Rosacea [1st ed.] 9783030520960, 9783030520977

Table of contents :
Front Matter ....Pages i-xiii
Introduction to Clinical Rosacea (Jonathan K. Wilkin, Jean S. McGee)....Pages 1-13
Pathophysiology of Rosacea (Ethan A. Lerner, Ferda Cevikbas)....Pages 15-21
Genetics of Rosacea (Anusha M. Kumar, Yi-Hsien Shih, Anne Lynn S. Chang)....Pages 23-34
Evidence-Based Management (Adrian Pona, Abigail Cline, Sree S. Kolli, Sarah L. Taylor, Steven R. Feldman)....Pages 35-51
Difference in Vasoconstrictors: Oxymetazoline Versus Brimonidine (Adrian Pona, Abigail Cline, Steven R. Feldman)....Pages 53-65
Treatment of Ocular Rosacea (Christopher R. Fortenbach, Omar Jamal Tayl, Howard I. Maibach, Bobeck Modjtahedi)....Pages 67-75
Physical Modalities for the Treatment of Rosacea (Maja A. Hofmann, Percy Lehmann)....Pages 77-87
Rosacea and Gastrointestinal Comorbidities (Nita Katarina Frifelt Wienholtz, Jacob Pontoppidan Thyssen, Alexander Egeberg)....Pages 89-98
Rosacea and Neurological Comorbidities (Nita Katarina Frifelt Wienholtz, Jacob Pontoppidan Thyssen, Alexander Egeberg)....Pages 99-103
Rosacea and Cardiovascular Comorbidities (Nita Katarina Frifelt Wienholtz, Alexander Egeberg, Jacob Pontoppidan Thyssen)....Pages 105-112
Rosacea and Cancer (Nita Katarina Frifelt Wienholtz, Alexander Egeberg, Jacob Pontoppidan Thyssen)....Pages 113-120
Psychosocial Impact of Rosacea (Latrice M. Hogue, Sarah L. Taylor, Steven R. Feldman)....Pages 121-128
Demodex Folliculorum: Role of Pathogenesis or Association (Frank Powell, Ruth Foley, Solene Gatault)....Pages 129-139
Rosacea in Skin of Color (Tina Hsu, Ahuva Cices, Andrew F. Alexis)....Pages 141-147
Back Matter ....Pages 149-152

Citation preview

Updates in Clinical Dermatology Series Editors: John Berth-Jones · Chee Leok Goh · Howard I. Maibach

John Havens Cary Howard I. Maibach   Editors

Rosacea

Updates in Clinical Dermatology Series Editors: John Berth-Jones Chee Leok Goh Howard I. Maibach

More information about this series at http://www.springer.com/series/13203

John Havens Cary  •  Howard I. Maibach Editors

Rosacea

Editors John Havens Cary Louisiana State University New Orleans LA USA

Howard I. Maibach Dermatology Clinic University of California San Francisco San Francisco CA USA

ISSN 2523-8884     ISSN 2523-8892 (electronic) Updates in Clinical Dermatology ISBN 978-3-030-52096-0    ISBN 978-3-030-52097-7 (eBook) https://doi.org/10.1007/978-3-030-52097-7 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To my grandfather and my first mentor in the field of medicine, Dr. George Cary, and my first mentor in dermatology, Dr. Howard Maibach.

Preface

Rosacea has long been considered a chronic but often relatively benign dermatologic condition that has infrequently garnered extensive attention among clinicians and researchers. In recent years, this chronic condition has seen increased interest within the medical community, which has led to a new classification system proposed by the National Rosacea Society, development of several new treatments, and advances in the understanding of the pathophysiology. In addition, increasing evidence supports several comorbidities and a significant psychosocial impact associated with rosacea, dispelling the notion of rosacea as a benign disease. We have selected worldwide leaders in rosacea to summarize current knowledge and educate clinicians on the most pressing changes and research in the field of rosacea. We would like to thank all of our authors for their countless hours of research and years of valuable clinical expertise shared in each chapter. In addition, we would like to thank Maureen Alexander and Springer Publishing Company for their help in creation and execution of this project. We hope this book contributes to your further learning, provides value in clinical practice, and/or inspires further research in the field. Please let us know if you have any suggestions or corrections. New Orleans, LA, USA San Francisco, CA, USA

John Havens Cary Howard I. Maibach

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Contents

1 Introduction to Clinical Rosacea����������������������������������������������������   1 Jonathan K. Wilkin and Jean S. McGee 2 Pathophysiology of Rosacea������������������������������������������������������������  15 Ethan A. Lerner and Ferda Cevikbas 3 Genetics of Rosacea��������������������������������������������������������������������������  23 Anusha M. Kumar, Yi-Hsien Shih, and Anne Lynn S. Chang 4 Evidence-Based Management ��������������������������������������������������������  35 Adrian Pona, Abigail Cline, Sree S. Kolli, Sarah L. Taylor, and Steven R. Feldman 5 Difference in Vasoconstrictors: Oxymetazoline Versus Brimonidine��������������������������������������������������������������������������  53 Adrian Pona, Abigail Cline, and Steven R. Feldman 6 Treatment of Ocular Rosacea ��������������������������������������������������������  67 Christopher R. Fortenbach, Omar Jamal Tayl, Howard I. Maibach, and Bobeck Modjtahedi 7 Physical Modalities for the Treatment of Rosacea������������������������  77 Maja A. Hofmann and Percy Lehmann 8 Rosacea and Gastrointestinal Comorbidities��������������������������������  89 Nita Katarina Frifelt Wienholtz, Jacob Pontoppidan Thyssen, and Alexander Egeberg 9 Rosacea and Neurological Comorbidities��������������������������������������  99 Nita Katarina Frifelt Wienholtz, Jacob Pontoppidan Thyssen, and Alexander Egeberg 10 Rosacea and Cardiovascular Comorbidities �������������������������������� 105 Nita Katarina Frifelt Wienholtz, Alexander Egeberg, and Jacob Pontoppidan Thyssen 11 Rosacea and Cancer������������������������������������������������������������������������ 113 Nita Katarina Frifelt Wienholtz, Alexander Egeberg, and Jacob Pontoppidan Thyssen

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12 Psychosocial Impact of Rosacea ���������������������������������������������������� 121 Latrice M. Hogue, Sarah L. Taylor, and Steven R. Feldman 13 Demodex Folliculorum: Role of Pathogenesis or Association ���������������������������������������������������������������������������������� 129 Frank Powell, Ruth Foley, and Solene Gatault 14 Rosacea in Skin of Color ���������������������������������������������������������������� 141 Tina Hsu, Ahuva Cices, and Andrew F. Alexis Index���������������������������������������������������������������������������������������������������������� 149

Contents

Contributors

Andrew F. Alexis, MD, MPH  Department of Dermatology, Skin of Color Center, Mount Sinai Morningside and Mount Sinai West, Icahn School of Medicine at Mount Sinai, New York, NY, USA Ferda  Cevikbas, PhD Dermira, Inc., A Wholly-owned Subsidiary of Eli Lilly and Company, Menlo Park, CA, USA Anne Lynn S. Chang, MD  Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA Ahuva Cices, MD  Mount Sinai Hospital, Department of Dermatology, New York, NY, USA Abigail Cline, MD, PhD  Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA Alexander  Egeberg, MD, PhD  Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark Steven  R.  Feldman, MD, PhD Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Winston-­ Salem, NC, USA Department of Pathology, Wake Forest School of Medicine, Winston-­Salem, NC, USA Department of Social Sciences & Health Policy, Wake Forest School of Medicine, Winston-Salem, NC, USA Ruth  Foley, BA, PhD UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin, Ireland Christopher R. Fortenbach, MD, PhD  Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa Hospital and Clinics, Iowa City, IA, USA Solene  Gatault, PharmD, PhD UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin, Ireland Educational Research Centre, St. Vincent’s University Hospital, Dublin, Ireland

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Maja A. Hofmann, MD, PhD  Hospital Charité, Department of Dermatology, Venereology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany Latrice  M.  Hogue, MD Department of Dermatology, Emory School of Medicine, Atlanta, GA, USA Tina Hsu, MD  Washington University in St. Louis School of Medicine, St. Louis, MO, USA Sree  S.  Kolli, BA Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA Anusha  M.  Kumar, BS  Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA Percy  Lehmann, MD  Department of Dermatology, Allergy and Dermatosurgery, Helios-Universitätsklinikum Wuppertal, Wuppertal, Germany Ethan A. Lerner, MD, PhD  Program in Itch, Department of Dermatology, Massachusetts General Hospital, Cutaneous Biology Research Center, Charlestown, MA, USA Howard I. Maibach, MD  Dermatology Clinic, University of California San Francisco, San Francisco, CA, USA Jean S. McGee, MD, PhD  Beth Israel Deaconess Medical Center, Harvard Medical School, Department of Dermatology, Boston, MA, USA Bobeck  Modjtahedi, MD Department of Ophthalmology, Southern California Permanente Medical Group, Baldwin Park, CA, USA Eye Monitoring Center, Kaiser Permanente Southern California, Baldwin Park, CA, USA Adrian  Pona, MD Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA Frank  Powell, FRCPI, FRCPedin, FAAD UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin, Ireland Mater Private Hospital, Department of Dermatology, Dublin, Ireland Yi-Hsien Shih, MD  Department of Dermatology, Taipei Medical University Shuang Ho Hospital, New Taipei City, Taiwan Omar Jamal Tayl, BS Human Physiology  School of Osteopathic Medicine, Touro University Nevada, Henderson, NV, USA Sarah L. Taylor, MD, MPH  Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC, USA

Contributors

Contributors

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Jacob  Pontoppidan  Thyssen, MD, PhD, DmSci Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark Nita  Katarina  Frifelt  Wienholtz, MD Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark Jonathan  K.  Wilkin, MD Retired, George Town, Grand Cayman, The Cayman Islands

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Introduction to Clinical Rosacea Jonathan K. Wilkin and Jean S. McGee

 osacea Is a Syndrome and Not R a Pathogenically Defined Disease Rosacea is a common, chronic and costly disorder that is nosologically understood as a syndrome in which a large number of signs and symptoms are found to occur. Although the epicenter of rosacea is occupied by a few unfortunate patients with all of the signs and symptoms, most patients have fewer than the full set of these possible features. From completion of a senior dermatology elective to finishing a dermatology residency program and into clinical practice, healthcare professionals may reasonably expect to progress from recognition of fuller expressions of rosacea to more difficult cases approaching the syndromic periphery. Thus, like all syndromic medical conditions, such as systemic lupus erythematosus, rosacea is well-defined in its epicenter, and the diagnosis becomes less certain on moving outward to the periphery of fewer signs. Other facial dermatoses may occur along with rosacea, such as seborrheic dermatitis and acne,

J. K. Wilkin (*) Retired, George Town, Grand Cayman, The Cayman Islands J. S. McGee Beth Israel Deaconess Medical Center, Harvard Medical School, Department of Dermatology, Boston, MA, USA

which may modify the course and presentation of the rosacea. In addition, Plewig and Kligman have noted that it is helpful to detect even limited evidence of rosacea in patients who also have acne vulgaris, since they may give rise to “variants that are often difficult to treat” [1]. The identification of syndromes as specific disorders, especially those with many signs and symptoms, is based on descriptive features, unlike other disorders, such as tuberculosis and the hemoglobinopathies, for which the basic pathogenic mechanisms of the disease are well-­established. Currently, there is no well-­ established basic mechanism of disease established for rosacea. Despite its uncritical popularization as the putative mechanism for rosacea, the antimicrobial peptide LL-37 active cathelicidin peptide-­ mediated response is neither specific to rosacea, as it also occurs and may play a key role in atopic dermatitis, psoriasis, and hidradenitis suppurativa, hardly a phenotypically homogeneous group of dermatoses [2], nor is it general within rosacea, as it has not been documented in any phenotypic subtype of rosacea other than papulopustular rosacea. While the cathelicidin activation pathway is an observable phenomenon in papulopustular rosacea, its causal role even in this one phenotypic subtype has not been established; further, it may be simply an epiphenomenon, since, as pointed out by Holmes and Steinhoff, “it is not singularly responsible for rosacea inflammation” [3].

