Highlights of Skin Disease Education Foundation s 11th Annual Psoriasis Forum

Transcription

1 A CME/CE CERTIFIED SUPPLEMENT TO SUPPLEMENT 2 VOL. 34, NO. 2S MARCH 2015 EDITORS Kenneth A. Arndt, MD Philip E. LeBoit, MD Bruce U. Wintroub, MD Highlights of Skin Disease Education Foundation s 11th Annual Psoriasis Forum GUEST EDITORS Francisco A. Kerdel, BSc, MBBS Kristina Callis Duffin, MD, MS Kenneth B. Gordon, MD Craig L. Leonardi, MD Introduction S29 Identifying and Managing Complications and Comorbidities in Patients With Psoriasis S30 Update on New and Emerging Therapies in the Management of Psoriasis S34 TNF Inhibitors in Psoriasis: A Review S37 Screening and Monitoring Before and During Systemic Therapy: Recommendations for Patients With Psoriasis S40 Post-Test and Evaluation Form S43

2 Highlights of Skin Disease Education Foundation s 11th Annual Psoriasis Forum Release Date: April 2015 Expiration Date: April 30, 2016 Estimated Time to Complete Activity: 2.0 hours To get instant CME/CE credits online, go to 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 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 info@globalacademycme.com. Accreditation Statements Physicians: 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. 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 1.5 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 of New Jersey, 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/ This activity is awarded 1.94 contact hours. (60 minute CH) Nurses should only claim those contact hours actually spent participating in the activity. Target Audience This educational activity is intended for dermatologists, family physicians, physician assistants, nurses, nurse practitioners, and other clinicians who treat patients with psoriasis. Educational Needs The estimated 7 million Americans with psoriasis and their clinicians can now choose from an expanded and soon to be even longer list of effective and safe medications to treat their disease. This is especially true of systemic therapies used to treat patients with moderate to severe disease. The approval of several tumor necrosis factor (TNF) inhibitors for psoriasis was followed by the availability of biologic agents and small molecules that target other pathogenetic pathways. Additional agents having a variety of mechanisms of action currently are being investigated in phase III clinical trials. To ensure the optimum management of each patient, clinicians must remain up-to-date on ongoing research involving both currently available and emerging treatments. Clinicians will benefit from this educational activity, which provides an update regarding the effective and safe use of the systemic agents now available as well as the emerging therapies that show promise. The articles in this supplement focus on appropriate patient selection for various therapies, laboratory and other screening modalities prior to institution of treatment to identify infectious diseases and other comorbidities, recommendations for monitoring patients during treatment, and emerging therapies that may become available in the near future. Learning Objectives By reading and studying this supplement, participants should be better able to: Discuss the roles of topical and systemic therapies, including biologic and small molecule agents, in the treatment of moderate to severe psoriasis. Assess patients for comorbidities and manage psoriasis as well as associated comorbidities. Describe the mechanisms of action, efficacy, and safety of currently available and newly emerging biologic and small molecule agents used to treat psoriasis. Review their current practice protocols for screening and monitoring patients with psoriasis who are candidates for or are being treated with biologic and small molecule agents and update these as needed according to evidencebased recommendations. Incorporate updated monitoring strategies for the safe use of methotrexate and cyclosporine, as monotherapy or when combined with biologic agents. Evaluate the results of clinical studies on new and emerging treatments for psoriasis. Disclosure Declarations Individuals 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 non-profit 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 Kristina Callis Duffin, MD, MS, Grant/Research: AbbVie Inc., Amgen Inc., Bristol-Myers Squibb Company, Celgene Corporation, Eli Lilly and Company, Janssen Biotech, Inc., Pfizer Inc. and Stiefel Laboratories, Inc. Consultant: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis Pharmaceuticals Corporation, Pfizer, and XenoPort, Inc. Scientific Advisory Board: Eli Lilly and Janssen. Kenneth B. Gordon, MD, Grant/Research: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, and Merck & Co., Inc. Consultant: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Merck, Novartis and Pfizer. Francisco A. Kerdel, BSc, MBBS, Grant/Research: AbbVie, Amgen, AstraZeneca, Celgene, Galderma Laboratories, L.P., Janssen, Novartis, Pfizer and Valeant. Advisory Board: Celgene. Speakers Bureau: AbbVie, Amgen, Celgene, Galderma, and Janssen. Craig L. Leonardi, MD, Grant/Research: AbbVie, Amgen, Celgene, Coherus BioSciences, Dermira Inc., Eli Lilly, Galderma Laboratories, L.P., Janssen, LEO Pharma, Merck, Novartis, Pfizer, Sandoz Inc., Stiefel, and Wyeth. Consultant: AbbVie, Amgen, Dermira, Eli Lilly, Janssen, LEO, Pfizer, Sandoz, and UCB, Inc. Speakers Bureau: AbbVie and Celgene. 