Atopic Dermatitis by Integritas Communications

Date of Release: July 1, 2017 Date of Credit Expiration: July 1, 2018

This activity is jointly provided by Global Education Group and Integritas Communications. This activity is supported by an educational grant from Genzyme, a Sanofi Company, and Regeneron Pharmaceuticals.

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TABLE OF CONTENTS Faculty iv Preamble vi Chapter 1 The Causes and Consequences of Atopic Dermatitis

Jeffrey M. Weinberg, MD

Chapter 2 Evaluating Patients with 7 Moderate-to-Severe Atopic Dermatitis Robert E. Kalb, MD

Chapter 3 Current and Emerging Therapies for Atopic Dermatitis

Jeffrey M. Weinberg, MD

Chapter 4 Individualizing Maintenance Therapy for Moderate-to-Severe Atopic Dermatitis

Jeffrey M. Weinberg, MD

Chapter 5 Educating Patients and Improving Adherence

Robert E. Kalb, MD

Clinical Resource Centerâ&#x201E;˘

Supplemental Video Library 43

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ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

FACULTY Robert E. Kalb, MD Clinical Professor, Department of Dermatology SUNY at Buffalo School of Medicine and Biomedical Sciences Buffalo Medical Group, P.C. Buffalo, New York

Dr. Robert E. Kalb is a Clinical Professor of Dermatology at the State University of New York at Buffalo Jacobs School of Medicine and Biomedical Sciences, where his extensive teaching responsibilities include coordinating the fourth-year medical student dermatology rotation and working with dermatology and family medicine residents on a daily basis. He also chairs the dermatology department in private practice with the Buffalo Medical Group in Buffalo, New York. Dr. Kalb obtained his medical degree cum laude from Downstate Health Science Center in Brooklyn, New York, in 1982 and then completed his residency in dermatology at the College of Physicians and Surgeons at Columbia University in New York. Dr. Kalb has conducted numerous clinical trials investigating possible new treatments for psoriasis and other skin disorders. An invited lecturer at local, national, and international meetings, he has authored more than 60 articles in peerreviewed journals.

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FACULTY

Jeffrey M. Weinberg, MD Associate Clinical Professor of Dermatology Icahn School of Medicine at Mount Sinai New York, New York Director, Division of Dermatology Jamaica Hospital Medical Center Richmond Hill, New York

Dr. Jeffrey M. Weinberg is an associate clinical professor of dermatology at the Mount Sinai School of Medicine in New York City. In addition, he is acting director of the Division of Dermatology at Jamaica Hospital Medical Center. Dr. Weinberg graduated from the University of Pennsylvania School of Medicine in Philadelphia and completed an internship in medicine at Columbia-Presbyterian Medical Center in New York City. He then completed a residency in dermatology at the University of Pennsylvania School of Medicine. Dr. Weinberg is a Fellow of the American Academy of Dermatology, where he has served on several committees, and a member of the Dermatology Foundation. He is a diplomate of the American Board of Dermatology. Dr. Weinberg is on the editorial board and is a Senior Editor of Cutis. He is also an Associate Editor of the Journal of the American Academy of Dermatology. He is a member of the Medical Board of the National Psoriasis Foundation. His clinical research encompasses a variety of dermatology-related topics, including studies of diagnostic methods in the evaluation of onychomycosis. He has been principal or co-investigator for several clinical trials. In addition, he has written or co-authored numerous articles for professional journals such as Cutis, the Journal of the American Academy of Dermatology, and Blood, as well as reviews, book chapters, and abstracts.

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ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

PREAMBLE Target Audience The educational design of this activity addresses the needs of dermatologists, allergists/clinical immunologists, and other clinicians involved in the ongoing management of patients with moderate-to-severe atopic dermatitis.

Educational Objectives After completing this activity, the participant should be better able to: • Discuss atopic dermatitis pathophysiology, focusing on clinically relevant disease mechanisms, risk factors, and novel therapeutic targets • Comprehensively assess patients with atopic dermatitis to determine symptom severity, characterize potential phenotypes, identify comorbidities, and document treatment responses • Describe the clinical profiles of current and emerging biologic therapies for moderate-to-severe atopic dermatitis • Individualize therapy for moderate-to-severe atopic dermatitis to prevent outbreaks, maximize health-related quality of life, manage comorbidities, and minimize treatment-related adverse effects • Communicate with patients and, when necessary, caregivers to improve their understanding of atopic dermatitis and secondary complications, while facilitating shared decision-making