© Springer Nature Switzerland AG 2020 J. H. Cary, H. I. Maibach (eds.), Rosacea, Updates in Clinical Dermatology, https://doi.org/10.1007/978-3-030-52097-7_1

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 istory of Classification of Rosacea: H Distinction from Acne and Recognition of Phenotypic Subtypes Powell [4] nicely summarized the early historical background of the classification and diagnosis of rosacea, beginning with the original description “in exacting detail” by Robert Willan. Powell notes that in many of the early classifications from the eighteenth century up to that of Paul Gerson Unna (1850–1929), rosacea was classified among the sebaceous gland pathologies, based on the view of sebaceous gland dysfunction in rosacea. Subsequently, Radcliff-Crocker (1845–1909) observed that the erythema of rosacea was not associated with sebaceous glands and, instead, represented an abnormal dilatation of facial cutaneous blood vessels. As the sebaceous gland and follicle were not involved, he revised the name from “acne rosacea” to “rosacea.” By the last half of the twentieth century, the classifications of different experts in different countries had become largely aligned around the notion of rosacea having four or more phenotypic subtypes with some versions allowing for possible, but not obligatory, progression of these phenotypic subtypes as “stages” [1, 5–7]. While these classifications from different authors consistently recognized similar phenotypic subtypes, there were differences in their precise definitions, in the recognition of a few additional phenotypic subtypes, and in the estimations of the potential for progression into different or additional subtypes. In 2002 an “expert committee” of the National Rosacea Society (NRS) sought to develop a standardized classification system [8] that could “serve as a diagnostic instrument to investigate the manifestations and relationships of the several subtypes and potential variants of rosacea…. The committee based the standard classification system on…morphologic characteristics. This avoids assumptions on pathogenesis and progression…patients may have characteristics of more than one rosacea subtype at the same time.” The four phenotypic subtypes recognized as most useful and consistent, which were selected by the NRS from among the then recent classifications,

J. K. Wilkin and J. S. McGee

are (1) erythematotelangiectatic rosacea (ETR), (2) papulopustular rosacea (PPR), (3) phymatous rosacea, and (4) ocular rosacea. While the NRS “recognized” these four phenotypic subtypes and proposed precise definitions, it is important to remember (1) that these four phenotypic subtypes were not created, but only standardized, by the NRS in 2002 from similar classifications created by numerous rosacea specialists in different countries and (2) that the 2002 NRS classification stated that these four phenotypic subtypes may occur together in individual patients in any combination.

 he Four Classic Phenotypic T Subtypes of Rosacea Have Important Utilities The NRS definition of the four ­phenotypic subtypes of rosacea was intended to create a standard terminology to facilitate clear communication, and there is evidence of success for this goal of the “four phenotypic subtype classification” in multiple domains. First, in the differential diagnosis of rosacea, it is usually one of the phenotypic subtypes occurring without, or with only minimal evidence of, the other rosacea subtypes which presents the more difficult diagnostic challenge. Erythematotelangiectatic rosacea often occurs without evidence of PPR or phymatous rosacea, such that telangiectatic photoaging may be difficult to distinguish. The quality of the discussion embedded in the article by Helfrich et al. [9, 10], which carefully and thoughtfully analyzes the differences between erythematotelangiectatic rosacea and telangiectatic photoaging, is most successfully underpinned by the recognition of the phenotypically defined subtype of erythematotelangiectatic rosacea. Second, in epidemiology studies of rosacea and studies of progression of phenotypic subtypes, there are valuable observations, which are driven by the recognition of the four phenotypic subtypes of rosacea. The article by Tan et al. [11] adds considerable insights, including quantitative details on specific signs and evidence suggesting progression among phenotypic subtypes, beyond

1  Introduction to Clinical Rosacea

that of the original seminal epidemiology study by Berg and Liden [12] which documented the greater prevalence of the ETR over the PPR phenotypic subtype of rosacea. Third, molecular biology studies evaluating the potential for progression of rosacea rely on studies which are specific to the phenotypic subtypes of rosacea for their respective qualitative inflammatory events. Steinhoff’s group [13] has demonstrated both phenotypic subtype (clinically) and transient receptor potential vanilloid (TRPV) receptor expression (molecular biologically) intergrades concordantly bridging ETR and PPR, consistent with a progression of ETR into, or into a co-presentation with, PPR. Further, Steinhoff finds the phenotypic subtypes of rosacea useful in the discussion of the different kinds of erythema in rosacea [14]. Likewise, Lee’s group has detected a continuous spectrum of histological findings in rosacea which parallel clinical progression among the phenotypic subtypes [15]. Fourth, the therapeutic armamentarium for controlling rosacea is currently directed at specific phenotypic subtypes [16]. There is no individual product which is indicated to treat both ETR and PPR.  In fact, rosacea phenotypic subtype specificity in effectiveness is emphasized in the FDA-approved labeling for doxycycline (Oracea) [17], which states that “ORACEA is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. No meaningful effect was demonstrated for generalized erythema (redness) of rosacea.” In addition to effectiveness considerations, safety may also display a relative phenotypic subtype specificity. For example, the more irritating topical products approved for PPR are poorly tolerated by some patients with ETR.  In the USA most dermatologic care is provided by non-­ dermatologist physicians, and both they and some dermatologists have prescribed products indicated for the treatment of PPR to patients with ETR without any history of PPR.  Danby [18] points out that, for example, while the papulopustular phenotype of rosacea may respond to metronidazole, the erythema and telangiectasia do not, leading to frustrations among both physicians and patients and happiness among market-

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ers. While at the time of Danby’s writing, there were no available approved products effective for the ETR phenotypic subtype, today there are additional, approved products for treating specifically the ETR phenotypic subtype. This only adds to the importance of basing therapeutic strategies and selection of medical products on the determination of which phenotypic subtypes are present in sufficient severity in a particular to merit phenotypic subtype-specific treatment.

 he Flawed Proposal to Eliminate T the Classic Phenotypic Subtypes The 2017 Update by the National Rosacea Society [19] employs the term “phenotype” for the individual signs and symptoms of rosacea, proposes to eliminate subtypes, and replaces its 2002 Classification [8] (Tables.  1.1 and 1.2) and 2004 Severity Grading [20] of Rosacea in three domains: I. “Phenotypes” and Diagnostic Criteria: A. Diagnostic “Phenotypes” (these signs by themselves are diagnostic of rosacea): 1. Fixed centrofacial erythema in a characteristic pattern that may periodically intensify 2. Phymatous changes B. Major “Phenotypes” (two or more major signs may be considered diagnostic): 1. Flushing 2. Papules and pustules 3. Telangiectasia 4. Ocular manifestations (lid margin telangiectasia, interpalpebral conjunctival injection, spade-shaped infiltrates in the cornea, scleritis and sclerokeratitis) C. Minor “Phenotypes”: 1. Burning sensation 2. Stinging sensation 3. Edema 4. Dryness 5. Ocular manifestations (“honey crust” and collarette accumulation at the base of the lashes, irregularity of the lid margin, evaporative tear dysfunction, i.e., rapid tear breakup time)

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II. Utility The 2017 Update states that “The new classification’s common patterns or groupings of signs and symptoms are not to be considered subtypes or units for research or individual diagnosis and treatment.” III. Severity Assessment The 2017 Update acknowledges that “In 2004, the NRS expert committee published a standard grading system for rosacea…” and adds that (with the 2017 Update) “there is a need for a single updated scale that includes standardized severity assessments of the diagnostic, major, and secondary phenotypes of rosacea and can be used for all phototypes.” Table 1.1  Guidelines for the diagnosis of rosacea Presence of one or more of the following primary features:   Flushing (transient erythema)   Non-transient erythema   Papules and pustules  Telangiectasia May include one or more of the following secondary features:   Burning or stinging  Plaque   Dry appearance  Edema   Ocular manifestations   Peripheral location   Phymatous changes Table 1.2  Subtypes and variants of rosacea and their characteristics Characteristics Subtype  Erythematotelangiectatic flushing and persistent central facial erythema with or without telangiectasia  Papulopustular persistent central facial erythema with transient, central facial papules or pustules or both  Phymatous thickening skin, irregular surface nodularities, and enlargement. May occur on the nose, chin, forehead, cheeks, or ears  Ocular foreign body sensation in the eye, burning or stinging, dryness, itching, ocular photosensitivity, blurred vision, telangiectasia of the sclera or other parts of the eye, or periorbital edema Variant  Granulomatous noninflammatory; hard; brown, yellow, or red cutaneous papules; or nodules of uniform size

J. K. Wilkin and J. S. McGee

Surprisingly, the “2017 update by the NRS” of the standard classification (2017 Update) [19] eliminates the four classic phenotypic subtypes of rosacea. The 2017 Update asserts that “…the subtype designations were widely utilized individually and construed as distinct disorders, ignoring the frequent simultaneous occurrence of more than one subtype and the potential progression from one subtype to another.” However, the reference cited for this statement does not document any such misuse of the 2002 NRS Classification, and the 2002 NRS Classification clearly emphasized that the subtypes frequently occurred together. Although one possible example of ignoring the potential for ocular rosacea did occur in a 1998 published study [21], this was before, and therefore not attributable to, the 2002 NRS Classification. Wollina [22] cogently reminds us that “prior to the definition of subtypes clinicians would often discuss approaches to ‘rosacea’ in articles or at conferences without clearly defining the clinical subtype of the disease, as if the term ‘rosacea’ referred to a single entity.” Marks points out that rosacea may comprise more than one distinct dermatosis [23]; and the phenotypic subtype classification allows for a more definitive judgment on this issue awaiting additional scientific insights. The 2017 Update later asserts that “…the focus on subtypes tended to limit consideration of the full range of potential signs and symptoms that may occur in some individual patients and that, in some cases, may confound the assessment of severity.” Not only is there no evidence cited that supports this claim against the four phenotypic subtypes in the 2002 NRS Classification, but there is also no evidence provided which might indicate the 2017 Update would provide for a superior assessment of severity. In fact, bordering on the preposterous, the 2017 Update does not even offer any method for assessment of severity, merely stating that “There is a need for a single updated scale that includes standardized severity assessments of the diagnostic, major, and secondary phenotypes of rosacea and can be used for all phenotypes.” Lastly, the 2017 Update notes that “The phenotypes and diagnostic criteria are largely in agreement with