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: Geraldine Bocchieri, RN, BSN, Nurse, Department of Dermatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. Ms. Bocchieri has no relevant financial relationships to disclose. Field Testers: This activity was pilot-tested for time required by: Physicians: Lilia Correa, MD and Omar Noor, MD. Nurses: Janel Bowman, RN; Claudia Carron, MSN, RN, NE-BC; and Carol Ruland, RN. The field testers have no relevant financial relationships to disclose. Rutgers, The State University of New Jersey: Tristan Nelsen, MNM, CMP, and Elizabeth Ward, MSJ, have no relevant financial relationships to disclose. Global Academy for Medical Education Staff: Shirley V. Jones, MBA; Sylvia H. Reitman, MBA, DipEd; and Joanne Still, BA, have no relevant financial relationships to disclose. Off-Label/Investigational Use Disclosure This activity discusses the following investigational products, not yet approved: brodalumab, guselkumab, ixekizumab, and tildrakizumab. Also discussed is the investigational use in clinical trials of patients with psoriasis of the approved agent, tofacitinib. This continuing education supplement was developed from Skin Disease Education Foundation s 11th Annual Psoriasis Forum, held October 31, 2014, in Las Vegas, NV. The Guest Editors acknowledge the editorial assistance of Global Academy for Medical Education and Joanne Still, medical writer, in the development of this supplement. The manuscript was reviewed and approved by the Guest Editors as well as the Editors of Seminars in Cutaneous Medicine and Surgery. The ideas and opinions expressed in this supplement are those of the Guest Editors and do not necessarily reflect the views of the supporters, Global Academy for Medical Education, Rutgers, or of the Publisher. Jointly provided by Supported by educational grants from AbbVie Inc., Amgen Inc., Celgene Corporation, and Novartis Pharmaceuticals Corporation

3 STATEMENT OF PURPOSE Seminars in Cutaneous Medicine and Surgery presents well-rounded and authoritative discussions of important clinical areas, especially those undergoing rapid change in the specialty. Each issue, under the direction of the Editors and Guest Editors selected because of their expertise in the subject area, includes the most current information on the diagnosis and management of specific disorders of the skin, as well as the application of the latest scientific findings to patient care. EDITORS Kenneth A. Arndt, MD Clinical Professor of Dermatology, Emeritus Harvard Medical School Adjunct Professor of Surgery Dartmouth Medical School Hanover, New Hampshire Adjunct Professor of Dermatology Brown Medical School Providence, Rhode Island Philip E. LeBoit, MD Professor of Clinical Dermatology University of California, San Francisco San Francisco, California Bruce U. Wintroub, MD Associate Dean Professor and Chair of Dermatology School of Medicine University of California, San Francisco San Francisco, California Seminars in Cutaneous Medicine and Surgery (ISSN ) is published quarterly by Frontline Medical Communications Inc., 7 Century Drive, Suite 302, Parsippany, NJ Months of issue are March, June, September, and December. Periodicals postage paid at Parsippany, NJ, and additional mailing offices. POSTMASTER: Send address changes to Seminars in Cutaneous Medicine and Surgery, Subscription Services, 151 Fairchild Ave, Suite 2, Plainview, NY RECIPIENT: To change your address, contact Subscription Services at Editorial correspondence should be addressed to Kenneth A. Arndt, MD, Skincare Physicians of Chestnut Hill, 1244 Boylston St, Suite 302, Chestnut Hill, MA Correspondence regarding subscriptions or change of address should be directed to the Publisher, Subscription Services, 151 Fairchild Ave, Suite 2, Plainview, NY , Yearly subscription rate: $ per year. Prices are subject to change without notice. Current prices are in effect for back volumes and back issues. Single issues, both current and back, exist in limited quantities and are offered for sale subject to availability. Back issues sold in conjunction with a subscription are on a prorated basis. Copyright 2015 by Frontline Medical Communications Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Advertising representative: Sally Cioci, 7 Century Drive, Suite 302, Parsippany, NJ Phone: ; Fax: ; scioci@frontlinemedcom.com Publication of an advertisement in Seminars in Cutaneous Medicine and Surgery does not imply endorsement of its claims by the Editor(s) or Publisher of the journal. The ideas and opinions expressed in Seminars in Cutaneous Medicine and Surgery do not necessarily reflect those of the Editors or Publisher. Publication of an advertisement or other product mention in Seminars in Cutaneous Medicine and Surgery should not be construed as an endorsement of the product or the manufacturer s claims. Readers are encouraged to contact the manufacturer with any questions about the features or limitations of the products mentioned. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other health care professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Seminars in Cutaneous Medicine and Surgery is indexed in Index Medicus/MEDLINE and EMBASE/Excerpta Medica.

