levels were normal in ileal biopsies of Behçet patients in contrast to ankylosing spondylitis and Crohn’s patients. STAT-3 and IL-17A mRNA were also normal in Behçet patients, whereas TNF-alfa, IFN-gamma, and IL-12p35 mRNA levels were significantly similar to Crohn’s and higher than healthy controls.66 It was interesting to note that although the clinical and histological pictures of Behçet’s disease and Crohn’s disease are very similar, the cytokine profiles of the patients were quite different. The variation of cytokine profiles in Behçet patients with different clinical manifestations suggest that the disease may not be a homogenous entity. A cluster analysis performed demonstrated four different patterns of clinical involvement.67,68 The first consisted of mucocutaneous manifestations, the second superficial and deep vein thrombosis, the third eye disease, and the fourth papulopustular skin disease and arthritis. The last group also showed a familial occurrence,69 and an increased prevalence of enthesopathy on ultrasonography.31

Conclusions Some authors have attempted to classify Behçet’s disease among autoinflammatory diseases: A group of inherited disorders characterized by episodes of seemingly unprovoked, recurrent inflammatory attacks of innate-nature, mainly mediated by neutrophils.70 Levels of autoantibodies or antigen-specific T cells are not significantly elevated in these diseases. Recurrent lesions of Behçet’s disease; enhanced proinflammatory cytokine responses, such as IL-1 and IL18;71 and the occasional presence of MEVF mutations72 are features suggesting autoinflammation; however, the complex genetic nature of Behçet’s disease, compared to the usual monogenic inheritance observed in the classical autoinflammatory disorders, the presence of panuveitis, hypercoagulability, a clinical course that gets milder in older age, pathergy tests, and the absence of a childhood onset, paroxysmal attacks of serosal inflammation and fever strengthen the case against autoinflammation.73

References 1. Behçet H. Über rezidivierende aphthöse, durch ein Virus verursachte Geschwüre am Mund, am Auge und an den Genitalien. Dermatol Monatsschr. 1937;105:1152-1157.

M. Cem Mat et al. 2. Behçet H, Gözcü N. Üç nahiyede nüksi tavazzular yapan, ve hususi bir virus tesiri ile umumi intan hasıl ettiğine kanaatimiz artan (Entite morbide) hakkinda. Deri Hastaliklari ve Frengi Arşivi. 1938; 5:1863-1873. 3. Kartal Durmazlar SP, Kandi B. Naming dilemma of Behçet’s disease. J Turk Acad Dermatol. 2011;5(1). Jtad151r1.pdf. 4. Cho SB, Cho S, Bang D. New insights in clinical understanding of Behçet’s disease. Yonsei Med J. 2012;53:35-42. 5. Yurdakul S, Yazici Y. Epidemiology of Behçet’s syndrome and regional differences in disease expression. In: Yazici Y, Yazici H, eds. Behçet’s Syndrome. 1st ed. New York: Springer; 2010. p. 35-52. 6. Gül A, Ohno S. Genetics of Behçet’s disease. In: Yazici Y, Yazici H, eds. Behçet’s Syndrome. 1st ed. New York: Springer; 2010. p. 265-276. 7. Verity DH, Marr JE, Ohno S, Wallace GR, Stanford MR. Behçet’s disease, the Silk road and HLA-51: historical and geograhical perspectives. Tissue Antigens. 1999;54:213-220. 8. Yurdakul S, Günaydin I, Tüzün Y, et al. The prevalence of Behçet's syndrome in a rural area in northern Turkey. J Rheumatol. 1988;15: 820-822. 9. Tüzün Y, Yurdakul S, Cem Mat M, et al. Epidemiology of Behçet’s syndrome in Turkey. Int J Dermatol. 1996;35:618-620. 10. Azizlerli G, Köse AA, Sarica R, et al. Prevalence of Behçet’s disease in İstanbul Turkey. Int J Dermatol. 2003;42:803-806. 11. Cakir N, Dervis E, Benian O, et al. The prevalence of Behçet’s disease in rural western Turkey: a preliminary report. Clin Exp Rheumatol. 2004;22:53-55. 12. Idil A, Gürler A, Boyvat A, et al. The prevalence of Behçet’s disease above age of 10 years. The result of a pilot study conducted at the Park primary Health Care Center in Ankara Turkey. Ophthalmic Epidemiol. 2002;9:325-331. 13. Seyahi E, Tahir Turanli E, Mangan MS, et al. The prevalence of Behçet's syndrome, familial Mediterranean fever, HLA-B51 and MEFV gene mutations among ethnic Armenians living in Istanbul Turkey. Clin Exp Rheumatol. 2010;28:67-75. 14. Mahr A, Belarbi L, Wechsler B, et al. Population-based prevalence study of Behçet’s disease: differences by ethnic origin and low variation by age at immigration. Arthritis Rheum. 2008;58:3951-3959. 15. Ideguchi H, Suda A, Takeno M, Ueda A, Ohno S, Ishigatsubo Y. Behçet disease: evolution of clinical manifestations. Medicine (Baltimore). 2011;90:125-132. 16. Yazici H, Tüzün Y, Pazarli H, et al. Influence of age of onset and patient’s sex on the prevalence and severity of manifestations of Behçet’s syndrome. Ann Rheum Dis. 1984;43:783-789. 17. Yazici H, Tüzün Y, Pazarli H, et al. The long-term mortality and morbidity of Behçet’s syndrome: a 2-decade outcome survey of 387 patients followed at dedicated center. Medicine (Baltimore). 2003;82:60-76. 18. Gürler A, Boyvat A, Tursen U. Clinical manifestations of Behçet’s disease. An analysis of 2147 patients. Yonsei Med J. 1997;38:423-427. 19. Alpsoy E, Donmez L, Onder M, et al. Clinical features and natural course of Behçet’s disease in 661 cases: a multicenter study. Br J Dermatol. 2007;157:901-906. 20. International Study Group for Behçet's Disease. Criteria for diagnosis of Behçet's disease. Lancet. 1990;335:1078-1080. 21. Wray D, Graykowski EA, Notkins AL. Role of mucosal injury in initiating recurrent aphthous stomatitis. Br Med J (Clin Res Ed). 1981; 283:1569-1570. 22. Sharquie KE, Al-Araji A, Hatem A. Oral pathergy test in Behçet's disease. Br J Dermatol. 2002;146:168-169. 23. Mat C, Goksugur N, Ergin B, et al. The frequency of scarring after genital ulcers in Behçet’s syndrome: a prospective study. Int J Dermatol. 2006;45:554-556. 24. Demirkesen C, Tüzüner N, Mat C, et al. Clinicopathologic evaluation of nodular cutaneous lesions of Behcet syndrome. Am J Clin Pathol. 2001; 116:341-346. 25. Tunç R, Saip S, Siva A, Yazıcı H. Cerebral venous thrombosis is associated with major vessel disease in Behçet’s syndrome. Ann Rheum Dis. 2004;63:1693-1694.