1  Introduction to Clinical Rosacea

those recommended by the global rosacea consensus panel in 2016…” [19]. This acknowledgment in the 2017 Update of the provenance of the elimination of the four phenotypic subtypes of rosacea as the global ROSacea COnsensus (ROSCO) panel [24, 25] may provide insight into possible motivations for such a radical change away from the many similar classifications which included these phenotypic subtypes identified by expert dermatologists in multiple countries for decades prior to their standardization in the 2002 NRS Classification. Although the ROSCO classification paper states that “Subtype classification may not fully cover the range of clinical presentations and is likely to confound severity assessment…,” no evidence is provided to support such speculations, and no “improved” severity assessment methodology was proposed. The authors simply conclude that “…there is a clear need to transition beyond a subtype classification.” The article seems to imply that the phenotypic subtype classification originated with the 2002 NRS Classification; however, as noted above, the 2002 NRS Classification borrowed from multiple classifications which incorporated phenotypic subtypes recognized over the preceding decades by rosacea experts from multiple nations. The major contribution of the 2002 NRS Classification was simply to standardize the terminology in a consensus version of these earlier phenotypic subtype classifications.

 he Classic Phenotypic Subtypes T Are Useful and Will Persist A subsequent article from ROSCO followed, which provided rosacea treatment recommendations [26]. The authors emphasize that given “… the fact that no single treatment completely addresses all rosacea features, it is likely that multiple treatments will be needed to address the spectrum of features in an individual patient.” Danby’s observation cited above and several epidemiologic studies support the view that there are many patients with rosacea who have moderate to severe ETR without any evidence for

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PPR. Such patients should ordinarily not be given products indicated only for PPR.  It is unlikely that regulatory authorities would approve a combination product containing both an ETR treatment and a PPR treatment, or even separate treatment products shrink-wrapped together in a co-packaging configuration, since many patients only desire episodic, and not continuous, control of the erythema of ETR, and the papules and pustules come and go in crops in some patients with PPR. If a marketing group’s dream to develop a combination or co-packaged product to treat every feature of rosacea tout ensemble had the possibility of becoming a reality, the abandonment of the phenotypic subtypes of rosacea might be a tolerable simplification, especially for non-­ dermatological physicians caring for patients with skin disease. However, the clinical pharmacology of the treatments available and the current labeling of the regulatory authorities’ approved rosacea armamentarium can be reasonably expected to continue to impel the use of the phenotypic subtype approach to diagnosis and treatment. The proposal to lump all of the signs and symptoms of rosacea together, eliminating the phenotypic subtypes, is an unwarranted and extreme measure, exceeding any potential merit as an unoriginal reminder that the subtypes may occur together in the same individual. The 2017 Update appears to ignore that the message to not overlook any phenotypic subtype is already in the 2002 NRS Classification paper and in many of the articles preceding the 2002 NRS Classification which employ phenotypic subtypes in the classification of rosacea. In sum, the ancien régime of phenotypic subtypes long preceded the 2002 NRS Classification and will survive the current ROSCO panel and 2017 NRS Update, because phenotypic subtypes are (1) consistent with epidemiologic studies and empiric observations of dermatologists who provide care for patients with rosacea, (2) useful scientifically in molecular biology and histopathology studies of progression among the phenotypic subtypes, (3) in accord with the clinical pharmacology and regulation of medical products, and (4) essential for precise, scientific clinical discussions.

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Incidence

J. K. Wilkin and J. S. McGee

patient’s subjective experience. One also needs to be aware that certain clinical subtypes may overRosacea is an inflammatory facial dermatosis lap and coexist in one patient or may progress with an overall incidence of 1.65 per 1000 person-­ from one subtype to another. Furthermore, several years [27]. The incidence is significantly higher in key features of rosacea are also shared by other patients older than 30  years [28]. Depending on medical conditions. Therefore, a thorough histhe methodologies and the populations studied, tory-taking will allow a clinician to be judicious the prevalence varies widely from 1% to more in initiating further investigation, if necessary, to than 20% [29]. Rosacea is considered to be more rule out rosacea mimickers. prevalent in fair-skinned individuals but equally prevalent in both genders with the exception of a certain clinical subtype (e.g., phymatous rosacea History of Present Illness is more common in males) [29]. In skin of color, the clinical findings of rosacea, As with any basic history-taking, a clinician such as flushing, erythema, and telangiectasia, can should obtain information on the affected site, be difficult to appreciate. Therefore, rosacea may duration, associated symptoms, and any identifigo underdiagnosed, misdiagnosed, undertreated, able triggers. Rosacea typically affects the midor mistreated in these patients. In fact, a recent face convex surfaces, most commonly the cheeks, study found that patients of color received a diag- followed by the nose, the chin, and the forehead nosis of rosacea less frequently for a similar visit [34]. Rarely, rosacea can affect the neck and the that led to a rosacea diagnosis in white patients chest. Given that rosacea is a chronic, inflamma[30]. This study highlights that the prevalence of tory process, the disease duration generally rosacea in skin of color may be underestimated. As should be at least for 3  months. Patients with such, clinicians should carefully consider rosacea rosacea will frequently endorse associated sympin their differential diagnoses when patients of toms such as easy flushing along with burning, color report facial flushing, warmth, acneiform stinging, and dry skin. In fact, many patients with ETR cannot tolerate topical treatments indicated eruption, or ocular symptoms. In pediatric patients, rosacea is uncommon. for ETR, let alone many of the topical products However, for such cases, the mean age at the time indicated for PPR, due to these symptoms. of diagnosis is 6 years [31]. PPR and ocular rosa- Environmental factors can also play a significant cea are the two most common clinical subtypes role in triggering rosacea. UV radiation, heat, [32]. Vascular rosacea with flushing and ery- alcohol, coffee, smoking, and stress are common thema, but lacking telangiectasia, is seen in chil- exacerbating factors [35–37]. dren as well [32]. However, phymatous rosacea is only seen in adults [33]. Given that rosacea is rare in children, other papulopustular disorders, Past Medical History such as acne vulgaris, periorificial/perioral dermatitis, sarcoidosis, steroid-induced rosacea, and Rosacea is generally considered a condition limdemodicosis, must be excluded before arriving at ited to skin and eyes. However, associations exist the diagnosis of rosacea [32]. between rosacea and systemic comorbidities. A recent case-control study demonstrated that there is an increased risk of hyperlipidemia, hypertenHistory sion, and metabolic, cardiovascular, and gastrointestinal (GI) diseases for patients with rosacea, Taking a good history from a patient is essential in compared to control subjects without rosacea [38]. diagnosing rosacea and correctly assigning clini- Indeed, certain inflammatory GI diseases, such as cal subtypes. In fact, there are several features of ulcerative colitis, Crohn’s disease, and celiac disrosacea that may only be assessed based on ease, are genetically linked to rosacea at the HLA-

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DRA locus [39–41]. In addition, rosacea has been individuals without rosacea. Flushing can be shown to be associated with several autoimmune induced by heat, thermally hot foods and beverconditions, such as diabetes, celiac disease, multi- ages, spicy foods, and myriad medications. ple sclerosis, rheumatoid arthritis, Parkinson dis- Flushing occurs due to vascular reactivity; with ease, and migraine [42–45]. Moreover, rosacea is relaxation of the vascular smooth muscle, eryassociated with an increased risk of depression thema develops along with a subjective sense of and anxiety disorders [46, 47]. Therefore, it should warmth. Wet flushing refers to flushing which be a standard practice to assess for certain risk fac- occurs at the same time as the sweating [54]. In tors and comorbidities, especially for those dry flushing, a vasoactive agent acts only on the patients for whom early intervention may be vascular smooth muscle without any effect on beneficial. the sweat glands [54]. Wet flushing is induced by In fact, managing the comorbidities has been flutamide, leuprolide acetate, tamoxifen, and, in shown to improve control of rosacea symptoms. the setting of a low-grade fever, NSAIDs, while In one prospective study [48], 46% of patients dry flushing is induced by doxorubicin, cisplatin, with rosacea have been reported to suffer from interferon alfa, metoclopramide, and ethanol small intestinal bacterial overgrowth (SIBO). [54, 55]. The medication history should also When these patients with SIBO were treated with include over-the-­counter (OTC) agents. An OTC rifaximin, 78% of the patients experienced com- vasodilator such as niacin (as nicotinic acid) can plete resolution of cutaneous lesions. Likewise, induce more flushing in rosacea patients, as managing climacteric flushing can be beneficial mentioned above. in improving rosacea symptoms in women. Several hormonal and nonhormonal therapies have been demonstrated to be effective in meno- Family History pausal women at reducing the vasomotor activities that induce flushing [49, 50]. In other cases, Approximately half of rosacea patients report rosacea can flare or worsen indirectly with cer- having a family member afflicted with rosacea tain medications indicated for treatment of the [56]. In fact, a twin study estimates a genetic concomorbidities. Patients with hyperlipidemia on tribution at 46% [57]. A recent genome-wide nicotinic acid therapy can experience flushing, study has identified three human leukocyte antiespecially if they have underlying rosacea. gen (HLA) alleles and two single nucleotide Addition of aspirin or nonsteroidal anti-­ polymorphisms (SNPs) that are associated with inflammatory drugs (NSAIDs) to their treatment rosacea [39]. These HLA genes are linked to regimen can help to control flushing in these autoimmune diseases such as diabetes and celiac patients [51, 52]. Similarly, patients with hyper- disease. Rosacea is also linked to polymorphisms tension on vasodilators can experience intense in several genes, such as GST (glutathione flushing and, therefore, worsening of their rosa- S-transferase), BRNL2 (butyrophilin-like 2), and cea [53]. As such, past medical history should not HLA (human leukocyte antigen) [58]. At this only assess for potential comorbidities but also time, further investigations are still necessary to delineate the genetic risk factors for rosacea. associated medications.

