SKIN DISEASE EDUCATION FOUNDATION’S 39 Hawaii Dermatology€¦ · Onychomycosis and Tinea Pedis Using the Anti-TNF Agents in Psoriasis Impact of Psoriasis Therapy on Comorbid Conditions

A CME/CE CERTIFIED SUPPLEMENT TO

H I G H L I G H T S O F

Supported by educational grants from AbbVie Inc., Amgen Inc., Bayer Healthcare, and Valeant Pharmaceuticals North America LLC.

Jointly provided by

39th Annual

HawaiiDermatology

Seminar™

A CONTINUING MEDICAL EDUCATION CONFERENCE

SKIN DISEASE EDUCATION FOUNDATION’S

Introduction

Fungus: New Treatment Options for Toenail Onychomycosis and Tinea Pedis

Using the Anti-TNF Agents in Psoriasis

Impact of Psoriasis Therapy on Comorbid Conditions

What’s New in Acne

Rosacea: Pathogenesis and Therapy

Tattoo Treatment: Current State of the Art

Post-Test and Evaluation Form

FacultyJoseph F. Fowler, Jr, MDClinical Professor of DermatologyUniversity of LouisvilleLouisville, KentuckySkin Disease Education FoundationMedical Director, Medical Dermatology

Christopher B. Zachary, MBBS, FRCPProfessor and ChairDepartment of DermatologyUniversity of California, IrvineIrvine, CaliforniaSkin Disease Education FoundationMedical Director, Aesthetic and Procedural Dermatology

Roger I. Ceilley, MDClinical Professor of DermatologyThe University of IowaWest Des Moines, Iowa

Kristina Callis Duffin, MD, MSAssistant Professor, DermatologyUniversity of UtahSalt Lake City, Utah

Kenneth B. Gordon, MDProfessor of Dermatology Northwestern University Feinberg School of Medicine Chicago, Illinois

Linda F. Stein Gold, MDDirector of Dermatology Research Henry Ford Health System Detroit, Michigan

Jerry K. L. Tan, MD, FRCPCAdjunct ProfessorDepartment of MedicineUniversity of Western OntarioLondon, Ontario, Canada

Original Release Date June 2015

Most Recent Review Date June 2015

Expiration Date June 30, 2016

Estimated Time to Complete Activity

2.00 hours

39th Annual

HawaiiDermatology

Seminar™

A CONTINUING MEDICAL EDUCATION CONFERENCE

SKIN DISEASE EDUCATION FOUNDATION’S

5 IntroductionJoseph F. Fowler, Jr, MD Christopher B. Zachary, MBBS, FRCP

6 Fungus: New Treatment Options for Toenail Onychomycosis and Tinea PedisRoger I. Ceilley, MD

9 Using the Anti-TNF Agents in Psoriasis Kristina Callis Duffin, MD, MS

13 Impact of Psoriasis Therapy on Comorbid ConditionsKenneth B. Gordon, MD

16 What’s New in AcneLinda F. Stein Gold, MD

19 Rosacea: Pathogenesis and TherapyJerry K. L. Tan, MD, FRCPC

22 Tattoo Treatment: Current State of the ArtChristopher B. Zachary, MBBS, FRCP

24 Post-Test and Evaluation Form

Reprinted from Seminars in Cutaneous Medicine and SurgeryThe manuscript was originally published as a supplement to Seminars in Cutaneous Medicine and Surgery, Vol. 34, No. 4S, June 2015. It has been reviewed and approved by the faculty as well as the Editors of Seminars in Cutaneous Medicine and Surgery.

The Faculty acknowledge the editorial assistance of Global Academy for Medical Education, LLC, and Eileen McCaffrey, MA, medical writer, in the development of this supplement.

This continuing medical education (CME) supplement was developed from faculty presentations at the Skin Disease Education Foundation’s 39th Annual Hawaii Dermatology Seminar™, March 1-6, 2015. Neither the Editors of Dermatology News nor the Editorial Advisory Board nor the reporting staff contributed to its content. The opinions expressed are those of the faculty and do not necessarily reflect the views of the accredited provider or the Publisher.

Copyright © 2015 by Global Academy for Medical Education, LLC, Frontline Medical Communications Inc. and its Licensors. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. Global Academy for Medical Education, LLC, will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein.

2 globalacademycme.com/dermatology • Highlights of Skin Disease Education Foundation’s 39th Annual Hawaii Dermatology Seminar

A CME/CE CERTIFIED SUPPLEMENT TO

Roger I. Ceilley, MDClinical Professor of DermatologyThe University of IowaWest Des Moines, Iowa

Kristina Callis Duffin, MD, MSAssistant Professor, DermatologyUniversity of UtahSalt Lake City, Utah

Jerry K. L. Tan, MD, FRCPCAdjunct ProfessorDepartment of MedicineUniversity of Western OntarioLondon, Ontario, Canada

Linda F. Stein Gold, MDDirector of Dermatology Research Henry Ford Health System Detroit, Michigan

Kenneth B. Gordon, MDProfessor of Dermatology Northwestern University Feinberg School of Medicine Chicago, Illinois

Christopher B. Zachary, MBBS, FRCPProfessor and ChairDepartment of DermatologyUniversity of California, IrvineIrvine, CaliforniaSkin Disease Education FoundationMedical Director Aesthetic and Procedural Dermatology

Joseph F. Fowler, Jr, MDClinical Professor of DermatologyUniversity of LouisvilleLouisville, KentuckySkin Disease Education FoundationMedical Director Medical Dermatology

FAC

ULTY

Highlights of Skin Disease Education Foundation’s 39th Annual Hawaii Dermatology Seminar • globalacademycme.com/dermatology 3

Jointly provided by Supported by educational grants from AbbVie Inc., Amgen Inc., Bayer Healthcare,

and Valeant Pharmaceuticals North America LLC.

Highlights of Skin Disease Education Foundation’s 39th Annual Hawaii Dermatology SeminarOriginal Release Date: June 2015 Most Recent Review Date: June 2015 Expiration Date: June 30, 2016 Estimated Time to Complete Activity: 2.0 hours

To get instant CME/CE credits online, go to http://tinyurl.com/39HawaiiSupp. Upon successful completion of the online test and evaluation form, you will be directed to a Web page that will allow you to receive your certificate of credit via e-mail or you may print it at that time. If you have any questions or difficulties with this activity, please contact the Global Academy for Medical Education office at [email protected].

Inquiries may be directed to Global Academy for Medical Education [email protected] or (973) 290-8225.

Accreditation StatementsPhysicians: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Rutgers, The State University of New Jersey, and Global Academy for Medical Education, LLC. Rutgers, The State University of New Jersey, is accredited by the ACCME to provide continuing medical education for physicians. Rutgers, The State University of New Jersey, designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurses: Rutgers, The State University, Center for Continuing and Outreach Education (CCOE) is an approved provider of continuing nursing education by the New Jersey State Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. Provider Number P173-12/12-15. This activity is awarded 2.66 contact hours (60 minute CH). Nurses should only claim those contact hours actually spent participating in the activity. Target AudienceThis activity has been designed for dermatologists, primary care physicians, and other physicians, residents, nurses, nurse practitioners, physician assistants, pharmacists, and fellows who treat patients with skin diseases.

Statement of NeedThe growing body of evidence about the pathophysiology of skin diseases has broadened our understanding of these diverse conditions, as well as their effects on other aspects of health and quality of life. Psoriasis is an inflammatory disease that increases the risk of many other conditions. The provider managing the patient’s psoriasis must consider these potential and actual comorbidities when choosing psoriasis therapy and monitoring patients. The range of anti-tumor necrosis factor agents and other treatments for psoriasis increases the opportunity to tailor therapy to the patient’s responses, characteristics, comorbidities if any, and preferences.

Studies have shed light on the immune system underpinnings of rosacea in recent years, and new therapies have received US Food and Drug Administration approval for treatment of this condition. New agents also have been introduced for tinea pedis, toenail onychomycosis, and acne. Clinical trials have examined and validated some agents long used to treat skin conditions. Dermatologists also are called upon to remove tattoos; newer methods can reduce the time required for treatment and may improve results.

Learning ObjectivesBy reading and studying this supplement, participants should be better able to:• Differentiate the characteristics of the tumor necrosis factor (TNF) inhibitors

approved for use in treating psoriasis and apply that information to clinical practice.• Demonstrate familiarity with the impact of comorbid conditions on patients

with psoriasis and incorporate the effect of psoriasis therapy on those comorbidities into patient management.

• Integrate new therapies for rosacea into practice and describe current theories about rosacea pathophysiology.

• Explain the use of new treatments for tinea pedis and toenail onychomycosis.• Apply current knowledge about anti-acne antibiotic dosing, maintenance

therapy, topical therapy, and diet to clinical practice.• Identify current and updated techniques to improve tattoo removal.

Disclosure DeclarationsIndividuals in a position to control the content of this educational activity are required to disclose: 1) the existence of any relevant financial relationship with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients with the exemption of nonprofit or government organizations and non–health care related companies, within the past 12 months; and 2) the identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved.

Faculty Roger I. Ceilley, MD, Consultant: Ferndale Pharma Group, Inc, DUSA Pharmaceuticals, Inc., LEO Pharma Inc., Valeant Pharmaceuticals North America LLC, Xoft Inc.; Speakers Bureau: DUSA and LEO Pharma; Advisory Board: Ferndale, DUSA, Xoft Inc.Kristina Callis Duffin, MD, MS, Grant/Research: AbbVie Inc., Amgen Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Biotech, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Stiefel Laboratories, Inc., and XenoPort, Inc.; Consultant: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and XenoPort; Advisory Board: Eli Lilly and Janssen.Joseph F. Fowler, Jr, MD, Grant/Research: AbbVie, Allergan, Inc., Amgen, Anacor Pharmaceuticals, Inc., Celgene Corporation, Chugai Pharma USA LLC, Eli Lilly, Galderma Laboratories, L.P., Genentech Inc, Janssen, Johnson & Johnson, Merck & Co., Inc., Novartis, Onset Dermatologics LLC, Pfizer, Regeneron Pharmaceuticals, Inc, SmartPractice Dermatology/Allergy, Taisho Pharmaceutical Co., Taro Pharmaceutical Industries Ltd, and Valeant; Consultant: Bayer Healthcare, Galderma, Johnson & Johnson, Medimetriks Pharmaceuticals Inc, Ranbaxy Laboratories Limited, and SmartPractice; Speakers Bureau: Galderma, SmartPractice, and Valeant.Kenneth B. Gordon, MD, Grant/Research: AbbVie, Amgen, Celgene, Eli Lilly, Novartis, and Pfizer; Consultant: AbbVie, Amgen, Celgene, Eli Lilly, Novartis, and Pfizer.Linda F. Stein Gold, MD, Consultant: Allergan, Anacor Pharmaceuticals, Celgene, Eli Lilly, Galderma, LEO Pharma, Novartis, and Valeant; Speakers Bureau: Celgene, Galderma, LEO Pharma, Novartis, Taro, and Valeant; Advisory Board: Allergan, Anacor Pharmaceuticals, Celgene, Eli Lilly, Galderma, LEO Pharma, Novartis, Promius Pharma, LLC, and Valeant; Medical Legal Advisor: Hoffmann- La Roche Inc.Jerry K. L. Tan, MD, FRCPC, Grant/Research: Allergan, Bayer, Cipher Pharmaceuticals Inc, Dermira, Galderma, and Valeant; Consultant: Cipher Pharmaceuticals, Galderma, GlaxoSmithKline Pharmaceutical Company, Hoffmann-La Roche, Stiefel, and Valeant; Speakers Bureau: Cipher Pharmaceuticals, Galderma, Pierre-Fabre, and Valeant.Christopher B. Zachary, MBBS, FRCP, Consultant: Cutera, Inc. and ZELTIQ Aesthetics, Inc.; Speakers Bureau: Cynosure, Inc. and Solta Medical, a division of Valeant; Advisory Board: ZELTIQ.In order to help ensure content objectivity, independence, and fair balance, and to ensure that the content is aligned with the interest of the public, CCOE has resolved all potential and real conflicts of interest through content review by a non- conflicted, qualified reviewer. This activity was peer-reviewed for relevance, accuracy of content, and balance of presentation by: Zac Handler, MD, Brian Lee, MD, and Vijay Vanchinathan, MD, from Rutgers New Jersey Medical School, Department of Medicine, Division of Dermatology, Newark, NJ, and Geraldine Bocchieri, RN, BSN, Department of Dermatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. Dr Handler, Dr Lee, Dr Vanchinathan, and Ms Bocchieri have no relevant financial relationships to disclose. Field Testers: This activity was pilot-tested for time required by Physicians: Zac Handler, MD, Brian Lee, MD, and Vijay Vanchinathan, MD; Nursing: Kathleen Brown, LPN, Claudia Carron, MSN, RN, NE-BC, and Carol Ruland, RN. The field testers have no relevant financial relationships to disclose. CCOE Staff: Tristan Nelsen, MNM, CMP, and Elizabeth Ward, MSJ, have no rele-vant financial relationships to disclose. Global Academy for Medical Education Staff: Shirley V. Jones, MBA; Sylvia H. Reitman, MBA, DipEd; and Eileen McCaffrey, MA, have no relevant financial relationships to disclose.Off-Label/Investigational Use DisclosureThis activity discusses the off-label use of the following approved agents: adalim-umab, cyclosporine ophthalmic emulsion, doxycycline, etanercept, fluconazole, isotretinoin, itraconazole, ketoconazole, methotrexate, minocycline (oral and foam), secukinumab, ustekinumab, and tumor necrosis factor inhibitors as a class.


The breadth and diversity of dermatology, the speed at which our understanding of skin pathophysiology has improved, and the introduction of new therapies combine to make this field interesting and challenging. The expanding scope of our specialty also creates a broad range of educational needs for practicing clinicians.

Skin Disease Education Foundation’s 39th Annual Hawaii Dermatology Seminar™ offers updates from experts addressing a broad range of skin diseases, and covers advances in both medical and aesthetic dermatology. The articles in this educational supplement summarize the highlights of clinical sessions presented during the CME/CE conference by leading experts in the field of dermatology.

Tumor necrosis factor (TNF) inhibitors are the cornerstone of treatment for psoriasis, but choice of agent can be confusing. This supplement includes a comparison of the TNF inhibitors approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Psoriasis has been linked to an elevated risk of several comorbidities. Can choice of psoriasis therapy alleviate any of these conditions? Our faculty evaluates how risk or presence of comorbid conditions might inform the choice of psoriasis therapy, and whether control of psoriasis can alleviate any coexisting conditions.

