New Treatment Paradigms in Psoriasis: Understanding and ... · tarium of available agents for the...

EDITORS Kenneth A. Arndt, MDPhilip E. LeBoit, MDBruce U. Wintroub, MD

SUPPLEMENT 2

VOL. 37, NO. 2S

MARCH 2018

New Treatment Paradigms in Psoriasis: Understanding and Incorporating Recent

and Emerging Trends

GUEST EDITORS

M. Alan Menter, MD, Chair April W. Armstrong, MD, MPH

Kenneth B. Gordon, MD Jashin J. Wu, MD

Introduction S39

The Evolving Landscape of Psoriasis Treatment S40

Treating to Target—A Realistic Goal in Psoriasis? S45

Common and Not-So-Common S49 Comorbidities of Psoriasis

Practical Strategies for Optimizing S53 Management of Psoriasis

CME/CE Post-Test and Evaluation Form S57

A CME/CE CERTIFIED SUPPLEMENT TO

Supported by an independent educational grant from

Ortho Dermatologics

New Treatment Paradigms in Psoriasis: Understanding and Incorporating Recent and Emerging Trends

Original Release Date: March 2018Expiration Date: April 30, 2019Estimated Time to Complete Activity: 2.0 hours

Participants should read the activity information, review the activity in its entirety, and complete the online post-test and evaluation. Upon completing this activity as designed and achieving a passing score on the post-test, 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 out at that time. The online post-test and evaluation can be accessed at https://tinyurl.com/Psoriasis2018.Inquiries about CME accreditation may be directed to the University of Louisville Office of Continuing Medical Education & Professional Development (CME & PD) at [email protected] or 502-852-5329.CME/CE Accreditation StatementsPhysicians: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the University of Louisville and Global Academy for Medical Education, LLC. The University of Louisville is accredited by the ACCME to provide continuing education for physicians.The University of Louisville Office of Continuing Medical Education & Professional Development designates this enduring activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Joint Accreditation StatementIn support of improving patient care, this activity has been planned and implemented by Postgraduate Institute for Medicine and Global Academy for Medical Education.

Postgraduate Institute for Medicine is jointly accredited by the American Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team.Continuing Nursing EducationThe maximum number of hours awarded for this Continuing Nursing Education activity is 2.0 contact hours. Designated for 0.8 contact hours of pharmacotherapy credit for Advance Practice Nurses. Target AudienceThis journal supplement is intended for dermatologists, residents, internists, primary care practitioners, registered nurses, nurse practitioners, and physi-cian assistants who treat patients with psoriasis.Educational NeedsPsoriasis—a chronic, inflammatory, immune-system disease that affects approximately 8 million Americans—is often underdiagnosed. Many clinicians do not approach psoriasis as a systemic, immune-mediated disease with multiple comorbidities, including obesity, metabolic syndrome, cardiovascular disease, and psoriatic arthritis. Even though half of patients with psoriasis complain of arthritic pain, for example, more than two-thirds of dermatolo-gists lack confidence in screening for arthritic comorbidities. Clinicians also frequently fail to screen patients with psoriasis for cardiovascular risk factors, in part because they are unaware that the presence of psoriasis is associated with poor CV outcomes.Psoriasis is often undertreated. One recent survey found that two-thirds of patients with psoriasis reported being dissatisfied with their treatment; many discontinue treatment due to a lack of efficacy or because of adverse effects. Many clinicians fail to select a therapeutic option that addresses the needs of individual patients, and many neglect the importance of counseling patients adequately about the optimal use of medications or about what to expect from treatment. Complicating the situation is the fact that many clinicians do not adopt a treat-to-target strategy that establishes clear therapeutic goals based on treatment severity (including addressing quality-of-life issues) and that calls for adjusting the regimen as needed. Clinicians would benefit from education that describes the growing armamen-tarium of available agents for the treatment of psoriasis, explains the importance of identifying and managing common comorbidities of psoriasis, and presents current data on designing and deploying a treat-to-target strategy, including the use of topical agents and biologics, alone or in combination.

Learning ObjectivesBy reading and studying this supplement, participants should be better able to:• Explain the etiology and pathophysiology of psoriasis and its common

comorbidities• Diagnose and treat patients with psoriasis using treat-to-target guidelines• Select appropriate biologic therapies for patients with psoriasisDisclosure 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 non-profit or government organizations and non-health care related compa-nies, 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.April W. Armstrong, MD, MPH, Consultant: AbbVie Inc., Amgen Inc., Eli Lilly and Company, Janssen Biotech, Inc., Modernizing Medicine, Novartis Pharmaceuticals Corporation, Regeneron, Sanofi. Speakers Bureau: AbbVie Inc., Eli Lilly and Company, Janssen Biotech, Inc. Kenneth B. Gordon, MD, Consultant: AbbVie Inc., Amgen Inc., Almirall, S.A., Boehringer Ingelheim, Bristol Myers-Squibb Company, Celgene Corporation, Dermira, Inc., Eli Lilly and Company, LEO Pharma Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Sun Pharmaceutical Industries Ltd., UCB, Inc. Investigator: AbbVie Inc., Boehringer Ingelheim, Celgene Corporation, Novartis Pharmaceuticals Corporation.M. Alan Menter, MD, Advisory Board: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Boehringer Ingelheim, Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC. Consultant: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Avillion LLP, Boehringer Ingelheim, Eli Lilly and Company, Galderma S.A., Janssen Biotech, Inc., LEO Pharma Inc., Menlo Therapeutics Inc., Novartis Pharmaceuticals Corporation, Ortho Dermatologics, Pfizer Inc., Promius Pharma, LLC. Investigator: AbbVie Inc., Amgen Inc., Boehringer Ingelheim, Celgene Corporation, Dermira, Inc., Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron. Speakers Bureau: AbbVie Inc., Amgen Inc., Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC.Jashin J. Wu, MD, Contracted Research: AbbVie Inc., Amgen Inc., Eli Lilly and Company, Janssen Biotech, Inc., Novartis Pharmaceuticals Corporation, Regeneron.University of Louisville CME & PD Advisory Board and Staff Disclosures: The CME & PD Advisory Board and Staff have nothing to disclose.

CME/CE Reviewers: Timothy S. Brown, MD, Clinical Associate Professor, Division of Dermatology, Department of Medicine, University of Louisville School of Medicine. The Postgraduate Institute of Medicine planners and managers Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CHCP; Judi Smelker-Mitchek, MBA, MSN, RN; and Jan Schultz, MSN, RN, CHCP, have nothing to disclose.Global Academy for Medical Education Staff: Suzanne Bujara; Tristan M. Nelsen, MNM, CMP, HMCC; Sylvia H. Reitman, MBA, DipEd; and Ron Schaumburg have nothing to disclose.Off-Label/Investigational Use DisclosureThis CME/CE activity discusses the off-label use of certain approved medi-cations as well as data from clinical trials on investigational agents. Such material is identified within the text of the articles.

Jointly provided by

This continuing medical education (CME/CE) supplement was devel-oped from interviews with the faculty. The Guest Editors acknowledge the editorial assistance of Global Academy for Medical Education and Suzanne Bujara, 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 supporter, Global Academy for Medical Education, University of Louisville, Postgraduate Institute for Medicine, or the publisher.

Kenneth A. Arndt, MDClinical 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

EDITORS

Philip E. LeBoit, MDProfessor of Clinical Dermatology School of Medicine University of California, San Francisco San Francisco, California

Bruce U. Wintroub, MDAssociate Dean Professor and Chair of Dermatology School of Medicine University of California, San Francisco San Francisco, California

STATEMENT OF PURPOSESeminars 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.

Seminars in Cutaneous Medicine and Surgery (ISSN 1085-5629) is published quarterly by Frontline Medical Communications Inc., 7 Century Drive, Suite 302, Parsippany, NJ 07054-4609. Months of issue are March, June, September, and December. Periodicals postage paid at Parsippany, NJ, and additional mailing offices.

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March 2018, Vol. 37, No. 2S

New Treatment Paradigms in Psoriasis: Understanding and Incorporating Recent and Emerging Trends

TABLE OF CONTENTS

S39 IntroductionM. Alan Menter, MD

S40 The Evolving Landscape of Psoriasis Treatment April W. Armstrong, MD, MPH, Kenneth B. Gordon, MD, M. Alan Menter, MD, and Jashin J. Wu, MD

S45 Treating to Target—A Realistic Goal in Psoriasis?Kenneth B. Gordon, MD, April W. Armstrong, MD, MPH, M. Alan Menter, MD, and Jashin J. Wu, MD

S49 Common and Not-So-Common Comorbidities of PsoriasissM. Alan Menter, MD, April W. Armstrong, MD, MPH, Kenneth B. Gordon, MD, and Jashin J. Wu, MD

S53 Practical Strategies for Optimizing Management of PsoriasisJashin J. Wu, MD, April W. Armstrong, MD, MPH, Kenneth B. Gordon, MD, and M. Alan Menter, MD

S57 CME/CE Post-Test and Evaluation Form

Jashin J. Wu, MDDirector of Dermatology Research Department of Dermatology Kaiser Permanente Los Angeles Medical Center Los Angeles, California

GUEST EDITORS

April W. Armstrong, MD, MPHAssociate Professor of Clinical Dermatology Associate Dean for Clinical Research Keck School of Medicine of the University of Southern California Los Angeles, California

Kenneth B. Gordon, MDProfessor and Chair Department of Dermatology Medical College of Wisconsin Milwaukee, Wisconsin

M. Alan Menter, MD, ChairChairman, Division of Dermatology Baylor University Medical Center Dallas, Texas

Vol. 37, No. 2S, March 2018, Seminars in Cutaneous Medicine and Surgery S39

Vol. 37, No. 2S, March 2018

INTRODUCTION

Treating patients with psoriasis offers clinicians the opportunity to get back to their medical roots. Because the disease is multifaceted and challenging to manage, clinicians need to look beyond the skin for clues as to how they can best improve and relieve patients’ symptoms and signs.

This supplement represents the perspectives of myself and three of my colleagues, all respected and prolific research dermatologists: April W. Armstrong, MD, MPH, sets the stage with a primer on the pathophysiology of plaque psoriasis and how drug discovery has

led to breakthrough concepts of inflammation and the systemic nature of the disease. In her thorough walkthrough of the therapeutic landscape of treatment for patients with plaque psoriasis, Dr Armstrong discusses the benefits of the major therapeutic classes for plaque psoriasis, from topical agents to biologics.

Kenneth B. Gordon, MD, discusses the controversial concept of treating to target. The question he poses is: Whose target is it? Although traditional measures such as the Psoriasis Area and Severity Index and Physician Global Assessment might appear logical to clinicians, he emphasizes that patients’ individual needs, especially quality-of-life concerns, are equally important and suggests methods that are more patient-centric. In a case vignette, Dr Gordon illustrates the importance of selecting the right starting therapy—one that balances patients’ needs with appropriate efficacy.

Jashin J. Wu, MD, offers practical suggestions for helping patients obtain the greatest benefit from treatment. His sensible approach considers patients’ ages, lifestyles, and concomitant medications for maintaining a therapeutic regimen that sets the stage for success. Dr Wu also provides tips for mitigating risks with psoriasis treatment.

In my article, I address one of my favorite topics within the psoriasis spectrum: how comorbidities affect the course of the disease. I review the common diseases that ride alongside psoriasis, including arthritis/psoriatic arthritis and cardiovascular disease—as well as some that might not have been considered. I also recommend strategies to avoid flares and suggest therapeutic options that might treat the full spectrum of psoriasis.

Our hope is that, even if you do not routinely see patients with psoriasis, you will come away from this supplement with a greater understanding of this multisystemic disease. We will encourage you to look beyond the skin when treating patients with psoriasis, or at least to guide these individuals to find the right clinicians to address their needs. If we succeed in this endeavor, we will show that medical dermatology is still interesting and rewarding intellectually. We hope also to show that dermatologists and dermatologic clinicians need to be at the forefront in understanding, diagnosing, and treating psoriasis and all its manifestations and comorbidities.

M. Alan Menter, MDChairman, Division of Dermatology

Baylor University Medical CenterDallas, Texas

1085-5629/13/$-see front matter © 2018 Frontline Medical Communications doi:10.12788/j.sder.2018.008

Publication of this CME/CE article was jointly provided by University of Louisville, Postgraduate Institute for Medicine, and Global Academy for Medical Education, LLC, and is supported by an educational grant from Ortho Dermatologics. Dr Menter has received an honorarium for his participation in this activity. He acknowledges the editorial assistance of Suzanne Bujara, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

M. Alan Menter, MD, Advisory Board: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Boehringer Ingelheim, Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC. Consultant: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Avillion LLP, Boehringer Ingelheim, Eli Lilly and Company, Galderma S.A., Janssen Biotech, Inc., LEO Pharma Inc., Menlo Therapeutics Inc., Novartis Pharmaceuticals Corporation, Ortho Dermatologics, Pfizer Inc., Promius Pharma, LLC. Investigator: AbbVie Inc., Amgen Inc., Boehringer Ingelheim, Celgene Corporation, Dermira, Inc., Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron. Speakers Bureau: AbbVie Inc., Amgen Inc., Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC.

Address reprint requests to: M. Alan Menter, MD, 3900 Junius Street, Suite 145, Dallas, TX 75246; [email protected]

When researchers discovered in 1979 that the immuno-suppressant cyclosporine successfully cleared psoriatic plaques, the scientific community began to consider

psoriasis not “just a skin disease.”1,2 The cause of this chronic, multisystemic disease is dysregulation of the immune system.1 Approximately 3.2% of the American population has some form of psoriasis. Psoriasis vulgaris, the most common form of plaque psoriasis, affects 80% of people with psoriasis.1,3

The hallmarks of plaque psoriasis are red-pink plaques with silvery scales ranging in size from small to medium to large. They are symmetrically distributed on the scalp, elbows, knees, and lower torso.1 Plaques can also appear on the nails and intertriginous areas, such as the abdominal folds, axillae, inframammary folds, as well as the genitalia.1 Pruritus is among the most prominent and bothersome of psoriasis symptoms.1

Pathogenesis of PsoriasisThe inflammation and excess skin growth in psoriasis is the result of the interactions between the innate and adaptive immune systems; however, the adaptive immune system plays a key role.4 The inflam-matory process involves dendritic cells that secrete the cytokines interleukin (IL)-12 and IL-23, which then stimulate naïve T cells to differentiate into either type 1 or type 17 helper T cell (TH1, TH17) pathways (Figure 1).2,4

Over time it was determined that the TH17 pathways play a larger role in psoriasis than do the TH1 pathways. The TH1 pathways lead to the release of cytokines such as tumor necrosis factor (TNF)–alpha and interferon gamma. Activated TH17 cells produce inflammatory cytokines including IL-17A, IL-17F, IL-22, and TNF-alpha.5 The cytokines in turn cause skin thickening and erythema due to vasodilation and angiogenesis.1

■ AbstractThe process of discovering new drugs for plaque psoriasis has revealed much about the multisystemic nature of the disease. Current and emerging biologic agents may reliably achieve a Psoriasis Area and Severity Index (PASI 75) up to 90. Initially, clinicians select therapies based on the severity of the psoriasis. Although mild disease can be treated with topical agents, for patients with moderate to severe disease, concurrent therapy with oral systemic agents, biologics, and/or phototherapy needs to be considered. In some instances, clinicians may need to combine medications to provide patients with rapid relief of symptoms. Semin Cutan Med Surg 37(supp2):S40-S44 © 2018 published by Frontline Medical Communications

■ Keywords Biologics; phototherapy; psoriasis pathophysiology; systemic oral therapy; topical therapy

The Evolving Landscape of Psoriasis TreatmentApril W. Armstrong, MD, MPH,* Kenneth B. Gordon, MD,† M. Alan Menter, MD,‡ and Jashin J. Wu, MD§

* Associate Professor of Clinical Dermatology, Associate Dean for Clinical Research, Keck School of Medicine of the University of Southern California, Los Angeles, California

† Professor and Chair, Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin

‡ Chairman, Division of Dermatology, Baylor University Medical Center, Dallas, Texas

§ Director of Dermatology Research, Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California

Publication of this CME/CE article was jointly provided by University of Louisville, Postgraduate Institute for Medicine, and Global Academy for Medical Education, LLC, and is supported by an educational grant from Ortho Dermatologics. The authors have received an honorarium for their participation in this activity. They acknowledge the editorial assistance of Suzanne Bujara, medical writer, and Global Academy for Medical Education in the development of this continuing medical education journal article.