Behçet’s disease 26. Kucukoglu S, Tunc R, Cetinkaya F, et al. The importance of cutaneous ultrasonography on the differentiation of nodular skin lesions seen in patients with Behcet’s disease. Yonsei Med J. 2000;41:40. 27. Alpsoy E, Aktekin M, Er H, et al. A randomized, controlled and blinded study of papulopustular lesions in Turkish Behçet’s patients. Int J Dermatol. 1998;37:839-842. 28. Hatemi G, Bahar H, Uysal S, et al. The pustular skin lesions in Behcet's syndrome are not sterile. Ann Rheum Dis. 2004;63:1450-1452. 29. Ergun T, Gürbüz O, Doğusoy G, Mat C. Histopathologic features of the spontaneous pustular lesions of Behçet’s syndrome. Int J Dermatol. 1998;37:194-196. 30. Diri E, Mat C, Hamuryudan V, Yurdakul S, Hizli N, Yazici H. Papulopustular skin lesions are seen more frequently in patients with Behçet's syndrome who have arthritis: a controlled and masked study. Ann Rheum Dis. 2001;60:1074-1076. 31. Hatemi G, Fresko I, Taşcılar K, Yazıcı H. Entesopathy is increased among Behçet’s syndrome patients with acne and arthritis: an ultrasonographic study. Arthritis Rheum. 2008;58:1539-1545. 32. Oğuz O, Serdaroğlu S, Tüzün Y, et al. Acute febrile neutrophilic dermatosis associated with Behcet’s syndrome. Int J Dermatol. 1992; 31:645-646. 33. Azizlerli G, Ozarmağan G, Ovül C, Sarica R, Mustafa SO. A new kind of skin lesion in Behçet’s disease: extragenital ulcers. Acta Derm Venereol. 1992;72:286. 34. Altaç M, Tüzün Y, Yurdakul S, et al. The validity of the pathergy test (nonspecific skin hyperreactivity) in Behçet's disease: a double-blind study by independent observers. Acta Derm Venereol. 1982;62:158-159. 35. Yazici H, Tüzün Y, Tanman AB, et al. Male patients with Behçet's syndrome have stronger pathergy reactions. Clin Exp Rheumatol. 1985; 3:137-141. 36. Yazici H, Chamberlain MA, Tüzün Y, Yurdakul S, Müftüoglu A. A comparative study of the pathergy reaction among Turkish and British patients with Behçet's disease. Ann Rheum Dis. 1984;43:74-75. 37. Dilşen N, Koniçe M, Aral O, Ocal L, Inanç M, Gül A. Comparative study of the skin pathergy test with blunt and sharp needles in Behçet's disease: confirmed specificity but decreased sensitivity with sharp needles. Ann Rheum Dis. 1993;52:823-825. 38. Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, et al. Uveitis in Behçet disease: an analysis of 880 patients. Am J Ophthalmol. 2004; 138:373-380. 39. Özyazgan Y, Bodaghi B. Eye disease in Behçet’s syndrome. In: Yazici Y, Yazici H, eds. Behçet’s Syndrome. 1st ed. New York: Springer; 2010. p. 73-94. 40. Yurdakul S, Yazici H, Tüzün Y, Pazarli H, Yalçin B, Altaç M. The arthritis of Behçet’s disease: a prospective study. Ann Rheum Dis. 1983; 42:505-515. 41. Yazici H, Tuzlaci M, Yurdakul S. A controlled survey of sacroiliitis in Behçet’s disease. Ann Rheum Dis. 1981;40:558-559. 42. Ideguchi H, Suda A, Takeno M, et al. Characteristics of vascular involvement in Behçet’s disease in Japan: a retrospectif cohort study. Clin Exp Rheumatol. 2011;29:47-53. 43. Seyahi E, Yurdakul S. Behçet’s syndrome and thrombosis. Mediterr J Hematol Infect Dis. 2011;3:e2011026. (Epub 2011 Jul 8.). 44. Bayraktar Y, Balkanci F, Bayraktar M, Calguneri M. Budd-Chiari syndrome: a common complication of Behçet’s disease. Am J Gastroenterol. 1997;92:858-862. 45. Saadoun D, Asli B, Wechsler B, et al. Long-term outcome of arterial lesions in Behçet disease: a series of 101 patients. Medicine (Baltimore). 2012;91:18-24. 46. Hamuryudan V, Er T, Seyahi E, et al. Pulmonary artery aneurysms in Behçet syndrome. Am J Med. 2004;117:867-870. 47. Ozkan M, Emel O, Ozdemir M, et al. M-mode, 2-D and Doppler echocardiographic study in 65 patients with Behçet’s syndrome. Eur Heart J. 1992;13:638-641. 48. Geri G, Wechsler B, Thi Huong du L, et al. Spectrum of cardiac lesions in Behçet disease: a series of 52 patients and review of literature. Medicine (Baltimore). 2012;91:25-34.