Medication History

Social History

Flushing is one of the key primary features in rosacea. There is no specific flushing reaction for rosacea; instead, patients with rosacea often have more frequent and more intense flushing from the same factors that provoke flushing in

Smoking and alcohol consumption are modifiable lifestyle factors about which questions are routinely asked during a medical history. The link between smoking and rosacea still needs further validation. However, it appears that cigarette

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smoking may reduce the risk of developing rosacea. Past studies show that patients with rosacea smoke less frequently than the general population. In fact, cessation of smoking increased the risk of developing rosacea, while smoking reduced the same risk [56, 59]. While smoking may have potential beneficial effects in rosacea, as it is anti-inflammatory and it can impair peripheral microvascular relaxation, the overall risk-benefit calculus for the health of the patient should preclude the presence of rosacea as a reasonable excuse to either initiate smoking or avoid smoking cessation treatment. Alcohol consumption is generally considered an exacerbating factor. In fact, rhinophyma has been linked to excessive alcohol consumption [60]. However, alcohol consumption as a risk factor for developing rosacea is still considered controversial. Alcohol can certainly trigger flushing; however, multiple studies report no significant association between alcohol consumption and the risk of developing rosacea [27, 56]. At best, the most recent study reports a small increase in the risk and only with excessive alcohol consumption [27, 56].

Review of Systems Flushing alone can be a normal response to appropriate stimuli, such as social embarrassment; it is situational and transient. As such, a patient should not be labeled with rosacea based on flushing alone. However, flushing with systemic signs and symptoms can be a harbinger of rare medical conditions. Intermittent flushing with headache, palpitation, and diaphoresis should trigger a work-up for pheochromocytoma. Flushing with diarrhea and wheezing should prompt an investigation into the possibility of carcinoid syndrome. Generalized pruritus after a shower or history of unusual clotting problems should raise the clinician’s suspicion for polycythemia vera. Patients with presumed diagnosis of cutaneous rosacea should also be assessed for ocular symptoms. Approximately half of patients with ocular rosacea suffer from cutaneous rosacea [61, 62]. Without early intervention and appropriate manage-

ment, ocular rosacea can progress to a loss of vision in severe, albeit rare, cases [61, 62]. Therefore, a review of system for ocular symptoms, such as a foreign body or gritty sensation, pruritus, tearing, inability to wear contact lenses, or excessive use of eye drops for dry eyes or ­artificial tears, should be a standard component of any history.

Physical Exam There are no diagnostic or histologic tests to diagnose rosacea. Therefore, accurate diagnosis and classification of different clinical subtypes is based on obtaining a clear and thorough history and physical exam. There are two diagnostic cutaneous signs of rosacea: fixed centrofacial erythema and phymatous skin changes, presenting as patulous follicles with skin thickening [19, 54]. Phymatous changes can occur over several anatomical areas; however, the most common form is a rhinophyma, or a bulbous-appearing nose. Only one diagnostic sign may be sufficient to make the diagnosis of rosacea. There are other cutaneous signs of rosacea [19, 54]. These cutaneous signs, if two or more are present, may be considered diagnostic, despite the lack of the diagnostic signs above. The major cutaneous signs include flushing, papules and pustules, telangiectasia, and ocular manifestations. Flushing is most commonly limited to the cheeks. Unlike erythema, flushing is a dynamic process that may not be observed during a clinic visit. However, with disease progression, flushing may become more frequent and prolonged. It is important to note that erythema and flushing may not be easily appreciable in darker skin types. Therefore, clinicians may have to rely on the patient’s own report of these signs. Papules and pustules are dome-shaped, inflammatory lesions; they usually occur in crops in centrofacial distribution. They may be easily mistaken for the inflammatory lesions of acne vulgaris. However, acne generally presents with comedones, which are considered unrelated to rosacea. Telangiectasia are commonly seen in rosacea patients as well. Together, erythema (both transient and non-transient), papules and pustules,

1  Introduction to Clinical Rosacea

and telangiectasia in centrofacial distribution can diagnose rosacea with high sensitivity. Ocular rosacea can occur regardless of the severity of cutaneous rosacea or in the absence of any cutaneous signs and symptoms of rosacea [19, 54]. Cases of ocular rosacea should be referred to ophthalmologists, as certain patients may require a slit-lamp examination for further evaluation. However, dermatologists should be familiar with ocular signs that can be easily seen during a routine examination, including eyelid margin telangiectases, interpalpebral conjunctival telangiectases, Meibomian gland dysfunction (blepharitis), and chalazia [19, 54]. In fact, these signs are highly suggestive of ocular rosacea and should be managed appropriately. Lastly, a careful examination must differentiate between ETR and extrinsic photoaging [10, 54]. Both share physical findings such as erythema and telangiectasia; therefore, clinical distinction can be subtle. In terms of distribution, ETR is mainly limited to the central face, while extrinsic photoaging includes other photoexposed areas such as the preauricular and mandibular regions. Extrafacial involvement is rare in ETR, while the upper chest is a common site for photoaging. In order to assess erythema, one must first establish a baseline. Given that retroauricular skin is protected from UV exposure and is not a common site for rosacea, it can provide the baseline level of erythema. In contrast, the sternocleidomastoid (SCM) area can serve as an appropriate site for assessing both baseline erythema and that caused by photoaging. Finally, by comparing the malar region to the SCM area, one can determine the erythema contribution from rosacea alone.

Differential Diagnoses Rosacea is considered one of the greatest mimickers of other diseases. With its four clinical subtypes, presentations can include a wide range of signs and symptoms. Moreover, the overlap among the subtypes adds another layer of complexity in making the correct diagnosis. Facial erythema, flushing, papules and pustules, and telangiectasia are relatively straightforward physi-

9

cal findings. However, multiple medical conditions can present with any of these cutaneous signs. Therefore, taking a thorough history and understanding the subtlety of the physical findings can help to differentiate rosacea from its mimickers. Systemic lupus erythematosus (SLE) presents with malar erythema in half of the cases. Similar to ETR, the affected areas feel warm and somewhat edematous. In addition, photosensitivity is a common, shared feature experienced by both patients with rosacea and SLE.  On physical exam, however, one can appreciate the subtle difference in the quality of erythema [63]. In SLE, the erythema has a violaceous hue and its lateral margins usually have well-defined borders. Cutaneous findings in dermatomyositis (DM) can also be mistaken for ETR. The presence of heliotrope rash, the erythema on or around the eyelids, is one of the major criteria in the diagnosis of DM.  Rosacea, however, generally spares the periocular areas. DM can also present with nonspecific macular violaceous erythema in seborrheic distribution, which may be difficult to differentiate based on skin findings alone [64]. UV exposure is one of the exacerbating factors in rosacea. Therefore, photodermatoses, such as polymorphous light eruption (PMLE), can be confused with rosacea. PMLE is characterized by erythematous papules, papulovesicles, and plaques over the face and upper chest. However, it also involves other classically sun-exposed areas including the arms and the dorsal surfaces of the hands [65]. These areas are rarely, if ever, affected in rosacea. Unlike rosacea, PMLE is intermittent in duration and seasonal in onset, occurring in late spring and early summer months. PMLE also resolves quickly after eruption, usually within 1–7 days [65]. Contact dermatitis on the face, both irritant and allergic, should also be considered as a rosacea mimicker. When actively flaring, the affected areas present with significant erythema and scaling and sometimes even edema in severe cases. Patients report symptoms of pruritus, burning, and sensitivity to topical agents. However, the onset here is generally acute and completely selflimited, once the offending agent is identified and

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removed. Therefore, a complete history can often quickly rule out this mimicker. Acne is the most common skin disease in the USA. It presents with clinically noninflammatory comedones and inflammatory papules, pustules, and nodules over the face, chest, and back. Inflammatory lesions of acne and rosacea may appear identical, thereby making it difficult to differentiate between the two common skin conditions. However, patients with PPR lack comedones, unless they also have concomitant acne. Also, in rosacea, the inflammatory lesions are mostly limited to the face, while in acne they affect the chest and back as well. Most distinctively, some patients with PPR develop the inflammatory lesions in crops of the same stage, which would be very uncommon for acne lesions that come and go independently. On a separate note, monomorphic inflammatory papules should raise the clinician’s suspicion for topical steroid-­induced acne. Another common dermatosis is seborrheic dermatitis; it is a chronic, intermittent, inflammatory condition caused by a commensal yeast of the Malassezia species. Patients with seborrheic dermatitis present with erythematous, scaling patches in sebum-rich distribution of the scalp, face, and chest. It can be difficult to distinguish seborrheic dermatitis from rosacea, especially when it is limited to the face. Both entities can affect the perinasal and perioral areas with erythema and scaling. However, in seborrheic dermatitis, one can appreciate the greasy quality of the scales. In addition, it can affect the eyebrows and retroauricular skin, areas not typically affected by rosacea. Importantly, seborrheic dermatitis and rosacea may often coexist, and in such patients, seborrheic dermatitis must often be controlled before rosacea will improve. Rare medical conditions should also be entertained as differential diagnoses of rosacea, especially when patients present with systemic signs and symptoms. As mentioned above, a detailed review of systems is essential in the diagnosis of carcinoid syndrome, pheochromocytoma, and polycythemia vera. However, there are also rare conditions that are limited to the skin. Lupus miliaris disseminatus faciei (LMDF) is a chronic inflammatory skin disorder. LMDF presents as

asymptomatic red to yellowish brown papules on the face. It is self-limited but can leave scars after resolution. Given the morphology, it can be ­confused with rosacea and acne; however, the histology demonstrates characteristic caseating granulomas.

Histology Rosacea is mainly a clinical diagnosis; there are no definitive, characteristic, histologic changes associated with rosacea. Therefore, biopsy is seldom performed by clinicians when rosacea is suspected. Pathologic information is sought in the cases of atypical presentations or unclear differential diagnoses. Given the lack of characteristic histologic findings, clinicopathologic correlation is essential in the diagnosis of rosacea. In ETR, overall histologic changes are nonspecific. However, one characteristic change almost always seen is the presence of enlarged, dilated capillaries and postcapillary venules in the upper dermis, along with mild lymphocytic infiltration. The infiltration occurs throughout the dermis, mainly perivascular and interstitial in distribution, and is heavy in lymphocytes, admixed with mast cells and plasma cells [66, 67]. The lymphocytes are mainly of the CD4+ T cells [66]. The rosacea mimicker, lupus erythematosus (LE), can share certain histologic findings with rosacea, such as perivascular lymphocytic infiltration. However, the histology of LE also demonstrates perifollicular lymphocytic infiltration, as well as dermo-epidermal junction changes including basal layer vacuolization and thickening of the basement membrane, which are not seen in rosacea. Therefore, biopsy can serve as a helpful diagnostic tool in this setting. PPR is characterized by a mixed inflammatory infiltrate with plasma cells, neutrophils, and eosinophils [35, 68]. Such inflammation is present in both superficial and deep layers of the skin. Mast cells are abundant in the affected area; however, the number of mast cells has not been shown to be correlated with disease severity [67]. Pustules seen on pathology can be both follicular and extrafollicular [69]. Unlike with folliculitis, neutrophil collections are located around the infundibula and almost always associated with the presence of