Accumulating evidence suggests that rosacea, like psoriasis, is a disorder of the immune system – specifically, of innate rather than adaptive immunity. This CME/CE supplement summarizes those findings. It also reviews studies of new therapies for this condition, as well as new evidence validating the use of a commonly prescribed agent.

Moving from the face to the feet and from immune disorders to fungal infection, our faculty addresses the diagnosis and therapy for tinea pedis and toenail onychomycosis. The FDA last year approved two topical therapies developed specifically for toenail onychomycosis, and in 2013 approved a treatment for interdigital tinea pedis. These highlights summarize the evidence for these therapies, and also cover other publications about diagnosis and management of these infections.

Acne is a common problem in dermatological practice. Our faculty reviews recent studies addressing topics such as antibiotic dosing, maintenance therapy, diet, and treatment of acne on the trunk of the body.

In the realm of aesthetic medicine, this educational supplement addresses techniques for reducing the number of sessions required for tattoo removal and newer lasers that may improve removal of certain types of tattoos.

The broad range of dermatology care and new therapies for skin conditions challenge the busy clinician to remain abreast of the latest information. We hope that you can apply these updates from our seminar to your clinical practice.

Publication of this CME/CE article was jointly provided by Rutgers, The State University of New Jersey, and Global Academy for Medical Education, LLC with Skin Disease Education Foundation (SDEF) and is supported by educational grants from AbbVie Inc., Amgen Inc., Bayer Healthcare, and Valeant Pharmaceuticals North America LLC.

Dr Fowler and Dr Zachary have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Eileen McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Joseph F. Fowler, Jr, MD, Grant/Research: AbbVie, Allergan, Inc., Amgen, Anacor Pharmaceuticals, Inc., Celgene Corporation, Chugai Pharma USA LLC, Eli Lilly and Company, Galderma Laboratories, L.P., Genentech Inc, Janssen Biotech, Inc., Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Onset Dermatologics LLC, Pfizer Inc., Regeneron Pharmaceuticals, Inc, SmartPractice Dermatology/Allergy, Taisho Pharmaceutical Co., Taro Pharmaceutical Industries Ltd, and Valeant; Consultant: Bayer, Galderma, Johnson & Johnson, Medimetriks Pharmaceuticals Inc, Ranbaxy Laboratories Limited, and SmartPractice; Speakers Bureau: Galderma, SmartPractice, and Valeant.

Christopher B. Zachary, MBBS, FRCP, Consultant: Cutera, Inc. and ZELTIQ Aesthetics, Inc.; Speakers Bureau: Cynosure, Inc. and Solta Medical, a division of Valeant; Advisory Board: ZELTIQ.

Address reprint requests to: Christopher B. Zachary, MBBS, FRCP, Dermatology, UC Irvine Health, 118 Med Surge I, Irvine, CA 92697, [email protected].

Joseph F. Fowler, Jr, MDClinical Professor of Dermatology

University of LouisvilleLouisville, Kentucky

Skin Disease Education Foundation Director Medical Dermatology

Christopher B. Zachary, MBBS, FRCPProfessor and Chair

Department of DermatologyUniversity of California, Irvine

Irvine, CaliforniaSkin Disease Education Foundation Director

Aesthetic and Procedural Dermatology


Introduction

Onychomycosis is a common fungal infection affecting the nails. It occurs in roughly 10% of the general population, with higher prevalence in men, older individuals, and in

people with psoriasis, diabetes, or immunosuppressive condi-tions (eg, HIV).1-4 Dermatophytes are the most frequent cause of onychomycosis. Of these pathogens, Trichophyton rubrum is the most common, accounting for 70% of onychomycosis cases.5

Dermatophyte infection of the toenails is usually not a primary condition but is secondary to tinea pedis, a dermatophyte infection of the soles of the feet and interdigital spaces.1 T. rubrum is also a common cause of tinea pedis.6 Prevalence of subclinical derma-tophyte infection of the toenail is higher among patients with tinea pedis but clinically normal toenails (n=35) compared with individuals without tinea pedis (n=66) (17% vs 1.5%; P=0.0066).7 Patients with either tinea pedis or toenail onychomycosis should be evaluated for the other infection.

If topical therapy is chosen for toenail onychomycosis, then separate agents must be prescribed to treat tinea pedis.

Tinea Pedis TherapyTwo topical antifungal agents are commonly used to treat tinea pedis. Luliconazole 1% cream received approval from the US Food and Drug Administration (FDA) in 2013 for the treatment of interdigital tinea pedis, but has been available in Japan for many years. It appears to inhibit the synthesis of ergosterol, a

constituent of fungal cell membranes.8 According to an animal study, it was more effectively retained in the stratum corneum than terbinafine cream.9 Luliconazole 1% cream is also indicated for tinea cruris and tinea corporis.8 Naftifine 2%, available as a gel or cream, is also FDA-approved specifically for interdigital tinea pedis. It interferes with sterol biosynthesis, decreasing the amount of ergosterol.10,11

A publication of two phase III trials (n=1,174) of naftifine 2% gel reported efficacy rates separately for interdigital (43.3%) and moccasin-type tinea pedis (56.7%). Rates of complete clearance, effective treatment, and mycological cure were similar for patients with interdigital and moccasin-type tinea pedis at 4 weeks post- treatment (22% vs 20%, 52% vs 51%, and 62% vs 65%, respectively).12

OnychomycosisSome clinicians incorrectly view onychomycosis as a cosmetic condition not worthy of treatment. However, this infection is progressive if untreated. It can disrupt skin integrity, permanently damage the nail plate, and spread to other individuals and to other body parts on the infected individual.1,13

The most sensitive diagnostic test for onychomycosis is periodic acid–Schiff staining (82% sensitivity in one analysis).14 The severity of onychomycosis can be scored based on the proportion of a nail affected multiplied by the proximity of the infection to the nail matrix (Figure 1), with 10 points added if dermatophytoma (longi-tudinal streak or a patch) or subungual hyperkeratosis (>2 mm) is present (Figure 2). Mild disease is classified as a score of 5 or less, moderate as 6 to 15, and severe as 16 to 35. Severe involvement requires systemic treatment and carries a poorer prognosis. Host-related poor prognostic factors include immunosuppression, poor peripheral circulation, and poorly controlled diabetes.15

Oral Therapies Systemic agents used to treat onychomycosis include terbinafine, itraconazole, and fluconazole. A meta-analysis reported a myco-logical cure rate of 76% ± 3% with terbinafine (n=18 studies, 993 patients), 63% ± 7% with itraconazole pulse therapy (n=6 studies, 318 patients), and 48% ± 5% with fluconazole (n=3 studies, 131 patients).16

A trial of terbinafine (12 or 16 weeks of therapy, 5-year follow-up) in toenail onychomycosis reported complete cure (ie, mycological plus clinical cure) in 35% of patients and mycological cure in 46% of patients.17 The recommended dose for toenail onychomycosis is 250 mg once daily for 12 weeks.18

A pulse regimen is FDA-approved for fingernail infection but not toenail infection.19 Among patients receiving itraconazole for toenail onychomycosis in three double-blind, controlled trials (n=110), complete cure was reported in 14% of patients and mycological cure in 54% of patients. Therapy was deemed effective (mycological cure plus clear or minimal nail involvement) in 35% of those receiving itraconazole. Mean time to effective therapy was about 10 months. The recommended dose of itraconazole for toenail onychomycosis is 200 mg once daily for 12 consecutive weeks.19

Fluconazole is sometimes used off-label to treat onychomycosis. When given once weekly for up to 1 year (n=362), it has produced clinical cure rates of 37% (150 mg/wk), 46% (300 mg/wk), and

AbstractToenail onychomycosis and tinea pedis are common, often coexisting, fungal infections. The former, in particular, may be viewed incorrectly as not worthy of treatment. However, infection is progressive if not addressed and can permanently damage the nail plate. It can also spread to other individuals. New topical therapies have been introduced in recent years for both infections.Semin Cutan Med Surg 34(supp4):S62-S64 © 2015 published by Frontline Medical Communications

Keywords Onychomycosis, tinea pedis, luliconazole, naftifine, terbinafine, itraconazole, fluconazole, efinaconazole, tavaborole

* Clinical Professor of Dermatology, The University of Iowa, West Des Moines, Iowa.


Dr Ceilley has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Eileen McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Roger I. Ceilley, MD, Consultant: Ferndale Pharma Group, Inc, DUSA Pharmaceuticals, Inc., LEO Pharma Inc., Valeant Pharmaceuticals North America LLC, Xoft Inc.; Speakers Bureau: DUSA and LEO Pharma; Advisory Board: Ferndale, DUSA, Xoft Inc.

Address reprint requests to: Roger I. Ceilley, MD, RCI, LLC, 1280 Burr Oaks Drive, West Des Moines, IA 50266; [email protected].


Fungus: New Treatment Options for Toenail Onychomycosis and Tinea PedisRoger I. Ceilley, MD*

48% (450 mg/wk) at 6-month post-therapy follow-up. Clinical cure was defined as a clinically normal target nail with complete regrowth of healthy tissue. Mean time to clinical success was 6.6, 6.2, and 6.7 months with 150-, 300-, and 450-mg weekly doses, respectively.20 The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with a statin.21 Consider advising patients on statin therapy to withhold that agent on the day they take fluconazole. The once-weekly regimen may improve adherence.

Notably, ketoconazole oral tablets are no longer indicated for cutaneous fungal infections. The FDA withdrew the indication as of July 2013 due to the risk of severe liver injury and adrenal gland problems.22 Topical formulations of ketoconazole are unaffected by this change.

Consider obtaining a complete blood count and hepatic panel prior to initiating oral antifungal therapy.4 Fluconazole and terbinafine have rarely been associated with serious hepatic toxicity.18,21 Itraconazole is metabolized primarily in the liver.19 Patients at elevated risk for hepatic or other adverse events, or receiving medications that may interact with antifungal therapy, should be monitored closely.

Systemic therapy does not cure all patients. Reasons for treat-ment failure include treatment nonadherence, incorrect diagnosis, a nondermatophyte pathogen, and patient factors (eg, immuno-compromised, poorly controlled diabetes, peripheral vascular disease).4 A certain level of recurrence is associated with systemic antifungal therapy. A 7-year prospective study (n=73) reported a 16.4% recurrence at a mean of 3 years following successful therapy. The recurrence rate was higher following treatment with itraconazole than with terbinafine (35.7% vs 11.9%, respectively; P=0.046).23

Topical TherapiesMild to moderate onychomycosis may respond to topical antifungal therapy alone. The FDA approved two topical agents in 2014 that were developed specifically for toenail onychomycosis: efinaconazole 10% solution and tavaborole 5% solution.24-26 Each agent is indicated for 48 weeks of therapy. Many patients prefer topical therapy to systemic therapy. Laboratory monitoring is not required, and the most common side effects are local (application site vesicles and pain with efinaconazole, application site exfoliation and erythema with tavaborole, and ingrown toenails and application site dermatitis with both agents).25,26

Efinaconazole is a non-lacquer alcohol-based triazole anti-fungal agent characterized by low surface tension (desirable for application to a dry nail plate surface) and a low (ie, desirable) level of keratin binding.24,25 Two identically designed phase III studies in patients with toenail distal lateral subungual onycho-mycosis (20%-50% clinical involvement) randomized patients (3:1) to efinaconazole or vehicle once daily for 48 weeks (study 1: n=870; study 2: n=785). Mycological cure rates of 55.2% and 53.4% were reported at 4 weeks post-treatment in the two studies (P<0.001 vs vehicle).27

Complete cure (0% clinical involvement of target toenail and negative potassium hydroxide [KOH] examination and fungal culture) lagged behind mycological cure (17.8% and 15.2% in the two studies at week 52; P<0.001 vs vehicle).27 Nonetheless, it is noteworthy that the rate of mycological cure in these studies appears comparable to the 54% level reported with oral itracon-azole.19 An additional advantage of efinaconazole is that its nail penetration does not appear to be influenced by nail polish.28

Tavaborole, a boron-based molecule, represents a new class of antifungals.29 It inhibits a fungal aminoacyl-transfer ribonucleic acid synthetase necessary for protein synthesis.26,29

Two phase III studies including patients with distal subun-gual onychomycosis affecting 20% to 60% of a great toenail were randomized (2:1) to tavaborole or vehicle for 48 weeks (study 1: n=593; study 2: n=601). At 4 weeks post-treatment cessation, myco-logical cure rates were 31.1% and 35.9% in the two studies. Clear or almost clear rates were 26.1% and 27.5%. As with efinaconazole, complete cure (clinical and mycological cure) lagged behind myco-logical cure (6.5% vs 9.1%; P≤0.001 vs vehicle). Also noteworthy is that fungal cultures were negative at week 52 in 87.0% and 85.4% of

10 points ifdermatophytoma

or subungualhyperkeratosis

(>2 mm)

Proximity of disease to matrix/involvement from distal edge

% of nail involved

2. 11%-25%

3. 26%-50%

4. 51%-75%

5. 76%-100%

1. 0-10%1. <1/4

2. 1/4–1/2

4. >3/4

3. >1/2–3/4

Source: Carney C, et al. Arch Dermatol. 2011;147(11):1277-1282.

FIGURE 2 Onychomycosis Severity Index.Multiply score (boldface numerals in each bar) for % nail involved × proximity to matrix, + 10 if dermatophytoma or subungual hyperkeratosis (>2 mm).


The nail is divided transversely into quarters. Involvement of the distal quarter is given a score of 1 (distal groove in red); if involvement extends to the first half of the nail, it is given a score of 2; the third quarter, a score of 3; and the proximal quarter, a score of 4. Involvement of the lunula (aqua) and the proximal nail fold (red) represents matrix involvement and is given a score of 5.Source: Courtesy of Roger I. Ceilley, MD.

Proximal nail fold

1

2

3

4

5

Distal groove

Lunula

FIGURE 1 Proximity to Matrix Scoring.

patients treated with tavaborole. Negative fungal culture is distinct from mycological cure in that the latter was defined as negative KOH wet mount and negative fungal culture.29

SummaryThe current classification system for onychomycosis divides cases into mild, moderate, and severe disease.15 Severe disease requires oral therapy. Two recently FDA-approved topical anti-fungal agents—efinaconazole 10% solution and tavaborole 5% solution—have demonstrated effectiveness in mild to moderate onychomycosis. Topical luliconazole 1% cream and naftifine 2% cream and gel offer effective options for tinea pedis. Patients with either toenail onychomycosis or tinea pedis should be evaluated for the other fungal infection.