441 49. Cheon JH, Çelik AF, Kim WH. Behçet’s disease: gastrointestinal involvement. In: Yazici Y, Yazici H, eds. Behçet’s Syndrome. 1st ed. New York: Springer; 2010. p. 165-188. 50. Akman-Demir G, Serdaroğlu P, Tascı B. Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients. Brain. 1999;122:2171-2182. 51. Siva A, Kantarci OH, Saip S, et al. Behçet’s disease; diagnostic and prognostic aspects of neurological involvement. J Neurol. 2001;248: 95-103. 52. Ideguchi H, Suda A, Takeno M, et al. Neurological manifestations of Behçet’s disease in Japan: a study of 54 patients. J Neurol. 2010;257: 1012-1020. 53. Uluduz D, Kürtüncü M, Yapıcı Z, et al. Clinical characteristics of pediatric onset neuro-Behçet’s disease. Neurology. 2011;77: 1900-1905. 54. de Menthon M, Lavalley MP, Maldini C, Guillevin L, Mahr A. HLAB51/B5 and the risk of Behçet’s disease: a systematic review and meta-analysis of case control genetic association studies. Arthritis Rheum. 2009;61:1287-1296. 55. Sakaguchi T, Ibe M, Miwa K, et al. Predominant role of N-terminal residue of nonamer peptides in their binding to HLA-B*5101 molecules. Immunogenetics. 1997;46:245-248. 56. Duymaz-Tozkır J, Uyar AF, Norman PJ, et al. Distribution of killer immunoglobulin like receptor 3DL1/3DS1 alleles in Behçet’s disease. Arthritis Rheum. 2008;58(Suppl):S855. 57. Meguro A, Inoko H, Ota M, et al. Genetics of Behçet’s disease inside and outside the MHC. Ann Rheum Dis. 2012;69:747-754. 58. Maldini C, Lavalley MP, Cheminant M, et al. Relationships of HLA-B51 or B5 genotype with Behçet’s disease clinical characteristics: systematic review and meta-analyses of observational studies. Rheumatology (Oxford). 2012;51:887-900. 59. Remmers EF, Cosan F, Kirino Y, et al. Genome-wide association study identifies variants in the MHC class I, IL10 and IL-23RIL12RB2 regions associated with Behçet’s disease. Nat Genet. 2010; 42:698-702. 60. Mizuki N, Meguro A, Ota M, Ohno S, Shiota T, Kawagoe T. Genomewide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nat Genet. 2010;42:703-706. 61. Fresko I. 15th International Congress on Behçet’s Disease 13-15 July 2012, Yokohama, Japan. Clin Exp Rheumatol. 2012;30(Suppl 72): S118-S128. 62. Direskeneli H, Fujita H, Akdis CA. Regulation of Th17 and regulatory T cells in patients with Behçet’s disease. J Allergy Clin Immunol. 2011; 128:665-666. 63. Hamzaoui K. Th17 cells in Behçet’s disease: a new immunoregulatory axis. Clin Exp Rheumatol. 2011;29(Suppl 67):S71-S76. 64. Geri G, Terrier B, Rosenzwajg M, Wechsler B, Touzot M, Seilhean D. Critical role of IL-21 in modulating Th17 and regulatory T cells in Behçet’s disease. J Allergy Clin Immunol. 2011;128:655-664. 65. Kim J, Park JA, Lee EY, Lee YJ, Song YW, Lee EB. Imbalance of Th17 to Th1 cells in Behçet’s disease. Clin Exp Rheumatol. 2010; 28(Suppl 60):S16-S19. 66. Ferrante A, Ciccia F, Principato A, et al. A Th1 but not a Th17 response is present in the gastrointestinal involvement of Behçet’s disease. Clin Exp Rheumatol. 2010;28(Suppl 60):S27-S30. 67. Tunc R, Keyman E, Melikoglu M, Fresko I, Yazici H. Target organ associations in Turkish patients with Behçet’s disease: a cross sectional exploratory factor analysis. J Rheumatol. 2002;29: 2393-2396. 68. Yazici H, Ugurlu S, Seyahi E. Behçet’s Syndrome: is it one condition? Clin Rev Allergy Immunol. 2012;43:275-280. 69. Karaca M, Hatemi G, Sut N, Yazici H. The papulopustular lesion/arthritis cluster in Behçet’s syndrome also clusters in families. Rheumatology (Oxford). 2012;51:1053-1060. 70. Stojanov S, Kastner DL. Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rheumatol. 2005; 17:586-599.

442 71. Musabak U, Pay S, Erdem H, et al. Serum interleukin-18 levels in patients with Behçet’s disease. Is its expression associated with disease activity or clinical presentations? Rheumatol Int. 2006: 545-550.

M. Cem Mat et al. 72. Rabinovich E, Shinar Y, Leiba M, et al. Common FMF alleles may predispose to development of Behçet’s disease with increased risk for venous thrombosis. Scand J Rheumatol. 2007;36:48-52. 73. Yazici H, Fresko I. Clin Exp Rheumatol. 2005;23(4Suppl 38):S1-S2.

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Contemporary Dermatology

Dermatologic Disquisitions and Other Essays Edited by Philip R. Cohen, MD Caretaker of The Skin Edited by Andrzej Grzybowski, MD, PhD Erratum The International Academy of Cosmetic Dermatology (IACD) Officers Dermatology Around the World IACD Membership Application

Clinics in Dermatology (2014) 32, 444–447

DERMATOLOGIC DISQUISITIONS AND OTHER ESSAYS Edited by Philip R. Cohen, MD

Improving patients’ satisfaction with care Steven R. Feldman, MD, PhD ⁎ Department of Dermatology, Wake Forest University School of Medicine, 4618 Country Club Road, Winston-Salem, NC 27104

Introduction The socioeconomic current of our society continues to flow toward placing greater emphasis on “value,” measuring how much is being spent and what outcomes are being achieved. This is certainly true in medicine, where electronic data collection is allowing progressively more detailed assessment of patients’ outcomes (albeit with considerable limitations). Three of the most important outcomes that contribute to the value of medical care are objective improvement patients have in their disease, patients’ subjective satisfaction with the treatment outcome, and patients’ overall satisfaction with their care. Clinical trials measure objective and subjective improvements in disease, providing information about the value of treatment; patients’ satisfaction with care is at times an unappreciated outcome when medicine is viewed from a purely biophysiologic perspective. From the patient perspective, satisfaction with care is perhaps the most direct measure of benefit in the calculation of value. Although physicians can appreciate great joy when achieving objective success in clearing a disease and terrible frustration when being unable to achieve objective success, having very happy patients or very sad patients—the extremes of the patient satisfaction with care outcomes— may be equally or even more impactful on physicians’ perceptions of how the day is going, independent of patients’ objective treatment outcomes. We can expect that measure-

⁎ Corresponding author. Tel.: 336-716-7740; fax: 336-716-7732. E-mail address: [email protected]. (S.R. Feldman). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.10.004

ment of satisfaction will grow in importance as health care is systematized, providing a complementary countermeasure to cost reduction.

Patient satisfaction measurement My interest in patient satisfaction began when the medical center at which I work began doing patient satisfaction surveys. I prided myself in giving patients great care, specializing in psoriasis, giving patients the right diagnosis and the right treatment. The patient satisfaction surveys revealed that too many of my patients were (profoundly) unhappy with the care I provided them. This negative feedback was helpful to me, making me aware of problems that I did not know existed in my performance as a physician. Recognizing the importance of patient satisfaction feedback, I developed an online patient satisfaction survey website (that doubled as a physician rating website) that facilitated low-cost, detailed patient satisfaction data collection. What factors determine patients’ satisfaction with care? Let’s cut to the chase. Based on quantitative data from the online surveys that were collected, there is only one factor that matters much. It is not patient demographics, nor how long patients wait in the waiting room, nor how much time the physician spent with the patient. It is also not whether the treatment of the patient’s condition was effective. The one factor that determines patients’ satisfaction with care is whether patients perceive that their physicians care about them.1 Note that patients’ satisfaction is not determined by whether the physician cares; I cared deeply about my

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patients; yet, many were still unhappy. What determines patients’ satisfaction with care is patients’ perception of whether the physician cares. Systematic qualitative assessment of patient comments collected on the online patient satisfaction website found seven factors were associated with patient satisfaction, and many, if not all, of these tie into patients’ perceptions of how caring the physician is (Table 1).2