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Demodex [66]. Ruptured follicles may resemble 3. Holmes AD, Steinhoff M.  Integrative concepts of rosacea pathophysiology, clinical presentation the pathology of acne. However, the lack of retenand new therapeutics. Exp Dermatol. 2017;26(8): tional elements such as comedones can differenti659–67. ate rosacea from acne [66]. Solar elastosis is 4. Powell F.  Rosacea: diagnosis and management. New York: CRC Press; 2008. commonly seen and highlights the role of UV exposure and free radical damage in rosacea [70]. 5. Sobye P. Aetiology and pathogenesis of rosacea. Acta Derm Venereol. 1950;30(2):137–58. Both ETR and PPR share several histologic 6. Wilkin JK.  Rosacea. A review. Int J Dermatol. features described above including lymphohistio1983;22:393–400. cyte dermal infiltration (both perivascular and 7. Wilkin JK. Rosacea: pathophysiology and treatment. Arch Dermatol. 1994;130(3):359–62. perifollicular), vascular changes, solar elastosis, 8. Wilkin J, Dahl M, Detmar M, Drake L, Feinstein A, and presence of Demodex. In 1 retrospective Odom R, Powell F.  Standard classification of rosastudy [15], histological findings in 226 patients cea: report of the National Rosacea Society Expert Committee on the classification and staging of rosawith rosacea (52 patients with ETR and 174 cea. J Am Acad Dermatol. 2002;46(4):584–7. patients with PPR) were analyzed, and the fre 9. Helfrich YR, Maier LE, Cui Y, Fisher GJ, Chubb H, quency of each histologic feature was compared Fligiel S, Sachs D, Varani J, Voorhees J.  Clinical, between the two subtypes. The intensity of derhistologic, and molecular analysis of differences between erythematotelangiectatic rosacea mal inflammatory infiltration was higher in PPR and telangiectatic photoaging. JAMA Dermatol. than ETR, as well as the intensity of infiltration 2015;151(8):825–36. into hair follicles. On the other hand, there was 10. Wilkin JK.  Erythematotelangiectatic rosacea and no difference in frequency between the two subtelangiectatic photoaging: same, separate, and/or sequential? JAMA Dermatol. 2015;151(8):821–3. types for vascular changes, solar elastosis, and presence of Demodex. Moreover, cases of ETR 11. Tan J, Blume-Peytavi U, Ortonne JP, Wilhelm K, Marticou L, Baltas E, Rivier M, Petit L, Martel P. An can progress to PPR, as perifollicular inflammaobservational cross-sectional survey of rosacea: clinitory infiltration becomes severe leading to develcal associations and progression between subtypes. Br J Dermatol. 2013;169(3):555–62. opment of granulomatous reaction. This suggests 1 2. Berg MATS, Liden STURE. An epidemiological study that rosacea exhibits a spectrum of histological of rosacea. Acta Derm Venereol. 1989;69(5):419–23. findings in accordance with clinical progression 13. Sulk M, Seeliger S, Aubert J, Schwab VD, Cevikbas F, between the two subtypes. Rivier M, Nowak P, Voegel JJ, Buddenkott J, Steinhoff M. Distribution and expression of non-neuronal tranRare clinical subtypes include granulomatous sient receptor potential (TRPV) ion channels in rosarosacea and phymatous rosacea. Histologically, cea. J Investig Dermatol. 2012;132(4):1253–62. granulomatous rosacea demonstrates non-­ 14. Steinhoff M, Schmelz M, Schauber J.  Facial erycaseating epithelioid granulomas in the dermis thema of rosacea–aetiology, different pathophysiologies and treatment options. Acta Derm Venereol. [68]. Serial sectioning can sometimes reveal 2016;96(5):579–89. Demodex involvement [68]. In rhinophyma, there 15. Lee WJ, Jung JM, Lee YJ, Won CH, Chang SE, is sebaceous gland hyperplasia with extremely Choi JH, Moon KC, Lee MW.  Histopathological large lobules but with intact normal gland archianalysis of 226 patients with rosacea according to rosacea subtype and severity. Am J Dermatopathol. tecture [68]. The infundibula are also enlarged 2016;38(5):347–52. and filled with lamellar keratin in the background 16. Powell FC.  Rosacea. N Engl J Med. of extensive dermal fibrosis [68]. 2005;352(8):793–803.

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12 20. Wilkin J, Dahl M, Detmar M, et  al. Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2004;50:907–12. 21. Wilkin JK.  Use of topical products for main taining remission in rosacea. Arch Dermatol. 1999;135(1):79–80. 22. Wollina U. Classical clinical presentations of rosacea. In: Pathogenesis and treatment of acne and rosacea. Berlin, Heidelberg: Springer; 2014. p. 653–9. 23. Marks R.  Rosacea. Hopeless hypothesis, marvel ous myths and dermal disorganization. In: Acne and related disorders. London: Dunitz; 1989. p. 293–9. 24. Tan J, Almeida LMC, Bewley A, Cribier B, Dlova NC, Gallo R, Kautz G, Mannis M, Oon HH, Rajagopalan M, Thiboutot D, Troielli P, Webster G, Wu Y, van Zuuren EJ, Schaller M, Steinhoff M. Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel. Br J Dermatol. 2017;176(2):431–8. 25. Wilkin J.  Updating the diagnosis, classification and assessment of rosacea by effacement of subtypes. Br J Dermatol. 2017;177(2):597–8. 26. Schaller M, Almeida LMC, Bewley A, Cribier B, Dlova NC, Kautz G, Mannis M, Oon HH, Rajagopalan M, Steinhoff M, Troielli P, Webster G, Wu Y, van Zuuren E, Tan J, Thiboutot D. Rosacea treatment update: recommendations from the global ROSacea COnsensus (ROSCO) panel. Br J Dermatol. 2017;176(2):465–71. 27. Spoendlin J, Voegel JJ, Jick SS, Meier CR. A study on the epidemiology of rosacea in the UK. Br J Dermatol. 2012;167(3):598–605. 28. Chosidow O, Cribier B.  Epidemiology of rosacea: updated data. In: Annales de dermatologie et de venereologie, vol. 138. Paris: Elsevier Masson; 2011. p. S179–83. 29. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013;69(6):S27–35. 30. Al-Dabagh A, Davis SA, McMichael AJ, Feldman SR.  Rosacea in skin of color: not a rare diagnosis. Dermatol Online J. 2014;20(10):p.13. 31. Donaldson KE, Karp CL, Dunbar MT. Evaluation and treatment of children with ocular rosacea. Cornea. 2007;26(1):42–6. 32. Kellen R, Silverberg NB.  Pediatric rosacea. Cutis. 2016;98(1):49–53. 33. Kroshinsky D, Glick SA. Pediatric rosacea. Dermatol Ther. 2006;19(4):196–201. 34. Bolognia JL, Jorizzo JL, Schaffer JV. Rosacea and related disorders. In: Powell FC, Raghallaigh SN, ed. Dermatology. 3rd ed. China: Elsevier Saunders; 2009:561–569. 35. Cribier B.  Rosacea under the microscope: characteristic histological findings. J Eur Acad Dermatol Venereol. 2013;27(11):1336–43. 36. Ozkol HU, Calka O, Akdeniz N, Baskan E, Ozkol H. Rosacea and exposure to tandoor heat: is there an association? Int J Dermatol. 2015;54(12):1429–34.

J. K. Wilkin and J. S. McGee 37. Muller MD, Sauder CL, Ray CA.  Mental stress elicits sustained and reproducible increases in skin sympathetic nerve activity. Physiol Rep. 2013; 1(1):e00002. 38. Rainer BM, Fischer AH, Da Silva DLF, Kang S, Chien AL.  Rosacea is associated with chronic systemic diseases in a skin severity–dependent manner: results of a case-control study. J Am Acad Dermatol. 2015;73(4):604–8. 39. Chang ALS, Raber I, Xu J, Li R, Spitale R, Chen J, Kiefer AK, Tian C, Eriksson NK, Hinds DA, Tung JY.  Assessment of the genetic basis of rosacea by genome-wide association study. J Investig Dermatol. 2015;135(6):1548–55. 40. Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar J-P, Goyette P, Scott R, Xu W, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH, Barmada MM.  Ulcerative colitis–risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet. 2009;41(2):216. 41. Weinstock LB, Steinhoff M. Rosacea and small intestinal bacterial overgrowth: prevalence and response to rifaximin. J Am Acad Dermatol. 2013;68(5): 875–6. 42. Egeberg A, Hansen PR, Gislason GH, Thyssen JP. Clustering of autoimmune diseases in patients with rosacea. J Am Acad Dermatol. 2016;74(4):667–72. 43. Egeberg A, Hansen PR, Gislason GH, Thyssen JP.  Exploring the association between rosacea and Parkinson disease: a Danish nationwide cohort study. JAMA Neurol. 2016;73(5):529–34. 44. Egeberg A, Ashina M, Gaist D, Gislason GH, Thyssen JP.  Prevalence and risk of migraine in patients with rosacea: a population-based cohort study. J Am Acad Dermatol. 2017;76(3):454–8. 45. Spoendlin J, Voegel JJ, Jick SS, Meier CR. Migraine, triptans, and the risk of developing rosacea: a population-­based study within the United Kingdom. J Am Acad Dermatol. 2013;69(3):399–406. 46. Gupta MA, Gupta AK, Chen SJ, Johnson AM. Comorbidity of rosacea and depression: an analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey—outpatient department data collected by the US National Center for Health Statistics from 1995 to 2002. Br J Dermatol. 2005;153(6):1176–81. 47. Egeberg A, Hansen PR, Gislason GH, Thyssen JP. Patients with rosacea have increased risk of depression and anxiety disorders: a Danish nationwide cohort study. Dermatology. 2016;232(2):208–13. 48. Parodi A, Paolino S, Greco A, Drago F, Mansi C, Rebora A, Parodi A, Savarino V.  Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication. Clin Gastroenterol Hepatol. 2008;6(7):759–64.