4 March 2015, Vol. 34, No. 2S TABLE OF CONTENTS Highlights of Skin Disease Education Foundation s 11th Annual Psoriasis Forum S29 Introduction S30 Identifying and Managing Complications and Comorbidities in Patients With Psoriasis Kristina Callis Duffin, MD, MS Craig L. Leonardi, MD S34 Update on New and Emerging Therapies in the Management of Psoriasis Kenneth B. Gordon, MD Craig L. Leonardi, MD S37 TNF Inhibitors in Psoriasis: A Review Francisco A. Kerdel, BSc, MBBS S40 Screening and Monitoring Before and During Systemic Therapy: Recommendations for Patients With Psoriasis Kristina Callis Duffin, MD, MS S43 Post-Test and Evaluation Form GUEST EDITORS Francisco A. Kerdel, BSc, MBBS, Chair Director of Inpatient Dermatology University of Miami Hospital Professor of Dermatology and Vice Chairman Florida International University Miami, Florida Kenneth B. Gordon, MD Professor of Dermatology Northwestern University Feinberg School of Medicine Chicago, Illinois Kristina Callis Duffin, MD, MS Assistant Professor, Dermatology University of Utah Salt Lake City, Utah Craig L. Leonardi, MD Clinical Professor of Dermatology Saint Louis University Central Dermatology St Louis, Missouri

5 Vol. 34, No. 2S, March 2015 INTRODUCTION Clinicians who treat patients with psoriasis today practice in times that are both more challenging and potentially more rewarding than ever. Both are presented by a rapidly evolving body of knowledge and literature regarding the pathophysiology and, therefore, the treatment of psoriasis. This continuing medical education activity is derived from selected presentations offered at the Skin Disease Education Foundation (SDEF) 11th Annual Psoriasis Forum. The articles chosen for inclusion in this supplement provide highlights of the presentations that were deemed most relevant and practically helpful to our colleagues in clinical practice. In the first article, the authors discuss some of the most important disease states that commonly exist with psoriasis as comorbid conditions, including those that may increase morbidity and mortality and adversely affect quality of life. They also address the multiple comorbidities that increase the risk for cardiovascular disease in patients with psoriasis, and the use of biologic therapy in patients with psoriasis who have comorbid conditions or complications. Following the introduction of TNF inhibitors, further advances in the understanding of psoriasis pathophysiology led to the development of yet more choices for the effective and safe treatment of patients who are candidates for systemic therapy. These newer and emerging treatments, discussed in the second article, include the interleukin (IL)-12/23 blocker ustekinumab (approved in 2009); the IL-17 inhibitors secukinumab (approved in January 2015) and ixekizumab; the IL-17 receptor blocker brodalumab; the IL-23 blockers tildrakizumab and guselkumab; and the small molecules apremilast (approved in 2014) and tofacitinib. The tumor necrosis factor (TNF) inhibitors were the first biologic agents to be approved by the US Food and Drug Administration for the treatment of psoriasis and remain a cornerstone of treatment for patients with moderate to severe disease. The third article in this supplement reviews the mechanisms of action and efficacy and safety data on adalimumab, etanercept, and infliximab (the 3 TNF inhibitors approved for psoriasis), and summarizes some observations from both clinical and research experience that may help clinicians maximize the efficacy of these agents. The fourth article provides a practical approach to screening patients prior to initiation of treatment with biologic agents and other systemic treatments as well as monitoring patients during therapy. The goal of such surveillance is to individualize treatment outcomes for optimum efficacy and minimum adverse events. In addition to the articles in this supplement, readers are invited to access selected presentations from the 2014 forum. These are available online at We hope our colleagues find this supplement and the presentations helpful. Francisco A. Kerdel, BSc, MBBS Director of Inpatient Dermatology University of Miami Hospital Professor of Dermatology and Vice Chairman Florida International University Miami, Florida Journal Supplement Chair 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., Celgene Corporation, and Novartis Pharmaceuticals Corporation. Dr Kerdel has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Joanne Still, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article. Francisco A. Kerdel, BSc, MBBS, Grant/Research: AbbVie, Amgen, AstraZeneca, Celgene, Galderma Laboratories, L.P., Janssen, Novartis, Pfizer and Valeant. Advisory Board: Celgene. Speakers Bureau: AbbVie, Amgen, Celgene, Galderma, and Janssen. Address reprint requests to: Francisco A. Kerdel, BSc, MBBS, Florida Academic Dermatology Centers, 1400 NW 12 Avenue, Suite 4, Miami, FL 33136; dr.kerdel@fadcenter.com /13/$-see front matter 2015 Frontline Medical Communications doi: /j.sder Vol. 34, No. 2S, March 2015, Seminars in Cutaneous Medicine and Surgery S29