Improving patients’ satisfaction with care Although I have provided hard data on factors that affect patients’ satisfaction with care, my suggestions for improving patients’ satisfaction with care have not been rigorously tested in blinded, controlled trials. I believe, nevertheless, that it is critical to do those things that make patients perceive they are seeing a caring physician. I will categorize these approaches into three phases: before the patient sees the physician, seeing the physician, and after the visit. I would also refer you to a marvelous resource written by Dr. Victor Marks and colleagues from the Department of Dermatology and Dermatologic Surgery, Geisinger Health System, Danville, Pennsylvania.3 Presenting patient satisfaction from a “service excellence” point of view, they describe the importance of service excellence and provide a “how to” list with 27 specific standards for achieving service excellence. The caring (or uncaring) nature of a physician will be perceived to some extent before seeing the physician. The ease of contacting the physician’s office for an appointment, parking, the state of the waiting room, and the friendliness

Table 1 Qualitative analysis of patient satisfaction comments from an online patient satisfaction/physician rating website (www.DrScore.com) a Things patients liked • •

•

•

• • •

Access Communication -Listening, partnership, giving information Personality/demeanor (projecting empathy) -Humaneness, caring, support, trust, family/children Medical care -Technical competence, time diagnoses, treatment, thoroughness Follow-up, test results, referrals Facilities Office staff/coordination a

Adapted from Anderson et al.2

Things patients did not like Poor access Poor communications -Poor listening -Lack of partnership -Did not communicate information

• •

Poor follow-up Lack of interpersonal skills -“Took an apparent disinterest in my health”

• •

of check-in staff all reflect, in the patient’s mind, on how caring the physician is (regardless of whether those factors are under the physician’s control). It is frightful to me what the check-in window of our former office communicated to patients (Figure 1). How long patients wait in the waiting room is associated with patient satisfaction, but the effect appears to be mediated by perceptions of caring. If patients wait a long time in the waiting room but the physician is still able to communicate that he or she is a caring physician, then patients tend to be highly satisfied with their care; the problem is that it is difficult to make patients realize you are a caring physician if you have kept them waiting a long time. The human mind perceives things less in terms of absolute values and more in terms of context and contrast; how the physician is perceived may be largely determined by the context set before the patient sees his or her physician. The interaction with the physician is certainly critical as well. To begin with, I open the door to the examination room slowly, communicating to patients that I am not in a hurry (even though I ran to the room because I am in a hurry). Introducing oneself to all family and friends in the room communicates caring as well. Dermatologists are very efficient at assessment of skin disease and may be able to make the diagnosis of a skin disease and perhaps even choose appropriate treatment from the door of the room. Such efficiency may leave patients feeling as though the physician did not take time to do a thorough examination, did not take patients’ concerns into account, and did not care about the patient. To make sure patients feel they received a thorough examination, it is helpful to palpate lesions (touch also directly communicates caring) and to examine (or at least pretend to examine) lesions with a large, lighted magnifier (the very large one with impressive LED lights that I use was purchased for just a few dollars from eBay). I will query patients, “I bet the previous treatment you used was frustrating.” The purpose of this query is to communicate to patients that I understand their concerns and frustration, not to obtain information; I rarely get useful information from their response, because if a patient had a treatment that worked well and that he or she liked, the patient would not be in my office seeking treatment. In addition, involving patients in the choice of treatment—to the extent that they wish to be involved—helps patients feel that the physician includes them as a partner in treatment. Follow-up is a critical aspect of making patients feel cared for. Blood tests and biopsy results should be communicated to patients in a timely way assiduously (both for quality of care and medicolegal reasons). Giving patients easy access to return visits or other means to contact the office may be very valuable for building the perception of caring. As an academic physician-scientist, I do not see as many patients as a dermatologist in full-time clinical practice. I regularly give patients my cell phone number as a means to follow up, to answer any questions that come up, and most importantly, to make clear to patients how much I care about them. If I am

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Fig. 1 What a check-in window should NOT look like. This is the check-in window at our former office. The blinds and windows communicate that we may shut you out at any time because we do not care about you. The disheveled, cluttered desk communicates that we do not care much about the quality of what we do. All the posted signs are consistent in suggesting that we care more about your wallet than we care about you.

doing my job well, there should be few, if any, questions for which they need to call. Most patients are so respectful of physicians that they do not call, even if they have an issue that could be solved with the call. Giving a personal cell phone number to every patient may not be practical for a dermatologist seeing large numbers of patients, although it may be a very valuable approach to improving satisfaction in patients whom the dermatologist recognizes are at risk for poor patient satisfaction.

Conclusions Is there an argument to be made that patients’ satisfaction with care is not an important outcome to achieve? The idea that physicians should only have to worry about objective outcomes and not about patient satisfaction—that is, that unsatisfied patients can just go somewhere else—leaves me distressed in a couple of ways. First, this attitude, to whatever extent it occurs, would make physicians look bad. Second, perhaps I am projecting, but I find it hard to believe that physicians are not dedicated to making their patients happy. One of the arguments against the use of objective treatment outcomes as a measure of value is that it is difficult to account for the baseline severity of disease (renowned physicians who attract the sickest patients could have the worst treatment outcomes). This objection applies to patient satisfaction as a measure of quality as well: Some

patients are harder to please than others (I imagine my North Carolina population may be easier to please than folks in New York City). Physicians, nevertheless, have tremendous control over patient satisfaction and need not despair that patient satisfaction is something they will be rated on but cannot control. The impression that patients are not very happy with their physicians (which may be based on selected coverage in the media, for it is not likely for the front page of the newspaper to cover any of the millions of regular, happy patient visits that happen every day; the bias happens in the office, too, considering how unlikely it is for a dermatologist to see a patient thoroughly happy with the care they received from another physician [if they were happy, why would they go to another physician?]) is widely inaccurate. Our recent report on patient satisfaction with dermatologists revealed that dermatologists’ mean patient satisfaction score is a healthy 9.5 on a 0 to 10 scale.4 Folks like me, with a 9.1 out of 10, have plenty of room for improvement. I hope that nothing in this paper is interpreted as suggesting that physicians do not have to give patients accurate diagnoses or the best possible treatment. On the contrary, I take as a given that physicians are dedicated to giving patients great medical care, but great medical care involves more than just the right diagnosis and treatment. Great medical care includes providing a service that patients recognize as being great. Finally, if all we really did care about were objectively successful treatment outcomes, patients’ satisfaction with care would still be important to achieve in order to obtain good adherence to treatment needed for optimal objective treatment outcomes.