References 1. Ameen M, Lear JT, Madan V, Mohd Mustapa MF, Richardson M. British

Association of Dermatologists’ guidelines for the management of onychomycosis 2014. Br J Dermatol. 2014;171(5):937-958.

2. Gupta AK, Jain HC, Lynde CW, Macdonald P, Cooper EA, Summerbell RC. Prevalence and epidemiology of onychomycosis in patients visiting physicians’ offices: A multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol. 2000;43(2 pt 1):244-248.

3. Saunte DM, Holgersen JB, Haedersdal M, et al. Prevalence of toe nail onychomy-cosis in diabetic patients. Acta Derm Venereol. 2006;86(5):425-428.

4. Westerberg DP, Voyack MJ. Onychomycosis: Current trends in diagnosis and treatment. Am Fam Physician. 2013;88(11):762-770.

5. Tosti A. Onychomycosis Clinical Presentation. 2015. http://emedicine.medscape.com/article /1105828-clinical#a0218. Accessed May 17, 2015.

6. Havlickova B, Czaika VA, Friedrich M. Epidemiological trends in skin mycoses worldwide. Mycoses. 2008;51(suppl 4):2-15.

7. Walling HW. Subclinical onychomycosis is associated with tinea pedis. Br J Dermatol. 2009;161(4):746-749.

8. Luzu [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals; 2013.9. Koga H, Nanjoh Y, Kaneda H, Yamaguchi H, Tsuboi R. Short-term therapy with

luliconazole, a novel topical antifungal imidazole, in guinea pig models of tinea corporis and tinea pedis. Antimicrob Agents Chemother. 2012;56(6):3138-3143.

10. Naftin gel, 2% [package insert]. Greensboro, NC: Merz Pharmaceuticals, LLC; 2013.

11. Naftin cream, 2% [package insert]. Greensboro, NC: Merz Pharmaceuticals, LLC; 2012.

12. Stein Gold LF, Parish LC, Vlahovic T, et al. Efficacy and safety of naftifine HCl Gel 2% in the treatment of interdigital and moccasin type tinea pedis: Pooled results from two multicenter, randomized, double-blind, vehicle-controlled trials. J Drugs Dermatol. 2013;12(8):911-918.

13. Daniel RC. Onychomycosis: Burden of disease and the role of topical antifungal treatment. J Drugs Dermatol. 2013;12(11):1263-1266.

14. Wilsmann-Theis D, Sareika F, Bieber T, Schmid-Wendtner MH, Wenzel J. New reasons for histopathological nail-clipping examination in the diagnosis of onycho-mycosis. J Eur Acad Dermatol Venereol. 2011;25(2):235-237.

15. Carney C, Tosti A, Daniel R, et al. A new classification system for grading the severity of onychomycosis: Onychomycosis Severity Index. Arch Dermatol. 2011;147(11):1277-1282.

16. Gupta AK, Ryder JE, Johnson AM. Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol. 2004; 150(3):537-544.

17. Darkes MJ, Scott LJ, Goa KL. Terbinafine: A review of its use in onychomycosis in adults. Am J Clin Dermatol. 2003;4(1):39-65.

18. Lamisil [package insert]. East Hanover, NJ: Sandoz Pharmaceuticals Corp; 2015.19. Sporanox [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014.20. Scher RK, Breneman D, Rich P, et al. Once-weekly fluconazole (150, 300, or

450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol. 1998;38(6 pt 2):S77-86.

21. Diflucan [package insert]. New York, NY: Pfizer Inc.; 2014.22. FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole)

oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm. Accessed May 17, 2015.

23. Piraccini BM, Sisti A, Tosti A. Long-term follow-up of toenail onychomycosis caused by dermatophytes after successful treatment with systemic antifungal agents. J Am Acad Dermatol. 2010;62(3):411-414.

24. Del Rosso JQ. The role of topical antifungal therapy for onychomycosis and the emergence of newer agents. J Clin Aesthet Dermatol. 2014;7(7):10-18.

25. Jublia [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2015.

26. Kerydin [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, Inc.; 2014.

27. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68(4):600-608.

28. Zeichner JA, Gold LS, Korotzer A. Penetration of (14C)-efinaconazole topical solu-tion, 10%, does not appear to be influenced by nail polish. J Clin Aesthet Dermatol. 2014;7(9):34-36.

29. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: Results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015;73(1):62-69.


Tumor necrosis factor (TNF) is among the cytokines that play key roles at multiple points in the pathophysiology of psoriasis.1 It induces the release of interleukin (IL)-23 from

dendritic cells and contributes to the differentiation of T cells into the production of IL-17, another important substance in the psoriasis inflammatory cascade. TNF regulates tissue remodeling and expression of genes for inflammatory responses. It appears to act synergistically with IL-17 to induce changes in psoriasis-related gene expression.1

Five TNF-α inhibitors are available in the United States. Three of these agents are FDA-approved for both psoriasis and psoriatic arthritis (PsA)—etanercept, adalimumab, and infliximab—and two agents are FDA-approved for PsA but not psoriasis—golimumab and certolizumab.2-6 Certolizumab is now in phase III trials for use in psoriasis (http://dermira.com/dermira-and-ucb-announce-start-of-phase-3-program-for-cimzia- certolizumab-pegol-in-psoriasis/). The Table on page 10 summa-rizes some of the characteristics of and differences among the agents that are currently approved for psoriasis.

EtanerceptUnlike the other two anti-TNF-α agents FDA-approved for psori-asis, etanercept is a fusion protein of the TNF receptor rather than a monoclonal antibody.2,3,6 The recommended dosage is 50 mg twice weekly for 3 months, followed by 50 mg once weekly thereafter.2

Advantages of etanercept include extensive experience (FDA-approved 10 years ago for plaque psoriasis), consistent efficacy across clinical studies (~50% of patients achieving Psoriasis Area and Severity Index [PASI] 75),7-9 and long-term safety.9 Nearly half (49%) of participants in a randomized, placebo-controlled, double-blind, parallel-group, phase III clinical trial achieved PASI 75 (ie, ≥75% improvement) with etanercept 50 mg twice weekly at week 12. This proportion rose to 59% after 24 weeks on this high dose.7 Response is dose dependent, with higher efficacy at higher doses. Proportions achieving PASI 90 (≥90% improvement) with high-dose etanercept were 22% and 30% at weeks 12 and 24, respectively.7

Another phase III study of etanercept in plaque psoriasis produced similar results: At week 12, 49% of patients randomized to high-dose therapy (50 mg twice weekly) achieved PASI 75 and 21% achieved PASI 90.8 This study reduced the highest dose to 25 mg twice weekly after 12 weeks, yet 54% of those whose dose was reduced from 50 to 25 mg twice weekly at week 12 achieved PASI 75 at week 24. As in the other phase III trial, response rates rose with dose: 34% of those initiated at the lower dose (25 mg twice weekly) achieved PASI 75 at week 12. A long-term extension of a phase III randomized study (n=591) reported that at 96 weeks, 51.6% of patients demonstrated PASI 75 and 23.2% attained PASI 90 with etanercept 50 mg twice weekly.9

Etanercept has the lowest efficacy (measured as PASI 75 at 10 to 16 weeks) of all the anti-TNF agents approved by the FDA for the treatment of psoriasis, with the caveat that this comparison does not come from head-to-head studies.7,8,10-13 Anecdotally, patients and clinicians often observe a reduction in efficacy when patients decrease the dose from 50 mg twice weekly to weekly at 12 weeks, as recommended in the prescribing information.2 It is FDA-approved for PsA and has demonstrated long-term safety, with rates of exposure-adjusted adverse events (other than injec-tion site reactions) and infections over 96 weeks similar to those of placebo.9 It requires the most frequent injection schedule of the three anti-TNF inhibitors that are FDA-approved for plaque psoriasis.2,3,6 Only non-neutralizing antibodies have been observed, which did not affect efficacy or safety.9 Etanercept syringes or autoinjectors can be stored at room temperature for up to 14 days prior to use, which offers convenience for patients who travel.2

Combining etanercept with other agents can increase its effi-cacy. Adding no more than two courses of clobetasol propionate foam to etanercept for up to 2 weeks (at weeks 11 and 12, and weeks 23 and 24) increases the proportion of patients achieving PASI 75 at week 12 (65.2% with combination [n=295] vs 48.3% with etanercept alone [n=297]; P<0.001), though not at week 24.14

Adding narrow-band ultraviolet light B therapy to etanercept (single-arm study, 86 patients) led to 85% of patients achieving PASI 75 and 58% reaching PASI 90 at 12 weeks.15 Combining methotrexate (7.5-15 mg/wk; n=239) or placebo (n=239) with

AbstractThe introduction of tumor necrosis factor (TNF) inhibitors greatly improved the level of care available for patients with psoriasis. The three anti-TNF medications that have received approval by the US Food and Drug Administration (FDA) for use in plaque psoriasis have many similarities and differences in terms of efficacy, safety, dosage route and frequency, and effectiveness in comorbid conditions. Familiarity with their characteristics can inform the choice of therapy for each patient. This article reviews the major clinical trials of each agent as well as real-world evidence.Semin Cutan Med Surg 34(supp4):S65-S68 © 2015 published by Frontline Medical Communications

Keywords Psoriasis, tumor necrosis factor inhibitors, efficacy, safety, psoriatic arthritis

* Assistant Professor, Dermatology, University of Utah, Salt Lake City, Utah.


Dr Duffin has received an honorarium for her participation in this activity. She acknowledges the editorial assistance of Eileen McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Kristina Callis Duffin, MD, MS, Grant/Research: AbbVie Inc., Amgen Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Biotech, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Stiefel Laboratories, Inc., and XenoPort, Inc.; Consultant: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and XenoPort; Advisory Board: Eli Lilly and Janssen.

Address reprint requests to: Kristina Callis Duffin, MD, MS, University of Utah, 30 North 1900 East 4A330, Salt Lake City, UT 84132; [email protected]


Using the Anti-TNF Agents in PsoriasisKristina Callis Duffin, MD, MS*

etanercept (50 mg twice weekly for 12 weeks followed by 50 mg once weekly for 12 weeks) was associated with significantly higher rates of achieving PASI 75 at week 24 (77.3% vs 60.3%; P<0.0001). Methotrexate was associated with a higher incidence of elevated hepatic transaminases classified as adverse events (2.9% with methotrexate, 1.7% with placebo).16

AdalimumabTwo major clinical trials documented the efficacy of adalim-umab in plaque psoriasis. Nearly three-quarters (71%) of the 814 patients randomized to adalimumab (40 mg every other week) in the Randomized controlled EValuation of adalimumab Every other week dosing in moderate to severe psoriasis TriAL (REVEAL) attained PASI 75 at week 16,10 substantially more than the roughly 50% reaching this threshold at week 12 with etanercept in pivotal studies.7-9 Nearly half (45%) of patients receiving adalimumab achieved PASI 90 at 16 weeks, and 20% of patients reached PASI 100.10

In the Comparative Study of Humira vs Methotrexate vs Placebo in Psoriasis Patients (CHAMPION; n=271), 79.6% of adalimumab-treated patients achieved PASI 75 at week 16, compared with 35.5% receiving methotrexate and 18.9% random-ized to placebo (P<0.001, adalimumab vs either comparator). Response with adalimumab was rapid (57% improvement in mean PASI at week 4), possibly due to the loading dose (80 mg initial dose).11 The study discontinuation rate was higher with methotrexate than with adalimumab, primarily because of hepatic-related adverse events. Methotrexate reduces adalimumab clearance, though no dose adjustment of either agent is required.3

One of the primary disadvantages of using adalimumab is its association with the formation of anti-drug antibodies and a resultant loss of drug efficacy. In REVEAL, 8.8% of patients had detectable anti-adalimumab antibodies (AAA) at least once over a 1-year period. Nearly half (43%) of AAA-positive patients and 28% of AAA-negative patients lost an adequate response to the drug.10 The prescribing information reports an immunogenicity rate of 20.8% in the subset of patients with psoriasis in which AAA could be measured. The rate of AAA formation in patients with rheumatoid arthritis (RA) is lower when methotrexate is added to adalimumab.3 Clinicians may wish to consider adding methotrexate to adalimumab, especially in patients with severe psoriasis and PsA who have failed other therapies.

InfliximabThis monoclonal antibody, delivered by intravenous infusion, displays a rapid onset of action and the highest efficacy rates of all three anti-TNF agents approved for the treatment of plaque psoriasis. Again, this comparison is not based on head-to-head trials but on proportions of patients achieving PASI 75 at 10 to 16 weeks in landmark trials.7,8,10-13 In two phase III studies, 80% and 75.5% of patients randomized to infliximab at the recom-mended dose of 5 mg/kg reached PASI 75 at week 10; 57% and 45.2% reached PASI 90 at week 10.12,13 Infliximab requires an induction period with infusions at 0, 2, and 6 weeks, followed by infusions every 8 weeks.6

Efficacy in these studies for patients receiving 5 mg/kg every 8 weeks was sustained at week 24 or 26 (PASI 75 in 82% and 78%, PASI 90 in 58% and 56%) but declined at week 50 (PASI 75 in 61% and 54.5%, PASI 90 in 45% and 34.3%).12,13 Giving infliximab as needed (ie, when PASI response drops below 75) led to a greater reduction in efficacy.13 It is important for clinicians to explain to patients the need to obtain the infusion on schedule even if their skin is clear, as delaying a dose until symptoms recur can lead to loss of efficacy. Increasing the dose to 7.5 or 10 mg/kg, or reducing the dose interval (eg, to every 6 weeks) at the first sign of a dimi-nution in efficacy, can forestall further reduction in effectiveness.17 Adding another immunosuppressive agent such as methotrexate can also increase efficacy (documented in RA18), decrease the risk of anti-drug antibodies, and reduce the risk of infusion reac-tions,19 though it may also increase the risk of serious infections.6

Along with the loss of efficacy, the high risk of infusion reac-tions is one of the major drawbacks to treatment with infliximab. Infusion reactions have been reported in 20% of clinical trial participants, compared with 10% of those randomized to placebo. Manifestations can range from flu-like symptoms to dyspnea or anaphylaxis.6 Infusion reactions were two to three times more common in patients who developed anti-drug antibodies, and occurred more frequently in those who were re-treated following a break in therapy.6 A serum sickness-like reaction that can occur following therapy is also more common among patients who develop anti-drug antibodies, and in those who stop and then restart infliximab therapy.6 Anti-drug antibodies were detected in 19% of patients receiving infliximab for psoriasis through week 46 in one study.12 The prescribing information reports rates of 36% and 51% in patients with psoriasis treated for 1 year.6

TABLE Characteristics of TNF Inhibitors Approved for Use in Plaque Psoriasis

Etanercept Adalimumab Infliximab

Structure Fusion protein of the TNF receptor

Human monoclonal antibody Chimeric monoclonal antibody

Half-life 5-6 days 10-20 days 8-10 days

Dose/frequency Self-administered, 50 mg subcutaneous injection, 2x/wk for 3 mo, then weekly

Self-administered, 40 mg; 80 mg on day 1, then 40 mg on day 8, then every other week

IV infusion, 5 mg/kg; weeks 0, 2, 6, then every 8 weeks

Efficacy* 49% at week 127,8 and 51.6% at week 969 with 50 mg 2x/wk

71% and 79.6% at week 1610,11 80% and 75.5% at week 10, 61% and 54.5% at week 50 (5 mg/kg)12,13

PsA FDA-approved FDA-approved FDA-approved

*% reaching PASI 75 at specified time points in phase III clinical trials referenced.