6 Identifying and Managing Complications and Comorbidities in Patients With Psoriasis Kristina Callis Duffin, MD, MS,* and Craig L. Leonardi, MD Abstract The common comorbidities of cutaneous psoriasis include psoriatic arthritis (PsA), Crohn s disease, uveitis, and depression. In addition, cardiovascular disease risk factors (including metabolic syndrome) are seen more frequently among patients with psoriasis, and strong epidemiologic evidence has demonstrated that psoriasis is independently associated with myocardial infarction. Because these comorbid conditions and other medical complications adversely affect morbidity and mortality in patients with psoriasis, dermatologists can play an important role in promptly identifying and, when necessary, referring patients for further workup and treatment when signs or symptoms of these comorbidities or complications are observed. Semin Cutan Med Surg 34(supp2):S30-S published by Frontline Medical Communications Keywords Biologic agents; cardiovascular disease risk factors; chronic kidney disease; immune-mediated inflammatory diseases; psoriasis; psoriatic arthritis; viral hepatitis P soriasis is a multifaceted disease that is associated with multiple disease states including psoriatic arthritis (PsA), Crohn s disease, uveitis, and depression and behaviors (specifically, excess alcohol use and cigarette smoking). All of these have the potential to increase morbidity and mortality and to adversely affect quality of life for patients with psoriasis. In addition, psoriasis is associated with multiple comorbidities that increase the risk for cardiovascular disease (CVD), including obesity, dyslipidemia (hypertriglyceridemia and low high-density lipoprotein [HDL] level, hypertension, and elevated fasting serum * Assistant Professor, Dermatology, University of Utah, Salt Lake City, Utah. Clinical Professor of Dermatology, Saint Louis University, Central Dermatology, St Louis, Missouri. 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., Celgene Corporation, and Novartis Pharmaceuticals Corporation. Dr Duffin and Dr Leonardi have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Joanne Still, 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, Amgen, Bristol-Myers Squibb Company, Celgene, Eli Lilly and Company, Janssen Biotech, Inc., Pfizer Inc., and Stiefel Laboratories, Inc. Consultant: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and XenoPort, Inc. Scientific Advisory Board: Eli Lilly and Janssen. Craig L. Leonardi, MD, Grant/Research: AbbVie, Amgen, Celgene, Coherus BioSciences, Dermira Inc., Eli Lilly, Galderma Laboratories, L.P., Janssen, LEO Pharma, Merck, Novartis, Pfizer, Sandoz Inc., Stiefel, and Wyeth. Consultant: AbbVie, Amgen, Dermira, Eli Lilly, Janssen, LEO, Pfizer, Sandoz, and UCB, Inc. Speakers Bureau: AbbVie and Celgene. Address reprint requests to: Craig L. Leonardi, MD, Central Dermatology, 1034 S. Brentwood Boulevard, St Louis, MO 63117; craig.leonardi@centralderm.com. glucose level. Moreover, psoriasis is independently associated with myocardial infarction (MI). Although dermatologists may not treat these conditions per se, awareness of psoriasis comorbidities and complications is crucial so that patients can be promptly identified and referred, when necessary, to colleagues in the appropriate specialties. This article focuses on identifying and managing complications and comorbidities in patients with psoriasis and offers practical observations about biologic therapy in this patient population. Psoriasis and CVD Risk Factors and MI Severe psoriasis is associated with an increased prevalence of metabolic syndrome, defined as the presence of 3 or more of the following: increased waist circumference (abdominal obesity), hypertension, hypertriglyceridemia, reduced HDL, and insulin resistance/increased serum glucose. Metabolic syndrome is recognized as a chronic inflammatory state and is associated with marked increases in cardiovascular mortality; an estimated 25% of individuals in the United States today have metabolic syndrome. 1 In a landmark study, Sommer and colleagues 2 demonstrated an increased prevalence of metabolic syndrome in patients with moderate to severe psoriasis. In this study, investigators at the University of Kiel, Germany, compared the charts of 580 patients who were hospitalized for plaque psoriasis with the records of more than 1,000 patients who were admitted for localized melanoma surgery during the same time period. The charts, screened for the presence of concomitant internal diseases, showed that the patients with psoriasis also had significantly greater prevalence of diabetes (P<0.0001), hyperlipidemia (P<0.01), coronary heart disease (P<0.01), and arterial hypertension (P<0.0001) than those in the comparator group. Strong associations between psoriasis and CVD risk factors also have been demonstrated in population-based studies, including a study from the University of Pennsylvania based on the United Kingdom s General Practice Research Database. 3 In addition, a systematic review of the literature and meta-analysis from Armstrong and colleagues 4 showed that patients with psoriasis had a 59% increased prevalence of diabetes and an increased risk for developing the disease in those who were not already diagnosed. These investigators also noted that in patients with severe psoriasis especially younger patients the risk for developing diabetes may be even higher. The correlation between psoriasis and obesity was first observed by Henseler and colleagues in 1995, 5 and, more recently, Sterry and coworkers reviewed clinical trials on the use of biologic agents in patients with psoriasis and found that subjects weighed much more than the population norm. In that study, 46% of the 3,700 patients with moderate to severe psoriasis in were found to be obese in trials evaluating etanercept, and a review of 10,000 patients with moderate to severe psoriasis showed that these patients had an average body mass index of 30.6 kg/m 2. 6 In a pediatric population of 600 patients between 5 and 17 years of age, Paller and colleagues 7 found that those with psoriasis had significantly greater odds than controls of being overweight or obese. S30 Seminars in Cutaneous Medicine and Surgery, Vol. 34, No. 2S, March Frontline Medical Communications /13/$-see front matter doi: /j.sder