Patient satisfaction

References 1. Uhas AA, Camacho FT, Feldman SR, Balkrishnan R. The relationship between physician friendliness and caring, and patient satisfaction findings from a Internet-based survey. Patient. 2008;1:91-96. 2. Anderson R, Barbara A, Feldman S. What patients want: A content analysis of key qualities that influence patient satisfaction. J Med Pract Manage. 2007;22:255-261. 3. Marks VJ, Hutchison R, Todd M. Service excellence in dermatology. Semin Cutan Med Surg. 2004;23:207-212. 4. Camacho FT, Balkrishnan R, Khanna V, et al. How happy are dermatologists’ patients? A review of a study examining patients’ perceptions of dermatology practices. Dermatologist. 2013;21:38-42. Steven R. Feldman, MD, PhD, appointed in Dermatology, Pathology, and Public Health Sciences at Wake Forest University School of Medicine, directs the Center for Dermatology Research, a health services research center whose mission is to improve the care of patients with skin disease. His chief clinical interest is psoriasis, and he has served two terms as a member of the Medical Board of the National Psoriasis Foundation. Feldman’s research on indoor

447 tanning provided a firm foundation for the recognition and scientific study of tanning addiction. His studies on patients’ adherence are transforming how physicians understand and enhance patients’ use of treatment for chronic skin diseases. Feldman is chief science officer for Causa Research, a company that provides an adherence-improving solution to health care stakeholders. His general weakness in the area of interpersonal skills and resulting poor patient satisfaction led him to create the www.DrScore.com patient satisfaction survey/physician rating website. Feldman is a frequent speaker to lay groups, physicians, and industry professionals, and has published more than 600 papers in peer-reviewed journals. He is editor of five dermatology publications, has a regular column on patient adherence in PM360: The Essential Resource for Pharma Marketers, and is author of Practical Ways to Improve Patients’ Treatment Outcomes. Feldman is most passionate about biases contributing to misperceptions and conflicts in and beyond dermatology, and he wrote the book Compartments: How the Brightest, Best Trained, and Most Caring People Can Make Judgments That Are Completely and Utterly Wrong to help make the world a better place.

Please submit contributions to the section to Philip R. Cohen, MD, at [email protected]

Clinics in Dermatology (2014) 32, 448–450

CARETAKER OF THE SKIN Edited by Andrzej Grzybowski, MD, PhD

Robert Koch (1843-1910) and dermatology on his 171st birthday Andrzej Grzybowski, MD, PhD a,b,⁎, Krzysztof Pietrzak, MD, PhD c a

Department of Ophthalmology, Poznan City Hospital, ul. Szwajcarska 3, 61-285 Poznań, Poland of Ophthalmology, Poznań City Hospital, Poland b Department of Ophthalmology, University of Warmia and Mazury, ul. Żołnierska 14C, Olsztyn, Poland c Department of Orthopaedics and Traumatology, ul. 28 Czerwca 1956 137, Poznan University of Medical Sciences, Poland

Abstract Robert Koch (1843-1910) received the Nobel Prize in Medicine in 1905 for his studies of tuberculosis. He contributed significantly to microbiology, isolating also cholera and anthrax pathogens, and introducing several postulates in this field. In addition, he developed staining methods, as well as culturing and microscopic techniques. Many of his achievements have also influenced dermatology. This contribution reviews his life and major achievements on the occasion of the 171st anniversary of his birth.

Introduction

His early life and education

Microorganisms are responsible for many skin diseases.1-4 Robert Koch's scientific breakthroughs made it possible to find out and to establish the relationship between germs and specific diseases, because it was Koch who proved that every contagious disease is caused by a specific pathogen. He isolated the tuberculosis, cholera, and anthrax pathogens and correlated them with their cutaneous manifestations. He significantly contributed to staining methods, plus culturing and microscopic techniques, which continue to be used in contemporary dermatologic practice.5,6

Robert Koch (Figure 1) was born on December 11, 1843, in Clausthal, Germany. His father, Hermann, was a mining engineer, who in the Harz Mountains in collaboration with Alfred Nobel participated in tests on applications of nitroglycerin. From his early childhood, Robert Koch was a fast learner, proving to be an eager student, especially of biology. In 1862, he enrolled at the University of Gottingen to study biology, only to change to medicine at the same university two terms later. During his medical studies he was profoundly influenced by one of his professors, Jacob Henle (1809-1885), an anatomist. This was also the time when he conceived of the idea that infections are caused by parasites hosted by humans.1 Koch earned his MD degree in 1866. In recognition of his numerous publications and awards, he was conferred the title of doctor without the need for preparing a dissertation. Later, he went to Berlin, where during his studies in chemistry he

⁎ Corresponding author. Tel.: + 48 505 074 224. E-mail address: [email protected] (A. Grzybowski). 0738-081X/$ – see front matter http://dx.doi.org/10.1016/j.clindermatol.2013.10.005

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Additional research progress

Fig. 1

Robert Koch (1843-1910).

was inspired by Rudolf Virchow (1821-1902). The next year, he started as an assistant in Hamburg, only to move shortly thereafter to Langenhagen to become a general practitioner. From 1869, he treated patients in Rakoniewice in province Wielkopolska (Poland). Wielkopolska was a part of Poland under the rule of the Prussian emperor. In 1870-1872, he volunteered as an army physician, serving in the FrancoPrussian War, providing him with the opportunity to study the diseases that afflicted the solders.7

Koch was reassured that each contagious disease is caused by a specific pathogen. He isolated a bacterium that was responsible for wound infections: Staphylococcus spp.10 The concept of culturing microorganisms in a laboratory was proposed by Louis Pasteur (1822-1895); however, it was Koch who implemented it into practice. Koch's ambition was to culture anthrax strains in vitro on media developed by him and to take images of such bacteria. He was improving both microorganism imaging and microscopy techniques, being the first one to incorporate an artificial source of light in a microscope.8 In 1879, Koch moved to Breslau (now Wrocław, Poland) and in a few months was offered a post at the Imperial Health Office. He organized a team of specialists, and they excelled in perfecting bacterial culturing techniques. For instance, he found that agar media is perfect for culturing, and his student Julius Petri (1852-1921) developed a special glass container, subsequently referred to as the Petri dish. Koch was the first scientist to culture specific microorganisms on liquid and solid media. He vastly contributed to isolating, culturing, and dying techniques, many of which constitute the fundamentals of modern microbiological diagnostics.11 Many bacteriologists, including Joseph Lister (18271912), greatly appreciated such endeavors, whereas others like Virchow and Pasteur disapproved of them. Such unfavorable opinions expressed by Pasteur, apart from his own ambitions, could partially be attributed to nationalism— Franco-Prussian aversion in the postwar era. Koch's works were pioneering in respect to their methodology: he was very particular about the size of a sample, the control group, and the possibility of duplicating the experiment.1

Tuberculosis research Research on anthrax From 1872 to 1880, he practiced general medicine in Wolsztyn in Wielkopolska. He held the position of a district physician who was responsible not only for treatment, but also for general sanitary inspection and epidemics control. In the building where he lived, apart from his medical practice, he had arranged a room for a laboratory. He fitted it out with a microscope, microtome, incubator, and a cabinet dark room. Koch's patients, mostly Poles, were very fond of him, and soon his practice generated enough funds so that he could continue his research without financial constraints.7,8 Koch started anthrax research in Wolsztyn. He transfered the blood from autopsy material collected from a mouse that was killed within 24 hours to a skin lesion of a healthy mouse. It was the first direct evidence for the relationship between bacteria presence and disease pathology.9

Koch then focused on studying tuberculosis, which at the time was responsible for every seventh death in Europe. He was the first person to visualize the tubercle bacillus under the microscope. Koch presented on March 24, 1882, at the meeting of the Society of Physiology in Berlin, his up-to-date knowledge on the tubercle bacilli, his method of isolation and culturing, and results from infecting other animals.12,13 Senior members of the German society, namely Virchow, left the meeting without a word. Other participants queued to the microscope to see the newly discovered microorganisms. The meeting proceeded in complete silence without any comments and applause. The next day, Koch's name appeared in the world headlines. He had become both a scientific and a public celebrity. To commemorate this event, World Tuberculosis Day now falls on March 24.