TNF Inhibitors in Children With PsoriasisNo anti-TNF inhibitors are FDA-approved for children with psoriasis. However, the efficacy of etanercept in children and adolescents (n=211, ages 4-17 years old) has been documented in a rigorously conducted randomized controlled trial. A total of 57% of patients receiving etanercept achieved PASI 75 at week 12.20 Long-term follow-up demonstrated continued efficacy (PASI 75 in 61% at week 96) and safety (five serious adverse events, none of which were treatment-related).21 Most children and adolescents regained efficacy after withdrawal and re-treatment; 80% of the 65 patients maintained or regained PASI 75 under such circumstances.22

Use in Patients With Comorbid ConditionsRoughly 30% of patients with psoriasis also have PsA.23 All three anti-TNF agents approved by the FDA for psoriasis are also marketed for use in PsA. Efficacy (measured as a 20% improvement, or ACR20) is similar for all three agents: 59%, 58%, and 58% for etanercept, adalimumab, and infliximab at weeks 12, 12, and 14, respectively.24-26

Obesity affects an estimated 13% to 34% of individuals with chronic plaque psoriasis.27 Of the three TNF inhibitors approved for psoriasis, only infliximab offers weight-based dosing.6 This may be an advantage when treating patients who are obese. Adalimumab and infliximab are FDA-approved for use in Crohn’s disease and ulcerative colitis3,6; psoriasis has been associated with both of these conditions.28

Real-World EvidenceA study including 713 patients from 10 outpatient clinics at a single point in time reported somewhat lower efficacy with TNF inhibi-tors than the rates observed in clinical trials (Figure).29 Eligible patients were those receiving phototherapy or commonly used systemic therapies. The primary outcome was achieving a score of clear or almost clear (0-1) on the Physician’s Global Assessment (PGA) scale. Among the most commonly used treatments, rates of reaching this threshold were 47.7% for adalimumab, 36.1% for the non-TNF biologic agent ustekinumab, 34.2% for etanercept, 27.6% for narrow-band UV-B, and 23.8% for methotrexate.29

Other noteworthy findings from this study were that less than 5% of patients were treated with infliximab, and many patients were treated with higher than recommended doses. Specifically, 30% of patients receiving etanercept were treated with 50 mg twice weekly despite having passed the 12-week mark. Roughly 11.5% of patients treated with adalimumab received the agent weekly rather than every other week as recommended, or injected double the recommended dose every other week.29

SafetyConsiderations with all three TNF inhibitors approved by the FDA for plaque psoriasis include risk of serious infections (eg, tuberculosis, bacterial sepsis, invasive fungal infections), onset or exacerbation of demyelinating diseases (eg, multiple sclerosis, optic neuritis) or heart failure, risk of lymphoma or leukemia, or a lupus-like syndrome.2,3,6 An ongoing observational study (N=12,095) of patients receiving or eligible to receive biologic or other systemic therapy for psoriasis has reported that exposure to infliximab (hazard ratio [HR], 3.101, P<0.001) or other biologics (HR, 1.954, P=0.005) predicted the risk of serious infections. Use of biologics did not predict the risk of death, malignancy, or major adverse cardiac events compared with nonbiologic therapy.30

SummaryTNF inhibitors have revolutionized the field of psoriasis manage-ment. These agents are now the cornerstone of therapy for psoriasis and PsA. Their efficacy rates are high, they have been thoroughly evaluated in controlled clinical studies, and they can be used in combination with other medications to improve safety and efficacy.

Distinguishing factors among the three anti-TNF agents approved by the FDA for use in psoriasis and PsA therapy include the following:• When comparing the proportion of patients who achieve

PASI 75 at 10 to 16 weeks in clinical trials, etanercept offers the lowest rate of efficacy (~50% at 12 weeks, compared with 71% and 80% at week 16 with adalimumab10,11 and 75.5% and 80% at week 10 with infliximab12,13).

• Infliximab is associated with the loss of efficacy over time.12,13 • Etanercept is not associated with neutralizing anti-drug

antibodies, unlike adalimumab and infliximab.3,6,9

• Etanercept’s efficacy in the pediatric population has been evaluated in a randomized controlled trial.

• Etanercept requires the most frequent dosing.2,3,6

• Risk of infusion reaction is high with infliximab.6

• Infliximab offers weight-based dosing, which may be helpful in patients who are obese.6

References1. Lowes MA, Suarez-Farinas M, Krueger JG. Immunology of psoriasis. Annu Rev

Immunol. 2014;32:227-255.

2. Enbrel [package insert]. Thousand Oaks, CA: Amgen Inc; 2013.

3. Humira [package insert]. North Chicago, IL: AbbVie Inc; 2014.

4. Simponi [package insert]. Horsham, PA: Janssen Biotech, Inc; 2013.

5. Cimzia [package insert]. Smyrna, GA: UCB, Inc; 2013.

6. Remicade [package insert]. Horsham, PA: Janssen Biotech, Inc; 2015.

7. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349(21):2014-2022.

8. Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled trial of etanercept in psoriasis: Safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005;152(6):1304-1312.

9. Tyring S, Gordon KB, Poulin Y, et al. Long-term safety and efficacy of 50 mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol. 2007; 143(6):719-726.

10. Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol. 2008;58(1):106-115.

11. Saurat JH, Stingl G, Dubertret L, et al. Efficacy and safety results from the random-ized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol. 2008;158(3):558-566.

12. Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: A phase III, multicentre, double-blind trial. Lancet. 2005;366(9494):1367-1374.

13. Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of contin-uous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2007;56(1):31.e1-e15.


0

10

20

30

40

50

60

70

80

90

100

Methotrexate

23.8%

Adalimumab

47.7%

Etanercept

34.2%

Ustekinumab

36.1%

NB-UVB

27.6%

% o

f pat

ient

s

Current treatment

P<0.001

NB-UVB=narrow-band UV-B; PGA=Physician’s Global Assessment. Source: Used with permission. Gelfand JM, et al. Arch Dermatol. 2012;148(4):487-494.

FIGURE The Real World: Cross-Sectional Data.Primary end point: Clear/minimal on PGA at any time point. Enrollment started February 2010.

14. Lebwohl MG, Kircik L, Callis Duffin K, et al. A randomized study to evaluate the efficacy and safety of adding topical therapy to etanercept in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2013;69(3):385-392.

15. Kircik L, Bagel J, Korman N, et al. Utilization of narrow-band ultraviolet light B therapy and etanercept for the treatment of psoriasis (UNITE): Efficacy, safety, and patient-reported outcomes. J Drugs Dermatol. 2008;7(3):245-253.

16. Gottlieb AB, Langley RG, Strober BE, et al. A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2012;167(3):649-657.

17. Kalb RE,Gurske J. Infliximab for the treatment of psoriasis: Clinical experi-ence at the State University of New York at Buffalo. J Am Acad Dermatol. 2005;53(4):616-622.

18. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41(9):1552-1563.

19. Kapetanovic MC, Larsson L, Truedsson L, Sturfelt G, Saxne T, Geborek P. Predictors of infusion reactions during infliximab treatment in patients with arthritis. Arthritis Res Ther. 2006;8(4):R131.

20. Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008;358(3):241-251.

21. Paller AS, Siegfried EC, Eichenfield LF, et al. Long-term etanercept in pediatric patients with plaque psoriasis. J Am Acad Dermatol. 2010;63(5):762-768.

22. Siegfried EC, Eichenfield LF, Paller AS, Pariser D, Creamer K, Kricorian G. Intermittent etanercept therapy in pediatric patients with psoriasis. J Am Acad Dermatol. 2010;63(5):769-774.

23. Gladman D, Antoni C, Mease P, Clegg D, Nash P. Psoriatic arthritis: Epidemiology, clinical features, course, and outcome. Ann Rheum Dis. 2005;64(suppl 2):ii14-ii17.

24. Antoni C, Krueger GG, de Vlam K, et al. Infliximab improves signs and symp-toms of psoriatic arthritis: Results of the IMPACT 2 trial. Ann Rheum Dis. 2005;64(8):1150-1157.

25. Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52(10):3279-3289.

26. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: Safety, efficacy, and effect on disease progression. Arthritis Rheum. 2004;50(7):2264-2272.

27. Roongpisuthipong W, Pongpudpunth M, Roongpisuthipong C, Rajatanavin N. The effect of weight loss in obese patients with chronic stable plaque-type psoriasis. Dermatol Res Pract. 2013;2013:795932.

28. Cohen AD, Dreiher J, Birkenfeld S. Psoriasis associated with ulcerative colitis and Crohn’s disease. J Eur Acad Dermatol Venereol. 2009;23(5):561-565.

29. Gelfand JM, Wan J, Callis Duffin K, et al. Comparative effectiveness of commonly used systemic treatments or phototherapy for moderate to severe plaque psoriasis in the clinical practice setting. Arch Dermatol. 2012;148(4):487-494.

30. Gottlieb AB, Kalb RE, Langley RG, et al. Safety observations in 12095 patients with psoriasis enrolled in an international registry (PSOLAR): Experience with infliximab and other systemic and biologic therapies. J Drugs Dermatol. 2014;13(12):1441-1448.


P soriasis has been associated with an increased risk of a variety of concomitant conditions (Table 1). The link between psoriasis and at least some associated comorbidities

is thought to be T-cell and cytokine (eg, tumor necrosis factor [TNF]) activation.1,2 Recent studies have evaluated if psoriasis treatment—especially treatment directed at the underlying inflammation—affects these comorbidities and if any improve-ment in comorbidities associated with psoriasis treatment is linked to psoriasis treatment response (Table 2 on page 15).

Chronic Kidney DiseaseA recently published claims data analysis (n=143,883 with psoriasis and n=689,702 without psoriasis) reported an association between severe psoriasis and an increased risk of incident chronic kidney disease (CKD), independent of risk factors (eg, age, sex, hyperten-sion, diabetes, cardiovascular disease [CVD], body mass index, and use of nonsteroidal anti-inflammatory drugs [NSAIDs]).2 Specifically, individuals with severe psoriasis had nearly twice the risk of incident CKD compared with controls, after risk factor adjustment. Severe psoriasis was also associated with a four-fold increased incident risk of end-stage renal disease (Table 1). Among those with severe psoriasis, younger age was associated with a higher relative risk of CKD.2 Further study is needed to evaluate if psoriasis therapy can alleviate concomitant CKD.

Impact on Choice of Psoriasis Therapy and Patient MonitoringOf all the conditions associated with psoriasis, CKD probably has the greatest impact on the choice of psoriasis therapy. Patients with psoriatic arthritis (PsA) are often prescribed NSAIDs, which are associated with deterioration of kidney function3 as well as acute renal failure.4 The dosage of apremilast must be reduced to 30 mg once daily (from twice daily) in patients with severe renal impairment (creatinine clearance <30 mL/min).5

Methotrexate is eliminated primarily through the kidneys so that excretion is reduced in patients with impaired renal function. As reduced kidney function is common in older individuals, consider using only low doses of methotrexate in these individuals, with close monitoring for toxicity.6 Consider monitoring renal function in older adults using creatinine clearance rather than serum creati-nine as the latter may overestimate renal function in this population. Cyclosporin A is associated with nephrotoxicity and should not be prescribed for patients with impaired renal function.7

Crohn’s DiseasePsoriasis has been linked to a roughly four-fold increased risk for developing Crohn’s disease (CD) in the Nurses’ Health Study (Table 1). Risk of CD was even higher among women with psori-asis and PsA (relative risk [RR], 6.43, 95% confidence interval [CI] 2.04-20.32).8 Psoriasis and CD share autoinflammatory pathophysiology as well as genetic associations,9 which may explain the comorbidity. Clinicians should ask patients with psoriasis about gastrointestinal symptoms. Patients who report persistent diarrhea should be evaluated for possible CD.

Impact on Choice of Psoriasis TherapyPatients with both CD and psoriasis may benefit from therapy with the anti-TNF agents adalimumab or infliximab; these two agents are approved by the US Food and Drug Administration (FDA) for both conditions.10,11 Ustekinumab, an interleukin [IL]-23 and 12 antagonist that has received FDA approval for use in plaque psoriasis, is under study as a therapy for CD.12,13

AbstractSeveral conditions have been associated with psoriasis, including chronic kidney disease, Crohn’s disease, depression, and cardiovascular disease. Psoriasis also negatively impacts patients’ economic health in terms of employment and work productivity. Clinicians should be aware of these potential comorbidities and consider them when monitoring patients and choosing psoriasis therapy. Recent studies have evaluated if treating psoriasis can alleviate these comorbidities. Semin Cutan Med Surg 34(supp4):S69-S71 © 2015 published by Frontline Medical Communications

Keywords Psoriasis, chronic kidney disease, Crohn’s disease, depression, cardiovascular disease, economic health, treatment

* Professor of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.


Dr Gordon has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Eileen McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Kenneth B. Gordon, MD, Grant/Research: AbbVie Inc., Amgen Inc., Celgene Corporation, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, and Pfizer Inc.; Consultant: AbbVie, Amgen, Celgene, Eli Lilly, Novartis, and Pfizer.

Address reprint requests to: Kenneth B. Gordon, MD, 925 Sutton Drive, Northbrook, IL 60062; [email protected].