1  Introduction to Clinical Rosacea 49. Cheema D, Coomarasamy A, El-Toukhy T.  Non-­ hormonal therapy of post-menopausal vasomotor symptoms: a structured evidence-based review. Arch Gynecol Obstet. 2007;276(5):463–9. 50. Bachmann GA.  Menopausal vasomotor symptoms: a review of causes, effects and evidence-based treatment options. J Reprod Med. 2005;50(3):155–65. 51. Wilkin JK, Wilkin O, Kapp R, Donachie R, Chernosky ME, Buckner J.  Aspirin blocks nicotinic acid– induced flushing. Clin Pharmacol Ther. 1982;31(4): 478–82. 52. Wilkin JK, Fortner G, Reinhardt LA, Flowers OV, Kilpatrick SJ, Streeter WC.  Prostaglandins and nicotinate-­provoked increase in cutaneous blood flow. Clin Pharmacol Ther. 1985;38(3):273–7. 53. Wilkin JK.  Vasodilator rosacea. Arch Dermatol. 1980;116(5):598. 54. Saleem MD, Wilkin JK.  Evaluating and optimizing the diagnosis of erythematotelangiectatic rosacea. Dermatol Clin. 2017;36(2):127–34. 55. Wilkin JK.  Flushing reactions in the cancer chemotherapy patient: the lists are longer but the strategies are the same. Arch Dermatol. 1992;128(10):1387–9. 56. Abram K, Silm H, Maaroos HI, Oona M.  Risk factors associated with rosacea. J Eur Acad Dermatol Venereol. 2010;24(5):565–71. 57. Aldrich N, Gerstenblith M, Fu P, Tuttle MS, Varma P, Gotow E, Cooper KD, Mann M, Popkin DL. Genetic vs environmental factors that correlate with rosacea: a cohort-based survey of twins. JAMA Dermatol. 2015;151(11):1213–9. 58. Yazici AC, Tamer L, Ikizoglu G, Kaya TI, Api H, Yildirim H, Adiguzel A.  GSTM1 and GSTT1 null genotypes as possible heritable factors of rosacea. Photodermatol Photoimmunol Photomed. 2006;22(4):208–10. 59. Breton AL, Truchetet F, Véran Y, Doumat-Batch F, Baumann C, Barbaud A, Schmutz J-L, Bursztejn

13 AC. Prevalence analysis of smoking in rosacea. J Eur Acad Dermatol Venereol. 2011;25(9):1112–3. 60. Curnier A, Choudhary S. Rhinophyma: dispelling the myths. Plast Reconstr Surg. 2004;114(2):351–4. 61. Vieira ACC, Höfling-Lima AL, Mannis MJ.  Ocular rosacea: a review. Arq Bras Oftalmol. 2012;75(5):363–9. 62. Vieira AC, Mannis MJ.  Ocular rosacea: com mon and commonly missed. J Am Acad Dermatol. 2013;69(6):S36–41. 63. Olazagasti J, Lynch P, Fazel N. The great mimickers of rosacea. Cutis. 2014;94(1):39–45. 64. Okiyama N, Kohsaka H, Ueda N, Satoh T, Katayama I, Nishioka K, Yokozeki H. Seborrheic area erythema as a common skin manifestation in Japanese patients with dermatomyositis. Dermatology. 2008;217(4):374–7. 65. Naleway AL, Greenlee RT, Melski JW. Characteristics of diagnosed polymorphous light eruption. Photodermatol Photoimmunol Photomed. 2006;22(4):205–7. 66. Aroni K, Tsagroni E, Kavantzas N, Patsouris E, Ioannidis E. A study of the pathogenesis of rosacea: how angiogenesis and mast cells may participate in a complex multifactorial process. Arch Dermatol Res. 2008;300(3):125–31. 67. Ramelet AA, Perroulaz G.  Rosacea: histopathologic study of 75 cases. In: Annales de dermatologie et de venereologie, vol. 115(8). Paris: Masson; 1988, p. 801–6. 68. Aroni K, Tsagroni E, Lazaris AC, Patsouris E, Agapitos E. Rosacea: a clinicopathological approach. Dermatology. 2004;209(3):177–82. 69. Powell FC.  The histopathology of rosacea: ‘where’s the beef? Dermatology. 2004;209(3):173–4. 70. Cribier B. Pathophysiology of rosacea: redness, telangiectasia, and rosacea. In: Annales de dermatologie et de venereologie, vol. 138. Paris: Elsevier Masson; 2011. p. S184–91.

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Pathophysiology of Rosacea Ethan A. Lerner and Ferda Cevikbas

Introduction Rosacea is common, with a prevalence as high as 22% in certain predisposed population of Northern Europe. The prevalence in the USA is estimated to be lower and to affect approximately 2% of the population. Rosacea is characterized by facial erythema and telangiectasias that manifest as redness and symptoms of burning, stinging, and flushing. Trigger factors are diverse and are present in daily life, including sunlight, caffeine, alcohol, spicy food, emotional stress, exercising, and heat. These lead to a challenging quality of life for many rosacea patients. The diverse clinical presentations of rosacea had been summarized within four subtypes classified by the National Rosacea Society Expert Committee in 2002: (1) Patients with erythematotelangiectatic rosacea (ETR) are characterized with clinical symptoms of permanent erythema and increased redness due to

E. A. Lerner (*) Program in Itch, Department of Dermatology, Massachusetts General Hospital, Cutaneous Biology Research Center, Charlestown, MA, USA e-mail: [email protected] F. Cevikbas (*) Dermira, Inc., A Wholly-owned Subsidiary of Eli Lilly and Company, Menlo Park, CA, USA e-mail: [email protected]

flushing as well as telangiectasias. (2) Papulopustular rosacea (PPR) signifies rosacea patients with papules and pustules as the name indicates. (3) Patients with phymatous rosacea (PhR) present with rhinophyma. (4) Ocular rosacea is the fourth subtype. A major update to the classification [1] incorporates additional details, including burning or stinging, edema, and dryness, as noted elsewhere in this volume. The diversity of clinical presentations and the multitude of trigger factors have contributed to the elusive nature of the pathophysiology. It is apparent that rosacea is triggered by various stimuli which engage different systems such as the innate and adaptive immunity, the neuronal network, as well as the vascular system resulting in activation of various receptors which in turn activate different signaling pathways and exert diverse physiological effects. One major step in understanding the pathogenesis was made when antimicrobial peptides (AMPs) were identified as possible triggers in rosacea [2]. These AMPs are differentially processed yielding products that are pro-inflammatory and influence the vascular system rather than attacking microbes. Yet, it is not fully understood whether the dysregulation of AMPs is initiator and driver or a biological consequence of the pathophysiology in rosacea. We discuss current understanding of the pathophysiology of the rosacea with a goal of identifying promising targets.

© Springer Nature Switzerland AG 2020 J. H. Cary, H. I. Maibach (eds.), Rosacea, Updates in Clinical Dermatology, https://doi.org/10.1007/978-3-030-52097-7_2

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Current Concepts of the Pathophysiology The pathogenesis of rosacea remains elusive, particularly compared to the progress made in other major inflammatory skin diseases such as atopic dermatitis and psoriasis. It is understood that a combination of factors, ranging from genetic predisposition, immune and neurovascular dysfunction, as well as environmental stimuli, contributes to the pathogenesis. The discovery of antimicrobial peptides (AMPs) was considered a milestone in understanding the pathophysiology. The role of certain AMPs, namely, cathelicidins and defensins, became prominent actors on the rosacea stage, although other cast members are involved. These AMPs combat bacterial, fungal, and viral infections. Evolutionary, Fitzpatrick skin types I and II and those from Northern Europe and Celtic ancestry are frequently affected by rosacea, suggesting that redness can be related to skin type. Genetic variants and risk loci as well as single nucleotide polymorphisms (SNPs) have been identified, together providing insight into the idea of genetic predisposition to rosacea. Given the findings that certain populations are more predisposed, it suggests that an evolutionary relevant cause led to genetic variation to adapt to the environment. One might expect that genetic heritage and predisposition would point to certain differences in gene expression. Indeed, some genes are upregulated in multiple and some only in certain subtypes of rosacea compared to normal skin. A few of the upregulated genes are involved in mast cell recruitment, the activation of which results in release of neuropeptides and immune modulators. Additionally, tissue remodeling genes such as matrix metalloproteinases (MMPs) and collagen types I and III are upregulated in rosacea lesions. These extracellular matrix molecules modulate the vascular cell biology of the tissue and influence the pathology of rosacea-affected skin [3]. Recently, a gene that belongs to the neuronal family of transient receptor potential cation channel subfamily V (TRPV) has emerged as a potential link between neuroimmune and vascular system in rosacea. TRP channels are nonselective cation channels

that are localized on sensory nerves and nonneuronal cell types [3]. When activated, TRP channels can induce the release of neuropeptides and act as signal transducers in neurogenic inflammation, pain, and itch. TRPV4 is activated by UV radiation and might be the driver of the flaring reaction to UV exposure in rosacea [3]. In summary, the current paradigm of rosacea pathophysiology favors interplay between genetic factors, innate and adaptive immune system, neuroimmune interaction, and vascular effects [4].

Genes in Rosacea With a high prevalence in patients of light skin color, rosacea has also been diagnosed in patients of Asian, Latin-American, American-African, and African ethnicities [5–7]. Family history is a risk factor in the development of rosacea. Studies with monozygous and heterozygous twins revealed that genetic factors account for about half of the risk of being affected by rosacea [8]. Monozygous twins are affected with similar clinical scores and severity of rosacea. Genome-wide association study (GWAS) linked SNPs to rosacea in European patient population [9]. Only the SNP rs763035, which is intergenic between the human leukocyte antigen (HLADRA) and butyrophilin-­like 2 (BTLN2), was replicated in a different group of patients [9]. Both genes are associated with the acquired immune system, the major histocompatibility complex. Immunohistochemistry with antibodies directed against HLA-DRA and BTNL2 revealed differentiated, but also overlapping, distribution. HLA was mostly localized in perifollicular inflammatory infiltrates and Langerhans and endothelial cells, whereas BTNL2 was predominantly detected in keratinocytes, perifollicular inflammatory infiltrates, and endothelial cells in PPR skin samples [2]. Additionally, a case of polymorphism in NOD/ CARD15 has been reported; however, this provides limited insight into the overall impact in rosacea subtypes. In a group of 45 patients, polymorphisms in glutathione S-transferase (GST) were found to be associated with increased disease

2  Pathophysiology of Rosacea

risk. GSTs are enzymes that catalyze the formation of reactive oxygen species (ROS); hence the identified polymorphisms might cause heightened levels of oxidative stress and drive the pathogenesis [10–12]. In transcriptomic profile analyses of patient samples, consistent with the interplay of the different systems, genes of the innate immune system are expressed in ETR, PPR, and PhR.  Interestingly, the transcriptomic analysis displayed an overlap of genes indicating that there might be a progression from early inflammatory stage into the hyperglandular phymatous subtype in some patients [13]. In PPR and PhR subtypes, genes of the adaptive immunity are mostly detected indicating a predominance in these stages. In ER rosacea, neuropeptides, matrix remodeling genes such as MMPs and collagens, innate immune genes, and inflammatory marker molecules such as tumor necrosis factor-α (TNFα) are upregulated. Another study compared the expression profile of neuroimmune and neurovascular markers between the different rosacea subtypes with lupus erythematosus [13]. Interestingly, all subtypes shared overexpression of TRPA1, a different family member of the TRP channels, vasoactive intestinal peptide (VIP), CAMP, and pituitary adenylate cyclase-activating peptide-1 (PACAP). PACAP and VIP are both vasoactive neuropeptides that can regulate vasodilation, plasma extravasation, and neurogenic inflammation [14]. Additionally, both neuropeptides can recruit mast cells and thereby communicate with the immune system [15].