450 Based on his research of tuberculosis, Koch postulated four concepts related to contagious disease pathogenicity: 1. A pathogen may be considered a cause of the disease if it is found in every patient suffering from the disease. 2. A pathogen should grow on a culture medium. 3. If a pathogen is taken from a culture plate and introduced into a susceptible organism, it causes a disease. 4. A pathogen, extracted from the material taken from an ill patient, should grow, producing pure strains of the same bacilli. Such well-formulated postulates were a novelty in science. Many scientists would not admit this concept of disease understanding. For instance, Virchow believed until his death that tumors caused tuberculosis, whereas Koch's postulates were soon adopted in the research of other contagious diseases.14 A few pathogens do not meet Koch's criteria; for example, the leprosy bacillus has never been successfully cultured in laboratory.15

Recognition On December 10, 1905, Koch received the Nobel Prize in Medicine for his studies of tuberculosis.16,17 He died on May 27, 1910, having suffered a fatal heart attack on the terrace of a hotel in Baden-Baden. According to his last will and testament, his ashes were buried in the Institute of Infectious Diseases in Berlin. At present, the memory of his life and work is cultivated by international societies, such as the Koch Institute in Berlin and the community in Wolsztyn, where in the house, where he used to live a museum has been established.18

Personal life In 1868, Koch married Emilie (Emmy) Adolfine Fraatz, who had been his school-years girlfriend. They had one daughter, Gertrud, who collaborated with her father and helped him in his research. Although the Kochs were a happy family, he had an affair in 1893 with Hedwig Freiburg, an actress 30 years his junior. His subsequent marriage to her electrified both the scientific community and the tabloid newspapers. Hedwig would then accompany him on his numerous foreign trips. Koch was an enthusiast of works of the arts, played piano, sang, and drew.7 Koch grew up in the cult of Goethe. He remained a fan of his literature for the rest of life. Koch's

A. Grzybowski, K. Pietrzak knowledge of art was so great that when he was traveling abroad he was a living guide to museums for his friends.

Conclusions Koch's achievements included discoveries of the pathogens for tuberculosis, cholera, anthrax, and staphylococcal infections. He introduced a number of diagnostic methods beginning from microscopic imaging to culturing on various media. His idée fixe since childhood was: Never be idle. There are not many people who would be so preoccupied with their idée fixe as Robert Koch.

References 1. Blevins S, Bronze M. Robert Koch and the ‘golden age’ of bacteriology. Int J Infect Dis.. 2010;14:744-751. 2. Bravo F. Gotuzzo E. Cutaneous tuberculosis. Clin Dermatol. 2007;25: 173-180. 3. Witkowski J, Parish LC. The story of anthrax from antiquity to the present: a biological weapon of nature and humans. Clin Dermatol. 2002;20:336-342. 4. Cieslak T, Talbot T, Hartstein B. Biological warfare and the skin I: bacteria and toxins. Clin Dermatol. 2002;20:346-354. 5. Ruocco E, Baroni A, Donnarumma G, Ruocco V. Diagnostic procedures in dermatology. Clin Dermatol. 2011;29:548-556. 6. Siddiqui A, Bernstein J. Chronic wound infection: Facts and controversies. Clin Dermatol. 2010;28:519-526. 7. Zwolska Z. Koch i jego dokonania- rys historyczny. Post Mikrobiol. 2010;49:139-150. 8. Münch R. Robert Koch. Microbes Infect. 2003;5:69-74. 9. Koch R. Die Ätiologie der Milzbrand-Krankheit, begründet auf die Entwicklungsgeschichte des Bacillus Anthracis. In: Beiträge zur Biologie der Pflanzen, 1876;2:5-27. 10. Koch R. Untersuchungen über die Aetiologie der Wundinfectionskrankheiten. F.C.W. Vogel: Leipzig, Germany. 1878. 11. Koch R. Investigations into the Etiology of Traumatic Infective Diseases. London: The New Sydenham Society. 1880. 12. Koch R. Aetiologie der Tuberkulose. Berliner Klinische Wochenschrift. 1882;19:221-230. 13. Kaufmann S. A short history of Robert Koch's fight against tuberculosis: Those who do not remember the past are condemned to repeat it. Tuberculosis. 2003;83:86-90. 14. Daniel T. The history of tuberculosis. Respir. Med. 2006;100:1862-1870. 15. Gerber R, Rea T. Mycobacterium leprae. In: Mandell G, Benett J, Dolin T, eds. Mandell, Douglas, and Benett's Principles and Practice of Infectious Diseases. 5th ed. New York: Churchill Livingstone; 2000. p. 2608-2616. 16. Kaufmann SH, Schaible UE. 100th anniversary of Robert Koch's Noble Prize for the discovery of the tubercle bacillus. Trends Microbiol. 2005;13:469-475. 17. Nobel Lectures, Physiology or Medicine 1901–1921. Amsterdam, the Netherlands: Elsevier Publishing Company. 1967. 18. http://www.muzea-wolsztyn.com.pl/muzeum_kocha.html. Accessed 15 August 2013.

Clinics in Dermatology (2014) 32, 451

Erratum

Erratum to “Adjuvant drugs in autoimmune bullous diseases, efficacy versus safety: Facts and controversies” [Clin Dermatol 2010; 28:337-343] Ada Lo Schiavo, MD⁎, Rosa Valentina Puca, MD, Vincenzo Ruocco, MD, Eleonora Ruocco, MD, PhD Department of Dermatology, Second University of Naples, Via Sergio Pansini 5, 80131 Naples, Italy In the May-June 2010 article entitled “Adjuvant drugs in autoimmune bullous diseases, efficacy versus safety: Facts and controversies” (Clin Dermatol 2010; 28: 337-343), the surname of the first author was listed incorrectly. The author's correct surname is Lo Schiavo.