TABLE 1 Psoriasis and Risk of Comorbidities

Condition Risk associated with psoriasis*

CKD Adjusted HR 1.93; 95% CI 1.79–2.08†2

ESRD Adjusted HR 4.15; 95% CI 1.70–10.11†2

Crohn’s diseaseAdjusted RR, 4.00; 95% CI 1.72–9.27 (NHS) 3.76; 95% CI 1.82–7.74 (NHS II)8

Depression Adjusted HR 1.39; 95% CI 1.37–1.4116

MACE Adjusted HR 1.53; 95% CI 1.26–1.85†24

CV death Adjusted HR 1.57; 95% CI 1.26–1.96†26

UnemploymentAdjusted OR, 1.78; 95% CI 1.40–2.26 vs mild psoriasis†30

*Compared with controls without psoriasis unless otherwise noted; †Severe psoriasis; CI=confidence interval; CKD=chronic kidney disease; CV=cardiovascular; ESRD= end-stage renal disease; HR=hazard ratio; MACE=major adverse cardiovascular events; NHS=Nurses’ Health Study (1996–2008); NHS II=Nurses’ Health Study II (1991–2007); OR=odds ratio; RR=relative risk.


Impact of Psoriasis Therapy on Comorbid Conditions Kenneth B. Gordon, MD*

Secukinumab, an IL-17A antagonist approved by the FDA for use in plaque psoriasis and PsA, has exacerbated CD in studies evaluating active CD.14 A proof-of-concept study evaluating secukinumab as a treatment for CD (n=59) reported superior results with placebo, along with an increased rate of serious adverse events (14 events in 10 patients [7 receiving secukinumab, 3 randomized to placebo]).15 Consider avoiding use of this secukinumab in patients with active CD.

DepressionRisk of depression, anxiety, and suicidality is 39%, 31%, and 44% higher, respectively, in people with psoriasis (n=146,042 with mild psoriasis, n=3,956 with severe psoriasis) compared with controls (n=766,950), according to an analysis of electronic medical records from the UK-based General Practice Research Database (GPRD). Severe psoriasis was associated with a higher risk of depression than mild psoriasis (72% and 38%, respectively; hazard ratio [HR] 1.72, 95% CI 1.57-1.88; and HR 1.38, 95% CI 1.35-1.40, respectively). Risk of depression was higher in younger patients than in older patients with mild psoriasis.16

A case-control study using information from an outpatient data-base in Germany reported similar findings (3,147 with psoriasis matched to 3,147 without psoriasis). The adjusted risk of depres-sion associated with psoriasis was 49% higher with psoriasis (odds ratio [OR] 1.49; 95% CI 1.20-1.86).17

Effect of Psoriasis Therapy on DepressionEvidence suggests that treating psoriasis does alleviate symp-toms of depression. Patients randomized to receive etanercept for moderate to severe psoriasis (n=311) were more likely than those receiving placebo (n=306) to show at least a 50% improvement in depression symptoms (Hamilton Rating Scale for Depression [HAM-D] or the Beck Depression Inventory [BDI]) in one study. Roughly one-third of the participants had mild or moderate to severe depression at baseline, based on BDI scores.18

Ustekinumab (45 or 90 mg) therapy has also been associ-ated with improvements in depression and anxiety symptoms compared with placebo (n=1,230 with moderate to severe psori-asis).19 Specifically, depression and anxiety scores improved by 29.3% and 13.9% (Hospital Anxiety and Depression Scale–Depression [HADS-D] and Hospital Anxiety and Depression Scale–Anxiety [HADS-A], respectively) at 12 weeks in patients randomized to treatment with ustekinumab compared with those receiving placebo (P<0.001). Improvement in Psoriasis Area and Severity Index (PASI) scores at week 12 was significantly though modestly correlated with easing of depression and anxiety symptoms (r=0.32 and r=0.24, respectively; P<0.0001 for each correlation).19 The proportion of patients with mild to severe anxiety or depression symptoms fell from baseline to week 12 by 34% and 55%, respectively, in the ustekinumab groups, but increased by 1.4% and 10.2%, respectively, in those randomized to placebo (P<0.001 vs placebo for each value).

These changes occurred in a population in which about one-fourth (26.7%) of participants displayed depression and two-fifths (40.3%) showed anxiety symptoms at baseline (HADS-D or HADS-A scores ≥8), with roughly one-tenth (11%) and one-fifth (20%) meeting the criteria for moderate to severe depression or anxiety (HADS-D or HADS-A scores ≥11). Impact of disease on quality of life was high at baseline, with 54.6% of study partici-pants reporting Dermatology Life Quality Index [DLQI] scores >10. Those assigned to ustekinumab saw DLQI scores improve by 76.2% at week 12 compared with placebo (P<0.001).19

Another investigation found that improvement in depression symptoms (measured by the Zung Self-rating Depression Scale [ZDS]) among patients with moderate to severe psoriasis (n=96) randomized to receive adalimumab was significantly correlated with

improvement in PASI (r=0.5; P<0.0001) and in the DLQI (r=0.5; P<0.0001). Depression symptoms were significantly more likely to improve in adalimumab responders (≥PASI 75 at week 12 or termination of therapy) than in nonresponders (Table 2). Baseline levels of depression were similar for both adalimumab and placebo groups as measured by mean ZDS scores, proportions with ZDS score ≥50, and proportion reporting a history of depression.20

Nonbiological therapy also has been associated with improve-ment in depression and anxiety. The proportions of patients with definite depression or anxiety (measured on the HADS-D and HADS-A, respectively) decreased significantly from pre- to post-treatment with 1 month of the modified Goeckerman regimen (diluted topical tar treatment followed by phototherapy; n=48).21 Specifically, rates of definite depression fell from 20% to 3%, and rates of definite anxiety decreased from 24% to 5%.21

Cardiovascular DiseaseSimilar to psoriasis, atherosclerosis, CVD, and myocardial infarction (MI) have been linked to immunological abnormali-ties and markers of system inflammation.22 Psoriasis has been associated with an increased risk of MI,23 major adverse cardio-vascular events (MACE),24,25 and CV mortality26 in analyses of data from the UK GPRD.

The risk of MI in patients with psoriasis was higher among younger patients and those with severe psoriasis compared with older patients and those with less severe psoriasis.23 Adjusted RR of MI was 1.08 (95% CI 1.03-1.13) for a 60-year-old with mild psori-asis, 1.29 (95% CI 1.14-1.46) for a 30-year-old with mild psoriasis, 1.36 (95% CI 1.13-1.64) for a 60-year-old with severe psoriasis, and 3.10 (95% CI 1.98-4.86) for a 30-year-old with severe psoriasis.

After adjustment for CV risk factors, severe psoriasis was associated with a 53% increased risk for MACE (Table 1) as well as a 6.2% attributable risk of MACE over 10 years.24 It has also been linked to an increased risk of CV death (Table 1); the risk was higher among younger patients, with a nearly 2.7-fold increased risk for a 40-year-old with severe psoriasis and a 1.9-fold increased risk for a 60-year-old with severe psoriasis (RR 2.69; 95% CI 1.45-4.99, and RR 1.92; 95% CI 1.41-2.62, respectively).26

A meta-analysis confirmed these findings, reporting a 39% increased risk of CV death and a 70% increased risk of MI with severe psoriasis, and a 29% increased risk of MI with mild psoriasis (RR 1.39; 95% CI 1.11-1.74; RR 1.70; 95% CI 1.32-2.18; RR 1.29; 95% CI 1.02-1.63). These investigators attributed 1,269 excess CV deaths and 6,479 excess MIs per year in the United States to psoriasis.25

Effect of Psoriasis Therapy on Risk of Cardiovascular DiseaseData indicate that methotrexate reduces CV risk, and that anti-TNF therapy leads to a greater degree of risk reduction than methotrexate.27,28 A meta-analysis reported that methotrexate therapy was associated with a 21% lower risk of CVD (n=10 studies, 95% CI 0.73-0.87, P<0.001), and an 18% lower risk of MI (n=5, 95% CI 0.71-0.96, P=0.01). Most studies (9 of 10) included evaluated patients treated for rheumatoid arthritis, with one study focused on psoriasis and one study focused on polyarthritis.27

Analysis of a US claims database (2000-2011) focused on indi-viduals with psoriasis and compared CVD risk in those prescribed either methotrexate (n=8,581) or a TNF inhibitor (n=9,148). At 12 months, use of an anti-TNF agent rather than methotrexate was associated with significantly lower incidence of a major CV event (1.87% vs 5.52%; P<0.01). Each incremental 6 months of cumula-tive TNF inhibitor exposure was associated with a 12% reduction in risk of a major CV event over a median of 23 months.28

Still unanswered is the question of whether the difference in CV risk reduction results from anti-TNF agents reducing inflamma-tion more effectively or of some other effect of the medications.


Economic HealthMultiple studies of data from National Psoriasis Foundation surveys indicate that psoriasis, especially severe disease, nega-tively affects income and ability to work. Among individuals working full time, the probability of low income (<$30,000) was significantly higher among individuals with severe psoriasis compared with mild psoriasis (21% vs 13%, P=0.0002) based on 2003-2005 survey data (n=601). Compared to individuals with mild disease, those with severe psoriasis were less likely to work full time (56.1% vs 62.0%; P=NS) and more likely to cite their disease as the reason for not working (17% vs 6%; P=0.01).29

A subsequent analysis (2003-2011; n=5,604) reported that 12% of patients with psoriasis were unemployed, and 92% of those cited psoriasis alone or along with PsA as the sole reason for not working. Less than half (48%) worked full time, 11% worked part time, and 22% were retired. As in the earlier study, psoriasis severity was linked to unemployment. Individuals with severe psoriasis were nearly twice as likely to be unemployed as those with mild disease, after adjustment for age and sex (Table 2). Disease-related absenteeism is common among individuals with psoriasis. Nearly half (49%) of the employed individuals reported regularly missing work due to psoriasis.30

Impact of Psoriasis Therapy on Work ProductivityDoes psoriasis therapy improve income, ability to work, or work productivity? A study of 246 patients receiving etanercept for moderate to severe psoriasis reported significant reductions in degree of work impairment as measured by the Work Productivity and Activity Impairment questionnaire. Over the first 3 months of treatment, mean degree of impairment while working decreased from 22.7% to 6.6% (P<0.0001). Mean activity impairment outside of work also decreased from 31.4% to 12.9% (P<0.0001). These improvements were sustained at 12 months.31

Adalimumab therapy has also been associated with improved work productivity and reduced total activity impairment when compared with placebo, according to an analysis of data from the Randomized controlled EValuation of adalimumab Every other week dosing in moderate to severe psoriasis TriAL (REVEAL).32 Only adalim-umab responders (ie, ≥PASI 75 at week 16) demonstrated significant improvement compared with baseline in total work productivity impairment, total activity impairment, absenteeism, and presen-teeism (ie, present but less effective at work).32

SummaryPatients with psoriasis, especially severe disease, face a higher risk of developing renal, gastrointestinal, CV, and psychiatric comorbidities as well as a higher likelihood of unemployment and low income.2,8,16,24,26,30 Therapy for psoriasis has been linked to improvements in depression, CV risk, and work produc-tivity.20,27,28,31,32 Clinicians managing patients with psoriasis should screen and monitor patients for these concomitant conditions and consider them in their choice of therapy.

References1. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet.

2007;370(9583):263-271.2. Wan J, Wang S, Haynes K, Denburg MR, Shin DB, Gelfand JM. Risk of moderate

to advanced kidney disease in patients with psoriasis: Population based cohort study. BMJ. 2013;347:f5961.

3. Gooch K, Culleton BF, Manns BJ, et al. NSAID use and progression of chronic kidney disease. Am J Med. 2007;120(3):280.e1-7.

4. Huerta C, Castellsague J, Varas-Lorenzo C, Garcia Rodriguez LA. Nonsteroidal antiinflammatory drugs and risk of ARF in the general population. Am J Kidney Dis. 2005;45(3):531-539.

5. Otezla [package insert]. Summit, NJ: Celgene Corp; revised December 2014.6. Methotrexate tablets [package insert]. Fort Lee, NJ: Dava Pharmaceuticals; revised

September 2010.7. Neoral [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.8. Li WQ, Han JL, Chan AT, Qureshi AA. Psoriasis, psoriatic arthritis and increased

risk of incident Crohn’s disease in US women. Ann Rheum Dis. 2013;72(7):1200-1205.9. Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more

than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40(8):955-962.10. Humira [package insert]. North Chicago IL: AbbVie Inc; revised December 2014.11. Remicade [package insert]. Horsham, PA: Janssen Biotech Inc; revised January 2015.12. Tuskey A, Behm BW. Profile of ustekinumab and its potential in patients with

moderate-to-severe Crohn’s disease. Clin Exp Gastroenterol. 2014;7:173-179.13. Sandborn WJ, Gasink C, Gao L-L, et al. Ustekinumab induction and maintenance

therapy in refractory Crohn’s disease. N Engl J Med. 2012;367(16):1519-1528.14. Cosentyx [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp;

January 2015.15. Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A mono-

clonal antibody, for moderate to severe Crohn’s disease: Unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61(12):1693-1700.

16. Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of depression, anxiety and suicidality in patients with psoriasis: A population-based cohort study. Arch Dermatol. 2010;146(8):891-895.

17. Schmitt J, Ford DE. Psoriasis is independently associated with psychiatric morbidity and adverse cardiovascular risk factors, but not with cardiovascular events in a popu-lation-based sample. J Eur Acad Dermatol Venereol. 2010;24(8):885-892.

18. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367(9504):29-35.

19. Langley RG, Feldman SR, Han C, et al. Ustekinumab significantly improves symptoms of anxiety, depression, and skin-related quality of life in patients with moderate-to-severe psoriasis: Results from a randomized, double-blind, placebo-controlled phase III trial. J Am Acad Dermatol. 2010;63(3):457-465.

20. Menter A, Augustin M, Signorovitch J, et al. The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: A randomized clinical trial. J Am Acad Dermatol. 2010;62(5):812-818.

21. Chern E, Yau D, Ho JC, et al. Positive effect of modified Goeckerman regimen on quality of life and psychosocial distress in moderate and severe psoriasis. Acta Derm Venereol. 2011;91(4):447-451.

22. Kolliker Frers RA, Bisoendial RJ, Montoya SF, et al. Psoriasis and cardiovascular risk: Immune-mediated crosstalk between metabolic, vascular and autoimmune inflammation. IJC Metab Endocr. 2015;6:43-54.

23. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735-1741.

24. Mehta NN, Yu Y, Pinnelas R, et al. Attributable risk estimate of severe psoriasis on major cardiovascular events. Am J Med. 2011;124(8):775.e1-6.