Statement of Need/Program Overview Atopic dermatitis is a chronic inflammatory condition with manifestations in the skin and in other organ systems throughout the body.1 Increasing in prevalence over the last 2 decades, the disease places tremendous burdens on patients, caregivers, and other family members.1,2 Our evolving understanding of disease pathophysiology and widespread effects on patient health and quality of life highlight the need for prompt diagnosis and proactive management.3,4 Moreover, research into the mechanisms underlying atopic dermatitis pathogenesis and progression has led to new approaches for disease characterization and treatment.5,6 The goal of this eHealth Source™ activity is to educate clinicians on atopic dermatitis pathoetiology, best practices in patient evaluations, and the clinical profiles of treatment options for moderate-to-severe disease, including a biologic therapy recently approved by the US Food and Drug Administration (FDA). With the overall goal of improving outcomes for patients with moderate-to-severe atopic dermatitis, this educational activity integrates published clinical data and the experience of expert faculty to provide actionable recommendations on individualizing care and improving patient-clinician communication.

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PREAMBLE

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References

1. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015:66(suppl 1):8-16. 2. Drucker AM, et al. The burden of atopic dermatitis: summary of a report for the National Eczema Association. J Invest Dermatol. 2017;137(1):26-30. 3. Eichenfield LF, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351. 4. Sidbury R, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71(2):327-349. 5. Ungar B, et al. An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease. J Invest Dermatol. 2017;137(3):603-613. 6. Simpson EL, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348.

Physician Accreditation Statement 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 Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation Global Education Group designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Global Contact Information For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

Instructions to Receive Credit In order to receive credit, participants must complete the preactivity questionnaire, postactivity questionnaire, and program evaluation at www.exchangecme.com/ ADeHealth. Participants must also score at least 70% on the posttest.

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ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

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System Requirements PC

MAC

• Microsoft Windows 2000 SE or above. • Flash Player Plugin (v7.0.1.9 or greater) • Internet Explorer (v5.5 or greater), or Firefox • Adobe Acrobat Reader

• MAC OS 10.2.8 • Flash Player Plugin (v7.0.1.9 or greater) • Safari • Adobe Acrobat Reader • Internet Explorer is not supported on the Macintosh

Fee Information & Refund/Cancellation Policy There is no fee for this educational activity.

Disclosure of Conflicts of Interest Global Education Group (Global) requires instructors, planners, managers, and other individuals and their spouses/life partners who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The faculty reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Robert E. Kalb, MD Grant/Research Support: AbbVie Inc., Amgen Inc., Boehringer-Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., LEO Pharma Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Inc.; Honoraria: AbbVie Inc., Dermira, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sun Pharmaceutical Industries Ltd. Jeffrey M. Weinberg, MD Grant/Research Support: Regeneron Pharmaceuticals, Inc. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Kara Kaufman

Nothing to disclose

Ashley Marostica, RN, MSN

Nothing to disclose

Andrea Funk

Nothing to disclose

Laura Gilsdorf

Nothing to disclose

Jim Kappler, PhD

Nothing to disclose

Rose O’Connor, PhD

Nothing to disclose

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PREAMBLE

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global Education Group (Global) and Integritas Communications do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturerâ&#x20AC;&#x2122;s product information, and comparison with recommendations of other authorities.

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ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

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CHAPTER 1

Causes and Consequences of Atopic Dermatitis Jeffrey M. Weinberg, MD

topic dermatitis is an increasingly common, chronic inflammatory disease that affects up to 20% of children and 10% of adults in the United States.1,2 Diagnostic manifestations of this remittingrelapsing dermatitis include pruritus and eczema, which commonly are accompanied by xerosis, edema, or erythema.3 Patients with moderateto-severe disease—estimated to be as many as 30% of cases—face particularly deleterious consequences, including markedly low healthrelated quality of life, high levels of psychological distress, and increased prevalence of a number of psychiatric diseases.4-9 Unfortunately, despite daily therapy, many of these individuals continue to suffer from diseaserelated burdens. For example, most patients with moderate-to-severe atopic dermatitis report daily itching, significant pain and/or discomfort, and disrupted sleep on most nights (Figure 1).10,11 Other disease-related issues relate to common atopic comorbidities (eg, asthma, allergic rhinitis,

Itch Frequency

86% reported itch occurring every day

Itch Duration

42% reported itch lasting ≥18 hours/day

Itch Severity

61% reported “severe” or “unbearable” itch

Pain/Discomfort

77% reported “moderate” or “extreme” pain or discomfort

Sleep Disturbances

55% reported sleep disturbances ≥5 nights/week

FIGURE 1. Patient-reported burdens of moderate-tosevere atopic dermatitis.10,11

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ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

food allergies), increased cardiovascular risk (eg, central obesity, elevated systolic blood pressure), and direct and indirect economic burdens (see link to supplementary VIDEO 1).12,13 To manage heterogeneous disease presentations and take advantage of a changing treatment landscape, clinicians need to be conversant about key pathophysiologic processes in atopic dermatitis development, recommended parameters for patient evaluations, and the efficacy and safety of available treatment options.