DOI of original article: http://dx.doi.org/10.1016/j.clindermatol.2009. 06.018. ⁎ Corresponding author. Tel.: +39 081 566 68 28; fax: +39 081 546 87 59. E-mail address: [email protected] (A. Lo Schiavo). 0738-081X/$ – see front matter © 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.clindermatol.2014.01.002

The International Academy of Cosmetic Dermatology (IACD) Officers Officers President Lawrence Charles Parish, MD 1760 Market Street Philadelphia, PA 19103, USA [email protected]

Secretary/Treasurer-General Larry E. Millikan, MD Tulane Dermatology 2321 13th Street Meridian, MS 39301, USA [email protected]

Vice President, North America Anthony V. Benedetto, DO 1200 Locust Street Philadelphia, PA 19107, USA [email protected]

Vice President, Europe Joseph L. Pace, MD 59 Marquis Scicluna Street Naxxar NXR03, Malta [email protected]

Vice President, South America Marcia Ramos-e-Silva, MD, PhD Rua Soracaba, 464/205 Rio de Janeiro RJ 22271-110 Brazil [email protected]

Vice President, Asia Henry H. Chan, MD, FRCP (UK) 16 Ice House Street, 13th Floor Central Hong Kong [email protected]

Vice President, Africa Mohamed Amer, MD 9 Gabalyia Street El-Tonsy Building Zamalek Cairo, Egypt [email protected]

Vice President, Australasia Greg Goodman, MBBS 443-449 Toorak Road, 8th Floor Toorak, Victoria, Australia 3142 [email protected]

Legal Counsel Janet E. Bauman, Esq. Wynnewood, PA, USA [email protected]

Executive Secretary, IACD Ana Gjeci 1508 Creswood Road Philadelphia, PA 19115, USA Tel: 215-677-3060 Cell: 267-438-2543 Fax: 215-695-2254 E-mail: [email protected] Web: www.IACDworld.org

Board of Directors Sarah Brenner, MD Tel-Aviv, Israel Jack Britt, BA, DHL Greensboro, North Carolina, USA Geert Cauwenbergh, PhD Plainsboro, New Jersey, USA William H. Eaglstein, MD Coral Gables, Florida, USA Howard Epstein, PhD Philadelphia, Pennsylvania, USA Timothy Corcoran Flynn, MD Cary, North Carolina, USA Zoe Diana Draelos, MD High Point, North Carolina, USA Ibrahim Galadari, MD Dubai, United Arab Emirates Ricardo Luis Galimberti, MD Buenos Aires, Argentina Anthony A. Gaspari, MD Baltimore, MD, USA Jim Hartman Greensboro, North Carolina, USA Jo-Ann Kalaka-Adams Sea Bright, New Jersey, USA Henry Kamps, AB Richmond, Virginia, USA Paula Karam, MD Beirut, Lebanon Andreas D. Katsambas, MD Athens, Greece Lincoln Krochmal, MD Palo Alto, California, USA Oumeish Y. Oumeish, MD Amman, Jordan Jennifer L. Parish, MD Philadelphia, Pennsylvania, USA Francisco Perez Atamoros, MD Mexico City, Mexico Vesna Petronic-Rosic, MD, MSc Chicago, Illinois, USA Antonio Picoto, MD Lisbon. Portugal Andre Rougier, PhD Levallois, France Torleif Roykenes Basel, Switzerland Virendra N. Sehgal, MD New Delhi, India Riccarda Serri, MD Milan, Italy Nikolai K. Tzankov, MD, PhD Sofia, Bulgaria Jouni J. Uitto, MD, PhD Philadelphia, Pennsylvania, USA Snejina Vassileva, MD, PhD Sofia, Bulgaria Daniel Wallach, MD Paris, France Oliverio Welsh, MD Monterrey, Mexico Ronni Wolf, MD Tel-Aviv, Israel Xue Jun Zhu, MD Beijing, China To acess website: http://www.IACDWorld.org

Dermatology Around the World 2014 May 7–10 73rd Annual Meeting of the Society for Investigative Dermatology, Albuquerque , NM Contact: Tel: 216.579.9300; Fax: 216.579;9333; E-mail: [email protected]; Web: www.sidnet.org May 21–23 ISAD 2014: 8th George Rajka International Symposium on Atopic Dermatitis, Nottingham, United Kingdom Contact: Prof Hywel Williams. Tel: +44(0)115 84668625; E-mail: [email protected] May 22–25 EADV Spring Symposium, Belgrade, Serbia Contact: Tel: +32-2-650-0090; Fax: +32 2-650-0098; E-mail: [email protected]; Web: www.eadv.org May 30 – June 1 12th Congress of Baltic Association of Dermatovenerologists, Riga, Latvia Contact: Ms Natalia Veksha, Congress Secretary; web: [email protected] June 12–14 12th European Congress of the Society for Pediatric Dermatology (ESPD), Kiel, Germany Contact: MCI Deutschland GmbH-Berlin Office, Markgrafenstraße 56, 10117 Berlin, Germany; Tel: +49 (0)30 20 45 90; Fax: +49 (0)30 20 45 950; E-mail: [email protected]; Web: www.mci-group.com/germany July 1–3 94th Annual Meeting of the British Association of Dermatologist, Glasgow, Scotland Contact: Conference and Events Services, British Association of Dermatologists, Willan House, 4 Fitzroy Square, London, W1T, 5HQ, UK; Tel: +44 (0)20 7391 6343; E-mail: [email protected]; Web: www.wccs2014.org July 9 – 12 40th Annual Meeting of the Society for Pediatric Dermatology, Coeur d'Alene, ID Contact: Web: www.pedsderm.net July 10 – 13 CosdermIndia: 18th Annual Meeting of the Cosmetic Dermatology Society (India), Mumbai India Contact: Ms. Jyotika Kothare, COSMETIC DERMATOLOGY SOCIETY (INDIA), 105 Maker Bhavan III, New Marine Lines, Mumbai – 400020, India; Tel. : 91 22 22064545, 22065555, 22061414; E-mail: [email protected]; Web: www.cosdermindia2014.com July 18– 20 10th World Congress of the International Academy of Cosmetic Dermatology, Rio de Janeiro, Brazil Contact: E-mail: [email protected]; Web: www.iacdRio2014.com.br August 6–10 Summer Meeting of the American Academy of Dermatology, Chicago, IL Contact: American Academy of Dermatology, E. Woodfield Road, Schaumburg, IL 60173 Tel: +1.708.330.9830; Fax: +1.708.330.0050; E-mail: [email protected]; Web: www.aad.org September 3–6 World Congress on Cancer of the Skin, Edinburgh, Scotland Contact: Conference and Events Services, British Association of Dermatologists, Willan House, 4 Fitzroy Square, London, W1T, 5HQ, UK; Tel: +44 (0)20 7391 6343; E-mail: [email protected]; Web: www.wccs2014.org September 10–12 XXXV Symposium of the International Society of Dermatopathology, Jerusalem, Israel Contact: Ofakim Travel & Congresses LTD. 80 Menahem Begin Street, Tel Aviv 67138 Israel;Tel: +972.(0)3.7610.804/5; Web: www.ofakim-knasim.com September 18–20 IUSTI Malta, St Julians, Malta Contact: E-mail: [email protected]; Web: www.iustimalta2014.org October 8–12 23rd EADV Congress, Amsterdam, The Netherlands Contact: EADV; Tel: +32-2-650-0090; Fax: +32 2-650-0098; E-mail: [email protected]; Web: www.eadv.org December 11–13 Psoriasis: From Gene to Clinic, London, United Kingdom Contact: Conference and Events Services, British Association of Dermatologists, Willan House, 4 Fitzroy Square, London, W1T, 5HQ, UK; Tel: +44 (0)20 7391 6343; E-mail: [email protected]; Web: www.wccs2014.org 2015 March 20–24 73rd Annual Meeting of the American Academy of Dermatology, San Francisco, CA Contact: American Academy of Dermatology, E. Woodfield Road, Schaumburg, IL 60173 Tel: +1.708.330.9830; Fax: +1.708.330.0050; E-mail: [email protected]; Web: www.aad.org