25. Armstrong EJ, Harskamp CT, Armstrong AW. Psoriasis and major adverse cardio-vascular events: A systematic review and meta-analysis of observational studies. J Am Heart Assoc. 2013;2(2):e000062.

26. Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Patients with severe psoriasis are at increased risk of cardiovascular mortality: Cohort study using the General Practice Research Database. Eur Heart J. 2010;31(8):1000-1006.

27. Micha R, Imamura F, Wyler von Ballmoos M, et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol. 2011;108(9):1362-1370.

28. Wu JJ, Poon KT, Channual JC, Shen A. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148(11):1244-1250.

29. Horn EJ, Fox KM, Patel V, Chiou CF, Dann F, Lebwohl M. Association of patient-reported psoriasis severity with income and employment. J Am Acad Dermatol. 2007;57(6):963-971.

30. Armstrong AW, Schupp C, Wu J, Bebo B. Quality of life and work productivity impairment among psoriasis patients: Findings from the National Psoriasis Foundation survey data 2003-2011. PLoS One. 2012;7(12):e52935.

31. Vender R, Lynde C, Ho V, Chau D, Poulin-Costello M. Work productivity and healthcare resource utilization outcomes for patients on etanercept for moderate-to-severe plaque psoriasis: Results from a 1-year, multicentre, open-label, single-arm study in a clinical setting. Appl Health Econ Health Policy. 2012;10(5):343-353.

32. Kimball AB, Yu AP, Signorovitch J, et al. The effects of adalimumab treatment and psoriasis severity on self-reported work productivity and activity impair-ment for patients with moderate to severe psoriasis. J Am Acad Dermatol. 2012;66(2):e67-e76.

TABLE 2 Unemployment and Psoriasis Severity

Unadjusted Odds Ratio

95% Confidence Interval

Mild psoriasis 1 –

Moderate psoriasis 0.99 0.77–1.26

Severe psoriasis 1.75 1.38–2.21

Adjusted Odds Ratio

95% Confidence Interval

Mild psoriasis 1 –

Moderate psoriasis 0.99 0.77–1.28

Severe psoriasis 1.78 1.40–2.26

Age 1.03 1.02–1.04

Sex Male 1 – Female 2.33 1.93–2.83

Source: Armstrong AW, et al. PLoS One. 2012;7(12):e52935.


Systemic and topical antibiotics form the cornerstone of acne therapy. Studies have examined if increasing the dose of oral antibiotics improves efficacy. Minocycline (extended release)

has demonstrated similar efficacy compared with placebo at daily doses of 1, 2, and 3 mg/kg in patients with moderate to severe facial acne treated for 12 weeks (n=233, a randomized, double-blind study). Each dose reduced the number of inflammatory acne lesions by roughly 50% from baseline. However, higher doses were associated with increased incidence of side effects (acute vestib-ular and central nervous system adverse events).1

In contrast, higher doses of doxycycline calcium do lead to improved efficacy. A randomized, double-blind phase II study evaluating 3 doses (0.6, 1.2, and 2.4 mg/kg daily, or placebo for 12 weeks in patients with moderate to severe inflammatory acne) found that only the highest dose yielded results superior to those of placebo. Efficacy was measured as change in inflammatory lesion count and Investigator’s Global Assessment (IGA) score. Incidence of gastrointestinal adverse events also rose with dose.2

Maintenance TherapyOnce acne is under control, can treatment be stopped or stepped down? Two studies found that topical therapy was sufficient to maintain efficacy achieved with systemic antibiotic plus topical treat-ment. Patients with severe acne were randomized to an induction regimen of doxycycline plus either vehicle or adapalene 0.1% – benzoyl peroxide 2.5% for 12 weeks. Those who achieved at least 50% global improvement then received maintenance therapy with either the topical regimen or vehicle for 24 weeks. Starting with systemic plus topical therapy and continuing with topical main-tenance therapy yielded the best results: 50.0% of participants assigned to these regimens were rated “clear” or “almost clear” and total lesion count fell by 76% at week 36. Comparable figures for those started with combination therapy but maintained on vehicle were 26.2% and 51%, respectively. Initiating therapy with both topical and systemic treatment led to faster onset of action compared with systemic therapy alone (P<0.05 at week 2).3

A similar study with oral minocycline (100 mg twice daily) and topical tazarotene (0.1%) as induction therapy found that main-tenance results were similar with systemic therapy only, topical therapy only, or both treatments.4 Patients with moderately severe to severe acne who achieved at least 75% global improvement after a 12-week initiation phase were randomized (n=90) to continue both therapies or to continue one of the treatments plus a placebo for another 12 weeks. More than 80% of patients in each group maintained at least a 50% global improvement from baseline, and more than half retained at least a 75% global improvement at the end of the maintenance phase. Topical tazarotene was sufficient to maintain the benefit induced with systemic plus topical treatment.4

Topical Antibiotic TherapyBenzoyl PeroxideBenzoyl peroxide cleanser (6%) applied to the face once daily for 3 weeks reduced counts of antibiotic-resistant facial Propionibacterium acnes. Participants (n=30) were acne free but had high counts of organisms resistant to erythromycin (30/30), clindamycin (25/25), tetracycline (29/30), doxycycline (25/30), and/or minocycline (19/30). Total P. acnes counts and counts of each resistant strain decreased by at least 2log after 3 weeks of treatment.5

Benzoyl peroxide efficacy for acne on the back varied with formulation. Two weeks of once-daily therapy with a topical emollient “leave-on” foam benzoyl peroxide (5.3%) significantly reduced counts of P. acnes on the back (n=20 adults). P. acnes colonies were reduced by 1.9log at week 1 and by 2.1log at week 2. In contrast, 2 weeks of therapy with a benzoyl peroxide wash (8%) had little or no effect on P. acnes counts.6

Another study evaluated a higher-concentration (9.8%) benzoyl peroxide emollient foam to be left on the back for 2 minutes. It was compared with a 5.3% emollient foam (used once daily for 2 weeks). Efficacy as measured by reduction of P. acnes organisms on the back was similar with the two products.7 Patients with acne on the trunk of the body therefore appear to benefit from a “leave-on” or short-contact product rather than a wash. Patients should be informed that benzoyl peroxide typically bleaches towels and other fabrics, so that white towels may be a good choice while using these treatments.

AbstractRecent studies about the treatment of acne address antibiotic dosing, maintenance therapy, topical antibiotics and benzoyl peroxide in facial and trunkal acne, the link between antibiotics and risk of inflammatory bowel disease, and the role of diet in acne. Semin Cutan Med Surg 34(supp4):S72-S74 © 2015 published by Frontline Medical Communications

Keywords Acne, antibiotic dosing, minocycline, doxycycline, benzoyl peroxide, isotretinoin, diet, lauric acid, probiotics

* Director of Dermatology Research, Henry Ford Health System, Detroit, Michigan.


Dr Stein Gold has received an honorarium for her participation in this activity. She acknowledges the editorial assistance of Eileen McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Linda F. Stein Gold, MD, Consultant: Allergan, Inc., Anacor Pharmaceuticals, Inc., Celgene Corporation, Eli Lilly and Company, Galderma Laboratories, L.P., LEO Pharma Inc., Novartis Pharmaceuticals Corporation, and Valeant Pharmaceuticals North America LLC; Speakers Bureau: Celgene, Galderma, LEO Pharma, Novartis, Taro, and Valeant; Advisory Board: Allergan, Anacor Pharmaceuticals, Celgene, Eli Lilly, Galderma, LEO Pharma, Novartis, Promius Pharma, LLC, and Valeant; Medical Legal Advisor: Hoffmann- La Roche Inc.

Address reprint requests to: Linda F. Stein Gold, MD, 2360 Heronwood Drive, Bloomfield Hills, MI 48302; [email protected].

What’s New in AcneLinda F. Stein Gold, MD*


Acne Medication and Inflammatory Bowel Disease: Antibiotics?A retrospective cohort study using a UK database (n=94,487 with acne) found that tetracycline antibiotics, especially doxycycline, may be associated with an increased risk of inflammatory bowel disease (IBD) and especially of Crohn’s disease (CD) (Table). Individuals exposed to a tetracycline class antibiotic had a 39% increased risk of developing IBD (hazard ratio [HR] 1.39; 95% CI 1.02-1.90).8

Analysis of data from the University of Manitoba IBD Epidemiologic Database (2001-2008; n=2,234 with IBD and 22,346 controls) and the Manitoba Drug Program Information Network also reported an association of IBD with a history of receiving at least three courses of oral antibiotics. A total of 12% of those with IBD received at least three antibiotic prescriptions 2 years before their first IBD diagnosis date, compared with 7% of controls.9

Diet and Acne Acne is ubiquitous in Western societies but absent in at least two non-Westernized populations (Kitavan people on the Trobriand Islands near Papua New Guinea and the Aché hunter-gatherers of Paraguay). Genetic influences may contribute to this finding. However, diet may also be a factor. The Kitavan people, in particular, consume a diet with a low glycemic index, consisting of tubers, fruit, fish, and coconut.10 Foods with a high glycemic index, such as those commonly consumed in a Western diet, lead to increased levels of insulin in the blood. Insulin and insulin growth factor 1 (IGF-1) stimulate androgen synthesis. Androgens, in turn, stimulate the production of sebum, required for acne development.10

Compared with a high-glycemic-load diet, eating low-glycemic-load foods for 12 weeks reduced lesion count and free androgen index in 43 males with acne. Patients eating the low-glycemic-load diet also lost weight, a confounding factor.11

Milk consumption has been associated with acne. A prospective cohort study of boys (mean age, 11.75 years at baseline; n=4,273) found that higher consumption of skim milk (>2 servings/day) was associated with higher prevalence of acne (multivariate preva-lence ratio, 1.19, 95% CI 1.01-1.40; P=0.02 for trend).12 Milk may affect acne formation, as it contains androgens. Additionally, milk consumption has been associated with higher levels of IGF-1, which stimulates androgen synthesis.10,12 Whey protein supple-mentation (eg, used to gain weight and/or build muscle) has also been temporally associated with acne development in case reports. Acne did not respond to oral antibiotics, topical retinoids, and benzoyl peroxide but resolved in four of five patients upon discon-tinuation of whey protein supplementation.13

Coconut Oil, ProbioticsLauric acid, a main ingredient in coconut oil, has demonstrated greater antimicrobial effectiveness against P. acnes than benzoyl peroxide. The minimal inhibitory concentration for lauric acid against P. acnes in vitro was 15 times lower than that of benzoyl peroxide. Lauric acid also reduced inflammation without cyto-toxicity to sebocytes in an animal model, and retained its killing effectiveness in this model when delivered intradermally and epicutaneously.14 Lauric acid is poorly soluble in water but retained its anti-P. acnes effectiveness when incorporated into a liposome formulation in an experimental study.15

Bowe and Logan have reviewed small studies in non-English language journals of oral probiotic supplements in acne. Adding 250 mg of freeze-dried Lactobacillus acidophilus and Bifidobacterium bifidum to standard care improved clinical outcomes compared with standard care only. Probiotics were also associated with better tolerance and adherence to antibi-otic therapy. Another study reported shortened time to clinical improvement after adding probiotics. A third publication indi-cated that consuming a Lactobacillus-fermented dairy beverage was associated with significantly reduced total lesion counts and reduced sebum production.16

New Topical AntibioticA topical clindamycin phosphate 1.2% and benzoyl peroxide 3.75% (clindamycin-BP 3.75%) aqueous gel received approval by the US Food and Drug Administration (FDA) for acne in patients ages 12 years and older as of November 2014.17 Compared with vehicle, clindamycin-BP 3.75% reduced inflammatory and nonin-flammatory lesions as well as acne severity at 12 weeks in a double-blind controlled study (n=498). The agent was well toler-ated, with no withdrawals due to adverse events.18

SummaryAntibiotics, both topical and systemic, remain the key to acne therapy. Oral doxycycline is characterized by a dose-response curve, while oral minocycline effectiveness does not increase with dose.1,2 Once systemic plus topical therapy has led to at least a 50% global improvement in acne, topical therapy is sufficient to maintain efficacy.3,4 Benzoyl peroxide topical wash is effective on the face but not on the back; a leave-on, short-contact prepara-tion is superior for trunkal acne.5-7 Systemic antibiotic therapy should be used for the shortest possible time, as antibiotic use has been associated with an increased risk for IBD.8,9 Consumption of skim milk and whey protein supplements has been associated with acne in an observational study and case reports, respectively.12,13 A small study has reported a link between a low-glycemic-load diet and improvement in acne lesion count, though weight loss may confound results.11 Clindamycin-BP 3.75% gel, which received FDA approval for use in acne as of November 2014, offers another option for treatment.17

TABLE Risk of IBD Associated With Tetracycline Class Antibiotics8

Hazard Ratios (95% Confidence Interval)

IBD UC CD

Doxycycline 1.63 (1.05–2.52) 1.06 (0.53–2.13) 2.25 (1.27–4.00)

Minocycline 1.19 (0.79–1.79) 1.10 (0.76–1.82) 1.28 (0.72–2.30)

Tetracycline/oxytetracycline 1.43 (1.02–2.02) 1.27 (0.78–2.07) 1.61 (0.995–2.63)

CD=Crohn’s disease; IBD=inflammatory bowel disease; UC=ulcerative colitis.


References1. Stewart DM, Torok HM, Weiss JS, Plott RT. Dose-ranging efficacy of new once-

daily extended-release minocycline for acne vulgaris. Cutis. 2006;78(4 suppl):11-20.2. Leyden JJ, Bruce S, Lee CS, et al. A randomized, phase 2, dose-ranging study in

the treatment of moderate to severe inflammatory facial acne vulgaris with doxy-cycline calcium. J Drugs Dermatol. 2013;12(6):658-663.

3. Tan J, Stein Gold L, Schlessinger J, et al. Short-term combination therapy and long-term relapse prevention in the treatment of severe acne vulgaris. J Drugs Dermatol. 2012;11(2):174-180.

4. Leyden J, Thiboutot DM, Shalita AR, et al. Comparison of tazarotene and minocycline maintenance therapies in acne vulgaris: A multicenter, double-blind, randomized, parallel-group study. Arch Dermatol. 2006;142(5):605-612.

5. Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propionibacterium acnes suppressed by a benzoyl peroxide cleanser 6%. Cutis. 2008;82(6):417-421.

6. Leyden JJ. Efficacy of benzoyl peroxide (5.3%) emollient foam and benzoyl peroxide (8%) wash in reducing Propionibacterium acnes on the back. J Drugs Dermatol. 2010;9(6):622-625.