I nnate Immunity and Adaptive Immunity The innate immune system is considered to contribute to rosacea. Innate immunity is activated through Toll-like receptors (TLRs), a receptor group that recognizes diverse patterns of environmental factors. TLRs respond to microbial components, chemicals, and other extrinsic stimuli. TLRs also recognize intrinsic signals such as tissue damage. In rosacea-affected skin, the role of microorganisms such as the Demodex mite has been discussed for many years. Common com-

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mensals such as Demodex folliculorum and brevis are more intensely distributed in rosacea skin. Demodex mites are thought to affect structural components such as hair follicles or sebaceous glands, leading to tissue damage and activation of TLRs [16]. It remains to be further determined whether the dense distribution of the microorganisms Demodex remains is associated with the pathology of disease or whether the increased density is another secondary effect in rosacea patients. When activated, TLRs coordinate the release of cytokines and antimicrobial peptides, such as cathelicidin. TLR-2 is overexpressed in rosacea skin and its activation leads to kallikrein5 (KLK5) production which in turn increases ­ cAMP levels [17, 18]. KLK5 is the predominant serine protease which cleaves cathelicidin into its active peptide form, LL-37. Besides being overexpressed in rosacea skin, KLK5 and LL-37 differ from forms found in healthy skin. The shortened form of LL-37 regulates processes such as leukocyte chemotaxis, angiogenesis, and extracellular matrix remodeling and mimics the rosacea pathology in mice when injected into the skin [17, 19–21]. LL-37 has antimicrobial activity against bacteria, fungi, and parasites and triggers immune activation by inducing expression of pro-inflammatory cytokines. LL-37 degranulates mast cells through activation of mas-related G protein-coupled receptor X2 (MrgprX2). Mast cells (MCs) have been proposed to be the key mediators of the LL-37-driven inflammatory processes in rosacea [22]. Mast cell-deficient mice or stabilizing mast cells from degranulation significantly inhibited the LL-37-induced inflammatory cascade associated with telangiectasia and erythema [22]. Besides being the primary source of cathelicidin [23, 24], MCs actively participate in the pathogenesis via release of neuro- and vasoactive molecules [3]. Additionally, the LL-37 mast cell-mediated effects can depend on the neuronal receptor TRPV4 (Fig. 2.1) which links the innate immune system with the neuronal one [25]. Besides the innate immunity, the adaptive immune system shows high density of T-cells in rosacea skin [26]. Analysis of different rosacea subtypes revealed a predominant TH1-/TH17-­associated

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Fig. 2.1  Pathophysiology of rosacea. Schematic illustration of the interplay between genetic factors, immune and neurovascular dysregulation, as well as the influence of environmental factors to drive the rosacea pathophysiology. Single nucleotide polymorphisms (SNPs) have been associated with increased predisposition of rosacea in affected patients. Innate and adaptive immunity plays a major role and leads to the release of pro-inflammatory mediators and increased protease activity. The immune signature is mostly defined by TH1 and TH17 cell infiltrates. The human beta-defensin cathelicidin, which in its short form is LL-37, has been suggested to be a key driver in rosacea. There is new evidence that proposes LL-37 to activate directly the GPCR MrgprX2 which thereafter

activates TRPV4 channel for further signaling in mast cells. Mast cells have gained attraction as innate immunity cell components that are detected in various stages of rosacea. Neuropeptides such as substance P (SP), calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide (PACAP), and possibly other neuroactive peptides have effects on the vasculature that results in the flushing in rosacea patients. Besides, TRP channels on sensory nerves are important parts of the complex interplay and might regulate the pain, stinging, and burning sensation in patients and possibly drive the responses to UV lights. The role of microorganisms such as the Demodex in rosacea has been discussed. (Modified with permission from Ahn and Huang [31])

gene profile, including p­ ro-­inflammatory cytokines such as interferon-γ and IL-22 and IL-17, both of which augment LL-37 levels [27]. LL-37 induces cytokines such as IL-8 associated with TH1/TH17 immunity [28]. The findings suggest an absence of timely separation of innate and adaptive immunity in rosacea skin. Various chemokines that play a role in angiogenesis as well as neutrophil attraction such as CXCL1, CXCL2, CXCL5, and CXCL6 are overexpressed suggesting a role in pro-inflammatory and pro-angiogenetic changes in rosacea skin [26]. Regulatory CD4+/CD25+ T-cells are increased in rosacea as compared to other autoimmune diseases, suggesting the phenotype of infiltrating cells in rosacea is more preserved [29]. Intriguingly, IL-18, a key regulator of CD8+T-cells, was upregulated in rosacea. IL-18 modulates the immune responses by activating TH1-mediated responses [30] and influences the expression of

erythroid differentiation regulator 1 (Erdr1), which acts as a survival factor for different cell types. Erdr1 also exerts a functional role in UV-induced oxidative stress by regulating ROS levels. ROS can promote pro-inflammatory responses and aggravate reactions of rosacea skin to UV light. Hence, Erdr1 seems to exacerbate rather than protect against excessive ROS responses. Moreover, mouse studies have shown Erdr1 to be a potent inhibitor of VEGF and the angiogenetic processes and might be of potential target value [2].

Neuroimmune and Neurovascular Dysregulation Skin hypersensitivity; signs of flushing, stinging, and burning; and the multiple reactions to irritants that activate neuronal receptors move rosa-

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cea into the category of neurogenic inflammatory diseases. Aside from vasoactive molecules, neuropeptides, involved in vasodilation and neurogenic responses, are upregulated in rosacea patients. Among such neuropeptides, PACAP, VIP, CGRP, and SP have been implicated in neurovascular functions. These peptides are released from cutaneous sensory nerves and act directly on blood vessels or other skin structures and cell types [14]. Besides vasoactive properties, SP has also been suggested to regulate mast cell degranulation, endothelial cell proliferation, and neurogenic inflammation. UVB exposure, one of the trigger factors of rosacea [31], may induce SP release along with CGRP, which then can induce mast cell degranulation [32, 33]. Initially identified as the ligand for the tachykinin receptor neurokinin-­ 1 (NK1R), SP has been recently shown to activate the promiscuous Mrgpr receptor family member MrgprX2 [34, 35]. We previously mentioned MrgrpX2 in the context of the rosacea-­related peptide LL-37 [12], suggesting cross functional activity of MrgprX2  in innate immunity and neurogenic inflammation. PACAP upregulates MC proteases as well as MMP-1 and MMP-9, proteins that are crucial in tissue remodeling and cleavage of the pro-protein into LL-37 [17]. PACAP and LL-37 are synergistic and crucial in the development of rosacea symptoms [22]. Sensitivity of rosacea skin might be additionally based on the increased expression of TRP channels on sensory neurons as well as different immune cells in all rosacea subtypes [36]. TRPV1, initially discovered as the receptor for capsaicin, the pungent ingredient of hot pepper, is involved in vasoregulation, thermoregulation, noxious heat detection, inflammation, pain, and itch; hence it fulfills many of the rosacea-­ immanent features. TRPV2, expressed in immune cells such as macrophages and mast cells and fibroblasts in rosacea skin, might modulate immune responses [36] and cutaneous vasodilation based on labeling studies in rosacea skin. Functional studies could further highlight the role of TRPV2 and TRP channels in rosacea. One of the most recent findings sheds light on TRPV4 as a signal transducer of mast cell degranulation in rosacea pathophysiology as

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mentioned in the context of LL-37 and MrgprX2 [22, 25]. In addition, TRPV4 is thought to contribute to rosacea pathology via UVB-induced activation on keratinocytes [37]. In this scenario, endothelin-1 (ET-­1), an upstream neuropeptide of TRPV4 and crucial in the thermosensitive response to UVB-­induced pain [38], explains the dysregulated neuroimmune- vascular axis induced by UVB light.

 ovel Insights and Promising N Targets The erythematous appearance of rosacea is unique compared to other inflammatory skin diseases. Multiple trigger factors contribute to the symptoms of flushing, erythema, papules, and pustules in association with the development of glandular hyperplasia and fibrotic tissue. It is not clear how the trigger factors induce phenotypes nor whether the clinical appearance is the result of the combination and selective engagement of the trigger factors or predisposition, nor the pathophysiology over time. Increased vascular instability due to the neuronal activation and vascular effects might result in damage and inflammation and tissue changes that become persistent, including development of telangiectasia [39]. It is not clear how the same pathways that are activated in ETR and PPR cause different clinical symptoms in subtypes. It is not known whether differences in the activity of pattern recognition receptors (PRR), increased sensitization of TRP channels, and increased perivascular, perifollicular, and lymphocyte infiltration might cause clinical manifestation of pustules and papules. In phymatous forms of rosacea, fibrotic processes are triggered by chronic persistent damage, ongoing inflammation, increased extracellular matrix alteration, and angiogenesis. Mast cell numbers are elevated in the different stages of rosacea. Novel insight into the role of mast-cell-specific receptors such as MrgprX2, which is activated by the putatively key player LL-37, suggests that MrgrpX2 might be a potential target to address inflammation and corroborate the neuronal axis to TRP channels (Fig. 2.1).

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Future Studies

Conclusion

The complexity of trigger factors and the diverse clinical phenotypes seen in rosacea make it difficult to understand the pathophysiology of rosacea and thus the identification of precise targets. Most of the current treatment approaches are directed toward the inflammatory axis and do not address the roles of vascular dysregulation and neuronal contributions. Even though the genetic predisposition has been emphasized, the responsible genes remain to be identified. It remains unclear whether a genetic predisposition is necessary for the development of rosacea and to what extent this is shared among different ethnic populations. The lack of reasonable mouse models makes it difficult to evaluate the role of LL-37. Although transcriptomic and proteomic analysis will provide signatures in rosacea, it is not clear if such data will impact understanding. Another important question to address is whether the neuronal responses are the drivers of innate and adaptive immunity actions. Studies in which specific neuronal receptors have been ablated or neuronal depletion could be performed in animal models are of value to investigate the interplay between the neuronal and immune system. However, this would demand a better knowledge of the neuronal mediators, receptors, and contributions besides the neuronal population. Therefore, a combination of agents that target the neurogenic inflammation to block erythema, the major feature in rosacea, might be best to suppress the manifestation and simultaneously impact secondary features such as burning and stinging sensations. Many more questions arise which will help in understanding rosacea pathophysiology: If treated successfully, could the progression into the fibrotic stage be prevented? What is the molecular initiator of fibrosis and how similar is this process to other tissue fibrosis? In which stage do different immune cells versus residential skin cells predominate? And what is the cellular and molecular distinction of trigeminal neurons that lead to rosacea?