April W. Armstrong, MD, MPH, Consultant: AbbVie Inc., Amgen Inc., Eli Lilly and Company, Janssen Biotech, Inc., Modernizing Medicine, Novartis Pharmaceuticals Corporation, Regeneron, Sanofi. Speakers Bureau: AbbVie Inc., Eli Lilly and Company, Janssen Biotech, Inc. Kenneth B. Gordon, MD, Consultant: AbbVie Inc., Amgen Inc., Almirall, S.A., Boehringer Ingelheim, Bristol Myers-Squibb Company, Celgene Corporation, Dermira, Inc., Eli Lilly and Company, LEO Pharma Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Sun Pharmaceutical Industries Ltd., UCB, Inc. Investigator: AbbVie Inc., Boehringer Ingelheim, Celgene Corporation, Novartis Pharmaceuticals Corporation.M. Alan Menter, MD, Advisory Board: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Boehringer Ingelheim, Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC. Consultant: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Avillion LLP, Boehringer Ingelheim, Eli Lilly and Company, Galderma S.A., Janssen Biotech, Inc., LEO Pharma Inc., Menlo Therapeutics Inc., Novartis Pharmaceuticals Corporation, Ortho Dermatologics, Pfizer Inc., Promius Pharma, LLC. Investigator: AbbVie Inc., Amgen Inc., Boehringer Ingelheim, Celgene Corporation, Dermira, Inc., Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron. Speakers Bureau: AbbVie Inc., Amgen Inc., Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC.Jashin J. Wu, MD, Contracted Research: AbbVie Inc., Amgen Inc., Eli Lilly and Company, Janssen Biotech, Inc., Novartis Pharmaceuticals Corporation, Regeneron.

Address reprint requests to: April W. Armstrong, MD, MPH, Office of the Dean, Keck School of Medicine, University of California, 1975 Zonal Avenue, Los Angeles, CA 90089; [email protected]

S40 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 2S, March 2018© 2018 Frontline Medical Communications 1085-5629/13/$-see front matter

10.12788/j.sder.2018.009

■ FIGURE 1 Maintenance Phase of Psoriasis With Putative Targets of Current and Emerging DrugsAMP= antimicrobial peptides; DC=dendritic cell; IFN=interferon; IL=interleukin; R=receptor; TH=T helper; TNF=tumor necrosis factor.

Source: Johnson-Huang LM, et al.2

TNFα

IL-12

IL-17

IL-22 Production of AMPsand chemokines;

epidermal hyperplasiaTNFα inhibitors

p40 antibodies

IL-22 antibodies

IL-17 or IL-17R antibodies

TNFα inhibitors

Keratinocyte?

Myeloid DC

IFNγTH1

TNFαIL-23 TH17

TH22

IL-19, IL-20, IL-24

IL-17 and IL-23 and their receptors play a crucial role in psori-asis because they respond to dendritic and T-cell cytokines.5 The three approved IL-17 inhibitors exert a slightly different effect on the IL-17 signaling pathway.6 The first two agents approved, secukinumab and ixekizumab, neutralize IL-17A, whereas broda-lumab blocks the IL-17A receptor.6

IL-23 is one of the key cytokines that affect the production of IL-17.6 Ustekinumab, an IL-23 inhibitor, targets the shared p40 subunit of the IL-12 and IL-23 cytokines.2 Guselkumab and tildrakizumab, and the investigational agent, risankizumab, bind to the p19 subunit of the IL-23 cytokine.7

Our understanding of the inflammatory cascade that results in psoriasis continues to evolve. For example, the enzyme phos-phodiesterase-4 (PDE-4) has been found in many inflammatory cells, and its role is being elucidated in psoriasis.8 In preclinical studies, the small molecule apremilast, a PDE-4 inhibitor, blocked proinflammatory cytokines responsible for chronic inflammatory diseases such as psoriasis and psoriatic arthritis (PsA) in humans.8 By blunting the expression of the cytokines TNF-alpha, IL-12, and IL-23, apremilast reduced keratinocytes and skin thickness.8

Landscape of Psoriasis TreatmentPrior American Academy of Dermatology (AAD) guidelines, which are currently being updated, recommend that clinicians first ascertain whether a patient with psoriasis also has PsA.3 Patients who have PsA require systemic medications that treat both psori-asis and PsA.3

If a patient does not have concurrent PsA, the AAD treatment algo-rithm recommends using topical therapies for mild disease (Figure 2).9 For patients with moderate to severe psoriasis, the use of biologics, oral systemic medications, and phototherapy is required.3

Topical TherapiesTopical therapies for psoriasis include topical corticosteroids, topical vitamin D analogues, and keratolytic agents.1

The most commonly used topical agents in psoriasis are corti-costeroids, which reduce swelling and redness through their anti-inflammatory effects.1 Examples of topical steroids include betamethasone dipropionate, clobetasol propionate, desox-imetasone, fluocinonide, fluticasone propionate cream, and hydrocortisone.1 Topical steroids, which are applied once or twice daily, come in a variety of strengths and vehicles: ointments, creams, foams, lotions, shampoos, sprays, tape, and gels.1

In the last decade, innovations in topical treatment for psoriasis have focused on combinations such as topical steroids with vitamin D analogues, which reduce skin cell growth and scaling.1 Examples of this combination are betamethasone, dipropionate, and calcipot-riene (vitamin D3)—which are available in multiple vehicles, with the current foam vehicle shown to be optimal with only once daily appli-cation.1,10,11 These topical medications represent advances in vehicle technology, whereby different active ingredients can be combined in an efficacious and safe manner to confer therapeutic effect.1

PhototherapyPhototherapy has evolved from using broadband UVB to narrow-band UVB.1 Psoralen plus UVA (PUVA), although frequently more effective, poses a higher risk of skin cancer. A typical regimen starts with narrow-band UVB 3 times a week for 3 months. If patients improve, they can decrease the frequency to weekly UVB therapy.1

Office-based UVB phototherapy is the predominant type of administration; an office treatment may take less than 5 minutes. Home UVB is an option, but because units intended for home use are calibrated at a lower strength, home treatment can take up to an hour, which poses a risk that patients may not adhere to an effective regimen.

The advantage of phototherapy is that it does not create adverse immunosuppressive effects that potentially result from use of topical and systemic therapies.1 In short-term data, UVB therapy has not been definitively linked to skin cancer; however, the poten-tial risk of skin cancer with cumulative long-term UVB therapy is an ongoing concern.

Targeted light therapy treatments using an excimer laser can deliver higher-dose UVB therapy to focused, sensitive areas such as the scalp.12 This therapy is not available in most offices.

Oral Systemic TherapyPatients with moderate to severe psoriasis benefit most from systemic therapies.1 Traditional oral therapies used for psoriasis include methotrexate, cyclosporine, and acitretin. A newer oral therapy for psoriasis is apremilast.

Methotrexate. The oral and injectable antimetabolite metho-trexate increases extra-cellular adenosine with its anti-inflammatory properties.1 Methotrexate is the mainstay of systemic treatment for psoriasis in the US and Europe, despite its significant adverse effects on major organs—liver function enzyme elevation, bone marrow suppression, and pulmonary fibrosis—which limit its long-term use.1 Methotrexate is contraindicated in women who are actively conceiving, pregnant, or lactating.1 Warren and colleagues found that at week 16, 41% of patients who received subcutaneous MTX achieved PASI 75 vs 10% of those in the placebo group.13

Cyclosporine. Although the calcineurin inhibitor cyclosporine is effective, it is reserved for short-term interventional use in patients with psoriasis who are experiencing flares.1 Because long-term use of cyclosporine is associated with hypertension and irreversible renal damage, it is typically used for no more than 3 to 6 months and then discontinued.

Acitretin. The oral retinoid acitretin has been used with variable success for pustular psoriasis and palmoplantar psoriasis. It has a synergistic effect when combined with UV therapy.1 Patients using a combination of acitretin and UV therapy can reduce the UV dose. Acitretin has modest efficacy in patients with moderate to severe psoriasis. Significant potential adverse effects include dyslipidemia and less frequently liver function test abnormalities.1


April W. Armstrong, MD, MPH, Kenneth B. Gordon, MD, M. Alan Menter, MD, and Jashin J. Wu, MD

■ FIGURE 2 American Academy of Dermatology Psoriasis Treatment AlgorithmMTX=methotrexate; PUVA=psoralen-ultraviolet A; TNF=tumor necrosis factor; UVB=ultraviolet B.

Source: American Academy of Dermatology.9

Yes No

LimitedDisease

ExtensiveDisease

UVB/PUVA Systemic Biologic

Psoriasis ± Psoriatic Arthritis

Topicals/Targeted Phototherapy

Anti-TNF± MTX

Lack of Effect

Apremilast, an oral PDE-4 inhibitor approved in 2014, is modestly effective in patients with psoriasis and PsA. Its short-term, ie, initial first month of therapy, effect on the immune system is not well understood. Common adverse effects include diarrhea, nausea, and rare cases of upper respiratory tract infection, and headache.1 Warnings for apremilast include rare cases (1%) of depression.14

Biologic TherapyFor patients whose psoriasis is moderate to severe, biologics play a significant role in therapy because they target the specific cytokines that cause inflammation and skin lesions.1 Before starting a biologic regimen, it is essential that clinicians ascertain the patient’s PsA status. Biologics can be prescribed with oral systemic and topical agents concurrently.

TNF-alpha inhibitors are monoclonal antibodies that block TNF, a cytokine that can induce inflammation. When introduced more than a decade ago, these biologics changed the landscape of psoriasis treatment for patients with moderate to severe disease who had not achieved adequate control of their symptoms. TNF-alpha inhibitors also significantly benefit people who have PsA.

Etanercept, approved by the US Food and Drug Administration (FDA) in 2004, was among the first of the biologics to appear on the market for psoriasis. Etanercept is now approved for use in both adults and children with moderate to severe psoriasis.15 In pivotal trials, injectable etanercept demonstrated efficacy at 12 weeks, as defined by a Psoriasis Area and Severity Index (PASI) score of 75, in 49% of patients receiving etanercept 50 mg in the twice-weekly (BIW) group, 34% of patients in the 25-mg BIW group, and 3% in the placebo group (P<0.0001 for each etanercept group vs placebo).16 At week 24, 54% of patients whose dose was reduced from 50 mg BIW to 25 mg BIW achieved PASI 75, as did 45% of patients receiving continuous 25 mg BIW and 28% of the group that received placebo followed by etanercept 25 mg BIW.16

Common adverse effects of etanercept include infections and injection site reactions.15 Etanercept use in the psoriasis popu-lation has not been associated with significantly increased risk of serious infections compared to placebo. Long-term registry data with etanercept also demonstrated a tolerable safety profile. Patients with a history or signs and symptoms of tuberculosis need to be evaluated and appropriately treated, if necessary, before etanercept is considered.17

Adalimumab, approved in 2006, neutralizes the tumor necrosis factor responsible for inflammation in psoriasis.18 In the phase 3 trial, 71% of patients who received adalimumab achieved PASI 75 vs 7% of patients given placebo at week 16.18

Like etanercept, adalimumab was well tolerated in clinical trials.18 However, because serious infections can occur, patients must be screened carefully before initiating therapy with adalim-umab.19 Children and adolescents are also at a slight increased risk for malignancies such as lymphoma.19

Infliximab, administered intravenously, was approved in 2006 for the treatment of plaque psoriasis.20 At week 10, 75.5% of patients receiving infliximab 5 mg/kg vs .5% of patients receiving placebo achieved PASI 75.21 Despite the efficacy and safety of infliximab, dermatologists tend to use other TNF-alpha agents because few practices are equipped to administer drugs intravenously. Although adverse events in the pivotal trials were mild, postmarketing surveillance found that patients can develop serious infections and malignancies. Infliximab is contraindicated at higher doses in patients with heart failure.22

Ustekinumab, approved in 2009 for moderate to severe plaque psoriasis and in late 2017 for adolescent psoriasis, blocks the IL-12 and IL-23 cytokines.23 In the PHOENIX 1 pivotal trial, 67.1% of patients who received ustekinumab 45 mg and 66.4% of patients who received ustekinumab 90 mg achieved PASI 75 scores vs 1% of those who received placebo at week 12

(P<0.0001).23 The study found that dosing ustekinumab every 12 weeks maintained efficacy for 1 year or more in most patients.23

The PHOENIX 2 trial found that more partial responders (patients who had achieved ≥50% but <75% PASI improvement from baseline) who received the higher dose of ustekinumab (90 mg) every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose of 90 mg every 12 weeks (68.8% vs 33.3%; 95% confidence interval [CI], 12.7-58.1; P=0.004).24 Common adverse events include upper respiratory infection, head-ache, and fatigue.25 As is the case with other biologics, patients treated with ustekinumab are at risk for infection and should not initiate treatment if they have an active infection.25

Secukinumab, approved in 2015, was the first IL-17A ligand inhibitor indicated for moderate to severe plaque psoriasis.26 In a pooled analysis of four phase 3 trials involving nearly 1,400 patients worldwide, secukinumab demonstrated peak effi-cacy at week 16, with 75.6% of patients achieving PASI 90 and 47.2% achieving PASI 100.27 The 150-mg and 300-mg doses of secukinumab were tested in these trials (ERASURE, FIXTURE, FEATURE, and JUNCTURE). Patients received weekly injec-tions for the first 5 weeks, followed by maintenance doses every 4 weeks for up to 52 weeks. As measured by PASI 90/100 in a multiple imputation (to replace missing data), secukinumab 300 mg at week 52 achieved a 62.9%/37.9% response in North American (NA) patients, respectively, and 70.2%/42.0% in non-NA patients, respectively. Secukinumab 150 mg achieved a PASI 90/100 response in 30.9%/17.5% of NA patients, respectively, and in 53.9%/26.9% of non-NA patients, respectively. Both populations had similar adverse events. The most common adverse effect was nasophar-yngitis, followed by upper respiratory tract infection.27 There were rare cases of Crohn disease and ulcerative colitis in the trials.

Ixekizumab, also an IL-17A ligand inhibitor injectable, was approved in 2016 for patients with moderate to severe plaque psoriasis.28 In a pooled analysis (N=3,866 patients) of the phase 3 pivotal trials (UNCOVER 1-3), at week 12 ixekizumab demon-strated superiority vs both placebo and etanercept, as measured by the static Physician Global Assessment (sPGA) and PASI 75 (both P<0.001).29 At week 12, patients who received ixekizumab achieved PASI 75/90/100 of 90%/70%/40%, respectively. Adverse event rates were similar between the ixekizumab and etanercept groups; injec-tion site reaction was the most common adverse event.29 In the ixekizumab-treated group, patients reported more injection site pain and nausea than did patients treated with etanercept. Candida infections occurred in 0.5% of patients treated with placebo, in 0.7% in the etanercept group, in 0.6% treated with ixekizumab every 4 weeks, and 1.4% treated with ixekizumab every 2 weeks.29 Rare cases of Crohn disease and ulcerative colitis occurred during clinical trials.

Brodalumab, an IL-17 receptor A inhibitor, was approved in 2017 for patients with moderate to severe plaque psoriasis.30 In a pooled analysis of the three phase 3 trials (AMAGINE 1, 2, and 3), 4,373 patients with psoriasis were assessed based on the PASI 75 and an sPGA score of 0 (clear) or 1 (almost clear) by week 12 on treatment.31 The PASI 75 response rates for brodalumab 210 mg in AMAGINE 1, 2, and 3 were 83%, 86%, and 85%, respectively. Brodalumab 210 mg was statistically superior to ustekinumab at 12 weeks as measured by PASI 90, PASI 100, and sPGA 0 or 1 (P<0.01). The pooled adverse event rate at 12 weeks in the three studies was 57.6% among patients taking brodalumab 210 mg every 2 weeks and 51.0% among patients on placebo.31 The most commonly reported adverse events were nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Brodalumab is available only through a Risk Evaluation and Mitigation Strategy (REMS) program because it has a black box warning for suicidal ideation and behavior.30 Longer-term studies are warranted to assess the safety of patients with depression and other mental health disorders.