April 16–18 4th World Congress of Dermoscopy, Vienna, Austria Contact: MCI, Markgrafenstr. 56, 10117 Berlin, Germany; Tel: +49 (0)30 / 20 45 90; Fax: +49 (0)30 / 20 45 950; E-mail: [email protected]; Web: www.dermoscopy-congress2015.com May 6–9 74th Annual Meeting of the Society for Investigative Dermatology, Atlanta, GA Contact: Tel: 216.579.9300; Fax: 216.579;9333; E-mail: [email protected]; Web: www.sidnet.org June 8–13 23rd World Congress of Dermatology, Vancouver, BC, Canada Contact: Web: www.derm2015.org July 7–9 95th Annual Meeting of the British Association of Dermatologist, Manchester, United Kingdom Contact: Conference and Events Services, British Association of Dermatologists, Willan House, 4 Fitzroy Square, London, W1T, 5HQ, UK; Tel: +44 (0)20 7391 6343; E-mail: [email protected]; Web: www.wccs2014.org July 9–12 41st Annual Meeting of the Society for Pediatric Dermatology, Boston, MA Contact: Web: www.pedsderm.net Aug 19 – 23 Summer Meeting of the American Academy of Dermatology, New York, NY Contact: American Academy of Dermatology, E. Woodfield Road, Schaumburg, IL 60173 Tel: +1.708.330.9830; Fax: +1.708.330.0050; E-mail: [email protected]; Web: www.aad.org October 8–11 24th EADV Congress, Copenhagen, Denmark Contact: Tel: +32-2-650-0090; Fax: +32 2-650-0098; E-mail: [email protected]; Web: www.eadv.org November 5–8 11th World Congress of the International Academy of Cosmetic Dermatology, Singapore Contact: E-mail: [email protected]; Web: www.wcocd2015.com 2016 March 4–8 74th Annual Meeting of the American Academy of Dermatology, Washington, DC Contact: American Academy of Dermatology, E. Woodfield Road, Schaumburg, IL 60173 Tel: +1.708.330.9830; Fax: +1.708.330.0050; E-mail: [email protected]; Web: www.aad.org May 11–14 75th Annual Meeting of the Society for Investigative Dermatology, Scottsdale, AZ Contact: Tel: 216.579.9300; Fax: 216.579;9333; E-mail: [email protected]; Web: www.sidnet.org July 5 – 7 96th Annual Meeting of the British Association of Dermatologist, Birmingham, United Kingdom Contact: Conference and Events Services, British Association of Dermatologists, Willan House, 4 Fitzroy Square, London, W1T, 5HQ, UK; Tel: +44 (0)20 7391 6343; E-mail: [email protected]; Web: www.wccs2014.org July 27–31 Summer Meeting of the American Academy of Dermatology, Boston, MA Contact: American Academy of Dermatology, E. Woodfield Road, Schaumburg, IL 60173 Tel: +1.708.330.9830; Fax: +1.708.330.0050; E-mail: [email protected]; Web: www.aad.org September 28–October 2 25th EADV Congress, Vienna, Austria Contact: Tel: +32-2-650-0090; Fax: +32 2-650-0098; E-mail: [email protected]; Web: www.eadv.org 2017 March 3–7 75th Annual Meeting of the American Academy of Dermatology, Orlando, FL Contact: American Academy of Dermatology, E. Woodfield Road, Schaumburg, IL 60173 Tel: +1.708.330.9830; Fax: +1.708.330.0050; E-mail: [email protected]; Web: www.aad.org July 26–30 Summer Meeting of the American Academy of Dermatology, New York, NY Contact: American Academy of Dermatology, E. Woodfield Road, Schaumburg, IL 60173 Tel: +1.708.330.9830; Fax: +1.708.330.0050; E-mail: [email protected]; Web: www.aad.org September 13–17 26th EADV Congress, Geneva, Switzerland Contact: Tel: +32-2-650-0090; Fax: +32 2-650-0098; E-mail: [email protected]; Web: www.eadv.org 2018 February 16–20 76th Annual Meeting of the American Academy of Dermatology, San Diego, CA Contact: American Academy of Dermatology, E. Woodfield Road, Schaumburg, IL 60173 Tel: +1.708.330.9830; Fax: +1.708.330.0050; E-mail: [email protected]; Web: www.aad.org

2019 March 1–5 77th Annual Meeting of the American Academy of Dermatology, Washington, DC Contact: American Academy of Dermatology, E. Woodfield Road, Schaumburg, IL 60173 Tel: +1.708.330.9830; Fax: +1.708.330.0050; E-mail: [email protected]; Web: www.aad.org July 24–28 Summer Meeting of the American Academy of Dermatology, New York, NY Contact: American Academy of Dermatology, E. Woodfield Road, Schaumburg, IL 60173 Tel: +1.708.330.9830; Fax: +1.708.330.0050; E-mail: [email protected]; Web: www.aad.org

Please send announcements of Dermatology and related meetings to: Hirak Routh, MBBS, Managing Editor, 1760 Market Street, #301, Philadelphia, PA 19103 USA; Fax: 215.563.3044; E-mail: [email protected]

The purpose of our academy is new and unrivaled, bringing together dermatologists and cosmetic surgeons with members of the pharmaceutical and cosmetic industry. Cosmetic and pharmaceutical chemists will have the opportunity for an open and free interchange with physicians in an atmosphere conducive to learning. Members will receive the subscriptions to the official journals of the IACD, including Clinics in Dermatology, at no additional charge. Corporate memberships are available at the Silver, Gold and Platinum levels.

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