OUTSIDE-IN vs INSIDE-OUT PATHOETIOLOGY in ATOPIC DERMATITIS Although the pathogenesis of atopic dermatitis has not been completely elucidated, complex interactions among defects in the skin barrier, dysregulated immune responses, and environmental factors are known to play prominent roles (Figure 2).14 Strong genetic contributions were first detailed in observational studies showing that parents of patients with atopic dermatitis often have a history of the disease and concordance rates are higher for monozygotic twins compared with dizygotic twins.15

Abnormal skin barrier

Increased antigen entry

LC activation Decreased ceramide, filaggrin, and AMPs

T-cell activation Release of proinflammatory mediators ď&#x192;ŠTh2 cell inflammation

FIGURE 2. Pathogenic processes in atopic dermatitis.14 AMP, antimicrobial peptides; LC, Langerhans cells; Th2, T helper 2.

CHAPTER 1 Causes and Consequences of Atopic Dermatitis

Subsequent analyses have identified numerous genetic loci that raise the risk of atopic dermatitis development.16 Two different—but not mutually exclusive—models have been proposed to describe the initial events that lead to atopic dermatitis. In the “outside-in” hypothesis, the disease results from skin barrier defects and increased transcutaneous penetration by allergens and microbes, leading to hyperactive immunologic responses.17,18 Other evidence supports an “inside-out” model, in which atopic dermatitis is primarily initiated by dysregulated cutaneous immune and inflammatory processes, which in turn cause a breakdown of the skin barrier.17,18 The “outside-in” model is supported by the identification of deactivating polymorphisms in the filaggrin gene in some patients.19 The structural protein encoded by this gene binds keratin filaments into dense bundles at the boundary between the granular layer and stratum corneum, and serves as a proteolytic precursor to natural moisturizing factor components that help maintain adequate skin hydration.20-23 In various studies, 20% of patients with atopic dermatitis and up to 50% of those with severe disease produce a truncated form of filaggrin.19,24 Other potentially causative factors in the skin include deficiencies in ceramides (waxy lipid molecules that are the primary component of the stratum corneum) and cathelicidins (antimicrobial peptides found in the lysosomes of macrophages, polymorphonuclear leukocytes, and keratinocytes).21 Often exacerbated by pruritus-induced scratching and the resulting mechanical damage, these aberrations can contribute to transepidermal water loss and dermal penetration by allergens and microbes.21 A number of other studies have focused on cutaneous inflammation and dysregulated immunologic mechanisms as initial steps in the development of atopic dermatitis. For example, genetic studies have linked atopic dermatitis to polymorphisms in proinflammatory and immune-related genes, such as those encoding interleukin-4 (IL-4), IL-13, IL-4 receptor α, and cluster of differentiation 14.25 Other research has shown that filaggrin expression is reduced under inflammatory conditions, providing a potential mechanistic link between early immune dysregulation and disruption of the skin barrier.19 Additional immunologic findings include the identification of relatively high levels of cytokines produced by the T helper 2 (Th2) and Th22 subsets of T cells in both acute and chronic atopic dermatitis lesions.14,26,27 The Th2 cytokines IL-4 and IL-13 both signal in part through IL-4 receptor α on keratinocytes, fibroblasts, and other cells to promote B cell differentiation, enhance class switching to immunoglobulin E