■ ■ ■ The Evolving Landscape of Psoriasis Treatment

S42 Seminars in Cutaneous Medicine and Surgery, Vol. 37, No. 2S, March 2018

Guselkumab, an IL-23 monoclonal antibody that binds to the p19 subunit of IL-23, was approved in 2017 for patients with moderate to severe psoriasis.32 Initially, the injectable is adminis-tered in one 100-mg/mL injection, followed by another injection 4 weeks later, and thereafter every 8 weeks.32 In a pooled analysis of 1,829 patients with moderate to severe psoriasis, guselkumab was superior to adalimumab in the VOYAGE 1 and 2 pivotal trials, as measured by the Investigator Global Assessment (IGA 0/1= cleared or minimal psoriasis; IGA 0=cleared).7 At week 24, patients treated with guselkumab achieved a response rate of 83.8% for IGA 0/1 and 52.1% for IGA 0 vs those treated with adalimumab, who achieved rates of 63.1% for IGA 0/1 and 30.2% for IGA 0.7 The most frequently reported adverse events included upper respiratory infections, headache, injection site reactions, arthralgia, diarrhea, gastroenteritis, tinea, and rare cases of herpes simplex infections.32

Tildrakizumab, another IL-23 inhibitor, has completed phase 3 trials (reSURFACE 1 and 2), and in March 2018 was approved by the FDA.33 Both injectable dosages of tildrakizumab (100 mg and 200 mg) were superior to etanercept and placebo. At 12 weeks, 66% of patients receiving 200 mg tildrakizumab and 61% receiving 100 mg tildraki-zumab achieved PASI 75, vs 6% for the placebo group and 48% in the etanercept group (P<0.0001 for comparisons of both tildrakizumab groups vs placebo; P<0.0001 for 200 mg vs etanercept and P=0.001 for 100 mg vs etanercept). There was one death in the reSURFACE 2 trial in a patient who received 100 mg of tildrakizumab; however, the cause of death could not be determined.33

Risankizumab, an immunoglobulin G1 (IgG1) monoclonal anti-body that also inhibits IL-23, completed phase 3 trials in 2017.34 In a phase 2 trial of 166 patients with moderate to severe psoriasis, risankizumab was superior to ustekinumab at week 12 (PASI 90, 77% vs 40%, respectively). Because of the small trial size, safety for the biologic could not be determined.34

Factors That Drive Treatment ChoiceWith so many new agents for psoriasis on or coming to the market, selecting the right initial therapy can be daunting. However, making the correct choice is crucial to alleviating the often overwhelming burden of psoriasis.35 Because both short- and long-term efficacy are essential to treatment choice, many clinicians opt for biologics, which can benefit patients who have comorbidities such as PsA.36

In addition, because multiple efficacious treatment options are available, it is important to understand established treatment targets and help patients achieve them.37 In the United States, the treatment target is long-term control of psoriasis such that patients will have 1% or less body surface area involvement when they have achieved the optimal dose. Treatment targets can be achieved with FDA-approved dosing, dose escalation of the same medication, or a combination of medications.37 Evaluation of benefits and risks on an individual basis is critical when working with patients toward these treatment goals.

Within the biologics class, for patients with both psoriasis and PsA, TNF-alpha inhibitors have longer-term data showing effi-cacy in PsA. Other considerations include patient weight, disease severity, and patient preference regarding injection frequency.36 For example, biologics that allow for weight-based dosing tend to be more effective in obese patients than are fixed-dose therapies.36

The safety profile of any therapy is a major consideration in treatment initiation because certain drug classes have shown a propensity for opportunistic infections. Progression of tubercu-losis or reactivation of hepatitis B are potential risks associated with TNF inhibitors, and therefore patients need to be screened and monitored for these potential risks.36

Patient preference and convenience should be factored into the treatment decision. The route of administration, dosing frequency, and concomitant medications all play a role in determining whether

patients will remain adherent to their regimens. Although office-based phototherapy may be effective for mild to moderate psoriasis, patients are often unable to attend the frequent phototherapy visits to the doctor’s office. Similarly, patients may be less adherent to an oral regimen that requires taking the medication more than once a day.

For biologics, the trend has been toward medications that have robust efficacy while requiring fewer injections. For patients already being treated with a systemic agent, adding another immunomodula-tory drug may alter their immune profile; therefore, one must perform a careful assessment of the safety profile of combined systemic agents.

ConclusionWhen the clinician selects the appropriate agent or combination therapy, patients with psoriasis can certainly expect to achieve signifi-cant relief from their symptoms. Clinicians need to first determine whether a patient has PsA and other comorbidities, because these factors will guide their medication choice. In general, therapeutic selection is based on the severity of the psoriasis, taking individual patient needs and preferences into account. Mild disease can usually be treated with topical agents, while for patients with moderate to severe psoriasis, clinicians need to consider biologics, oral systemic agents, and/or phototherapy as monotherapy or in combination.

References1. Greb JE, Goldminz AM, Elder JT, et al. Psoriasis. Nat Rev Dis Primers. 2016;2:16082.

doi: 10.1038/nrdp.2016.82. 2. Johnson-Huang LM, Lowes MA, Krueger JG. Putting together the psoriasis puzzle:

An update on developing targeted therapies. Dis Model Mech. 2012;5:423-433. 3. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psori-

asis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-850.

4. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361:496-509.5. Zeichner JA, Armstrong A. The role of IL-17 in the pathogenesis and treatment of psoriasis.

J Clin Aesthet Dermatol. 2016;9(suppl 1):S3-S6. 6. Lønnberg AS, Zachariae C, Skov L. Targeting of interleukin-17 in the treatment of psoriasis.

Clin Cosmet Investig Dermatol. 2014;7:251-259. 7. Gordon KB, Blauvelt A, Foley P, et al. Efficacy of guselkumab in subpopulations of

patients with moderate-to-severe plaque psoriasis: A pooled analysis of the phase III VOYAGE 1 and VOYAGE 2 studies. Br J Dermatol. 2018;178:132-139.

8. Schett G, Sloan VS, Stevens RM, Schafer P. Apremilast: A novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases. Ther Adv Musculoskelet Dis. 2010;2:271-278.

9. American Academy of Dermatology. Psoriasis clinical guideline. https://www.aad.org/ practicecenter/quality/clinical-guidelines/psoriasis. Accessed December 5, 2017.

10. Taclonex (calcipotriene and betamethasone dipropionate) [prescribing information]. Madison, NJ: LEO Pharma Inc; 2017.

11. Enstilar (calcipotriene and betamethasone dipropionate) [prescribing information]. Madison, NJ: LEO Pharma Inc; 2017.


April W. Armstrong, MD, MPH, Kenneth B. Gordon, MD, M. Alan Menter, MD, and Jashin J. Wu, MD

What’s Next When a Biologic Fails?Lynne is a woman in her early 50s who weighs 160 pounds. Her plaque psoriasis had been well controlled on a maintenance dose of adalimumab for at least 5 years. (She does not have PsA.) However, over the course of a year, she experienced several severe flares. This is not uncommon; some patients lose response to their initial biologic over time. In the context of this current biologic failure, dose escalation might help.

Lynne’s physician increased her usual dosage of 40 mg adali-mumab every other week to the off-label maintenance dosage of 40 mg every week.18 After 6 months, though, her flares did not improve.

Her physician added methotrexate 10 mg to Lynne’s weekly dose of adalimumab, but after 3 months, she continued to experience flares. Her physician decided to switch Lynne to guselkumab, the newest IL-23 blocker, and after 3 months, she reported that her flares subsided.

Key point: When a biologic fails after a prolonged period, it is time to consider escalating the dose, using combination therapy, or switching to a biologic with a different mechanism of action.

12. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol. 2010;62:114-135.

13. Warren RB, Mrowietz U, von Kiedrowski R, et al. An intensified dosing schedule of subcu-taneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): A 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:528-537.

14. Otezla (apremilast) [prescribing information]. Summit, NJ: Celgene Corporation; 2017.15. Enbrel (etanercept) [prescribing information]. Thousand Oaks, CA: Amgen Inc; 2017.16. Papp KA, Tyring S, Lahfa M, et al; for the Etanercept Psoriasis Study Group. A global

phase III randomized controlled trial of etanercept in psoriasis: Safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005;152:1304-1312.

17. Kimball AB, Rothman KJ, Kricorian G, et al. OBSERVE-5: Observational postmarketing safety surveillance registry of etanercept for the treatment of psoriasis final 5-year results. J Am Acad Dermatol. 2015;72:115-122.

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

19. Humira (adalimumab) [prescribing information]. North Chicago, IL: AbbVie Inc; 2017.20. Gall JS, Kalb RE. Infliximab for the treatment of plaque psoriasis. Biologics. 2008;2:

115-124.21. Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of continuous 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.e1-15.

22. Remicade (infliximab) [prescribing information]. Horsham, PA: Janssen Biotech Inc; 2017.23. Leonardi CL, Kimball AB, Papp KA, et al; PHOENIX 1 Study Investigators. Efficacy

and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371:1665-1674.

24. Papp KA, Langley RG, Lebwohl M, et al; PHOENIX 2 Study Investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371:1675-1684.

25. Stelara (ustekinumab) [prescribing information]. Horsham, PA: Janssen Biotech Inc; 2017.26. US Food and Drug Administration. FDA approves new psoriasis drug Cosentyx [press

release]. January 21, 2015. http://wayback.archive-it.org/7993/20171115021420/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm430969.htm. Accessed February 15, 2018.

27. Pariser D, Frankel E, Schlessinger J, et al. Efficacy of secukinumab in the treatment of moderate to severe plaque psoriasis in the North American subgroup of patients: Pooled analysis of four phase 3 studies. Dermatol Ther (Heidelb). 2008;8:17-32.

28. Taltz (ixekizumab) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; 2017.29. Papp KA, Leonardi CL, Blauvelt A, et al. Ixekizumab treatment for psoriasis: Integrated

efficacy analysis of three double-blinded, controlled studies (UNCOVER-1, UNCOVER-2, UNCOVER-3) [published online October 9, 2017]. Br J Dermatol. doi:10.1111/bjd.16050.

30. Siliq (brodalumab) [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2017.

31. Farahnik B, Beroukhim K, Abrouk M, et al. Brodalumab for the treatment of psoriasis: A review of phase III trials. Dermatol Ther (Heidelb). 2016;6:111-124.

32. Tremfya (guselkumab) [prescribing information]. Horsham, PA: Janssen Biotech Inc; 2017.33. Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept

for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): Results from two randomised controlled, phase 3 trials. Lancet. 2017;390:276-288.

34. Papp KA, Blauvelt A, Bukhalo M, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017;376:1551-1560.

35. Mrowietz U, Kragballe K, Nast A, Reich K. Strategies for improving the quality of care in psoriasis with the use of treatment goals—A report on an implementation meeting. J Eur Acad Dermatol Venereol. 2011;25(suppl 3):1-13.

36. Davison NJ, Warren RB, Mason KJ, et al. Identification of factors that may influence the selection of first-line biological therapy for people with psoriasis: A prospective, multicentre cohort study. Br J Dermatol. 2017;177:828-836.

37. Armstrong AW, Siegel MP, Bagel J, et al. From the Medical Board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis. J Am Acad Dermatol. 2017;76:290-298.


■ ■ ■ The Evolving Landscape of Psoriasis Treatment

Psoriasis and its comorbidities can significantly affect patients’ overall health and their quality of life. To achieve optimal results from therapy, clinicians need to collaborate with patients

to set long- and short-term goals: Is there a level of clearance or improvement that most patients find acceptable? Is there a target or number that accurately conveys response to therapy and that represents a realistic goal? Most important, in clinical care, are these targets—identified by analysis of populations—relevant to the patient in the office?

In psoriasis, there is a limited sense of what those endpoints are. However, the recent IHOPE study of >90,000 patients in the United Kingdom guides clinicians to reduce psoriasis so that it involves <10% of body surface area (BSA).1 The study compared BSA and mortality rates of patients with psoriasis and those without psoriasis from a British database. When adjusted for age, sex, and comorbidities, the risk of mortality in patients with BSA >10% was higher than that of people without psoriasis (Hazard Ratio [HR], 1.79; 95% confidence interval [CI], 1.23-2.59).1 These data suggest an initial goal of <10% BSA for all patients receiving psoriasis therapy.

Whose Target Is It?The question remains, however: With medications that regularly attain 90% improvement in Psoriasis Area and Severity Index score (PASI) or even in complete clearance, is there any evidence-based reason to attain very high levels of improvement? The National Psoriasis Foundation recommends a treat-to-target BSA goal of 1% or less (Table).2 Depending on the type and severity of a patient’s comorbidities, that may be an unreasonable target. Because limited BSA psoriasis is largely a quality-of-life (QOL) disease, there is no assurance that clearing a sizeable portion of BSA will necessarily yield positive QOL scores. Clinicians cannot overestimate the toll that a chronic disease like psoriasis has on a patient’s physical, social, and psychological well-being. What may matter more than the objective BSA number in assessing treat-ment efficacy is the subjective perspective of the patient.

The patient-reported Dermatology Life Quality Index (DLQI) assigns a score of 0 or 1 to psoriasis that does not have a signifi-cant impact on life. Studies reporting results using the DLQI reveal that different patients have varying levels of tolerance for psoriasis. For example, in studies of secukinumab, nearly 50% of patients had a PASI score of 75, which indicates that they still had substantial psoriasis, yet almost as many patients in that group also had a DLQI score of 0 or 1.3-5 That means that if the disease is having no further effect and the patient’s BSA is <10%, there would be no need to focus on a more aggressive target for therapy.

Plaque Location MattersFor a patient with psoriasis plaques on the face, any amount of surface area might be a tremendous burden. Likewise, hand or foot psoriasis can severely diminish QOL, even if the overall BSA is <10%. Because BSA does not encompass QOL, involvement of critical areas may cause BSA to underestimate the burden of the psoriasis.2 A clinician might have a treatment target of <1%, but if the plaque remains obvious on a patient’s cheek, the patient may still be dissatisfied with therapy.

■ AbstractFor many patients, the new biologic therapies for psoriasis can improve Psoriasis Area and Severity Index (PASI) scores in a relatively short time. But when results are less than optimal, patients often become frustrated. By providing effective medical treatment using a treat-to-target strategy, clinicians can relieve symptoms and halt disease progression. Although body surface area (BSA) and PASI scores are appropriate for analyzing results of clinical trials, clinicians need to use more patient-centered assessments of patients’ progress such as the Dermatology Life Quality Index (DLQI) and Psoriasis Symptom Inventory (PSI), as well as other validated patient-reported outcomes, which can enable them to set realistic and achievable goals for individual patients. Semin Cutan Med Surg 37(supp2):S45-S48 © 2018 published by Frontline Medical Communications

■ Keywords Body surface area (BSA); Dermatology Life Quality Index (DLQI); patient-reported outcomes; Psoriasis Area and Severity Index (PASI); quality of life (QOL); treat to target

Treating to Target—A Realistic Goal in Psoriasis?Kenneth B. Gordon, MD,* April W. Armstrong, MD, MPH,† M. Alan Menter, MD,‡ and Jashin J. Wu, MD§

* Professor and Chair, Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin

† Associate Professor of Clinical Dermatology, Associate Dean for Clinical Research, Keck School of Medicine of the University of Southern California, Los Angeles, California

‡ Chairman, Division of Dermatology, Baylor University Medical Center, Dallas, Texas



Kenneth B. Gordon, MD, Consultant: AbbVie Inc., Amgen Inc., Almirall, S.A., Boehringer Ingelheim, Bristol Myers-Squibb Company, Celgene Corporation, Dermira, Inc., Eli Lilly and Company, LEO Pharma Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Sun Pharmaceutical Industries Ltd., UCB, Inc. Investigator: AbbVie Inc., Boehringer Ingelheim, Celgene Corporation, Novartis Pharmaceuticals Corporation.April W. Armstrong, MD, MPH, Consultant: AbbVie Inc., Amgen Inc., Eli Lilly and Company, Janssen Biotech, Inc., Modernizing Medicine, Novartis Pharmaceuticals Corporation, Regeneron, Sanofi. Speakers Bureau: AbbVie Inc., Eli Lilly and Company, Janssen Biotech, Inc. M. Alan Menter, MD, Advisory Board: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Boehringer Ingelheim, Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC. Consultant: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Avillion LLP, Boehringer Ingelheim, Eli Lilly and Company, Galderma S.A., Janssen Biotech, Inc., LEO Pharma Inc., Menlo Therapeutics Inc., Novartis Pharmaceuticals Corporation, Ortho Dermatologics, Pfizer Inc., Promius Pharma, LLC. Investigator: AbbVie Inc., Amgen Inc., Boehringer Ingelheim, Celgene Corporation, Dermira, Inc., Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron. Speakers Bureau: AbbVie Inc., Amgen Inc., Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC.Jashin J. Wu, MD, Contracted Research: AbbVie Inc., Amgen Inc., Eli Lilly and Company, Janssen Biotech, Inc., Novartis Pharmaceuticals Corporation, Regeneron.