7 Kristina Callis Duffin, MD, MS, and Craig L. Leonardi, MD Psoriasis also has been shown to be an independent risk factor for MI. In a prospective, population-based cohort study using data from the General Practice Research Database from the United Kingdom, Gelfand and coworkers 8 compared the MI risk in patients with mild and severe psoriasis and a control population. The relative risk (RR) data were published for 2 age populations patients in their 30s and those in their 60s. In the younger age group, the adjusted RR for those with mild psoriasis was 1.29 (95% CI, ); the adjusted RR for those with severe psoriasis was 3.10 (95% CI, ). Among the patients in their 60s, the adjusted RR for those with mild psoriasis was 1.08 (95% CI, ); the adjusted RR for those with severe psoriasis was 1.36 (95% CI, ). Implications for Management: CVD Risk Factors/MI The increased cardiovascular risks seen in patients with psoriasis have been associated with 3 possible causes, including the use of antipsoriasis agents that contribute to dyslipidemia (ie, corticosteroids, acitretin, and cyclosporine), the increased prevalence of associated and/or independent risk factors (cigarette smoking and alcohol overuse in addition to the CVD risk factors discussed above), and uncontrolled inflammation leading to endothelial dysfunction and dyslipidemia. 9 However, in studies of MI risk in psoriasis that have controlled for dyslipidemic treatments and other factors, psoriasis has emerged as an independent risk factor for MI. 10,11 Because CVD risk factors are overrepresented in the population of patients with psoriasis, screening, monitoring, and prompt intervention are crucial. Hypertension, in particular, is problematic in patients with psoriasis for 2 reasons: blood pressure in these patients is especially difficult to control, and patients with hypertension tend to require more medications to control their psoriasis. 4 Thus, blood pressure should be checked every 1 to 2 years, and more frequently in patients at increased risk. Some studies show that the increased risk for CVD and MI that is associated with immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) and psoriasis may be mitigated by systemic therapy. Jacobsson and coworkers 12 found that treatment with tumor necrosis factor (TNF) inhibitors was associated with a lower incidence of first cardiovascular events in patients with RA. Among 531 patients with RA who were treated with TNF inhibitors, the age- and sex-adjusted incidence rate of the first CVD event was 14.0/1,000 person-years (PY) at risk (95% CI, ), with an age-adjusted hazard ratio of 0.46 (95% CI, ). Among the 452 patients with RA who did not receive anti-tnf therapy, the age- and sex-adjusted incidence rate of the first CVD event was 35.4/1,000 PY. These data suggest that anti- TNF therapy in patients with RA is associated with a lower risk for CVD, supporting the hypothesis linking inflammation and cardiovascular events. In a Veterans Affairs Medical Center study of 7,615 patients with psoriasis and 6,707 patients with RA, Prodanovich and coworkers 13 found that methotrexate treatment was associated with a reduced risk for CVD. Low-dose treatment was more effective than high-dose in this study, and the combination of methotrexate and folic acid was associated with the greatest risk reduction. In a retrospective cohort study using the database from California s Kaiser Permanente system, Wu and colleagues 14 demonstrated that patients with psoriasis who were treated with TNF inhibitors had a substantially lower hazard of MI compared to patients treated with topical therapy (adjusted hazard ratio, 0.50; 95% CI, ). The MI risk was also markedly lower in the TNF group compared to the cohort treated with phototherapy, although this difference did not reach statistical significance. Finally, in a retrospective, longitudinal cohort study from Denmark, Ahlehoff and colleagues 11 assessed the CVD event rates in more than 2,400 patients with severe psoriasis 693 patients treated with biologic agents, 799 treated with methotrexate, and the rest treated with other modalities. The primary CVD outcome events were death, MI, and stroke. During a 3-year period (with a mean follow-up of about 18 months), the investigators found a total of 105 individual primary outcome events; 6 of these were in patients treated with biologic agents and 33 occurred in patients treated with methotrexate, for risk reductions of almost 70% and almost 25%, respectively. A great deal of epidemiologic evidence shows that the incidence of CVD events is reduced in the setting of methotrexate and some biologic agents. The matter of causality warrants further study; in fact, clinical trials of several biologic agents now are under way, comparing reductions in cardiovascular inflammation with the biologic agents versus placebo. Psoriasis and Renal Complications The association between psoriasis and chronic kidney disease (CKD) is not widely recognized. Recently, Wan and colleagues 15 published the results of a population-based cohort study using The Health Improvement Network (THIN), an electronic medical records database from the United Kingdom. A total of 143,883 patients with psoriasis were categorized according to disease severity and treatments used; the records of 689,702 matched patients without psoriasis were used for comparison. Among the patients with psoriasis, 136,529 had mild disease and 7,354 had severe psoriasis, and the treatments used were methotrexate in 67%, cyclosporine in 10%, azathioprine in 10%, retinoids in 5%, and biologics in less than 1%. After the data were adjusted for confounding variables (including age, gender, diabetes, hypertension, the use of nephrotoxic drugs or nonsteroidal antiinflammatory drugs, and the presence of PsA), the investigators found an increase in CKD among the patients with severe psoriasis; it was particularly pronounced in the youngest age groups. Implications for Management: Renal Complications Screening tests prior to treatment with a biologic agent should include a complete blood count (CBC) and a complete metabolic panel. The biologic agents currently approved for the treatment of psoriasis (anti-tnf agents and interleukin-12/23 and -17A