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

antibodies, and reduce filaggrin and ceramide expression.26 IL-4 and IL-13 have also been shown to induce the expression of ß-defensins and cathelicidin, which are involved in susceptibility to such skin pathogens as Staphylococcus aureus and herpes simplex virus.14,26 Additionally, levels of IL-31—a cytokine produced by Th2 cells and mast cells that has been linked to pruritus—have been shown to correlate positively with atopic dermatitis severity.28,29 IL-31 is also an important regulator of keratinocyte differentiation and filaggrin expression.26,30 Increased expression of IL-25 and IL-33 by epithelial cells has also been detected in skin samples from affected patients, leading to downstream promotion of Th2 responses and additional effects on keratinocytes and skin barrier integrity.14 Finally, IL-22 produced by Th22 cells is thought to contribute to the transition from acute to chronic atopic dermatitis (see link to supplementary VIDEO 2).27 As the interconnected roles of various proinflammatory and immunologic mediators in atopic dermatitis development have emerged, clinical research has focused on understanding the potential benefits of inhibiting the activities of these factors in patients with atopic dermatitis. The results of these efforts have been mixed. For example, clinical trials examining biologic inhibitors of IL-5 as potential atopic dermatitis therapies have generally failed to demonstrate clear benefits.31 On the other hand, dupilumab—a monoclonal antibody designed to inhibit IL-4 and IL-13 signaling by targeting IL-4 receptor α—was recently approved by the US Food and Drug Administration for adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.32 Other targeted therapies in development include antibodies specific for IL-13, IL-22, or IL-31. In general, these targeted therapies should allow patients to benefit from treatment, while avoiding some of the more problematic side effects associated with other systemic treatment approaches, such as calcineurin inhibitors and oral corticosteroids.33,34 Additionally, welldocumented variability in atopic dermatitis severity, persistence, lesional characteristics, and comorbidities suggest that no single therapy will be the best choice for all patients with moderate-to-severe disease.14 This highlights the need for additional research to characterize potential clinical and molecular atopic dermatitis phenotypes as a foundation for the development of biomarkers and the ultimate goal of personalizing the choice of therapies across various patient cohorts.35

CHAPTER 1 Causes and Consequences of Atopic Dermatitis

KEY CLINICAL HIGHLIGHTS â&#x20AC;˘ Patients with moderate-to-severe atopic dermatitis often suffer from significant biopsychosocial and economic burdens despite treatment with commonly prescribed systemic therapies â&#x20AC;˘ Research into atopic dermatitis pathophysiology has identified potential contributions from disruptions in the skin barrier and from dysregulated cutaneous inflammatory and immunologic processes â&#x20AC;˘ New biologic therapies, including an FDA-approved inhibitor of IL-4 and IL-13 signaling, have been designed to target signaling factors that are central to atopic dermatitis development and persistence

REFERENCES 1. Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study. J Allergy Clin Immunol. 2013;132(5):1132-1138. 2. Hanifin JM, Reed ML. A population-based survey of eczema prevalence in the United States. Dermatitis. 2007;18(2): 82-91. 3. Eichenfield LF, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351. 4. Kiebert G, et al. Atopic dermatitis is associated with a decrement in health-related quality of life. Int J Dermatol. 2002;41(3):151-158. 5. Linnet J, Jemec GB. An assessment of anxiety and dermatology life quality in patients with atopic dermatitis. Br J Dermatol. 1999;140(2):268-272. 6. Howlett S. Emotional dysfunction, child-family relationships and childhood atopic dermatitis. Br J Dermatol. 1999;140(3):381-384. 7. Cheng CM, et al. Risk of developing major depressive disorder and anxiety disorders among adolescents and adults with atopic dermatitis: a nationwide longitudinal study. J Affect Disord. 2015;178:60-65. 8. Hughes JE, et al. Psychiatric symptoms in dermatology patients. Br J Psychiatry. 1983;143:51-54. 9. Carroll CL, et al. The burden of atopic dermatitis: impact on the patient, family, and society. Pediatr Dermatol. 2005;22(3):192-199. 10. Simpson EL, et al. Patient burden of moderate to severe atopic dermatitis (AD): insights from a phase 2b clinical trial of dupilumab in adults. J Am Acad Dermatol. 2016;74(3):491-498. 11. Whiteley J, et al. The burden of atopic dermatitis in U.S. adults: results from the 2013 National Health and Wellness Survey. Curr Med Res Opin. 2016:1-32. 12. Davis D. Practice Gaps. Pediatric atopic dermatitis and associated morbidities. JAMA Dermatol. 2015;151(2):152-153. 13. Silverberg JI. Health care utilization, patient costs, and access to care in US adults with eczema: a population-based study. JAMA Dermatol. 2015;151(7):743-752. 14. Peng W, Novak N. Pathogenesis of atopic dermatitis. Clin Exp Allergy. 2015;45(3):566-574. 15. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015;66 (suppl 1):8-16.