Address reprint requests to: Kenneth B. Gordon, MD, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226; [email protected]

Vol. 37, No. 2S, March 2018, Seminars in Cutaneous Medicine and Surgery S451085-5629/13/$-see front matter © 2018 Frontline Medical Communications 10.12788/j.sder.2018.010

■ ■ ■ Treating to Target—A Realistic Goal in Psoriasis?


Which Measure Is Best?Despite its limitations, BSA for plaque psoriasis is likely the best measure of physical disease burden that currently exists. It is quick, easily estimated and recorded, and is used in almost all dermatology offices. But trying to decrease the BSA as a treatment target can be daunting. It is possible for clinicians to get to a point where they have cleared a substantial proportion of plaques, yet the patient is still bothered by itching, pain, or unsightliness. These lingering annoyances diminish a patient’s QOL, and clinicians should acknowledge that at this juncture it is the patient who should set the treatment goals.

In a busy dermatology office, clinicians need a data point that is going to help them with decision making. The BSA, while not perfect, provides a quick and reproducible piece of information. If the patient is undressed, clinicians can derive a BSA score in a few seconds.2,6

Performing long, comprehensive QOL measures in the office may be more difficult. European dermatologists often use the DLQI, but in the United States few offices use it routinely because of time and logistical constraints.

Drug SelectionA common misconception is that certain psoriasis therapies, such as methotrexate, take longer to work, but mistakenly adhering to such myths can interfere with successful treatment. The multicenter METOP trial from the United Kingdom showed that subcuta-neous methotrexate does not become more effective after each successive dose.7 At week 16, 41% of methotrexate-treated patients achieved a PASI 75 response vs 10% of the placebo group (rela-tive risk [RR], 3.93; 95% CI, 1.31-11.81; P=0.0026).7 If patients did not achieve a PASI 50 score at week 8, they received a higher dose of methotrexate, from 17.5 mg/week for the first 16 weeks, to 22.5 mg/week. However, methotrexate appeared to reach peak effi-cacy around week 24 in the 52-week trial.7

A recent study with methotrexate found that it takes as little as 4 weeks to determine whether patients with psoriasis will respond to the systemic therapy.8 Methotrexate-treated patients who achieved PASI 25 at week 4 were more likely to respond at week 16. In contrast, in cases where patients have a <30% probability of response at week 16, a different therapeutic strategy should be considered.8

The phase 3 NAVIGATE trial, in which guselkumab was intro-duced after patients had not responded to ustekinumab therapy, provides a clear example of why it is important to wait until the third dose is administered. Approximately 30% of patients who had not responded fully at week 16 (when the third dose would be administered) eventually did respond when they received their third injection.9 However, patients treated with guselkumab fared better overall at week 52 than did patients treated with ustekinumab, with 50% and 24% achieving PASI 90, respectively.9

The National Psoriasis Foundation treat-to-target consensus recommends allowing 3 months for patients to respond to therapy.2 Ideally, 3 months after initiating treatment, the target BSA should be ≤3% or there should a BSA improvement of 75% or more from baseline.2 If a patient is not achieving any response, clinicians should discontinue treatment with the initial agent (Table).2

Efficacy is among the leading drivers in drug selection—and the lack of efficacy is the chief reason for therapeutic attrition. Systemic agents, and biologics specifically, are considered the go-to therapy because they treat moderate to severe plaque psoriasis as well as the common comorbidities. In systematic reviews, biologics in the aggregate can help up to 80% of patients achieve PASI 75.10 However, PASI scores do not reflect the whole clinical outcome because the trials often focus on short-term efficacy and may not incorporate health-related QOL concerns.10

One such QOL study compared the efficacy of three biologics—adalimumab, etanercept, and ustekinumab—for 1 year as measured by the DLQI and European Quality of Life score-5D (EQ-5D).10 Although there was no significant difference in the percentage of patients who received ustekinumab and adalimumab and who achieved a DLQI score of 0/1, adalimumab-treated patients were more likely than etanercept-treated patients to achieve a 0/1 DLQI score. Among the three biologics, there was no differ-ence in the EQ-5D score. Factors most frequently associated with poor response to treatment included being female, being a current smoker, having any comorbidity, and having a higher baseline DLQI score.10 For the EQ-5D score, each 10-year increase in age was associated with a lower EQ-5D score.10

■ TABLE Summary of National Psoriasis Foundation Consensus Targets for Plaque Psoriasisa

Preferred assessment instrument in clinical practice

BSA

Acceptable response after treatment initiation

Either BSA ≤3% or BSA improvement of ≥75% from baseline after 3 months of treatment

Target response after treatment initiation

BSA ≤1% at 3 months after treatment initiation

Target response during maintenance therapy

BSA ≤1% at every-6-month assessment intervals during maintenance therapy

BSA=body surface area.a Treatment targets apply to plaque psoriasis, and they are to be

discussed in the context of individualized evaluation of benefit-risk assessment and elicitation of patient preferences. They are not to be used to deny access to therapies.

Source: Armstrong AW, et al.2

Choosing Initial Therapy: Patient Preferences vs Medical NeedJared is a 30-year-old man who presents with psoriasis and psoriatic arthritis, which require treatment with a biologic. His plaque psoriasis covers 25% of his body, and his axial psoriatic arthritis stiffens his lower back and hips in the morning. Jared is otherwise healthy, with no history of multiple sclerosis or inflammatory bowel disease (IBD).

An anti-TNF or an anti–IL-17agent would be sensible choices because both classes are efficacious in psoriatic arthritis. Due to formulary restrictions, the likely choice will be the anti-TNF agent adalimumab. Contraindications to anti-TNF medications include multiple sclerosis, because these drugs can cause or exacerbate demyelinating disease.23

If Jared had painful axial psoriatic arthritis, an anti–IL-17 might be faster-acting. The anti–IL-17 agents secukinumab, ixekizumab, and brodalumab provide a more predictable and rapid response than anti-TNF agents.5,24 If he had IBD, anti–IL-17 agents would not be advisable because, in clinical trials, occasional new cases of IBD developed among patients with psoriasis.

Discontinuing a biologic regardless of the reason is also associ-ated with lower health-related QOL scores.10 Because biologics are immunomodulators, clinicians need to be alert for any infections that may arise.11 Occasionally, patients experience side effects, the most common being an infection while on a biologic. Although patients are at an increased risk of infection with biologics, some still get infections even without being on the medications. The dosages used in clinical trials become the required dosages in clinical practice, and third party payers frequently will not allow a change in dosing in clinical practice.

Dosing StrategiesThere is a dearth of evidence in prospective studies to guide clini-cians on adjusting the dose of psoriasis medications.12 A 3-year retrospective observational study found that clinicians increased the dose for 28.6% of patients and decreased the dose for 71.4%. The reason given for the increase was inadequate response in 60% of patients with plaque psoriasis and 40% of those with psoriatic arthritis. More than half of clinicians reduced the dose because of disease remission, 14% did so at the patients’ request, and 18% did so for unspecified reasons.12

Labeling for many antipsoriatic medicines includes step-down dosing—starting with a bolus dose and then gradually decreasing it. But some patients may fare worse when the dose is reduced.13 If there is some response, clinicians may obtain better results by increasing the dose or shortening the intervals between doses rather than switching to another agent.14

A systematic review of 23 studies that included 12,617 patients with psoriasis demonstrated that increasing the dose helps patients fare better overall than does decreasing the dose or switching to another agent.14 Patient nonresponders have better outcomes with continuous vs interrupted therapy for moderate to severe plaque psoriasis.14 Even with higher doses that are off-label, the benefits of dose escalation outweighed any adverse effects, which were mostly infections.14 However, more and larger studies are needed to examine the effect of off-label dosing on patients with psoriasis, so as to determine a more realistic risk-benefit ratio of dose escalation.

Follow-Up AssessmentsAlthough there is no firm, established timeline for follow-up visits, patients taking older systemic agents, such as methotrexate and cyclosporine, should be followed closely because they require routine laboratory tests, including complete blood count serum creatinine, blood urea nitrogen, uric acid, aspartate aminotrans-ferase, alanine aminotransferase, tests for hepatitis B and C viruses, and urinalysis.15 Indeed, long-term use of cyclosporine is not recom-mended because of the risk for nephrotoxicity and hypertension.15

When to follow up on patients taking the newer biologics is a subject of ongoing discussion. A consensus panel of the National Psoriasis Foundation has suggested that patients should undergo follow-up at 3 months after initiating a new therapy and again every 6 months during the maintenance phase.2 Experienced clinicians say that, for most patients, 8 weeks is sufficient to assess their prog-ress. What may also be important, especially to the patient, is the speed with which the agent works.

The follow-up for a certain medication may depend on the loading dose, subsequent doses, and the interval between dosing. A classic example is a patient who is on secukinumab and who does well in the first 5 weeks but who returns with flares 2 months later. Because the loading dosage (300 mg per week in weeks 1-4) is much higher than the follow-up dosage (300 mg every 4 weeks), some patients may be undermedicated if they receive the less-frequent maintenance dosage.16 Such a patient for whom the anti–interleukin

(IL)-17 medication works well—yet needs a more potent regimen—should probably be switched to another anti–IL-17 agent because it is mechanistically sound for the patient.17 Finding the right drug that gets the right levels for the patient is critical. If a patient is on secukinumab and does not respond, switching to another class of agent would be prudent. Clinicians can apply the same paradigm when prescribing either the anti–tumor necrosis factor (TNF) or the anti–IL-23 classes.

Adjusting Therapy: Dosing, SwitchingFor patients with moderate to severe psoriasis, clinicians change treatments due to inadequate disease control.18 In a 5-year analysis of insurance claims, Armstrong and colleagues reported that there were frequent changes among topical agents, oral systemic medi-cations, biologics, and phototherapy. Of the biologics studied, infliximab had the longest persistence, with a median 19 months of use.18 Overall, more patients stopped topical agents (15.9%) or phototherapy compared with those who stopped biologic or tradi-tional oral therapy (7.8%).18

The concept of changing to a therapy with a different mecha-nism of action was the focus of two papers in which the anti–IL-17 ixekizumab improved the signs and symptoms of psoriasis and psoriatic arthritis in patients who had originally failed on a TNF inhibitor.19 In the SPIRIT studies, at both the 2- and 4-week dosing intervals, ixekizumab reduced symptoms in 363 patients who were nonresponders to TNF inhibitors. The safety profile was similar to that seen in previous ixekizumab studies. In the UNCOVER-2 and UNCOVER-3 studies, both the every-2-week and every-4-week doses of ixekizumab were found to be superior to etanercept and placebo in the 12-week studies. The safety profile in these studies was comparable to that seen in previous ixekizumab and etaner-cept studies.20

Likewise, the IL-23 inhibitor guselkumab was found to be superior to the TNF inhibitor adalimumab when tested in subpop-ulations of patients with moderate to severe psoriasis (N=1,829).21 The subpopulations included more ethnically diverse patients, overweight and obese patients, and patients whose psoriasis had been present for a mean of 17 years. Previous studies of biologics, systemic agents, and phototherapy with these populations had lower efficacy. Among the subpopulations, guselkumab achieved an Investigator Global Assessment (IGA) score of 0/1 at week 16

Kenneth B. Gordon, MD, April W. Armstrong, MD, MPH, M. Alan Menter, MD, and Jashin J. Wu, MD


■ FIGURE Causes of Treatment Regimen FailuresPercentages do not add up to 100% because some patients were included in more than 1 category.

Source: Foster SA, et al.22

22.4

Switchingn=200N=891

49.9

Discontinuationn=445N=891

4.4

Dose Increasen=39

N=891

25.6

Augmentedn=228N=891

0

60

10

% A

mon

g Tr

eatm

ent F

ailu

res

40

30

50

20


vs placebo and at week 24 vs adalimumab. The VOYAGE 1 and VOYAGE 2 studies suggest that dosing based on patient character-istics such as weight and previous therapy can be effective.

No clear biomarkers exist that would enable clinicians to predict failure with biologic therapy (Figure).22 One study found that those more likely to fail biologic treatment include women and those taking concomitant medications such as topical agents (67.0% vs 58.4%; P<0.001), methotrexate (20.2% vs 7.3%; P<0.001), and cyclosporine (3.1% vs 1.0%; P<0.001).22 Their comorbidities included cerebrovascular disease, hypertension, chronic pulmonary disease, depression, and anxiety.22

Psoriasis is a multisystemic disease that affects the physical, psychological, and social well-being of patients. Clinicians need to be cognizant of these factors when initiating treatment, assessing progress, and changing regimens when patients are no longer obtaining relief. Thus long-term safe control is the ultimate goal.

ConclusionResearchers and clinicians are increasingly aware that patient-reported outcomes are essential for managing the care of patients with psoriasis because therapy should be based on QOL concerns. Although PASI and BSA scores are easily calculated, these tools do not provide a comprehensive assessment of a patient’s true prog-ress. Location of the plaque psoriasis may be just as important as the amount of BSA with lesions. Clinicians should be prepared to reassess their patients’ response to treatment and adjust the strategy accordingly, whether through dosage adjustments or a switch to an agent with a different mechanism of action, to achieve not just a reduction in psoriasis symptoms but to improve the overall QOL for patients.

References1. Noe MH, Shin DB, Wan MT, Gelfand JM. Objective measures of psoriasis severity

predict mortality: A prospective population-based cohort study. J Invest Dermatol. 2018;138:228-230.

2. Armstrong AW, Siegel MP, Bagel J, et al. From the Medical Board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis. J Am Acad Dermatol. 2017;76:290-298.

3. Elewski BE, Puig L, Mordin M, et al. Psoriasis patients with psoriasis Area and Severity Index (PASI) 90 response achieve greater health-related quality-of-life improvements than those with PASI 75-89 response: Results from two phase 3 studies of secukinumab. J Dermatolog Treat. 2017;28:492-499.

4. Puig L, Augustin M, Blauvelt A, et al. Effect of secukinumab on quality of life and psori-asis-related symptoms: A comparative analysis versus ustekinumab from the CLEAR 52-week study [published online October 21, 2017]. J Am Acad Dermatol. doi:10.1016/j.jaad.2017.10.025.

5. Armstrong AW, Papp K, Kircik L. Secukinumab: Review of clinical evidence from the pivotal studies ERASURE, FIXTURE, and CLEAR. J Clin Aesthet Dermatol. 2016;9(suppl 1):S7-S12.

6. Wu JJ, No DJ, Amin M. BSA75, BSA90, and BSA100: New clinical tools for measuring improvement in psoriasis. Cutis. 2017;99:418.

7. Warren RB, Mrowietz U, von Kiedrowski R, et al. An intensified dosing schedule of subcu-taneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): A 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:528-537.

8. Gordon KB, Betts KA, Sundaram M, et al. Poor early response to methotrexate portends inadequate long-term outcomes in patients with moderate-to-severe psoriasis: Evidence from 2 phase 3 clinical trials. J Am Acad Dermatol. 2017;77:1030-1037.

9. Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: Results of the randomized, double-blind, phase III NAVIGATE trial. Br J Dermatol. 2018;178:114-123.

10. Iskandar IYK, Ashcroft DM, Warren RB, et al. Comparative effectiveness of biological therapies on improvements in quality of life in patients with psoriasis. Br J Dermatol. 2017;177:1410-1421.

11. Badavanis G, Pasmatzi E, Monastirli A, Tsambaos D. Biologic agents in systemic derma-totherapy: Cutaneous and systemic side effects [published online May 18, 2017]. Curr Drug Saf. doi:10.2174/1574886312666170518124014.

12. Esposito M, Gisondi P, Conti A, et al. Dose adjustment of biologic therapies for psori-asis in dermatological practice: A retrospective study. J Eur Acad Dermatol Venereol. 2017;31:863-869.