inhibitors) are not metabolized through the kidneys and the pharmacokinetics of these agents are similar in patients with normal renal function. Several case reports have described the successful use of biologic agents in patients with chronic renal failure; however, it is important to remember that these patients are at high risk for infection, so monitoring is crucial. Comorbid Psoriatic Arthritis Approximately 70% of patients with PsA have had cutaneous disease for at least 10 years before the appearance of the first signs and symptoms of PsA, and an estimated 15% of patients with cutaneous psoriasis develop joint disease within the same year. 16 Therefore, dermatologists are likely to be the first clinicians to encounter patients with emerging manifestations of PsA. Early identification of joint disease and prompt and appropriate referral of such patients to rheumatology colleagues for collaborative patient management is essential. At each follow-up visit, patients should be asked about joint pain and stiffness and examined for swelling and other signs of inflammation, enthesitis, dactylitis, and nail disease. When treating patients with psoriasis in whom systemic therapy is indicated, many dermatologists seem to prefer biologic monotherapy over the use of a biologic plus methotrexate. The advantages of this approach are clear: many patients respond well to biologic monotherapy and the risk for toxicity is lower than with combination treatment. However, combination therapy administered in consultation with a rheumatologist should be considered in patients who have signs and symptoms of PsA. Vol. 34, No. 2S, March 2015, Seminars in Cutaneous Medicine and Surgery S31

8 Identifying and Managing Complications and Comorbidities in Patients With Psoriasis Psoriasis and Viral Hepatitis Hepatitis B and C virus (HBV and HCV) infections are common in the psoriasis patient population. Screening for these infections is strongly recommended prior to initiating therapy with biologic agents. Evidence indicates that biologic agents may be considered to treat psoriasis in carefully selected patients who have concomitant viral hepatitis infections. Some data demonstrate that etanercept may be beneficial in patients with HCV infection. Zein and colleagues 17 reported the results of a phase II randomized, controlled study in which etanercept was used as adjunctive treatment in patients with chronic HCV infection who were also receiving interferon alfa-2b and ribavirin. These investigators reported that patients who received concomitant treatment with antivirals and etanercept for 24 weeks had a significantly better virologic response than did the patients who received antivirals and placebo (P=0.04). In another systematic review, Brunasso and colleagues 18 considered the literature over a 20-year period ( ) reporting the use of anti-tnf agents in patients with chronic HCV infection. In the 37 publications reviewed, data were available for 153 patients who were treated for a mean duration of 11.9 months with adalimumab, etanercept, golimumab, or infliximab. Most of the patients (110) were treated with etanercept. In this series, the authors reported 1 confirmed case of HCV infection worsening and 5 with suspected worsening; 74 patients had stable liver function tests and viral loads; and HCV infection parameters had improved in 29 patients who were also treated with interferon and ribavirin. 18 Two reports of infliximab use in patients with HCV infection showed conflicting results. In one, HCV infection worsened in a patient with RA 19 ; in the other, HCV infection improved despite infliximab therapy in a patient with Crohn s disease who also received concomitant treatment with interferon and ribavirin. 20 In contrast, biologics must be used with great caution, if at all, in patients with a history of or current HBV infection. An increased risk for reactivation of HBV has been seen in patients with a positive HBV surface antigen, an HBV-positive core antibody only, or a high-titer viral load. Case reports have been published suggesting that patients with a positive core antibody can be treated successfully with biologic agents plus antiviral agents without reactivation. 21 Prior to initiating treatment with any biologic agent, screening should include testing for HBV and HCV, regardless of the presence or absence of known risk factors. Phototherapy with ultraviolet light should be the first line of therapy considered in patients with current or past HBV or HCV infections. Treatment with a biologic or systemic agent can be considered, but treatment should be in collaboration with the patient s gastroenterologist or hepatologist, and viral titers and liver function tests should be monitored by these specialists. Patients With Challenging Psoriasis Phenotypes Palmar Plantar Psoriasis Palmar plantar pustular or nonpustular psoriasis is likely a heterogeneous group of phenotypes that is known to be associated with cigarette smoking. This subtype is notoriously difficult to treat. Recent data from gene researchers show that many patients with acrodermatitis continua of Hallopeau or palmar plantar pustular psoriasis have mutations in 2 genes on the interleukin-1 pathway: AP1S3 and IL36RN. Biologic agents have been used to treat palmar plantar psoriasis with or without pustules, and a number of case report series and small trials support the use of etanercept, adalimumab, infliximab, and ustekinumab. All of these drugs have been shown to work in many patients, and all can rarely trigger flares in some patients. Because the likelihood of success and disease flares are unpredictable with biologics, cyclosporine which is likely to produce disease clearance and unlikely to trigger a flare may be a better first choice for bringing the disease under control. Later, for long-term control, transition to acitretin or one of the biologics can be considered. Psoriasis and Other Immune-Mediated Inflammatory Diseases Almost all dermatologists have seen patients with inflammatory bowel disease or other immune-mediated inflammatory diseases (IMIDs), particularly RA or ankylosing spondylitis, who develop new-onset psoriasis or experience psoriasis flares or psoriasiform eruptions during treatment with anti-tnf agents. Among these comorbid IMIDs, Crohn s disease is common and is a possible psoriasis phenotype. Interleukin (IL)-23R and IL-12B are identified polymorphisms shared by patients with psoriasis and Crohn s disease. The literature on inflammatory bowel disease and anti-tnf biologics suggests that it is possible to manage the psoriatic lesions without stopping anti-tnf therapy. 