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

16. Ellinghaus D, et al. High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat Genet. 2013;45(7):808-812. 17. Silverberg NB, Silverberg JI. Inside out or outside in: does atopic dermatitis disrupt barrier function or does disruption of barrier function trigger atopic dermatitis? Cutis. 2015;96(6):359-361. 18. Guttman-Yassky E, et al. Contrasting pathogenesis of atopic dermatitis and psoriasis--part I: clinical and pathologic concepts. J Allergy Clin Immunol. 2011;127(5):1110-1118. 19. Brown SJ, Irvine AD. Atopic eczema and the filaggrin story. Semin Cutan Med Surg. 2008;27(2):128-137. 20. Lopes C, et al. Filaggrin polymorphism Pro478Ser is associated with the severity of atopic dermatitis and colonization by Staphylococcal aureus. J Investig Allergol Clin Immunol. 2016;26(1):70-72. 21. Watson W, Kapur S. Atopic dermatitis. Allergy Asthma Clin Immunol. 2011;7 (suppl 1):S4. 22. Weidinger S, et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol. 2006;118(1):214-219. 23. Harding CR, et al. Filaggrin - revisited. Int J Cosmet Sci 2013;35(5):412-423. 24. Sandilands A, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet. 2007;39(5):650-654. 25. Hanifin JM. Evolving concepts of pathogenesis in atopic dermatitis and other eczemas. J Invest Dermatol. 2009;129(2):320-322. 26. Gandhi NA, et al. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15(1): 35-50. 27. Eyerich K, Eyerich S. Th22 cells in allergic disease. Allergo J Int. 2015;24(1):1-7. 28. Hawro T, et al. Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge. Allergy. 2014;69(1):113-117. 29. Ezzat MH, et al. Serum measurement of interleukin-31 (IL-31) in paediatric atopic dermatitis: elevated levels correlate with severity scoring. J Eur Acad Dermatol Venereol. 2011;25(3):334-339. 30. Cornelissen C, et al. IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J Allergy Clin Immunol. 2012;129(2):426-33,433 e1-8. 31. Kuek A, et al. Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad Med J. 2007;83(978):251-260. 32. Dupilumab [prescribing information]. Initial US approval 2017. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; March 2017. 33. Naesens M, et al. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009;4(2):481-508. 34. Manson SC, et al. The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use. Respir Med. 2009;103(7):975-994. 35. Bieber T. Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy. 2012;67(12):1475-1482.

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CHAPTER 2

Evaluating Patients With Moderate-to-Severe Atopic Dermatitis Robert E. Kalb, MD

omprehensively assessing patients who may have atopic dermatitis requires clinicians to evaluate a thorough history, cutaneous manifestations, environmental triggers, other potential risk factors, comorbidities, and effects on activities of daily living and quality of life.1,2 Rather than specific laboratory testing, atopic dermatitis is diagnosed based on a complete clinical picture of the patient that considers histologic features, the morphologies and distribution patterns of skin lesions, likely clinical courses (eg, frequent flares, remission/relapse), and additional subacute, acute, and chronic manifestations.1 Acute and subacute atopic dermatitis is often characterized by intense pruritus at erythematous papulovesicular lesions with excoriation and serous exudate, whereas chronic atopic dermatitis commonly manifests as lichenification, papules, and excoriations.2 A number of other disorders need to be excluded in the differential, including scabies, contact dermatitis (irritant or allergic), and psoriasis.1 Various groups have published criteria to help clinicians identify affected patients. For example, a working group from the American Academy of Dermatology (AAD) has recommended a list of essential, important, and associated features that should be considered in the diagnosis of atopic dermatitis (Table 1).1,3 Among the features listed as important by the AAD, family medical history can help identify at-risk individuals so patients should be queried. Studies have shown that up to 70% of patients with atopic dermatitis have a family history of atopic disease.4 In fact, having a parent who has received a diagnosis of an atopic disease can double or triple the likelihood of developing atopic dermatitis, a risk that further increases if both parents have a positive history.5,6 In addition to family atopic patterns, several other phenotypic characteristics should be considered as predictive of disease course and severity.7 For example, moderate-to-severe forms of atopic dermatitis often manifest in Download this activity and additional tools at

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

TABLE 1. Features to Be Considered in the Diagnosis of Atopic Dermatitis1,3 Essential Features: Must be present • Pruritus • Eczema (acute, subacute, chronic) –– Typical morphology and age-specific patterns • Facial, neck, or extensor involvement in infants and children • Current or prior flexural lesions in any age group • Sparing of groin and axillary regions

–– Chronic or relapsing history

Important Features: Seen in most cases, adding support to the diagnosis • Early age of onset • Atopy –– Personal and/or family history –– lgE reactivity

• Xerosis

Associated Features: These clinical associations are suggestive, but not indicative, of an AD diagnosis • Atypical vascular responses (eg, facial pallor, white dermographism, delayed blanch response) • Keratosis pilaris/pityriasis alba/hyperlinear palms/ichthyosis • Ocular/periorbital changes • Other regional findings (eg, perioral changes/ periauricular lesions) • Perifollicular accentuation/lichenification/prurigo lesions IgE, immunoglobulin E.