13. Edwards CJ, Fautrel B, Schulze-Koops H, Huizinga TWJ, Kruger K. Dosing down with biologic therapies: A systematic review and clinicians’ perspective. Rheumatology (Oxford). 2017;56:1847-1856.

14. Brezinski EA, Armstrong AW. Off-label biologic regimens in psoriasis: A systematic review of efficacy and safety of dose escalation, reduction, and interrupted biologic therapy. PLoS One. 2012;7:e33486.

15. Choi CW, Kim BR, Ohn J, Youn SW. The advantage of cyclosporine A and methotrexate rotational therapy in long-term systemic treatment for chronic plaque psoriasis in a real world practice. Ann Dermatol. 2017;29:55-60.

16. Cosentyx (secukinumab) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018.

17. Kerdel F, Zaiac M. An evolution in switching therapy for psoriasis patients who fail to meet treatment goals. Dermatol Ther. 2015;28:390-403.

18. Armstrong AW, Koning JW, Rowse S, Tan H, Mamolo C, Kaur M. Initiation, switching, and cessation of psoriasis treatments among patients with moderate to severe psoriasis in the United States. Clin Drug Investig. 2017;37:493-501.

19. Nash P, Kirkham B, Okada M, et al; SPIRIT-P2 Study Group. Ixekizumab for the treat-ment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: Results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389:2317-2327.

20. Griffiths CE, Reich K, Lebwohl M, et al; UNCOVER-2 and UNCOVER-3 Investigators. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): Results from two phase 3 randomised trials. Lancet. 2015;386:541-551.

21. Gordon KB, Blauvelt A, Foley P, et al. Efficacy of guselkumab in subpopulations of patients with moderate-to-severe plaque psoriasis: A pooled analysis of the phase III VOYAGE 1 and VOYAGE 2 studies. Br J Dermatol. 2018;178:132-139.

22. Foster SA, Zhu B, Guo J, et al. Patient characteristics, health care resource utilization, and costs associated with treatment-regimen failure with biologics in the treatment of psoriasis. J Manag Care Spec Pharm. 2016;22:396-405.

23. Enbrel (etanercept) [prescribing information]. Thousand Oaks, CA: Amgen Inc; 2017.24. Sawyer L, Fotheringham I, Wright E, Yasmeen N, Gibbons C, Holmen Møller A. The

comparative efficacy of brodalumab in patients with moderate-to-severe psoriasis: A systematic literature review and network meta-analysis [published online January 29, 2018]. J Dermatolog Treat. doi:10.1080/09546634.2018.1427205.

■ ■ ■ Treating to Target—A Realistic Goal in Psoriasis?

Scientific research continues to reveal the inflammatory process that is the basis of many chronic conditions, including psori-asis and its many associated comorbidities (Table).

Psoriatic arthritis (PsA) is among the most frequent of these comorbidities. Approximately 30% of patients with psoriasis have comorbid PsA. PsA onset typically occurs 5 to 10 years after the onset of psoriasis, ie, in the third to fifth decade of life; in children, the age of onset peaks between 11 and 12 years.1

Positioned on the frontlines for identifying PsA, dermatologists should be aware of the importance of evaluating patients for joint stiffness and pain. Physical examinations should include the fingers (dactylitis) and toes, Achilles tendon (enthesitis), sacroiliac, axial skeleton, and the large joints to identify evidence of swelling, inflam-mation, and nail disease (Figure). When examining patients who present with early onset of PsA, consider the following questions:• Does early morning stiffness last for ≥30 minutes, eg, hands,

feet, hips and other large joints, without clinical signs of PsA?• When is a rheumatologic consultation indicated?• PsA usually improves more dramatically than psoriasis.

When does the rheumatologist refer to the dermatologist?• Should dermatologists be ordering x-rays for suspected psori-

atic joint disease?• Can radiologists discern the early signs of PsA?There are several self-administered screening tools for PsA:• The Psoriasis Epidemiology Screening Tool (PEST) is a one-

page questionnaire with a body diagram allowing patients to identify painful joints2

• The Toronto Psoriatic Arthritis Screening Tool (TOPAS) is meant for the general population to determine whether a person might have PsA3

• The Psoriatic Arthritis Screening and Evaluation Tool (PASE) can distinguish between signs and clinical symptoms of PsA and those of osteoarthritis4

■ AbstractPlaque psoriasis is increasingly recognized as a multisystemic disease whose most common comorbidities include psoriatic arthritis, cardiovascular disease, metabolic syndrome, overweight/obesity, inflammatory bowel disease, and depression. The presence of such comorbidities affects the therapeutic choices for clinicians. Patients often visit dermatologists more frequently than they do other clinicians, so it is incumbent upon dermatologists to recognize and address early signs of psoriatic comorbidities to prevent further deterioration and improve their patients’ quality of life. Semin Cutan Med Surg 37(supp2):S49-S52 © 2018 published by Frontline Medical Communications

■ Keywords Cardiovascular disease; comorbidities; immune-mediated disorders; overweight/obesity; psoriasis; psoriatic arthritis; psychiatric disorders

Common and Not-So-Common Comorbidities of PsoriasisM. Alan Menter, MD,* April W. Armstrong, MD, MPH,† Kenneth B. Gordon, MD,‡ and Jashin J. Wu, MD§

* Chairman, Division of Dermatology, Baylor University Medical Center, Dallas, Texas


‡ Professor and Chair, Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin



M. Alan Menter, MD, Advisory Board: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Boehringer Ingelheim, Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC. Consultant: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Avillion LLP, Boehringer Ingelheim, Eli Lilly and Company, Galderma S.A., Janssen Biotech, Inc., LEO Pharma Inc., Menlo Therapeutics Inc., Novartis Pharmaceuticals Corporation, Ortho Dermatologics, Pfizer Inc., Promius Pharma, LLC. Investigator: AbbVie Inc., Amgen Inc., Boehringer Ingelheim, Celgene Corporation, Dermira, Inc., Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron. Speakers Bureau: AbbVie Inc., Amgen Inc., Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC.April W. Armstrong, MD, MPH, Consultant: AbbVie Inc., Amgen Inc., Eli Lilly and Company, Janssen Biotech, Inc., Modernizing Medicine, Novartis Pharmaceuticals Corporation, Regeneron, Sanofi. Speakers Bureau: AbbVie Inc., Eli Lilly and Company, Janssen Biotech, Inc. Kenneth B. Gordon, MD, Consultant: AbbVie Inc., Amgen Inc., Almirall, S.A., Boehringer Ingelheim, Bristol Myers-Squibb Company, Celgene Corporation, Dermira, Inc., Eli Lilly and Company, LEO Pharma Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Sun Pharmaceutical Industries Ltd., UCB, Inc. Investigator: AbbVie Inc., Boehringer Ingelheim, Celgene Corporation, Novartis Pharmaceuticals Corporation.Jashin J. Wu, MD, Contracted Research: AbbVie Inc., Amgen Inc., Eli Lilly and Company, Janssen Biotech, Inc., Novartis Pharmaceuticals Corporation, Regeneron.

Address reprint requests to: Address reprint requests to: M. Alan Menter, MD, 3900 Junius Street, Suite 145, Dallas, TX 75246; [email protected]

Vol. 37, No. 2S, March 2018, Seminars in Cutaneous Medicine and Surgery S491085-5629/13/$-see front matter © 2018 Frontline Medical Communications doi:10.12788/j.sder.2018.011

■ TABLE Comorbidities Associated With Psoriasis

Related to systemic inflammation

• Psoriatic arthritis • Atherosclerosis• Diabetes and insulin resistance• Hypertension• Metabolic syndrome• Myocardial infarction• Obesity

Related to lifestyle risk factors or to impaired quality of life

• Alcohol abuse• Anxiety• Depression• Smoking• Suicidal ideation

Related to treatment (eg, systemic agents, TNF-alpha inhibitors)

• Hepatotoxicity• Nephrotoxicity• Nonmelanoma skin cancer

TNF=tumor necrosis factor. Source: Gulliver W.9

Systemic agents are effective for treating patients with comorbid PsA and plaque psoriasis because they can ameliorate cutaneous as well as joint inflammation.5 Older systemic agents, such as metho-trexate and cyclosporine, are used less often because of concerns about toxicity and their inability to prevent further joint destruc-tion.5 Phototherapy and topical agents address skin symptoms of psoriasis but do not relieve the disabling joint pain of PsA.5

Cardiovascular disease has a strong association with psoriasis. This is in part due to the fact that several of the medications commonly prescribed for psoriasis, including corticosteroids, acitretin, and cyclosporine, can further worsen dyslipidemia.6 When controlled for dyslipidemia, psoriasis was found to be an indepen-dent risk factor for myocardial infarction (MI) in a prospective study comparing outcomes of patients with and without psoriasis.7

This was particularly striking in the cohort of patients in their 30s with severe psoriasis vs those in their 60s.7 In 30-year-old patients with mild or severe psoriasis, the adjusted relative risk (RR) of having an MI was 1.29 (95% confidence interval [CI], 1.14-1.46) and 3.10 (95% CI, 1.98-4.86), respectively. For 60-year-old patients with mild or severe psoriasis, the adjusted RR of having an MI was 1.08 (95% CI, 1.03-1.13) and 1.36 (95% CI, 1.13-1.64), respectively.7 In general, patients with severe psoriasis die approximately 4 years sooner than do patients without psoriasis.8

Recent studies have explored the association between psoriasis and the immune pathogenic mechanisms in cardiovascular diseases. Cytokines such as interleukin (IL)-1–beta, IL-6, and tumor necrosis factor (TNF)–alpha are involved in the pathophysiology of many conditions, including cardiovascular disease, diabetes, obesity, Crohn disease, and dyslipidemia.9 Genes that regulate some of these cytokines may be linked to psoriasis and its comorbidities.

Metabolic syndrome also shares a strong inflammatory associa-tion with psoriasis.10 The syndrome is diagnosed when at least three of five characteristics are present: increased waist circumference, hypertension, hypertriglyceridemia, reduced high-density lipopro-tein (HDL), and insulin resistance/increased serum glucose.10 In a chart comparison study of 580 patients, those with moderate to severe psoriasis who were admitted for melanoma surgery were more likely to have comorbid metabolic syndrome and its compo-nents than were patients in the control group: diabetes (P<0.0001), hyperlipidemia (P<0.01), coronary heart disease (P<0.01), and arterial hypertension (P<0.0001).11

The more severe the psoriasis, the greater the likelihood of meta-bolic syndrome.12 Furthermore, each component of metabolic syndrome is also independently associated with psoriasis.12 In a study of 44,715 patients (4,065 with psoriasis and 40,650 controls) in the United Kingdom, psoriasis severity correlated with metabolic syndrome in a dose-response paradigm: The adjusted odds ratio (OR) for patients with mild psoriasis was 1.22 (95% CI, 1.11-1.35) vs 1.98 (95% CI, 1.62-2.43) for severe psoriasis.12

Overweight and obesity, which contribute to metabolic syndrome, also have a dose-response relationship with psoriasis: The greater the body mass index (BMI), the likelier it is that psoriasis will occur.13 A Norwegian study of 8,752 men and women followed for 14 years found that individuals with a BMI of 27 kg/m2 had a 32% increased risk for psoriasis; the risk increased to 43% at a BMI of 28 kg/m2, and to 71% at a BMI of ≥30 kg/m2 in nonsmokers.13 Independent of BMI, there was a 70% to 90% increased risk of onset of psoriasis with weight gain for both men and women.13

Adipocytes and activated inflammatory macrophages can contribute to both psoriasis and overweight/obesity.13 Adipose tissue produces the hormones, adipokines, and proinflamma-tory cytokines responsible for psoriasis, namely IL-1, IL-6, and TNF-alpha.13

TNF-alpha was identified in 1993 as the first fat-secreted cytokine linked to insulin resistance.14 Since then, research has continued to show how TNF-alpha correlates with increased BMI, percentage of

body fat, and hyperinsulinemia.14 For example, TNF-alpha contrib-utes to insulin resistance by increasing free fatty acid production, reducing adiponectin synthesis, and impairing insulin signaling.14

Type 2 diabetes. Likewise, there is a strong association between psoriasis and type 2 diabetes that is also correlated with disease severity.15 A meta-analysis of 27 studies found that there was an overall propensity for diabetes prevalence in patients with psoriasis (OR, 1.59; 95% CI, 1.38-1.83).15 The pooled OR was 1.53 (95% CI, 1.16-2.04) for mild psoriasis and 1.97 (95% CI, 1.48-2.62) for severe psoriasis.15

Mansouri and colleagues16 discovered that psoriasis is an inde-pendent risk factor for the presence of coronary artery calcium (OR, 2.35; 95% CI, 1.12-4.94) in fully adjusted models. This suggests that, even after adjustment for BMI, people with psoriasis have levels of atherosclerosis comparable to those of people with type II diabetes.16 The study confirmed that people with psoriasis are three to five times more likely to have moderate to severe levels of coronary calcium compared to healthy controls.16

Early treatment of psoriasis with systemic or biologic immuno-modulating therapy has the potential to delay or prevent the onset of these comorbidities and decrease the risk of premature mortality.

Among the older systemic oral agents for psoriasis treatment, methotrexate was effective in reducing vascular inflammation in a study of 7,615 veterans with psoriasis and 6,707 with rheumatoid arthritis (RA).17 Compared with controls, patients who received methotrexate had a significant reduction in cardiovascular disease (psoriasis: RR, 0.73; 95% CI, 0.55-0.98; RA: RR, 0.83; 95% CI, 0.71-0.96). Low-dose methotrexate was more effective than the higher dose, and concomitant folic acid administration demon-strated the highest reduction in cardiovascular disease risk.17

In a retrospective study, Wu and colleagues18 found that TNF-alpha inhibitors or a combination of oral agents and photo-therapy were superior to topical monotherapy for lowering the risk of MI (50% and 46%, respectively). The researchers theorized that reducing inflammation led to a decrease in the risk of MI.18 When adjusted for age, TNF-alpha therapy was shown to have a greater effect in the age cohort >60 years, a difference attributed to the higher incidence of diabetes in that age group.18 Clearly, biologics and methotrexate confer a cardiovascular benefit beyond ameliorating psoriasis symptoms. A Danish registry study found that the cardio-vascular incidence rates per 1,000 patient-years were 6.0 (95% CI, 2.7-13.4), 17.3 (95% CI, 12.3-24.3), and 44.5 (95% CI, 34.6-57.0) for patients treated with biologic agents, methotrexate, and other thera-pies (retinoids, cyclosporine, and phototherapy), respectively.19,20

Psychiatric diseases/mood disorders—depression, anxiety, and suicidal ideation in particular—are seen at higher rates among patients with psoriasis compared with the general population.21 Wu and colleagues21 reported that, in a Danish registry, mental health disorders occurred in 3.1% of patients with psoriasis vs 2.2% of controls. Patients with psoriasis were more likely to be prescribed antipsychotics, anxiolytics, and antidepressants.21

A systematic review of global studies found that the prevalence of depression among patients with psoriasis ranged from 2.10% to 33.7% compared with a lower prevalence (0% to 22.7%) among healthy controls.21 Similarly, among patients with PsA, there is a greater risk for depression compared with patients with plaque psoriasis (incidence rate ratio [IRR], 1.22; 95% CI, 1.16-1.29, vs 1.14; 95% CI, 1.11-1.17).21 Depression and psoriasis are thought to share similar inflammatory cytokines.21 Whether or not there is a definite shared underpinning for both diseases, treatment for patients with comorbid depression is often more challenging to manage.21

Although prevalence data for anxiety are not as robust as the depression data for patients with psoriasis, one systematic review estimated that the prevalence of anxiety ranges from 1.81% to 22.7% among patients with psoriasis, compared with 1.35% to 11.1% among patients without psoriasis.21 Patients with psoriatic arthritis tend to have more severe anxiety than do those with plaque psoriasis.21


■ ■ ■ Common and Not-So-Common Comorbidities of Psoriasis

The prevalence of suicidality among patients with psoriasis can be as high as 37.4% during a lifetime vs 1.01% to 1.94% among the general population, with two-thirds of patients attributing their suicidal ideation to their psoriasis.21,22 Data are conflicting about whether there is a dose-response relationship between psoriasis severity and suicide.21 Clearly, however, comorbid depression confers greater risk for suicide among patients with psoriasis than does severity of the disease alone. In one UK study, major depression contributed to a 10-fold risk for suicide among patients with psoriasis.21

Appropriate treatment of psoriasis can ameliorate comorbid depression and anxiety.21 Papp and colleagues23 reported significant decreases in depression and anxiety, as measured by the Hospital Anxiety and Depression Scale (HADS), in patients treated with brodalumab 140 mg (n=219) or 210 mg (n=222) every 2 weeks, compared with patients who received placebo (n=220; P<0.0001 for brodalumab 140 or 210 mg vs placebo). Researchers also found that the TNF inhibitor adalimumab simultaneously decreased the Psoriasis Area and Severity Index (PASI) scores of >75% of patients studied and improved scores for depression (P<0.001).24

Opportunistic infections are a frequent adverse effect associated with TNF-alpha inhibitors. One study, for example, reported that the rate of serious infection was 4.02 per 100 patient-years (95% CI, 3.20-5.04).25 Gastrointestinal infections were the most common, followed by tuberculosis, extrapulmonary infections, and malignan-cies.25 Infections are also a concern with the newer biologics. In a phase 3 trial of secukinumab, a human anti–IL-17A monoclonal antibody, the most common adverse event was upper respiratory tract infection.26 At minimum, clinicians ought to screen patients every 3 months for infection, at least initially.