22 The options for therapy include adding narrow-band phototherapy, cyclosporine, or methotrexate, or switching to a different anti-tnf agent. In addition, 2 studies of ustekinumab therapy in patients with psoriasis and refractory Crohn s disease demonstrated that this biologic may be particularly helpful in this population. 23,24 Conclusion Psoriasis is a multifaceted disease that may occur in the setting of one or more comorbid conditions. Patients with new-onset psoriasis commonly have diabetes, liver disease, renal disease, and dyslipidemia at screening. Moreover, therapy for psoriasis may complicate a patient s condition, or a comorbid condition may complicate therapy. Dermatologists who treat patients with psoriasis have the responsibility to screen for potentially complicating and comorbid conditions and to monitor for such conditions during the course of treatment. References 1. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005; 365: Sommer DM, Jenisch S, Suchan M, Christophers E, Weichenthal M. Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis. Arch Dermatol Res. 2006;298: Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol. 2006;55: Armstrong A, Harskamp CT, Armstrong EJ. Psoriasis and the risk of diabetes. JAMA Dermatol. 2013;149: Henseler T, Christophers E. Disease concomitance in psoriasis. J Am Acad Dermatol. 1995;32: Sterry W, Strober BE, Menter A; International Psoriasis Council. Obesity in psoriasis: The metabolic, clinical and therapeutic implications. Report of an interdisciplinary conference and review. Br J Dermatol. 2007;157: Paller A, Mercy K, Kwasny MJ, et al. Association of pediatric psoriasis severity with excess and central adiposity: An international cross-sectional study. JAMA Dermatol. 2013;149: Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296: Kremers HM, McEvoy MT, Dann FJ, Gabriel SE. Heart disease in psoriasis. J Am Acad Dermatol. 2007;57: Gelfand JM, Troxel AB, Lewis JD, et al. The risk of mortality in patients with psoriasis: Results from a population-based study. Arch Dermatol. 2007;143: Ahlehoff O, Skov L, Gislason G, et al. Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: A Danish real-world cohort study. J Intern Med. 2013;273: Jacobsson LT, Turesson C, Gülfe A, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol. 2005;32: Prodanovich S, Ma F, Taylor HR, Pezon C, Fasihi T, Kirsner RS. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005;52: S32 Seminars in Cutaneous Medicine and Surgery, Vol. 34, No. 2S, March 2015

9 Kristina Callis Duffin, MD, MS, and Craig L. Leonardi, MD 14. Wu JJ, Poon KY, Channual JC, Shen AY. Association between tumor necrosis factor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148: 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. Br Med J. 2013;347:f Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol. 2005;53: Zein NN; for Etanercept Study Group. Etanercept as an adjuvant to interferon and ribavirin in treatment-naïve patients with chronic hepatitis C virus infection: A phase 2 randomized double-blind, placebo-controlled study. J Hepatol. 2005;42: Brunasso AM, Puntoni M, Gulia A, Massone C. Safety of anti-tumour necrosis factor agents in patients with chronic hepatitis C infection: A systematic review. Rheumatology. 2011;50: Uda H, Kuhara M, Nishimoto N, Saiki O. Progression of viraemia during treatment with infliximab in a patient with rheumatoid arthritis and chronic hepatitis C infection. BMJ Case Rep Abdelmalek MF, Liu C, Valentine J. Successful treatment of chronic hepatitis C with pegylated interferon, ribavirin, and infliximab in a patient with Crohn s disease. Am J Gastroenterol. 2007;102: Navarro R, Vilarrasa E, Herranz P, et al. Safety and effectiveness of ustekinumab and antitumour necrosis factor therapy in patients with psoriasis and chronic viral hepatitis B or C: A retrospective, multicentre study in a clinical setting. Br J Dermatol. 2013;168: Denadai R, Teixeira FV, Steinwurz F, Romiti R, Saad-Hossne R. Induction or exacerbation of psoriatic lesions during anti-tnf-α therapy for inflammatory bowel disease: A systematic literature review based on 222 cases. J Crohns Colitis. 2013;7: Kopylov U, Afif W, Cohen A, et al. Subcutaneous ustekinumab for the treatment of anti-tnf resistant Crohn s disease: The McGill experience. J Crohns Colitis. 2014;8: Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn s disease. N Engl J Med. 2012;367: Vol. 34, No. 2S, March 2015, Seminars in Cutaneous Medicine and Surgery S33