patients with untreated early-onset disease, whereas immunoglobulin E (IgE) sensitization is somewhat less frequent in female patients with late-onset disease.7,8 Individuals with early-onset disease also appear to be at increased risk for an “atopic march” to asthma, allergic rhinitis, and/or rhinoconjunctivitis, each of which affects a sizable population of

CHAPTER 2 Evaluating Patients with Moderate-to-Severe Atopic Dermatitis

patients with atopic dermatitis.7 Studies have shown that a fifth and a third of patients with atopic dermatitis have comorbid asthma and hay fever, respectively (Figure 1). Importantly, patients with severe, widespread disease and concomitant atopic conditions are at risk for poorer health outcomes.7,8 Thus, identifying these comorbid conditions or known risk factors is an important step in the selection of the preferred treatment approach for each patient.

Children With Atopic Disease During the Prior Year, %

40 35

No atopic dermatitis Atopic dermatitis

34.4

30 25

19.8

20 15 10

7.9 3.6

5 0

15.1

14.3

Asthma

Hay Fever

Food Allergy

Patients with severe AD were more likely to have asthma, severe allergic rhinitis, and/or food allergies.

FIGURE 1. Presence of other atopic diseases with atopic dermatitis.9 N=91,642 children aged 0 to 17 years who completed the 2007 National Survey of Childrenâ&#x20AC;&#x2122;s Health regarding the presence of atopic diseases in the prior 12 months.

IDENTIFYING ATOPIC and NONATOPIC TRIGGERS Food sensitization and allergy should be considered in all patients, as the latter has been linked to more severe phenotypes, including those associated with earlier disease onset and increased persistence.10 Although no laboratory or biomarker tests are required to diagnose atopic dermatitis or evaluate disease severity, IgE testing can help identify important triggers for some patients.1,2 Universal IgE is not

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

recommended, however, in part because allergen-specific IgE is a relatively nonspecific marker, with elevated levels identified in more than half of the general population in the United States.11 The National Institute of Allergy and Infectious Diseases and the AAD jointly recommend that clinicians consider limited testing for food and environmental allergens if (1) moderate-to-severe atopic dermatitis persists despite optimized management and topical therapies, and/or (2) the patient reports a history of an immediate allergic reaction to a specific food.12,13 Patients should also be screened for nonspecific and nonatopic triggers, some of which have been found to create greater diseaserelated issues than many allergy-related factors. Examples include body soaps, laundry products, rough fabrics or tight-fitting clothing, airborne irritants, and variations in temperature and humidity (see supplementary link to VIDEO 3).14 Identification of patient-specific triggers and appropriate avoidance measures can lengthen the intervals between symptomatic flares.

ASSESSING CLINICAL OUTCOMES in PATIENTS WITH DIAGNOSED ATOPIC DERMATITIS The AAD’s clinical practice guidelines, published in 2014, recommend that clinicians evaluate patients for the frequency and severity of itch, psychosocial effects, and persistence of disease.1 The AAD highlights patients’ self-assessment of pruritus as absolutely critical because itching has been repeatedly documented as a central contributor to disease morbidity.15,16 Although the pathophysiologic mechanisms that underlie atopic dermatitis–related pruritus remain an active area of research, multiple studies have shown that itch intensity is inversely correlated with patients’ quality of life.1,17,18 In addition, sleep disturbance is a symptom often underappreciated by providers.19 Some evidence has suggested sleep quality as a proxy measure of overall disease severity especially in children, but results obtained using a variety of sleep assessment instruments have not consistently correlated.19 Even so, all patients (and parents of affected children) should be specifically asked about sleep problems and their relationship to pruritus. Various clinical assessment tools have been developed to measure disease severity and serve as clinical trial endpoints. The most commonly used instruments include the Eczema Area and Severity Index (EASI), Investigator’s Global Assessment (IGA), Scoring Atopic Dermatitis

CHAPTER 2 Evaluating Patients with Moderate-to-Severe Atopic Dermatitis

(SCORAD), and Patient-Oriented Eczema Measure (POEM) severity scale.20-22 These instruments, however, were not developed and are not recommended for routine use in community-based practices.1 The same is generally true for the multitude of scales designed to evaluate quality of life and other psychological outcomes in patients with atopic dermatitis.1,23 Nevertheless, understanding the items included in these tools can help clinicians interpret newly published evidence and shape their evaluations of patients with moderate-to-severe disease. A selection of these tools may be found in the clinical resource center for this activity at www.ExchangeCME.com/ADResources.