Rosacea is a chronic inflammatory skin disease with various clinical subtypes and major and secondary manifestations that can lead to disfiguring facial changes. A multitude of triggers engage the neuronal, neurovascular, and immune systems to result in the disease manifestation of the clinical presentation with erythema in ETR, PPR, and the PhR rosacea as well as for patients suffering from ocular rosacea. It is important to build on the recent findings. The involvement of LL-37 as a key molecule that interacts with MrgprX2 on mast cells has provided a link between innate immunity and neuronal TRP channels. Similar findings could link the steps between innate and adaptive immunity with the neuronal contribution. Many questions remain to determine the elusive pathophysiology of rosacea to improve clinical diagnosis, identify biomarkers, and ultimately develop successful treatments. Acknowledgments  Illustration Guralnick, DGD LLC.

designed

by

Dani

References 1. Gallo RL, et  al. Standard classification and pathophysiology of rosacea: the 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2018;78:148–55. 2. Woo YR, Lim JH, Cho DH, Park HJ.  Rosacea: molecular mechanisms and management of a chronic cutaneous inflammatory condition. Int J Mol Sci. 2016;17(9):1562. 3. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69:S15–26. 4. Buddenkotte J, Steinhoff M.  Recent advances in understanding and managing rosacea. F1000Res. 2018;7. 5. Al-Dabagh A, Davis SA, McMichael AJ, Feldman SR.  Rosacea in skin of color: not a rare diagnosis. Dermatol Online J. 2014;20. 6. Dlova NC, Mosam A. Rosacea in black South Africans with skin phototypes V and VI.  Clin Exp Dermatol. 2017;42:670–3. 7. Bae YI, et  al. Clinical evaluation of 168 Korean patients with rosacea: the sun exposure correlates with the erythematotelangiectatic subtype. Ann Dermatol. 2009;21:243–9.

2  Pathophysiology of Rosacea 8. Aldrich N, et  al. Genetic vs environmental factors that correlate with rosacea: a cohort-based survey of twins. JAMA Dermatol. 2015;151:1213–9. 9. Chang ALS, et al. Assessment of the genetic basis of rosacea by genome-wide association study. J Invest Dermatol. 2015;135:1548–55. 10. Yamasaki K, Gallo RL. Rosacea as a disease of cathelicidins and skin innate immunity. J Investig Dermatol Symp Proc. 2011;15:12–5. 11. Yazici AC, et al. GSTM1 and GSTT1 null genotypes as possible heritable factors of rosacea. Photodermatol Photoimmunol Photomed. 2006;22:208–10. 12. Yu Y, et  al. LL-37-induced human mast cell activation through G protein-coupled receptor MrgX2. Int Immunopharmacol. 2017;49:6–12. 13. Schwab VD, et  al. Neurovascular and neuroimmune aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15:53–62. 14. Madva EN, Granstein RD. Nerve-derived transmitters including peptides influence cutaneous immunology. Brain Behav Immun. 2013;34:1–10. 15. Seeliger S, et  al. Pituitary adenylate cyclase activating polypeptide: an important vascular regulator in human skin in  vivo. Am J Pathol. 2010;177:2563–75. 16. Moran EM, Foley R, Powell FC. Demodex and rosacea revisited. Clin Dermatol. 2017;35:195–200. 17. Yamasaki K, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13:975–80. 18. Yamasaki K, et  al. TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes. J Invest Dermatol. 2011;131:688–97. 19. Koczulla R, et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest. 2003;111:1665–72. 20. Morizane S, Gallo RL.  Antimicrobial peptides in the pathogenesis of psoriasis. J Dermatol. 2012;39:225–30. 21. Morizane S, et  al. Cathelicidin antimicrobial pep tide LL-37  in psoriasis enables keratinocyte reactivity against TLR9 ligands. J Invest Dermatol. 2012;132:135–43. 22. Muto Y, et  al. Mast cells are key mediators of cathelicidin-­initiated skin inflammation in rosacea. J Invest Dermatol. 2014;134:2728–36. 23. Di Nardo A, Vitiello A, Gallo RL. Cutting edge: mast cell antimicrobial activity is mediated by expression of cathelicidin antimicrobial peptide. J Immunol. 2003;170:2274–8. 24. Di Nardo A, Yamasaki K, Dorschner RA, Lai Y, Gallo RL. Mast cell cathelicidin antimicrobial peptide prevents invasive group A Streptococcus infection of the skin. J Immunol. 2008;180:7565–73.

21 25. Mascarenhas NL, Wang Z, Chang Y-L, Di Nardo A.  TRPV4 mediates mast cell activation in cathelicidin-­induced rosacea inflammation. J Invest Dermatol. 2017;137:972–5. 26. Buhl T, et  al. Molecular and morphological characterization of inflammatory infiltrate in rosacea reveals activation of Th1/Th17 pathways. J Invest Dermatol. 2015;135:2198–208. 27. Sakabe J, et  al. Calcipotriol increases hCAP18 mRNA expression but inhibits extracellular LL37 peptide production in IL-17/IL-22-stimulated normal human epidermal keratinocytes. Acta Derm Venereol. 2014;94:512–6. 28. Chen X, et  al. Human antimicrobial peptide LL-37 modulates proinflammatory responses induced by cytokine milieus and double-stranded RNA in human keratinocytes. Biochem Biophys Res Commun. 2013;433:532–7. 29. Brown TT, Choi E-YK, Thomas DG, Hristov AC, Chan MP. Comparative analysis of rosacea and cutaneous lupus erythematosus: histopathologic features, T-cell subsets, and plasmacytoid dendritic cells. J Am Acad Dermatol. 2014;71:100–7. 30. Kim M, et  al. Recombinant erythroid differentiation regulator 1 inhibits both inflammation and angiogenesis in a mouse model of rosacea. Exp Dermatol. 2015;24:680–5. 31. Ahn CS, Huang WW. Rosacea pathogenesis. Dermatol Clin. 2018;36:81–6. 32. Niizeki H, Kurimoto I, Streilein JW.  A substance p agonist acts as an adjuvant to promote hapten-specific skin immunity. J Invest Dermatol. 1999;112:437–42. 33. Streilein JW, Alard P, Niizeki H.  A new concept of skin-associated lymphoid tissue (SALT): UVB light impaired cutaneous immunity reveals a prominent role for cutaneous nerves. Keio J Med. 1999;48:22–7. 34. Azimi E, et al. Dual action of neurokinin-1 antagonists on Mas-related GPCRs. JCI Insight. 2016;1:e89362. 35. Ali H.  Mas-related G protein coupled receptor-X2: a potential new target for modulating mast cell-­ mediated allergic and inflammatory diseases. J Immunobiol. 2016;1(4):115. 36. Sulk M, et  al. Distribution and expression of non-­ neuronal transient receptor potential (TRPV) ion channels in rosacea. J Invest Dermatol. 2012;132:1253–62. 37. Chen Y, et  al. TRPV4 moves toward center fold in rosacea pathogenesis. J Invest Dermatol. 2017;137:801–4. 38. Moore C, et al. UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling. Proc Natl Acad Sci U S A. 2013;110:E3225–34. 39. Lee WJ, et  al. Histopathological analysis of 226 patients with rosacea according to rosacea subtype and severity. Am J Dermatopathol. 2016;38:347–52.

3

Genetics of Rosacea Anusha M. Kumar, Yi-Hsien Shih, and Anne Lynn S. Chang

Background Rosacea is a chronic disease, characterized by flares of facial and/or ocular inflammation, whose genetic underpinnings require ongoing investigation. At least four standard subtypes of rosacea exist based on differences in clinical characteristics: erythematotelangiectatic (ETR), papulopustular (PPR), phymatous (PhR), and ocular [1–3]. These categories, however, do not adequately represent the many patients who have overlapping symptoms or progression between subtypes [4–8]. As a result, the National Rosacea Society published an updated classification system in 2017 that uses phenotypes as criteria for diagnosis [5]. Diagnostic phenotypes for rosacea include waxing and waning centro-facial erythema and phymatous change, while flushing, papules and pustules, telangiectasia, and ocular manifestations comprise the major phenotypes; one diag-

nostic phenotype or two major phenotypes are now sufficient for diagnosis [5]. Burning, stinging, edema, and dryness are listed as common secondary symptoms [5]. Though this phenotype-­ based approach intends to represent the multivariate components of rosacea pathophysiology [5, 6], any contributing genetic factors remain undefined. Nonetheless, a growing body of evidence supports a genetic etiology to rosacea [9]. ­ Epidemiologic studies suggest rosacea is more commonly diagnosed in certain demographic groups and populations. Several familial and twin studies highlight a genetic predisposition to rosacea. Genetic association studies and other in vitro analyses also identify critical molecular candidates for further investigation. Ultimately, these genetic insights may yield novel targets for testing in the clinical trials setting to improve treatments for rosacea.

Epidemiology A. M. Kumar (*) · A. L. S. Chang Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA e-mail: [email protected] Y.-H. Shih Department of Dermatology, Taipei Medical University Shuang Ho Hospital, New Taipei City, Taiwan

Epidemiologic data on rosacea varies by population studied and diagnostic methodology [10–13]. The reported prevalence of rosacea across populations ranges from 0.09% to 22% [10, 13]. Studies in Europe and North America appear to yield higher prevalence rates [5, 12–15]. Given this frequency and the prominence of erythema among Caucasians at upper latitudes (Fitzpatrick skin

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phototypes I–II), rosacea has colloquially been termed the “Curse of the Celts.” The pathogenesis of rosacea in Northern Europeans may relate to a mutation allowing vitamin D-independent cathelicidin antimicrobial peptide (CAMP) activation during UV-deficient winter months, for defense against infections [9, 16]. Though less frequent, rosacea does arise in skin of color, including but not limited to Asian, African, and Latin American populations [17– 23]. A retrospective chart review in South Africa found 15 rosacea cases out of 6700 patients with skin phototype V or VI [17]. Cross-sectional, multicenter studies in Colombia and Korea report overall prevalence rates of 2.85% [18] and 1.21% [19], respectively. Aside from obscured redness, other aspects of the rosacea clinical presentation differ among skin types and ethnicities. For example, rhinophyma appears uncommon among African Americans and Asians [15]. Together, the reduced prevalence and differing presentation of rosacea in non-European populations demand a higher index of suspicion to make a diagnosis. As a result, current statistics may underestimate the prevalence of rosacea in skin of color, potentially compounded by reduced healthcare-seeking behaviors in individuals with less prominent clinical signs and symptoms. While the literature often focuses on these population differences in rosacea prevalence, the diagnostic methodology used in data collection may have a greater impact on variation in observed prevalence rates across studies [11, 13]. A recent systematic review estimated 5.46% of the adult general population to have rosacea, while noting markedly different subgroup estimates: a 9.71% prevalence rate according to self-­report, 5.53% according to in-clinic diagnosis, and 1.05% according to healthcare database review [13]. With respect to other demographics, rosacea has been described to have a female predominance [5, 12, 24], though some studies call this into question on account of greater healthcare utilization by female rosacea cases [13]. More consistently, rosacea has been described as a disease of adults, most prominent in ages 45–60, with almost all cases occurring after the age of 30 [5, 13].

A. M. Kumar et al.

Overall, while the increased prevalence of rosacea in Northern European populations supports a genetic component to the disease, the variability in methodology among these epidemiologic studies limit the conclusions that can be drawn and highlight the need for more focused heritability and molecular investigations into rosacea.

Familial Inheritance Studies While population-level studies suggest a genetic predisposition to rosacea, support for the role of genetics in rosacea pathogenesis is apparent when considering familial inheritance. Statistics from case-control studies consistently indicate a significant portion of rosacea patients report a relative with rosacea [9, 25]. One such study in Estonia further quantifies the odds of having a positive family history of rosacea given a personal history of rosacea, relative to normal skin controls (OR 4.31, P