Malignancies. Although the data are inconsistent, some studies have found an association between psoriasis and malignancies.9 Some theorize that neoplasms share a common inflammatory

pathway, while others point to treatment-related causes, especially with high-dose methotrexate and psoralen ultraviolet A (PUVA) therapy.9 A large retrospective study of 153,197 patients with psoriasis who were on systemic agents showed an increased risk of Hodgkin lymphoma (RR, 3.18; 95% CI, 1.01-9.97) and cutaneous T-cell lymphoma (RR, 10.75; 95% CI, 3.89-29.76).9

Pain, as assessed by patient-reported outcome (PRO) instru-ments, is often overlooked in dermatology practices because many dermatologists assume that pain management is under the purview of rheumatologists. Approximately 42% of patients with plaque psoriasis have reported cutaneous pain, which they described as pruritic, aching, sensitive, burning, tender, and cramping.27 The cytokine IL-33 is implicated in both psoriasis and pain, but the common mechanism is not yet clear.27 In a study on psoriatic pain, Patruno and colleagues27 found that 43.6% of 163 patients with psoriasis had cutaneous pain, slightly more than had been reported in previous studies.

One useful tool for assessing pain is the Psoriasis Symptom Inventory (PSI), a PRO instrument that includes itch, redness, scaling, burning, cracking, stinging, flaking, and pain.28 In a substudy (N=661) of the phase 3 trial AMAGINE 1, PSI results showed that the IL-17 receptor antibody brodalumab was effective in clearing moderate to severe plaque psoriasis as well as comorbid pain.28

The Dermatology Life Quality Index (DLQI) is another PRO that has been validated to assess pain in patients with moderate to severe psoriasis.29 The CLEAR 52 trial demonstrated that secukinumab was more effective at relieving pain vs ustekinumab at weeks 16 and 52 (P<0.05) as measured by the DLQI. Moreover, secukinumab relieved itching 4 weeks faster and scaling 8 weeks faster than ustekinumab (P<0.001).29

Inflammatory bowel disease (IBD) and psoriasis are genetically linked; the risk for IBD is four times greater among patients with psoriasis than it is among healthy comparators.30 For people with PsA,

■ FIGURE The Many Presentations of Psoriatic Arthritis A. Skin and joints. B. Dactylitis. C. Enthesitis. D. Arthritis mutilans.Because joint disease usually presents 5 to 10 years after skin symptoms, dermatologists invariably see these patients first.

Source: Courtesy and copyright 2018 M. Alan Menter, MD.


M. Alan Menter, MD, April W. Armstrong, MD, MPH, Kenneth B. Gordon, MD, and Jashin J. Wu, MD

A. B.

C. D.

the risk for IBD—especially for comorbid Crohn disease—is even greater.30 Patients with comorbid psoriasis and Crohn disease tend to be younger at diagnosis than are those with psoriasis and ulcer-ative colitis (median, 25.8 years vs 37.3 years).30 The etiology of IBD remains unclear; some hypotheses point to an immune-mediated disorder, whereas others suggest autoimmune origins.31

Treatment for comorbid psoriasis and IBD traditionally calls for the use of TNF-alpha inhibitors.30 However, some studies para-doxically inculpate this class of agents as the cause of both IBD and psoriasis.30 Despite this, Eppinga and colleagues30 reported that most of the patients (n=385) in their IBD-psoriasis prevalence study used TNF-alpha inhibitors, followed by systemic steroids, metho-trexate, and nonsteroidal anti-inflammatory drugs. Preliminary evidence also suggests that IL-17 inhibitors may precipitate IBD in up to 2 out of 1,000 patients.32,33

Hepatic disease, another common comorbidity associated with psoriasis, is often overlooked.34 The hormone resistin and the cyto-kines TNF-alpha, IL-6, and IL-1–beta are associated with insulin resistance, fatty liver, and psoriasis, but their pathophysiologic mechanism of action is unclear.34 Roberts and colleagues34 identi-fied the prevalence of non-alcoholic fatty liver disease (NAFLD, 47%) and non-alcoholic steatohepatitis (NASH, 22%) in a cohort of military patients with psoriasis (N=103; mean age, 52.7 years).34 In patients with psoriasis, comorbid diabetes confers an even greater risk for NAFLD.34

Evidence is mounting that shows other comorbidities are also found in patients with psoriasis, including chronic obstructive pulmonary disease (COPD), renal disease, and obstructive sleep apnea (OSA).35,36 One British cross-sectional study of 69,000 patients revealed an association with renal disease and psoriasis (adjusted OR, 1.28; 95% CI, 1.11-1.48; P<0.05) and showed that the prevalence of renal disease increases with psoriasis severity.35 At this time, the link between psoriasis and COPD or OSA is based on case reports; more rigorous studies are needed to clearly estab-lish the connection.36

Lifestyle choices such as tobacco and alcohol use can exacerbate psoriasis. A UK study found a paradox in the comorbidity of smoking: While smoking was positively linked to psoriatic arthritis (Hazard Ratio [HR], 1.27; 95% CI, 1.19-1.36), it found no such association with plaque psoriasis (HR, 0.91; 95% CI, 0.84-0.99).37 Another study, however, found that smoking duration and pack-years contributed to the risk of psoriasis (P<0.0001).38 The theory behind the smoking-psoriasis link is that nicotine and dioxin acti-vate T cells that produce cytokines IL-12, IL-17, and IL-22.38

In a study that surveyed the dietary habits of 1,206 patients with psoriasis, 13.6% of respondents said that alcohol was a main trigger for psoriasis flares, and 53.8% said that eliminating alcohol from their diet helped improve their symptoms.39 Patients with psoriasis who consume alcohol have a 60% greater risk of mortality than do their healthy peers.40 The top causes of alcohol-related death among patients with psoriasis were alcoholic liver disease (65.1%), fibrosis and cirrhosis of the liver (23.7%), and mental health disor-ders due to alcohol (7.9%).40 Other commonly cited dietary triggers were sugar (13.8%), tomato (7.4%), gluten (7.2%), and dairy (6%).39

ConclusionPsoriasis presents a multifaceted challenge to the clinician who enjoys the medical aspects of dermatology. As an immune-mediated inflammatory disease, psoriasis is associated with numerous comor-bidities. A dose-response relationship exists with psoriasis and its comorbidities: The more severe the psoriasis, the likelier an indi-vidual will have one or more comorbidities. To optimize the results of treatment for psoriasis, clinicians must look for—and address—the presence of concomitant disorders.

References1. National Psoriasis Foundation. About psoriatic arthritis. https://www.psoriasis.org/about-

psoriatic-arthritis. Accessed January 17, 2018.2. Helliwell PS. Psoriasis Epidemiology Screening Tool (PEST): A report from the GRAPPA

2009 annual meeting. J Rheumatol. 2011;38:551-552.3. Chandran V, Gladman DD. Toronto Psoriatic Arthritis Screening (ToPAS) questionnaire:

A report from the GRAPPA 2009 annual meeting. J Rheumatol. 2011;38:546-547. 4. Husni ME, Meyer KH, Cohen DS, Mody E, Qureshi AA. The PASE questionnaire:

Pilot-testing a psoriatic arthritis screening and evaluation tool. J Am Acad Dermatol. 2007;57:581-587.

5. Mease PJ, Menter MA. Quality-of-life issues in psoriasis and psoriatic arthritis: Outcome measures and therapies from a dermatological perspective. J Am Acad Dermatol. 2006;54: 685-704.

6. Kremers HM, McEvoy MT, Dann FJ, Gabriel SE. Heart disease in psoriasis. J Am Acad Dermatol. 2007;57:347-354.

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

8. 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;143:1493-1499.

9. Gulliver W. Long-term prognosis in patients with psoriasis. Br J Dermatol. 2008;159 (suppl 2):2-9.

10. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415-1428.11. 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;298:321-328.

12. Langan SM, Seminara NM, Shin DB, et al. Prevalence of metabolic syndrome in patients with psoriasis: A population-based study in the United Kingdom. J Invest Dermatol. 2012;132:556-562.

13. Danielsen K, Wilsgaard T, Olsen AO, Furberg AS. Overweight and weight gain predict psori-asis development in a population-based cohort. Acta Derm Venereol. 2017;97:332-339.

14. Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: An update. Clin Endocrinol (Oxf). 2006;64:355-365.

15. Armstrong AW, Harskamp CT, Armstrong EJ. Psoriasis and the risk of diabetes mellitus: A systematic review and meta-analysis. JAMA Dermatol. 2013;149:84-91.

16. Mansouri B, Kivelevitch D, Natarajan B, et al. Comparison of coronary artery calcium scores between patients with psoriasis and type 2 diabetes. JAMA Dermatol. 2016;152:1244-1253.

17. Prodanovich S, Ma F, Taylor JR, Pezon C, Fasihi T, Kirsner RS. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005;52:262-267.

18. Wu JJ, Poon KY, Channual JC, Shen AY. Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch Dermatol. 2012;148:1244-1250.

19. 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;273:197-204.

20. Wu JJ, Guérin A, Sundaram M, Dea K, Cloutier M, Mulani P. Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-α inhibitors versus metho-trexate. J Am Acad Dermatol. 2017;76:81-90.

21. Wu JJ, Feldman SR, Koo J, Marangell LB. Epidemiology of mental health comorbidity in psoriasis [published online November 10, 2017]. Dermatolog Treat. 2017;1-9. doi:10.1080/09546634.2017.1395800.

22. Wu JJ, Penfold RB, Primatesta P, et al. The risk of depression, suicidal ideation and suicide attempt in patients with psoriasis, psoriatic arthritis or ankylosing spondylitis. J Eur Acad Dermatol Venereol. 2017;31:1168-1175.

23. Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175:273-286.

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

25. Pereira R, Faria R, Lago P, Torres T, et al. Infection and malignancy risk in patients treated with TNF inhibitors for immune-mediated inflammatory diseases. Curr Drug Saf. 2017;12:162-170.

26. McInnes IB, Mease PJ, Kirkham B, et al; FUTURE 2 Study Group. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;386:1137-1146.

27. Patruno C, Napolitano M, Balato N, et al. Psoriasis and skin pain: Instrumental and biolog-ical evaluations. Acta Derm Venereol. 2015;95:432-438.

28. Viswanathan HN, Mutebi A, Milmont CE, et al. Measurement properties of the Psoriasis Symptom Inventory electronic daily diary in patients with moderate to severe plaque psoriasis. Value Health. 2017;20:1174-1179.

29. Puig L, Augustin M, Blauvelt A, et al. Effect of secukinumab on quality of life and psori-asis-related symptoms: A comparative analysis versus ustekinumab from the CLEAR 52-week study [published online October 21, 2017]. J Am Acad Dermatol. doi:10.1016/j.jaad.2017.10.025.

30. Eppinga H, Poortinga S, Thio HB, et al. Prevalence and phenotype of concurrent psoriasis and inflammatory bowel disease. Inflamm Bowel Dis. 2017;23:1783-1789.

31. Wen Z, Fiocchi C. Inflammatory bowel disease: Autoimmune or immune-mediated pathogenesis? Clin Dev Immunol. 2004;11:195-204.

32. Oussedik E, Patel NU, Cash DR, Gupta AS, Feldman SR. Severe and acute complications of biologics in psoriasis. G Ital Dermatol Venereol. 2017;152:586-596.

33. Amin M, Darji K, No DJ, Bhutani T, Wu JJ. Review of IL-17 inhibitors for psoriasis [published online November 10, 2017]. J Dermatolog Treat. 2017:1-6. doi:10.1080/09546634.2017.1395796.

34. Roberts KK, Cochet AE, Lamb PB, et al. The prevalence of NAFLD and NASH among patients with psoriasis in a tertiary care dermatology and rheumatology clinic. Aliment Pharmacol Ther. 2015;41:293-300.

35. Yeung H, Takeshita J, Mehta NN, et al. Psoriasis severity and the prevalence of major medical comorbidity: A population-based study. JAMA Dermatol. 2013;149:1173-1179.

36. Takeshita J, Grewal S, Langan SM, et al. Psoriasis and comorbid diseases: Epidemiology. J Am Acad Dermatol. 2017;76:377-390.

37. Nguyen UDT, Zhang Y, Lu N, et al. Smoking paradox in the development of psoriatic arthritis among patients with psoriasis: A population-based study. Ann Rheum Dis. 2018;77:119-123.

38. Lee EJ, Han KD, Han JH, Lee JH. Smoking and risk of psoriasis: A nationwide cohort study. J Am Acad Dermatol. 2017;77:573-575.

39. Afifi L, Danesh MJ, Lee KM, et al. Dietary behaviors in psoriasis: Patient-reported outcomes from a U.S. national survey. Dermatol Ther (Heidelb). 2017;7:227-242.

40. Parisi R, Webb RT, Carr MJ, et al. Alcohol-related mortality in patients with psoriasis: A population-based cohort study. JAMA Dermatol. 2017;153:1256-1262.


■ ■ ■ Common and Not-So-Common Comorbidities of Psoriasis


Improving Patient AdherenceAdherence to psoriasis therapy has been traditionally poor. For patients with mild to moderate psoriasis, topical therapy has an especially steep drop-off rate: A survey of 1,200 patients reported that 73% did not adhere to their topical treatment.1 Clinicians should be aware of the risk for nonadherence as they design and initiate treatment plans.

A key part of the strategy is careful follow-up. For patients with mild to moderate psoriasis who are prescribed topical therapy, a follow-up visit at 1 month is prudent. One study found that, with close monitoring, nonadherence can be reduced from 85% to 51%.1 In this study (N=40 patients with mild to moderate psoriasis), Alinia and colleagues1 demonstrated just how lamen-table compliance is for 1 year, even for the topical medication fluocinonide ointment. Electronic sensors in the medication cap accurately measured not only the number of times the medica-tion was used but also the dose per use.1 Adherence was better (although not statistically significant) in the intervention group, in which patients had to submit weekly reports online, vs those in the control group (50% vs 35%, respectively; P=0.08). None of the patients in the study used the medication as directed, and only 15% were adherent during clinical observation. Such find-ings highlight the need for a better therapeutic alliance between patients and their healthcare team.

To determine why nonadherence is so common, Choi and colleagues2 surveyed 26 dermatologists and 50 patients. Nearly two-thirds of the dermatologists reported that they spent only 5 to 10 minutes during the first psoriasis treatment consultation. No physician surveyed spent more than 20 minutes, and 54% asked about adherence only 20% of the time during follow-up visits.2 Patients surveyed said that dermatologists should spend more time explaining their therapy. Approximately one-third did not understand how to use the medications they were prescribed; nearly one-third of patients mistakenly thought the agents would improve their psoriasis in 1 to 2 weeks. More than half (54%) cited lack of efficacy as the chief reason for discontinuing a medica-tion.2 Clinicians face numerous time constraints, but they need to set patients’ expectations about the agents they prescribe. Some of the solutions that patients suggested in this survey are surprisingly simple and include establishing patient support groups, providing education about the incurable nature of psoriasis, and selecting the appropriate agents to align with patients’ preferences.2

A multinational study of 213 patients with psoriasis concluded that patient preferences on topical vehicles are diverse.3 Half of the patients in the study preferred the fixed combination of calci-potriol 50 µg/g and betamethasone 0.5 mg/g gel, while the others favored the same formulation in a foam.3 Both the gel and the foam were also compared with the latest topical treatment (LTT), which patients tended not to prefer if the LTT was an ointment or cream. Patients who preferred the foam said the primary reason was its sensation of immediate relief, while gel users cited the ease of application as the main reason for choosing that vehicle. Clinicians should take the attributes of topical agents into consid-eration when choosing a therapy for an individual patient: Is it odorless? Does it stain? Does it apply smoothly?