NONATOPIC COMORBIDITIES ASSOCIATED WITH ATOPIC DERMATITIS While there is an understandable focus on atopic comorbidities, a growing body of evidence has linked a number of nonatopic comorbid conditions with atopic dermatitis, including infectious, malignant, neuropsychiatric, cardiovascular, and cardiometabolic diseases.24 For instance, patients may be at increased risk for a number of extracutaneous infections (eg, streptococcal pharyngitis, upper and lower respiratory infections), warts, and infective endocarditis.24-26 Several studies have found higher rates of attention-deficit/hyperactivity disorder among children with atopic dermatitis, with research underway to further elucidate this potential association.27 Increased risks of depression, anxiety, and suicidal ideation have all been reported in cohorts with atopic dermatitis.28 Although a relationship between atopic dermatitis and cancers has not been clearly documented, some preliminary evidence suggests an increased incidence of lymphoma (but not leukemia or pancreatic, brain, and kidney cancers).29-31 Studies have also detailed a trend toward higher body mass index, central adiposity, and systolic hypertension.32,33 In fact, major adverse cardiovascular events (eg, myocardial infarction, stroke, and cardiovascular-related death) are more common in patients with severe atopic dermatitis, although the underlying mechanisms are not well understood.34,35 There is evidence, however, that systemic inflammatory signaling cascades involving cytokines, adipocytes, and other dysregulated immune processes likely contribute. Taken together, these data underscore the importance of screening patients with atopic dermatitis for nonatopic comorbid conditions and providing appropriate specialist referrals, especially since many patients may not regularly see other health care providers for longitudinal care.33,36

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

KEY CLINICAL HIGHLIGHTS • Recognizing clinical symptoms of atopic dermatitis and accurately differentiating them from the cutaneous features of other conditions is paramount • A comprehensive understanding of pruritus, sleep disturbances, and their effects on patient function and quality of life is essential to shape ongoing management plans • Patients should be specifically assessed for atopic and nonatopic comorbidities to guide treatment decisions for atopic dermatitis and the need for additional referrals

REFERENCES 1. Eichenfield LF, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351. 2. Schneider L, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol. 2013;131(2):295-299.e1-27. 3. Eichenfield LF, et al. Consensus conference on pediatric atopic dermatitis. J Am Acad Dermatol. 2003;49(6):1088-1095. 4. Wen HJ, et al. Predicting risk for early infantile atopic dermatitis by hereditary and environmental factors. Br J Dermatol. 2009;161(5):1166-1172. 5. Kuster W, et al. A family study of atopic dermatitis. Clinical and genetic characteristics of 188 patients and 2,151 family members. Arch Dermatol Res. 1990;282(2):98-102. 6. Wadonda-Kabondo N, et al. Association of parental eczema, hayfever, and asthma with atopic dermatitis in infancy: birth cohort study. Arch Dis Child. 2004;89(10):917-921. 7. Bieber T. Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy. 2012;67(12):1475-1482. 8. Watson W, Kapur S. Atopic dermatitis. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S4. 9. Silverberg JI, Simpson EL. Association between severe eczema in children and multiple comorbid conditions and increased healthcare utilization. Pediatr Allergy Immunol. 2013;24(5):476-486. 10. Tsakok T, et al. Does atopic dermatitis cause food allergy? A systematic review. J Allergy Clin Immunol. 2016;137(4):1071-1078. 11. Arbes SJ Jr, et al. Prevalences of positive skin test responses to 10 common allergens in the US population: results from the third National Health and Nutrition Examination Survey. J Allergy Clin Immunol. 2005;116(2):377-383. 12. Sidbury R, et al. Guidelines of care for the management of atopic dermatitis: Section 4. Prevention of disease flares and use of adjunctive therapies and approaches. J Am Acad Dermatol. 2014;71(6):1218-1233. 13. Boyce JA, et al. Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored expert panel report. J Allergy Clin Immunol. 2010;126(6):1105-1118. 14. Eichenfield LF, et al. Translating atopic dermatitis management guidelines into practice for primary care providers. Pediatrics. 2015;136(3): 554-565. 15. Dawn A, et al. Itch characteristics in atopic dermatitis: results of a web-based questionnaire. Br J Dermatol. 2009;160(3):642-624.