10 Update on New and Emerging Therapies in the Management of Psoriasis Kenneth B. Gordon, MD,* and Craig L. Leonardi, MD Abstract Tumor necrosis factor inhibitors are a mainstay of treatment for patients with psoriasis who require systemic therapy. Since the approval of several of these agents, other biologic agents and small molecules have been developed; some of these have been approved recently by the US Food and Drug Administration, and others have shown great promise in clinical trials. The currently available and emerging treatments for psoriasis offer clinicians and patients an expanded list of options for individualizing treatment, potentially resulting in higher levels of improvement in both the disease process and quality of life. Semin Cutan Med Surg 34(supp2):S34-S published by Frontline Medical Communications Keywords Apremilast; brodalumab; guselkumab; interleukin-17 inhibitors; interleukin-12/23 inhibitors; interleukin-23 inhibitors; ixekizumab; Janus kinase inhibitors; phosphodiesterase-4 inhibitors; psoriasis; secukinumab; tildrakizumab; tofacitinib; tumor necrosis factor inhibitors; ustekinumab L ess than 2 decades ago, systemic retinoids, methotrexate, and cyclosporine were the only systemic therapy options for managing patients with psoriasis in whom topical treatment or phototherapy was inadequate. Although the first biologics, alefacept and efalizumab, are no longer available, several tumor necrosis factor (TNF) inhibitors subsequently were approved for psoriasis. The availability of these anti-tnf agents led to large-scale use of biologic treatment for psoriasis. Since TNF inhibitors first became available, other biologics have been introduced and more are in development, offering ever increasing numbers of patients the chance to achieve substantial improvement in their disease. * Professor of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Clinical Professor of Dermatology, Saint Louis University, Central Dermatology, St Louis, Missouri. 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., Celgene Corporation, and Novartis Pharmaceuticals Corporation. Dr Gordon and Dr Leonardi have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Joanne Still, 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, Amgen, Celgene, Eli Lilly, Janssen, and Merck & Co., Inc. Consultant: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Merck, Novartis and Pfizer. Craig L. Leonardi, MD, Grant/Research: AbbVie, Amgen, Celgene, Coherus BioSciences, Dermira Inc., Eli Lilly, Galderma Laboratories, L.P., Janssen, LEO Pharma, Merck, Novartis, Pfizer, Sandoz Inc., Stiefel, and Wyeth. Consultant: AbbVie, Amgen, Dermira, Eli Lilly, Janssen, LEO, Pfizer, Sandoz, and UCB, Inc. Speakers Bureau: AbbVie and Celgene. Address reprint requests to: Kenneth B. Gordon, MD, 925 Sutton Drive, Northbrook, IL 60062; Gordon.kenneth@att.net S34 Seminars in Cutaneous Medicine and Surgery, Vol. 34, No. 2S, March 2015 This article highlights several of the newer agents now available or currently in clinical trials for the treatment of psoriatic disease (Table). These agents include the interleukin (IL)-12/23 blocker, ustekinumab; the IL-17 inhibitors secukinumab and ixekizumab; the IL-17 receptor blocker brodalumab; the IL-23 blockers tildrakizumab and guselkumab; and the small molecules, apremilast and tofacitinib. Interleukin-12/23 Blockade In 2009, the US Food and Drug Administration (FDA) approved the use of ustekinumab, a monoclonal antibody that binds to the p40 subunits found in both IL-12 and IL-23, for the treatment of patients with moderate to severe plaque psoriasis. In 2013, ustekinumab also was approved for the treatment of psoriatic arthritis. IL-12 plays an important role in the differentiation of T cells in the T-helper (T H ) 1 pathway: the inhibition of IL-12 results in downregulation of a number of T H 1-type cytokines, including interferon-γ, IL-2, and TNF-α. Blockade of IL-23 also causes the inhibition of IL-17 and all its isoforms, as well as the indirect inhibition of TNF-α. (IL-17 expressed by memory natural killer cells and T cells induces neutrophilia, enhances inflammation and angiogenesis, and has been shown to be increased in psoriatic skin.) The combined result of IL-12/23 blockade is a profound inhibitory effect on the inflammatory cascade in the skin. In the PHOENIX 1 study, designed to assess the efficacy of long-term use of ustekinumab for up to 76 weeks, the investigators noted both rapid onset of efficacy and a long duration of improvement. 1 The pivotal phase III trials of ustekinumab demonstrated that this agent has a rapid onset of action, with a marked response seen after administration of the second dose. The FDA-approved intermittent dosing schedule results in achievement of a steady state after about 5 doses of ustekinumab; in between the first 4 doses, patients should be informed that they are likely to see some minor reversal of benefit just prior to the next injection, followed by improvement. However, loss of benefit should decrease in each cycle. No rebound, per se, was seen in this trial. Several serious adverse events were seen in both phase III trials of ustekinumab (PHOENIX 1 and PHOENIX 2). 1,2 One case of angina and 1 case of stroke were reported among patients who received 45-mg doses of ustekinumab; 2 cases of cellulitis and 1 case of disseminated herpes zoster infection were seen in patients who were treated with 90 mg of ustekinumab, and in this same group, 1 patient had coronary artery bypass surgery and there was 1 fatality (attributed to congestive cardiomyopathy that was symptomatic before the beginning of the study). According to 5-year postmarketing surveillance data published in 2013, 3 serious adverse events included serious infections, melanoma and other malignancies, and major adverse cardiovascular events (MACE). A year-by-year comparison of data shows a decrease in the number of serious adverse events over the period from 2007 through 2011 in all but MACE, which remained relatively constant. However, it is well documented that patients with psoriasis have an increased incidence of cardiovascular risk factors, and this study as well as the clinical trials of the other biologic agents now in use for psoriasis was not powered to detect rare events or permit a reliable assessment of risk. Analyses of data from additional years of experience with ustekinumab (and the other biologic agents) should clarify the significance of these early safety signals Frontline Medical Communications /13/$-see front matter doi: /j.sder