■ AbstractApproximately 30% of patients with moderate plaque psoriasis and 20% of those with severe psoriasis have inadequate disease control with their current therapeutic regimens. Among the factors that affect treatment efficacy are drug selection and lack of patient adherence to treatment, which is often due to patient frustration that psoriasis is a chronic, multisystemic, and incurable disease. By forming a strong therapeutic alliance with patients and by asking them about their expectations for treatment, clinicians have a better chance of providing patients with more effective and durable relief from their psoriasis symptoms.Semin Cutan Med Surg 37(supp2):S53-S56 © 2018 published by Frontline Medical Communications

■ Keywords Adherence; biologics; combination therapy; systemic agents; topical agents

Practical Strategies for Optimizing Management of PsoriasisJashin J. Wu, MD,* April W. Armstrong, MD, MPH,† Kenneth B. Gordon, MD,‡ and M. Alan Menter, MD§

* Director of Dermatology Research, Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California


‡ Professor and Chair, Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin

§ Chairman, Division of Dermatology, Baylor University Medical Center, Dallas, Texas


Jashin J. Wu, MD, Contracted Research: AbbVie Inc., Amgen Inc., Eli Lilly and Company, Janssen Biotech, Inc., Novartis Pharmaceuticals Corporation, Regeneron.April W. Armstrong, MD, MPH, Consultant: AbbVie Inc., Amgen Inc., Eli Lilly and Company, Janssen Biotech, Inc., Modernizing Medicine, Novartis Pharmaceuticals Corporation, Regeneron, Sanofi. Speakers Bureau: AbbVie Inc., Eli Lilly and Company, Janssen Biotech, Inc. Kenneth B. Gordon, MD, Consultant: AbbVie Inc., Amgen Inc., Almirall, S.A., Boehringer Ingelheim, Bristol Myers-Squibb Company, Celgene Corporation, Dermira, Inc., Eli Lilly and Company, LEO Pharma Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Sun Pharmaceutical Industries Ltd., UCB, Inc. Investigator: AbbVie Inc., Boehringer Ingelheim, Celgene Corporation, Novartis Pharmaceuticals Corporation.M. Alan Menter, MD, Advisory Board: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Boehringer Ingelheim, Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC. Consultant: AbbVie Inc., Afecta Pharmaceuticals, Inc., Amgen Inc., Avillion LLP, Boehringer Ingelheim, Eli Lilly and Company, Galderma S.A., Janssen Biotech, Inc., LEO Pharma Inc., Menlo Therapeutics Inc., Novartis Pharmaceuticals Corporation, Ortho Dermatologics, Pfizer Inc., Promius Pharma, LLC. Investigator: AbbVie Inc., Amgen Inc., Boehringer Ingelheim, Celgene Corporation, Dermira, Inc., Eli Lilly and Company, Janssen Biotech, Inc., LEO Pharma Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron. Speakers Bureau: AbbVie Inc., Amgen Inc., Janssen Biotech, Inc., LEO Pharma Inc., Ortho Dermatologics, Promius Pharma, LLC.

Address reprint requests to: Jashin J. Wu, MD, Kaiser Permanente Los Angeles Medical Center, 1515 North Vermont Avenue, 5th Floor, Los Angeles, CA 90027; [email protected]

1085-5629/13/$-see front matter © 2018 Frontline Medical Communications doi:10.12788/j.sder.2018.012

Owing to their fast-acting efficacy and less-frequent adminis-tration, biologics do not have the same adherence issues that other psoriasis therapies have.4 Chan and colleagues4 found in their study of 106 patients that adherence was nearly 100% for patients taking biologics; adherence rates for oral therapy, phototherapy, and topical therapy were 96%, 93%, and 75%, respectively. Patient-reported attributes that adversely affected adherence included smoking, being busy, and feeling annoyed about their therapy.4

Another study (N=200) reported similar findings. Patients with moderate to severe psoriasis preferred biologics, but they differed in the attributes they preferred in therapy: treatment location, efficacy, and probability of adverse effects.5 Not surprisingly, patients who were employed preferred therapies that offered rapid efficacy, that were convenient, and that required infrequent admin-istration. Older patients in the study were most concerned about adverse effects but were less concerned about efficacy. Overall, more men than women rated efficacy as the most important attribute of a biologic.5 The results underscore the importance of asking patients what they value most in therapy, eg, rapid results, convenience, risk of adverse effects, or site of treatment (at home or in a clinic).

Once patients and clinicians establish a preferred treatment plan, clinicians should provide patients with written instructions and should set their expectations. It is critical to explain how soon they are likely to see results, what the potential side effects of the regimen are, and when to alert the clinician about adverse events. Patients also need to be aware if clinicians are using off-label dosing, because instructions that differ from product labeling may be confusing.

Combining Topical and Systemic AgentsAside from patient preferences, treatment decisions are based on disease severity, comorbidities, and symptoms.6 For patients who are adherent, topical therapies might suffice for mild to moderate psoriasis. Approximately 30% of patients with moderate and 20% of those with severe plaque psoriasis do not have adequate disease control with their current therapeutic regimens because they are receiving only topical therapy when they need more potent drugs.6

For patients whose initial monotherapy is proving less effec-tive than predicted, clinicians often consider the use of multiple topical agents or combinations of systemic and topical agents.6 Combination therapy can provide more rapid efficacy and has the advantage of reducing the dosage of individual agents, thus decreasing the risk for toxicity.7 Whereas patients with moderate to severe psoriasis need systemic agents or biologics, some might also require localized symptom relief for intractable lesions.8

The evidence on combination therapies is scant, but there have been some notable trials. The 16-week BELIEVE trial, which examined the efficacy of the tumor necrosis factor (TNF)–alpha inhibitor adalimumab (ADA) and topical calcipotriol/betametha-sone (C/B), found that for the first 4 weeks, combination therapy appeared to be more effective than adalimumab monotherapy (40.7% vs 32.4%, respectively, at week 4 [P=0.021]).9 At week 16, however, adalimumab monotherapy was slightly better than the combination biologic and topical therapy (64.8% for ADA + C/B vs 70.9% for ADA monotherapy [P=0.086]).9

A frequently used combination therapy, again with scant evidence available to support it, is topical calcipotriol/betamethasone and methotrexate.8 When topical agents are used concurrently as rescue therapy for the face or intertriginous regions in long-term studies of biologics or systemic therapies, their efficacy data are often omitted.8

Besides the combinations of systemic agents or biologics plus topical treatments, many topical agents are themselves combined or are used as adjuncts to phototherapy.8 Evidence is still needed to demonstrate whether synergistic effects of the topical agents might decrease the need for extended periods of phototherapy.8

In a systematic review of 66 combination therapies for plaque psoriasis, an overwhelming majority of studies favored combina-tion therapy vs monotherapy.10 The meta-analysis also found that combining topical therapies, such as vitamin A and D derivatives, was more effective than topical monotherapy. Although it may be common practice, adding a topical agent to a phototherapy regimen did not significantly contribute to plaque clearance.10

Fixed-dose combination topical therapies are also widely used because certain formulations are thought to provide complemen-tary effects on psoriasis plaques.11 Corticosteroids and vitamin D analogues, for example, provide different mechanisms of action that help to clear the lesions. Corticosteroids inhibit inflamma-tion and T-cell activation, and vitamin D analogues reduce the hyperproliferation of keratinocytes and provide homeostasis in the skin.11 The combination therapy allows for less-frequent

■ TABLE 1 Drugs and Other Substances That Induce or Exacerbate Psoriasis

Drug Class Substances and Other Triggers

• Antimalarials13

• Beta-blockers13

• Lithium13

• Nonsteroidal anti-inflammatory agents13

• Tetracyclines13

• Alcohol17

• Tobacco17

• Ultraviolet radiation14

Sources: Basavaraj KH, et al13; Wolf P, et al.14

■ ■ ■ Practical Strategies for Optimizing Management of Psoriasis


Mitigating Risks Associated With Psoriasis TreatmentHarm reduction should be a consideration when devising a treatment plan because some therapies need to be monitored more closely than others.

Biologics have warnings about the risk of infection. For example, patients taking biologics should be checked at least annually for tuberculosis with an interferon-gamma release assay or tuberculin skin test (purified protein derivative [PPD]) and other screenings for infections that are specifically mentioned in the label. For example, TNF inhibitors have a boxed warning about lymphoma.

Cumulative toxicity is rare with a biologic, but clinicians must be alert for patients who travel to areas in which tuberculosis, hepatitis C, or hepatitis B are endemic. If patients develop an infection, they need to know when they should call their physician.

A thorough history will help uncover any comorbid depression, a frequently occurring illness with psoriasis and one that is critical to identify before initiating treatment with the phosphodiesterase-4 inhibitor apremilast and the interleukin (IL)-17 inhibitor brodalumab, which both carry warnings about the potential for suicidal behavior.30,31 If in doubt about patients’ psychiatric status, a referral to a psychiatrist to assess their readiness for psoriasis treatment may be appropriate.32

When using phototherapy in conjunction with systemic agents, avoid the combination of cyclosporine and phototherapy, particularly psoralen ultraviolet A (PUVA), because that combination can increase the risk of skin cancers.6

Patients on methotrexate should take folic acid to reduce adverse effects, such as nausea and vomiting. Asking patients at every visit about their use of any concomitant medications can help avoid potential interactions that increase the risk for methotrexate side effects.33 Regular creatinine checks are also essential in patients with poor renal function. Methotrexate has been associated with malignant lymphoma and its label carries a boxed warning.6


Jashin J. Wu, MD, April W. Armstrong, MD, MPH, Kenneth B. Gordon, MD, and M. Alan Menter, MD

dosing of corticosteroids, which can lead to skin atrophy after long-term use. In a three-arm multicenter study, the combination calcipotriol/betamethasone dipropionate foam was significantly more effective in clearing plaques than were the individual topical agents after 4 weeks of treatment (P<0.001).11

Combination therapy with a systemic agent plus topical agents can also significantly improve quality of life because topical medications can quickly soothe painful, itchy lesions before the systemic agent can take effect. In a study of 114 patients, Psoriasis Area and Severity Index (PASI) and Psoriasis Disability Index (PDI) scores improved with the systemic agents cyclosporine or methotrexate plus topical clobetasol propionate (0.05%) + salicylic acid (3%) lotion for the scalp and betamethasone valerate (0.05%) cream for the body.12 The mean quality-of-life scores, as measured by the PDI, were 0.56 ± 0.18 for the topical-only group, 6.53 ± 0.46 for the methotrexate + topical group, and 7.18 ± 0.47 for the cyclosporine + topical group (P<0.001). PASI scores were also statistically significant between the topical monotherapy and combination therapy groups (P<0.001).12

When biologics show a loss of effect, adding methotrexate can boost their efficacy and reduce the anti-drug antibodies against the biologic.7 In a multinational registry of patients with psoriasis taking biologics, methotrexate was the most frequently used add-on agent. When methotrexate is added to biologics, the 1-year drug survival rate (how long a patient remains on a drug) is similar among the biologics: etanercept, adalimumab, inflix-imab, and ustekinumab with methotrexate had ranges of 43% to 92%, 28% to 83%, 65% to 87%, and 53% to 77%, respectively.7 No one biologic was superior to the others when paired with metho-trexate. Other therapies used as adjunctive agents with biologics, as recorded in the registries, include acitretin and cyclosporine, with methotrexate having the longest drug survival vs the other agents (103, 78, and 34 months, respectively).7

Treatment Considerations— Polypharmacy, Drug InteractionsPatients with psoriasis frequently have comorbidities that must be treated with other drugs, which can complicate treatment (Table 1).13,14 Before initiating treatment and during follow-up visits, clinicians need to take a thorough history to uncover poten-tial drug interactions.

Fortunately, biologics—the mainstays of psoriasis therapy—are relatively free of interactions. The biologics and methotrexate have a favorable risk/benefit profile. Combination therapy allows clini-cians to avoid higher doses of any single agent, which can reduce the risk of toxicity. In a meta-analysis of 41 randomized controlled trials (N=20,561 patients with moderate to severe psoriasis), meth-otrexate and the biologics adalimumab, etanercept, infliximab, ixekizumab, secukinumab, and ustekinumab were examined for efficacy relative to their tolerability.15 Although all the biologics significantly achieved PASI 75 and improved DLQI vs placebo at 12 to 16 weeks, ixekizumab and infliximab were less well-tolerated than the other biologics tested because of serious adverse effects leading to patient withdrawals. Of the agents tested, etanercept and methotrexate were deemed moderately efficacious compared with the other agents in the study.15

Before the introduction of biologics, most patients with moderate to severe psoriasis were treated with the systemic agents metho-trexate, acitretin, and cyclosporine.16 Although not as potent as biologics, these systemic drugs had documented serious adverse effects. Long-term use of methotrexate was linked to immu-nosuppression, bone marrow suppression, and hepatoxicity.16 Cyclosporine use was associated with hypertension, immunosup-pression, and nephrotoxicity.16 Acitretin use is thought to cause dyslipidemia, cheilitis, and hair loss. Unlike the biologics, the systemic agents each have several drug interactions (Table 2).17,18

In an effort to reduce the risk of hepatotoxicity while maintaining efficacy, acitretin and methotrexate were tested individually and in combination in 39 patients with plaque psoriasis.19 As measured by PASI 50 and 75 and DLQI, combination therapy was more effica-cious than were the individual acitretin and methotrexate regimens or placebo. Although there were no differences in lesion clearance among the actively treated groups, the combination group had lower histopathologic severity scores than did the individual agent groups. Combination therapy also reduced the risk for liver fibrosis compared with methotrexate alone.19

Infections are common in patients taking biologics. Tuberculosis, hepatitis B, hepatitis C, and postoperative infections are among the most prevalent in patients with psoriasis (see “Mitigating Risks Associated With Psoriasis Treatment” on page S54).6

■ TABLE 2 Methotrexate, Cyclosporine, and Acitretin Drug Interactions

Methotrexate Interactions17

Cyclosporine Interactions17

Acitretin Interactions18

• Acitretin• Adapalene• Azathioprine• Bexarotene• Chloramphenicol• Cyclosporine• Etretinate• Isotretinoin• Nonsteroidal

anti-inflammatory drugs

• Penicillins • Phenylbutazone• Phenytoin• Retinol• Salicylates • Sulfonamides• Tetracyclines• Theophylline• Trimethoprim

• Allopurinol• Amiodarone• Amphotericin• Bromocriptine• Cimetidine• Clarithromycin• Colchicine• Danazol• Diclofenac• Digoxin• Diltiazem• Erythromycin• Fluconazole• Gentamicin• HIV medications• Itraconazole• Ketoconazole• Lovastatin• Melphalan• Methotrexate• Methylprednisolone• Metoclopramide• Naproxen• Nicardipine• Nonsteroidal

anti-inflammatory drugs

• Potassium-sparing diuretics

• Prednisolone or rifabutin

• Quinupristin/ dalfopristin

• Ranitidine• Sulindac• Tacrolimus• Tobramycin• Trimethoprim• Vancomycin• Verapamil

• Alcohol• Corticosteroids• Cyclosporine• Glibenclamide/

glyburide• Methotrexate• Minocycline• Oral antidiabetic

agents• Phenytoin• Progestogen

contraceptives (in mini-doses)

• Tetracyclines• Vitamin A

(>4,000- 5,000 IU/d)

Sources: Saurat JH, et al17; Carretero G, et al.18

VaccinesIdeally, patients starting therapy for psoriasis should be up to date on their vaccinations.20 However, their treatment for psoriasis should not be delayed. In the case of hepatitis B, which requires a series of three vaccinations within a 6-month window, delaying psoriasis treatment could do more harm than good. Clinicians also need to be cautious about vaccinating with live vaccines when patients are on biologics because the immunomodulatory effects could leave patients vulnerable to infection.20

Treating the Whole PatientPsoriasis is a multisystemic disease, and different patients will perceive their illness differently. What some patients may deem a treatment success may be seen by others as a total failure. To some patients, a BSA of <1% could render them inconsolable if the remaining lesions are on their face or in an uncomfortable inter-triginous or genital region.