7. Leyden JJ, Del Rosso JQ. The effect of benzoyl peroxide 9.8% emollient foam on reduction of Propionibacterium acnes on the back using a short contact therapy approach. J Drugs Dermatol. 2012;11(7):830-833.

8. Margolis DJ, Fanelli M, Hoffstad O, Lewis JD. Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease. Am J Gastroenterol. 2010;105(12):2610-2616.

9. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics and new diagnoses of Crohn’s disease and ulcerative colitis. Am J Gastroenterol. 2011;106(12):2133-2142.

10. Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acne vulgaris: A disease of Western civilization. Arch Dermatol. 2002;138(12):1584-1590.

11. Smith RN, Mann NJ, Braue A, Makelainen H, Varigos GA. The effect of a high-protein, low glycemic-load diet versus a conventional, high glycemic-load diet on biochemical parameters associated with acne vulgaris: A randomized, investigator-masked, controlled trial. J Am Acad Dermatol. 2007;57(2):247-256.

12. Adebamowo CA, Spiegelman D, Berkey CS, et al. Milk consumption and acne in teenaged boys. J Am Acad Dermatol. 2008;58(5):787-793.

13. Silverberg NB. Whey protein precipitating moderate to severe acne flares in 5 teen-aged athletes. Cutis. 2012;90(2):70-72.

14. Nakatsuji T, Kao MC, Fang JY, et al. Antimicrobial property of lauric acid against Propionibacterium acnes: Its therapeutic potential for inflammatory acne vulgaris. J Invest Dermatol. 2009;129(10):2480-2488.

15. Yang D, Pornpattananangkul D, Nakatsuji T, et al. The antimicrobial activity of liposomal lauric acids against Propionibacterium acnes. Biomaterials. 2009;30(30):6035-6040.

16. Bowe WP, Logan AC. Acne vulgaris, probiotics and the gut-brain-skin axis – Back to the future? Gut Pathog. 2011;3:1.

17. Valeant Pharmaceuticals announces FDA approval of ONEXTON™ Gel for the treatment of acne vulgaris [press release]. http://ir.valeant.com/investor-relations/news-releases/news-release-details/2014/Valeant-Pharmaceuticals-Announces-FDA-Approval-Of-ONEXTON-Gel-For-The-Treatment-Of-Acne-Vulgaris/default.aspx. Accessed May 4, 2015.

18. Pariser DM, Rich P, Cook-Bolden FE, Korotzer A. An aqueous gel fixed combi-nation of clindamycin phosphate 1.2% and benzoyl peroxide 3.75% for the once-daily treatment of moderate to severe acne vulgaris. J Drugs Dermatol. 2014;13(9):1083-1089.


Rosacea is diagnosed based on the presence of one or more primary features: transient erythema (flushing), nontran-sient erythema (most common sign of rosacea), papules

and pustules, and/or telangiectasia (small blood vessel lines). Patients may also display one or more secondary features: burning or stinging, plaque, dry appearance, edema, ocular manifesta-tions, phymatous changes, and peripheral (ie, nonfacial) location of manifestations.1 Rosacea is divided into three cutaneous and one ocular subtype, plus one variant (granulomatous: character-ized by hard, brown, yellow, or red cutaneous papules or nodules of uniform size, generally less inflammatory than papules and pustules). Some evidence suggests that rosacea may evolve from one subtype to another; patients may also progress from mild to severe disease.1

Reported figures for incidence and prevalence vary, with the highest prevalence rates in people of northern European or Celtic ancestry (2.7%-10%).2 Rosacea is more common among women than men, and in individuals with fair skin. Incidence peaks between the ages of 30 and 50 years old.3 An estimated 16 million Americans have rosacea, according to the National Rosacea Society.4

PathogenesisA growing body of evidence has accumulated in recent years supporting the hypothesis that rosacea develops because of a disordered innate immune system.5 Individuals with rosacea express abnormally high levels of cathelicidin in facial skin, compared with matched control.6 A form of cathelicidin found in rosacea (LL-37) is typically present in neutrophils that are recruited to infected or injured skin. In patients with rosacea, this cathelicidin appears to result from abnormal activity of serine protease kallikrein 5 (KLK5; also known as stratum corneum tryptic enzyme). Injecting cathelicidin-producing peptides into murine skin produced skin inflammation resembling rosacea-like changes.5,6 Cathelicidins can cause both vasoactive and inflamma-tory changes, consistent with those observed in rosacea.5

Mast cells, found in increased numbers in the dermis of indi-viduals with rosacea, are among the primary sources of the cathelicidin peptide (LL-37) demonstrated to induce rosacea in murine skin. Mast cells have also been shown to mediate skin inflammation induced by cathelicidin.7

The skin of people with rosacea also expresses toll-like receptor 2 (TLR2) highly compared with healthy individuals. Increased TLR2 leads to increased production of cathelicidin. Recent exper-imental findings suggest that high levels of TLR2 in skin increases susceptibility to microbial and environmental stimuli, increasing cathelicidin and KLK5 expression.5

Reverse transcriptase polymerase chain reaction and gene array analysis support the concept of rosacea as an inflammatory disease. Proinflammatory genes involved in vasoregulation and neurogenic inflammation are upregulated in early rosacea, before clinical signs such as papules, nodules, or pustules have emerged. Different genes are upregulated in each subtype.3

A wide range of stimuli can trigger symptom exacerbations, including emotional stress, spicy food, hot beverages, alcohol consumption, high environmental temperatures, sun exposure, menopause, and microbes (Figure).5 Many of these same trig-gers activate the transient receptor potential vanilloid receptor 1 (TRPV1), a cell surface receptor nerve fiber. The density of TRPV1+ nerve fibers is increased in erythematotelangiectatic rosacea compared with healthy skin. In individuals with healthy skin, TRPV1 activation produces brief periods of flushing and burning pain. It has been suggested that patients with rosacea experience hyperactive or dysregulated TRPV1, with sustained flushing and neurogenic inflammation.3

TreatmentIt is important to set patients’ expectations appropriately regarding the benefits of therapy. Rosacea cannot be cured but treatment can control the disease’s signs and symptoms. Avoiding triggers, the use of gentle skin cleansers, and frequent moisturizing can help heal and minimize further skin damage. In the last few years, new treat-ments have been FDA-approved for some rosacea subtypes, and studies have documented the benefit of other treatments (Table).

Erythematotelangiectatic RosaceaIntense pulsed light has been used to treat rosacea for many years and is clinically accepted despite the absence of high-quality evidence supporting its value.8 A small (n=34) study reported

AbstractRecent studies have illuminated the pathophysiology of rosacea. Evidence supports the hypothesis that rosacea is caused by dysregulation of the innate immune system, resulting in vasoactive and neuroinflammatory consequences. New treatments have been approved by the US Food and Drug Administration (FDA) in recent years, and studies have further documented the benefit of other therapies.Semin Cutan Med Surg 34(supp4):S75-S77 © 2015 published by Frontline Medical Communications

Keywords Rosacea, inflammation, innate immunity, cathelicidins, brimonidine, ivermectin

* Adjunct Professor, Department of Medicine, University of Western Ontario, London, Ontario, Canada.


Dr Tan has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Eileen McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Jerry K.L. Tan, MD, FRCPC, Grant/Research: Allergan, Inc., Bayer, Cipher Pharmaceuticals Inc, Dermira, Galderma Laboratories, L.P., and Valeant Pharmaceuticals North America LLC; Consultant: Cipher Pharmaceuticals, Galderma, GlaxoSmithKline Pharmaceutical Company, Hoffmann-La Roche, Stiefel Laboratories, Inc., and Valeant; Speakers Bureau: Cipher Pharmaceuticals, Galderma, Pierre-Fabre, and Valeant.

Address reprint requests to: Jerry K. L. Tan, MD, FRCPC, 2224 Walker Road, Suite 300, Windsor, Ontario, NBW 5L7 Canada; [email protected].


Rosacea: Pathogenesis and Therapy Jerry K. L. Tan, MD, FRCPC*

significant improvements in erythema (46%) and telangiectasia by 55% from baseline after four treatments administered at 3-week intervals. Benefits were sustained at 6 months, with minimal and self-limiting side effects.9

Brimonidine gel 0.33%, a selective alpha2-adrenergic receptor agonist with vasoconstrictive activity, received FDA approval for persistent facial erythema of rosacea in August 2013.10,11 When studied at a concentration of 0.5%, it significantly reduced erythema severity compared with vehicle when applied once daily for 4 weeks in phase III studies. Benefit was observed within as little as 30 minutes of application. No tachyphylaxis or rebound was reported after treatment cessation.10 Efficacy was maintained over 1 year (n=345). Some patients experience exacerbation of rosacea signs and symptoms (flushing 10%, erythema 8%, rosacea 5%, and skin burning sensation 4%).12

Papulopustular RosaceaIsotretinoin has been used for decades to treat rosacea despite the lack of evidence-based support. A double-blind, randomized, 12-week study conducted in 35 centers in Germany (n=573 with papulopustular or phymatous rosacea) compared oral isotretinoin (0.1, 0.3, or 0.5 mg per kg body weight) to doxycycline (100 mg daily for 14 days, then 50 mg daily) and placebo. The 0.3 mg/kg dose proved to be the most effective, demonstrating significant superiority to placebo and noninferiority compared with doxy-cycline. Lesions were reduced by 90% with isotretinoin 0.3 mg/kg and by 83% with doxycycline. Investigators determined that isotretinoin led to complete remission in 24% of patients and marked improvement in another 57% of patients. Comparable figures for doxycycline were 14% and 55%, respectively. The safety profile of isotretinoin 0.3 mg/kg was similar to that observed when it is used in the treatment of acne.13

Ivermectin 1% cream received FDA approval for inflammatory rosacea lesions as of December 2014.14 Roughly 40% of patients with papulopustular rosacea randomized to ivermectin were rated “clear” or “almost clear” on the Investigator’s Global Assessment (IGA) in two 12-week phase III trials (38.4% and 40.1%, respec-tively; P<0.001 vs vehicle). Ivermectin reduced lesion count by 76% and 75% in the 2 trials. Fewer subjects reported dermatologic adverse events with ivermectin than with vehicle, and more subjects experienced no skin drying or itching as compared with vehicle.15

Once-daily ivermectin 1% also demonstrated superiority compared with an active control (twice-daily metronidazole cream 0.75%) for 16 weeks (n=962). Inflammatory lesions were reduced from baseline by 83% with ivermectin and by 73.7% with metro-nidazole (P<0.001). The proportion of subjects attaining “clear” or “almost clear” (IGA rating) was also superior with ivermectin (84.9% and 75.4%, respectively; P<0.001). Ivermectin demon-strated better local tolerability than the comparator.16

A low-dose formulation of oral minocycline (45 mg extended release, once daily) demonstrated efficacy in papulopustular rosacea, alone or when used with once-daily 15% azelaic acid. Participants in a double-blind study (n=60) were randomized to receive one of these regimens for 12 weeks. Both treatments significantly reduced lesion count and improved IGA and Clinical Erythema Assessment compared with baseline, with no significant difference in efficacy or safety between the two regimens. Benefits were maintained 4 weeks after therapy discontinuation.17

ROSACEA

Infection

Stress

DemodexEmotion

Food Sun

Temperature Alcohol

Source: Yamasaki K, Gallo RL. J Investig Dermatol Symp Proc. 2011;15(1):12-15

FIGURE Multiple and Diverse Triggers.

TABLE Rosacea Treatments and Mechanisms of Action

Mechanism of Action RetinoidsMetronidazole

TopicalAzelaic Acid

TopicalIvermectin

TopicalBrimonidine

TopicalCyclosporine

TopicalDoxycycline

po

Demodex +

TLR2 activation +

Serine protease activity + +

Th1 adaptive profile +

Vasodilation +

Reactive O2 & NO + + + +

Sebaceous hyperplasia + (po)

Source: Courtesy of Jerry K. L. Tan, MD, FRCPC.


Ocular RosaceaThe diagnosis of ocular rosacea is often missed, as symptoms are nonspecific and there is no specific test to confirm diagnosis.18 Most but not all patients also have cutaneous signs and symptoms of rosacea. Manifestations include watery or bloodshot eyes, sensa-tion of a foreign body, burning or stinging, dryness, itching, light sensitivity, and blurred vision. Ocular rosacea should be consid-ered in patients with corneal damage, a history of blepharitis, recurrent conjunctivitis, iritis, keratitis or styes (chalazion, horde-olum), and meibomian gland dysfunction. Periocular erythema, or telangiectases at the eyelid margins or lid, may be present. Ocular rosacea can lead to vision loss; treating cutaneous rosacea without addressing the ocular component may be insufficient to prevent this consequence.1

Treatment with cyclosporine ophthalmic emulsion 0.05% was associated with an increase in Schirmer test scores (a measure of tear production), compared with a decrease (worsening) with arti-ficial tears. Patients with rosacea-associated eyelid and corneal changes (ie, lid margin telangiectasia, meibomian gland inspis-sation, and/or fullness of the lid margin; n=37) were randomized to receive topical cyclosporine or artificial tears for 3 months. Quality-of-life scores also improved with therapy.19

SummaryAn increasing body of pathophysiologic evidence supports the hypothesis that rosacea results from disordered innate immunity, which leads to neuroinflammation and vasoactive changes.3,5-7 The introduction of brimonidine gel 0.33% for erythematotelangiec-tatic rosacea and ivermectin 1% cream for papulopustular rosacea offers new options for managing this common condition. A large (n=573), double-blind randomized trial has documented effi-cacy of oral isotretinoin (0.3 mg/kg) in papulopustular rosacea.13 Low-dose (45-mg), extended-release oral minocycline has demon-strated efficacy in papulopustular rosacea, alone or when used in conjunction with once-daily 15% azelaic acid.17 Topical cyclospo-rine 0.05% has demonstrated efficacy in ocular rosacea.19

References1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of

the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002;46(4):584-587.

2. Abram K, Silm H, Oona M. Prevalence of rosacea in an Estonian working popula-tion using a standard classification. Acta Derm Venereol. 2010;90(3):269-273.

3. Steinhoff M, Buddenkotte J, Aubert J, et al. Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15(1):2-11.

4. Society NR. If you have rosacea, you’re not alone. http://www.rosacea.org/patients/index.php. Accessed May 11, 2015.

5. Yamasaki K, Gallo RL. Rosacea as a disease of cathelicidins and skin innate immunity. J Investig Dermatol Symp Proc. 2011;15(1):12-15.

6. Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13(8):975-980.

7. Muto Y, Wang Z, Vanderberghe M, Two A, Gallo RL, Di Nardo A. Mast cells are key mediators of cathelicidin-initiated skin inflammation in rosacea. J Invest Dermatol. 2014;134(11):2728-2736.

8. van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MM, Charland L. Interventions for rosacea. Cochrane Database Syst Rev.. 2015;(4):CD003262.

9. Papageorgiou P, Clayton W, Norwood S, Chopra S, Rustin M. Treatment of rosacea with intense pulsed light: Significant improvement and long-lasting results. Br J Dermatol. 2008;159(3):628-632.

10. Fowler J Jr, Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: Results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12(6):650-656.

11. Galderma. Galderma receives FDA approval of Mirvaso® [press release]. 2013. http://www.galderma.com/Media/Press-releases/articleType/ArticleView/arti-cleId/41/Galderma-Receives-FDA-Approval-of-Mirvaso. Accessed May 7, 2015.

12. Mirvaso [package insert]. Fort Worth, TX: Galderma Laboratories; revised August 2013.

13. Gollnick H, Blume-Peytavi U, Szabo EL, et al. Systemic isotretinoin in the treat-ment of rosacea – doxycycline- and placebo-controlled, randomized clinical study. J Dtsch Dermatol Ges. 2010;8(7):505-515.

14. Galderma receives FDA approval of novel treatment option for rosacea patients [press release]. December 24, 2014. http://www.galderma.com/News/articleType/ArticleView/articleId/75/Galderma-Receives-FDA-Approval-of-Novel-Treatment-Option-for-Rosacea-Patients. Accessed July 21, 2015.

15. Stein L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: Results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13(3):316-323.

16. Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: A randomized, investigator-blinded trial. Br J Dermatol. 2015;172(4):1103-1110.

17. Jackson JM, Kircik LH, Lorenz DJ. Efficacy of extended-release 45 mg oral mino-cycline and extended-release 45 mg oral minocycline plus 15% azelaic acid in the treatment of acne rosacea. J Drugs Dermatol. 2013;12(3):292-298.

18. Vieira AC, Mannis MJ. Ocular rosacea: Common and commonly missed. J Am Acad Dermatol. 2013;69(6):S36-S41.

19. Schechter BA, Katz RS, Friedman LS. Efficacy of topical cyclosporine for the treatment of ocular rosacea. Adv Ther. 2009;26(6):651-659.


Quality-switched (Q-switched) lasers are the instrument of choice for tattoo removal. As many as 15 or 20 treatments can be required to remove professional tattoos.1 One of

the limiting factors in any one treatment session is the whitening that immediately follows Q-switched laser treatment. This reaction results from the formation of gas bubbles in the dermis. The bubbles lead to optical scattering, limiting laser penetration for the roughly 20 minutes required for the reaction to subside.2

R20 MethodIn an effort to shorten the number of sessions required for tattoo removal, Kossida and colleagues evaluated a method in which patients are treated in four consecutive passes separated by 20-minute intervals (the “R20 method”). Treatments were performed with a Q-switched alexandrite laser. Eighteen tattoos on 12 adults were divided in half, with half receiving the R20 treatment and half receiving a single pass from a laser. Reviewers blinded to treatment assignment evaluated tattoos 3 months later.2

Compared with results from a single pass, tattoo lightening was significantly more effective with the R20 method (P<0.01 for all tattoos). The majority (61%) of the tattoo sites treated with the R20 method cleared completely, compared with no tattoo sites with the single-pass method. No scarring or textural changes occurred, and no infection or postinflammatory hyperpigmen-tation was observed. One patient experienced transient mild

hypopigmentation, which had resolved completely at 6 months post-therapy. Investigators noted that less whitening developed immediately following each subsequent laser pass with the R20 method, potentially facilitating deeper optical penetration.2

R0 MethodThe R20 procedure is effective but the time required (≥1 hour) renders it impractical for the office setting. Applying topical perfluorodecalin (PFD) after a laser treatment resolves the imme-diate whitening reaction quickly, within a mean of 5 seconds (range 3-10 seconds).3 PFD works by absorbing the gas released in the dermis.4

Tattoos receiving three passes with PFD to remove the frosting after each pass (the “R0 method”) demonstrated fading equal to that observed with the R20 method, and superior to that seen following a single pass. Total treatment time with the R0 method in this study averaged 5 minutes,3 making it feasible for clinical practice. Figure below illustrates the impact of PFD on treat-ment results.

Laser Type, Pulse Width, and DurationThe tattoo color should be considered when choosing the type of laser. Any of the three types of Q-switched lasers (ruby [694 nm], alexandrite [755 nm], and Nd:YAG [only the 1064 nm]) can treat black or dark blue tattoos. Both the QS ruby and alexandrite lasers may cause hypopigmentation in darker skinned individuals, though these are preferred for removal of green pigment. Red or orange ink requires the Nd:YAG 532 nm laser.5

The particle size of tattoo pigments generally falls between 30 to 300 nm, with a thermal relaxation time (TRT) of approximately

PFD=perfluorodecalin; QSRL=quality-switched ruby laser. Source: Photos courtesy of Roy Geronemus, MD.

FIGURE Results Following Three Passes and Topical Perfluorodecalin. A. Blue and black tattooB. Significant fading 1 month post-single treatment with three passes QSRL with topical PFD. Total treatment time 4 minutes pre-treatment.

A. B.

AbstractLasers can remove tattoos effectively but many treatments can be required for effective fading. New techniques have been shown to improve the speed and practicality of therapy, and new lasers may improve fading of recalcitrant or multi-colored tattoos.Semin Cutan Med Surg 34(supp4):S78-S79 © 2015 published by Frontline Medical Communications

Keywords Tattoo removal, Q-switched lasers, perfluorodecalin, pico-second laser, R20, R0

* Professor and Chair, Department of Dermatology, University of California, Irvine, Irvine, California.


Dr Zachary has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Eileen McCaffrey, MA, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

Christopher B. Zachary, MBBS, FRCP, Consultant: Cutera, Inc. and ZELTIQ Aesthetics, Inc.; Speakers Bureau: Cynosure, Inc. and Solta Medical, a division of Valeant; Advisory Board: ZELTIQ.

Address reprint requests to: Christopher B. Zachary, MBBS, FRCP, Dermatology, UC Irvine Health, 118 Med Surge I, Irvine, CA 92697; [email protected].


Tattoo Treatment: Current State of the ArtChristopher B. Zachary, MBBS, FRCP*

10 nanoseconds or shorter. Lasers for treating tattoos should therefore have a pulse duration that matches these TRTs, in the nanosecond range (10−9 sec) or shorter. While the Q- switched lasers do provide the upper range of pulse durations, newer picosecond lasers offer pulse times measured in picoseconds (10−12 sec), which often improve tattoo removal.1

One study evaluated tattoo removal results with a picosecond laser in 12 green and/or blue pigment tattoos on 10 patients. Two of the tattoos had clinically apparent pigment after at least 10 prior treatments with traditional Q-switched lasers (designated recalcitrant tattoos); the remainder (n=10) were multicolored.6 Investigators used an alexandrite laser (755 nm) with variable pulse duration of 750 to 900 picoseconds, repetition rate of 5 Hz, and spot sizes from 3.0 to 3.6 nm. At 1-month follow-up after one treatment, 11 of the 12 tattoos demonstrated at least 75% clearance of the blue and/or green pigment. The remaining tattoo required two treatments to achieve >75% clearance. Patients reported average pain scores of 1.08 on a 10-point scale (1=no pain, 10=worst pain). One individual reported blistering.

SummaryThe traditional Q-switched lasers historically have provided vari-able outcomes. While some tattoos can be removed easily with these nanosecond devices, the multicolored tattoos, and others recalcitrant for various reasons, have often required numerous treatments and still had modest outcomes. The new treatments utilizing topical PFD between treatments can more efficiently fade tattoos. However, the biggest development has been the newer picosecond lasers because of their highly effective ability to remove blue and/or green tattoos more easily than the black or dark blue colors.

References1. Sardana K, Ranjan R, Ghunawat S. Optimising laser tattoo removal. J Cutan

Aesthet Surg. 2015;8(1):16-24.2. Kossida T, Rigopoulos D, Katsambas A, Anderson RR. Optimal tattoo removal

in a single laser session based on the method of repeated exposures. J Am Acad Dermatol. 2012;66(2):271-277.

3. Reddy KK, Brauer JA, Anolik R, et al. Topical perfluorodecalin resolves imme-diate whitening reactions and allows rapid effective multiple pass treatment of tattoos. Lasers Surg Med. 2013;45(2):76-80.

4. Shah SD, Aurangabadkar SJ. Newer trends in laser tattoo removal. J Cutan Aesthet Surg. 2015;8(1):25-29.

5. Ho SG, Goh CL. Laser tattoo removal: A clinical update. J Cutan Aesthet Surg. 2015;8(1):9-15.

6. Brauer JA, Reddy KK, Anolik R, et al. Successful and rapid treatment of blue and green tattoo pigment with a novel picosecond laser. Arch Dermatol. 2012;148(7):820-823.


1. Of the TNF inhibitors approved for the treatment of psoriasis, which has the highest efficacy rates (ie, proportions of patients achieving PASI 75 at 10 to 16 weeks) in landmark clinical trials for psoriasis?A. EtanerceptB. AdalimumabC. InfliximabD. Golimumab

2. Nearly half of those who develop anti-drug antibodies to which of the anti-TNF agents approved for the treatment of psoriasis experience a loss of adequate drug response?A. EtanerceptB. AdalimumabC. InfliximabD. Golimumab

3. Which of the following agents represents a new, boron-based class of antifungals approved to treat toenail onychomycosis?A. TavaboroleB. LuliconazoleC. EfinaconazoleD. Naftifine

4. Clinical trials of which one of the following topical antifungal agents have demonstrated a mycological cure rate in toenail onychomycosis comparable to that of oral itraconazole?A. TavaboroleB. LuliconazoleC. NaftifineD. Efinaconazole

5. Which of the following agents used to treat psoriasis has been shown to exacerbate Crohn’s disease in some cases?A. AdalimumabB. InfliximabC. SecukinumabD. Ustekinumab

6. Which of the following statements most accurately describes the relationship of psoriasis therapy to CVD risk? A. Psoriasis therapy does not affect CVD risk, regardless of specific

therapy usedB. Compared with methotrexate, anti-TNF therapy for psoriasis was

associated with significantly reduced risk of a major CV eventC. Compared with no therapy, methotrexate and anti-TNF therapy

each significantly reduced risk of CVD, and risk reduction is similar regardless of type of psoriasis therapy

D. Evidence demonstrates that reduced inflammation is responsible for the decreased risk of major CV events observed with anti-TNF therapy

7. The preponderance of evidence about rosacea pathophysiology indicates that rosacea results from:A. A disordered innate immune systemB. A disordered adaptive immune systemC. Something other than a disorder of the immune systemD. Little is known about rosacea pathophysiology

8. Which of the following treatments approved for rosacea has demonstrated superiority compared with metronidazole?A. Brimonidine B. IvermectinC. IsotretinoinD. Azelaic acid

9. Which of the following statements accurately describes the R20 and R0 methods of tattoo removal?A. Both involve multiple treatments in a single sessionB. R20 involves the use of topical perfluorodecalin to increase the

amount of tattoo ink removed at each treatmentC. R0 involves the use of topical perfluorodecalin to speed

resolution of the immediate whitening reaction and facilitate delivery of multiple treatments within a brief single session

D. A and C

10. Once acne has been controlled with 12 weeks of induction therapy with oral plus topical antibiotic therapy, which of the following best describes clinical trial findings regarding maintenance therapy?A. Continued therapy is unnecessary to maintain efficacy B. Continued therapy with either oral or topical therapy alone

is sufficient to maintain efficacyC. Oral therapy is required to maintain efficacy after successful

induction therapyD. Both oral and topical therapy must be continued to

maintain efficacy

Highlights of Skin Disease Education Foundation’s 39th Annual Hawaii Dermatology Seminar™ Post-Test and Evaluation FormOriginal Release Date: June 2015 • Most Recent Review Date: June 2015 • Expiration Date: June 30, 2016 • Estimated Time to Complete Activity: 2.0 hoursTo get instant CME/CE credits online, go to http://tinyurl.com/39HawaiiSupp. Upon successful completion of the online test and evaluation form, you will be directed to a Web page that will allow you to receive your certificate of credit via e-mail or you may print it at that time. If you have any questions or difficulties, please contact the Global Academy for Medical Education office at [email protected] CME/CE QUESTIONS

If you do not feel confident that you can achieve the above objectives to some extent, please describe why not.__________________________________________________________________________________________________________________________________________________________

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Differentiate the characteristics of the tumor necrosis factor (TNF) inhibitors approved for use in treating psoriasis and apply that information to clinical practice. 5 4 3 2 1

Demonstrate familiarity with the impact of comorbid conditions on patients with psoriasis and incorporate the effect of psoriasis therapy on those comorbidities into patient management. 5 4 3 2 1

Integrate new therapies for rosacea into practice and describe current theories about rosacea pathophysiology. 5 4 3 2 1

Explain the use of new treatments for tinea pedis and toenail onychomycosis. 5 4 3 2 1

Apply current knowledge about anti-acne antibiotic dosing, maintenance therapy, topical therapy, and diet to clinical practice. 5 4 3 2 1

Identify current and updated techniques to improve tattoo removal. 5 4 3 2 1

Rutgers, The State University of New Jersey, thanks you for your participation in this CME/CE activity. All information provided improves the scope and purpose of our programs and your patient care.

© 2015 Global Academy for Medical Education, LLC. All Rights Reserved.

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Roger I. Ceilley, MDAuthor demonstrated current knowledge of the topic. 5 4 3 2 1

Author was organized in the written materials. 5 4 3 2 1

Kristina Callis Duffin, MD, MSAuthor demonstrated current knowledge of the topic. 5 4 3 2 1


Joseph F. Fowler, Jr, MDAuthor demonstrated current knowledge of the topic. 5 4 3 2 1


Kenneth B. Gordon, MDAuthor demonstrated current knowledge of the topic. 5 4 3 2 1


Linda F. Stein Gold, MDAuthor demonstrated current knowledge of the topic. 5 4 3 2 1


Jerry K. L. Tan, MD, FRCPCAuthor demonstrated current knowledge of the topic. 5 4 3 2 1


Christopher B. Zachary, MBBS, FRCP Author demonstrated current knowledge of the topic. 5 4 3 2 1


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