Clinicians are well advised to ask patients what they expect from their treatment and to determine their chief complaints: Is the itching so unbearable that they are losing sleep? What therapies have failed them before? Will comorbidities such as psoriatic arthritis drive the choice of therapy toward biologics? Do they not want pills? Do they not want injections?

Other factors to consider include the patient’s age, weight, and pregnancy status. Children have fewer therapy options because methotrexate, cyclosporine, and acitretin do not have specific pedi-atric indications for plaque psoriasis.21-23 Several of the biologics, such as etanercept and ustekinumab, have been proved safe and effective in pediatric populations and are approved for pediatric psoriasis by the US Food and Drug Administration (FDA).24,25 Although some biologics such as adalimumab and infliximab have been approved for juvenile idiopathic arthritis in children as young as 2 years of age and for pediatric Crohn disease, they have not been approved for pediatric plaque psoriasis.26,27

In the real world, frequent off-label prescribing occurs. Bronckers and colleagues24 conducted a retrospective review of children (N=390; mean age, 8.4 years) with moderate to severe psoriasis. Methotrexate was the most commonly used medica-tion (69.2%), followed by biologic agents (mostly etanercept) (27.2%), acitretin (14.6%), and cyclosporine (7.7%). Nearly one in five patients received more than one medication. Of children who were prescribed methotrexate monotherapy, 48% experienced more than one adverse event. Folic acid taken six to seven times per week appeared to alleviate the adverse effects, though there is no consensus on pediatric dosing.24 Combination treatment, while providing rapid relief to teens and young adults who may be more self-conscious than older patients, could expose young patients to greater toxicity than monotherapy.6

Women of childbearing potential or those who are lactating need special consideration when designing a treatment plan for psoriasis. Methotrexate and retinoids like acitretin and tazarotene are terato-genic.6 Biologics are in pregnancy category B (no adequate controlled studies exist in pregnant women and no animal studies have shown risk to the fetus) and cyclosporine is in category C (animal reproductive studies have shown harm to the fetus and no adequate human studies exist).6,* If a woman needs a medication that poses a risk for teratoge-nicity, she must use two forms of contraception and continue them for 2 years after discontinuing the toxic therapy.6 As a possible alternative to systemic agents or biologics, phototherapy has yet to record birth defects in women who received such treatment during pregnancy.29

ConclusionMaintaining adherence to a psoriasis regimen starts with a strong therapeutic alliance: individualizing treatment, providing effective education and counseling, setting expectations, and closely following up with the patient. Because psoriasis is a disease with potentially profound detrimental effects on quality of life, one-size-fits-all measures of efficacy, such as PASI, may not fully capture the extent of patients’ symptom severity. Clinicians need to consider conve-nience, lifestyle, location of psoriatic lesions, and comorbidities when tailoring a treatment plan.

References1. Alinia H, Moradi Tuchayi S, Smith JA, et al. Long-term adherence to topical psoriasis

treatment can be abysmal: A 1-year randomized intervention study using objective elec-tronic adherence monitoring. Br J Dermatol. 2017;176:759-764.

2. Choi CW, Kim BR, Ohn J, Youn SW. The advantage of cyclosporine A and methotrexate rotational therapy in long-term systemic treatment for chronic plaque psoriasis in a real world practice. Ann Dermatol. 2017;29:55-60.

3. Hong CH, Papp KA, Lophaven KW, Skallerup P, Philipp S. Patients with psoriasis have different preferences for topical therapy, highlighting the importance of individualized treatment approaches: Randomized phase IIIb PSO-INSIGHTFUL study. J Eur Acad Dermatol Venereol. 2017;31:1876-1883.

4. Chan SA, Hussain F, Lawson LG, Ormerod AD. Factors affecting adherence to treatment of psoriasis: Comparing biologic therapy to other modalities. J Dermatolog Treat. 2013;24:64-69.

5. Kromer C, Schaarschmidt ML, Schmieder A, Herr R, Goerdt S, Peitsch WK. Patient pref-erences for treatment of psoriasis with biologicals: A discrete choice experiment. PLoS One. 2015;10:e0129120.

6. Young M, Aldredge L, Parker P. Psoriasis for the primary care practitioner. J Am Assoc Nurse Pract. 2017;29:157-178.

7. Busard CI, Cohen AD, Wolf P, et al. Biologics combined with conventional systemic agents or phototherapy for the treatment of psoriasis: Real-life data from PSONET registries [published online October 17, 2017 ]. J Eur Acad Dermatol Venereol. doi:10.1111/jdv.14583.

8. Wu JJ, Lynde CW, Kleyn CE. Identification of key research needs for topical therapy treat-ment of psoriasis – a consensus paper by the International Psoriasis Council. J Eur Acad Dermatol Venereol. 2016;30:1115-1119.

9. Thaçi D, Ortonne JP, Chimenti S, et al. A phase IIIb, multicentre, randomized, double-blind, vehicle-controlled study of the efficacy and safety of adalimumab with and without calcipotriol/betamethasone topical treatment in patients with moderate to severe psoriasis: The BELIEVE study. Br J Dermatol. 2010;163:402-411.

10. Bailey EE, Ference EH, Alikhan A, Hession MT, Armstrong AW. Combination treatments for psoriasis: A systematic review and meta-analysis. Arch Dermatol. 2012;148:511-522.

11. Segaert S, Shear NH, Chiricozzi A, et al. Optimizing anti-inflammatory and immunomodu-latory effects of corticosteroid and vitamin D analogue fixed-dose combination therapy. Dermatol Ther (Heidelb). 2017;7:265-279.

12. Karamata VV, Gandhi AM, Patel PP, Sutaria A, Desai MK. A study of the use of drugs in patients suffering from psoriasis and their impact on quality of life. Indian J Pharmacol. 2017;49:84-88.

13. Basavaraj KH, Ashok NM, Rashmi R, Praveen TK. The role of drugs in the induction and/or exacerbation of psoriasis. Int J Dermatol. 2010;49:1351-1361.

14. Wolf P, Weger W, Patra V, Gruber-Wackernagel A, Byrne SN. Desired response to photo-therapy vs photoaggravation in psoriasis: What makes the difference? Exp Dermatol. 2016;25:937-944.

15. Jabbar-Lopez ZK, Yiu ZZN, Ward V, et al. Quantitative evaluation of biologic therapy options for psoriasis: A systematic review and network meta-analysis. J Invest Dermatol. 2017;137:1646-1654.

16. Armstrong AW, Bagel J, Van Voorhees AS, Robertson AD, Yamauchi PS. Combining biologic therapies with other systemic treatments in psoriasis: Evidence-based, best-practice recommendations from the Medical Board of the National Psoriasis Foundation. JAMA Dermatol. 2015;151:432-438.

17. Saurat JH, Guérin A, Yu AP, et al. High prevalence of potential drug-drug interactions for psoriasis patients prescribed methotrexate or cyclosporine for psoriasis: Associated clinical and economic outcomes in real-world practice. Dermatology. 2010;220:128-137.

18. Carretero G, Ribera M, Belinchón I, et al; Psoriasis Group of the AEDV. Guidelines for the use of acitretin in psoriasis. Psoriasis Group of the Spanish Academy of Dermatology and Venereology. Actas Dermosifiliogr. 2013;104:598-616.

19. An J, Zhang D, Wu J, et al. The acitretin and methotrexate combination therapy for psoriasis vulgaris achieves higher effectiveness and less liver fibrosis. Pharmacol Res. 2017;121:158-168.

20. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psori-asis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-850.

21. Methotrexate [prescribing information]. Huntsville, AL: Dava Pharmaceuticals Inc; 2016.22. Sandimmune (cyclosporine) [prescribing information]. East Hanover, NJ: Novartis

Pharmaceuticals Corporation; 2015.23. Soriatane (acitretin) [prescribing information]. Research Triangle Park, NC: Stiefel

Laboratories Inc; 2017.24. Bronckers IMGJ, Seyger MMB, West DP, et al; for the Psoriasis Investigator Group (PsIG)

of the Pediatric Dermatology Research Alliance and the European Working Group on Pediatric Psoriasis (EWGPP). Safety of systemic agents for the treatment of pediatric psoriasis. JAMA Dermatol. 2017;153:1147-1157.

25. Enbrel (etanercept) [prescribing information]. Thousand Oaks, CA: Amgen; 2017.26. Humira (adalimumab) [prescribing information]. North Chicago, IL: AbbVie Inc; 2017.27. Remicade (infliximab) [prescribing information]. Horsham, PA: Janssen Biotech Inc; 2017. 28. US Food and Drug Administration. Pregnancy and lactation labeling (drugs) final

rule. December 3, 2014. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm. Accessed February 7, 2018.

29. Kim WB, Jerome D, Yeung J. Diagnosis and management of psoriasis. Can Fam Physician. 2017;63:278-285.

30. Otezla (apremilast) [prescribing information]. Summit, NJ: Celgene Corporation; 2017.31. Siliq (brodalumab) [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals

North America LLC; 2017.32. Wu JJ, Penfold RB, Primatesta P, et al. The risk of depression, suicidal ideation and suicide

attempt in patients with psoriasis, psoriatic arthritis or ankylosing spondylitis. J Eur Acad Dermatol Venereol. 2017;31:1168-1175.

33. Conway R, Carey JJ. Risk of liver disease in methotrexate treated patients. World J Hepatol. 2017;9:1092-1100.


■ ■ ■ Practical Strategies for Optimizing Management of Psoriasis

* As of June 2015, the FDA no longer uses pregnancy categories A, B, C, D, and X and instead requires a narrative description in the label about data or lack thereof.28


New Treatment Paradigms in Psoriasis: Understanding and Incorporating Recent and Emerging Trends Post-Test Original Release Date: March 2018 • Expiration Date: April 30, 2019 Estimated Time to Complete Activity: 2.0 hoursTo get instant CME/CE credits online, go to https://tinyurl.com/Psoriasis2018. 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].

1. What led to the discovery that psoriasis is a multisystemic disease?A. Patients’ frequent need for multiple regimens with both

topical and systemic drugsB. The significant clearance of psoriatic plaques with the

immunosuppressant cyclosporine C. The distribution of psoriasis plaques on the bodyD. The discovery of the interleukin (IL)-17 and IL-23

cytokines and the inflammatory pathway that contribute to psoriasis and its comorbidities

2. Which statement is true of biologic therapy?A. Many patients find initial treatments with them to cause

flu-like symptomsB. Biologics should not be combined with phototherapy

due to the potential for skin cancerC. It is best to rotate biologics with different mechanisms of

action before the biologic agent stops working effectivelyD. Many clinicians select biologics for patients who have

comorbidities such as psoriatic arthritis

3. What is the rationale for clearing psoriatic plaques?A. The risk for mortality increases as the body surface area

(BSA) increasesB. Clearing plaques can also alter the course of the

progression of comorbiditiesC. There is a proportionate improvement in patient quality-

of-life scores with BSA scores of <15%D. Both A and C

4. Based on a study by Gordon and colleagues, approximately how long does it take to determine whether a patient will respond to methotrexate?A. 4 weeksB. 16 weeksC. 24 weeksD. 30 weeks

5. Which statement is true of psoriatic arthritis?A. It manifests frequently in people aged ≥60 years B. The Psoriasis Epidemiology Screening Tool (PEST) can

distinguish between signs and clinical symptoms of psoriatic arthritis and those of osteoarthritis

C. Psoriatic arthritis commonly affects more than 65% of patients with plaque psoriasis

D. Psoriatic arthritis onset commonly peaks in children 11 to 12 years old

6. Which of the psoriasis comorbidities is not yet supported by a dose-response relationship?A. DiabetesB. CancerC. Overweight/obesityD. Metabolic syndrome

7. Which lifestyle choices are the most damaging for patients with plaque psoriasis?A. Sedentary lifestyleB. Lack of sleepC. Sun exposureD. Alcohol and smoking

8. Which psychiatric disorder does not have an association with psoriasis?A. Obsessive-compulsive disorderB. DepressionC. AnxietyD. Suicidal ideation

9. Which statement is true regarding adherence to antipsoriasis regimens?A. Topical agents have the greatest drug survival rate of all

the regimens, including phototherapyB. Phototherapy has a longer drug survival rate than the

IL-17 biologicsC. Biologics do not have the same adherence issues as do

topical agentsD. Patients taking combination regimens tend to be more

adherent than those on monotherapy

10. In women of childbearing potential, which agent(s) should be avoided?A. BiologicsB. RetinoidsC. ApremilastD. Cyclosporine

Questions: For each question or incomplete statement, choose the answer or completion that is correct. Circle the most appropriate response.

The University of Louisville, Postgraduate Institute for Medicine, and Global Academy for Medical Education thank you for your

participation in this CME/CE activity. All information provided improves the scope and purpose of our programs and your patients’ care.

FOR REVIEW PURPOSES ONLY. MUST BE COMPLETED ONLINE.

Please indicate your profession/background: (check one) MD/DO MSN/BSN/RN PA APN/NP PharmD/RPh Resident/Fellow Researcher Administrator Student

Other; specify ____________________________________________________

New Treatment Paradigms in Psoriasis: Understanding and Incorporating Recent and Emerging Trends Evaluation Form

Original Release Date: March 2018 • Expiration Date: April 30, 2019 • Estimated Time to Complete Activity: 2.0 hours

To assist us in evaluating the effectiveness of this activity and to make recommendations for future educational offerings, please take a few moments to complete this evaluation form. Your response will help ensure that future programs are informative and meet the educational needs of all participants. This page is for your reference only. CME/CE credit letters and long-term credit retention information will only be issued upon completion of the post-test and evaluation online at: https://tinyurl.com/Psoriasis2018.

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

Based on the content of this activity, what will you do differently in the care of your patients/regarding your professional responsibilities? (check one)

Implement a change in my practice/workplace. Seek additional information on this topic.Do nothing differently. Current practice/job responsibilities reflect activity recommendations.Do nothing differently as the content was not convincing. Do nothing differently. System barriers prevent me from changing my practice/workplace.

If you anticipate changing one or more aspects of your practice/professional responsibilities as a result of your participation in this activity, please briefly describe how you plan to do so.________________________________________________________________________________________________________________________

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If you are not able to effectively implement what you learned in this activity, please tell us what the system barriers are (eg, institutional systems, lack of resources, etc)?________________________________________________________________________________________________________________________

What topics do you want to hear more about, and what issue(s) regarding your practice/professional responsibilities will they address?________________________________________________________________________________________________________________________

Please provide additional comments pertaining to this activity and any suggestions for improvement.________________________________________________________________________________________________________________________

OVERALL EVALUATION Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree

The information presented increased my awareness/understanding of the subject. 5 4 3 2 1

The information presented will influence how I practice/do my job. 5 4 3 2 1

The information presented will help me improve patient care/my job performance. 5 4 3 2 1

The program was educationally sound and scientifically balanced. 5 4 3 2 1

Overall, the program met my expectations. 5 4 3 2 1

I would recommend this program to my colleagues. 5 4 3 2 1

April W. Armstrong, MD, MPHAuthor demonstrated current knowledge of the topic. 5 4 3 2 1

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

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


M. Alan Menter, MDAuthor demonstrated current knowledge of the topic. 5 4 3 2 1


Jashin J. Wu, MDAuthor demonstrated current knowledge of the topic. 5 4 3 2 1


© 2018 Global Academy for Medical Education, LLC. All Rights Reserved.

The University of Louisville, Postgraduate Institute for Medicine, and Global Academy for Medical Education thank you for your participation in this CME/CE activity. All information provided improves the scope and purpose of our programs and your patients’ care.

LEARNING OBJECTIVES: Having completed this activity, you are better able to: Strongly Agree Agree Somewhat Agree Disagree Strongly Disagree

Explain the etiology and pathophysiology of psoriasis and its common comorbidities. 5 4 3 2 1

Diagnose and treat patients with psoriasis using treat-to-target guidelines. 5 4 3 2 1

Select appropriate biologic therapies for patients with psoriasis. 5 4 3 2 1

FOR REVIEW PURPOSES ONLY. MUST BE COMPLETED ONLINE.

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