CHAPTER 2 Evaluating Patients with Moderate-to-Severe Atopic Dermatitis

16. Hon KL, et al. Does age or gender influence quality of life in children with atopic dermatitis? Clin Exp Dermatol. 2008;33(6):705-709. 17. Lewis-Jones S. Quality of life and childhood atopic dermatitis: the misery of living with childhood eczema. Int J Clin Pract. 2006;60(8):984-992. 18. Weisshaar E, et al. Itch intensity evaluated in the German Atopic Dermatitis Intervention Study (GADIS): correlations with quality of life, coping behaviour and SCORAD severity in 823 children. Acta Derm-Venereol. 2008;88(3):234-239. 19. Kong TS, et al. Correlation between severity of atopic dermatitis and sleep quality in children and adults. Ann Dermatol. 2016;28(3):321-326. 20. Hanifin JM, et al. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 2001;10(1):11-18. 21. Futamura M, et al. A systematic review of Investigator Global Assessment (IGA) in atopic dermatitis (AD) trials: Many options, no standards. J Am Acad Dermatol. 2016;74(2):288-294. 22. Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31. 23. Rehal B, Armstrong AW. Health outcome measures in atopic dermatitis: a systematic review of trends in disease severity and quality-of-life instruments 1985-2010. PLoS One. 2011;6(4):e17520. 24. Brunner PM, et al. Increasing comorbidities suggest that atopic dermatitis is a systemic disorder. J Invest Dermatol. 2017;137(1):18-25. 25. Patel D, Jahnke MN. Serious complications from Staphylococcal aureus in atopic dermatitis. Pediatr Dermatol. 2015;32(6):792-796. 26. Fukunaga N, et al. Pay attention to valvular disease in the presence of atopic dermatitis. Circ J. 2013;77(7):1862-1866. 27. Strom MA, et al. Association between atopic dermatitis and attention deficit hyperactivity disorder in U.S. children and adults. Br J Dermatol. 2016;175(5):920-929. 28. Kelsay K, et al. Addressing psychosocial aspects of atopic dermatitis. Immunol Allergy Clin North Am. 2010;30(3):385-396. 29. Deckert S, et al. Nonallergic comorbidities of atopic eczema: an overview of systematic reviews. Allergy. 2014;69(1):37-45. 30. Arellano FM, et al. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol. 2007;127(4):808-816. 31. Arellano FM, et al. Lymphoma among patients with atopic dermatitis and/or treated with topical immunosuppressants in the United Kingdom. J Allergy Clin Immunol. 2009;123(5):1111-1116, 116.e1-13. 32. Zhang A, Silverberg JI. Association of atopic dermatitis with being overweight and obese: a systematic review and metaanalysis. J Am Acad Dermatol. 2015;72(4):606-616.e4. 33. Silverberg JI, et al. Central obesity and high blood pressure in pediatric patients with atopic dermatitis. JAMA Dermatol. 2015;151(2):144-152. 34. Hjuler KF, et al. Increased prevalence of coronary artery disease in severe psoriasis and severe atopic dermatitis. Am J Med. 2015;128(12):1325-1334.e2. 35. Andersen YM, et al. Risk of myocardial infarction, ischemic stroke, and cardiovascular death in patients with atopic dermatitis. J Allergy Clin Immunol. 2016;138(1):310-312.e3.. 36. Davis D. Practice gaps. Pediatric atopic dermatitis and associated morbidities. JAMA Dermatol. 2015;151(2):152-153.

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

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CHAPTER 3

Current and Emerging Therapies for Atopic Dermatitis Jeffrey M. Weinberg, MD

omprehensive care for patients with moderate-to-severe atopic dermatitis should focus on preventing outbreaks, addressing comorbidities and secondary complications, and minimizing treatmentrelated adverse events.1,2 All patients should be counseled on the fundamentals of atopic dermatitis management, including proper skin care with moisturizers, warm baths or showers using mild soaps or nonsoap cleansers, antiseptic measures (eg, occasional baths with diluted bleach), and avoidance of known triggers.3 Many patients will also need medications to control symptoms and prevent disease flares.4 Atopic dermatitis is most often managed with topical therapies, including moisturizers, emollients, corticosteroids, calcineurin inhibitors, and other therapies detailed in Table 1.4 Clinicians should be aware of strengths, limitations, and prescribing recommendations for the various options within each of the topical classes. For example, in 2014 clinical practice guidelines from the American Academy of Dermatology (AAD), dozens of topical corticosteroids were categorized into 7 potency classes from “Very High Potency” to “Lowest Potency” based on vasoconstriction assays.4 During problematic acute flares, a higher- or medium-potency formulation may be the best option to gain control of symptoms, whereas the least-potent yet effective corticosteroid is generally recommended for long-term management to minimize treatment-related risks (see link to supplementary VIDEO 4).4 A relatively new addition to the topical armamentarium is the phosphodiesterase 4 inhibitor crisaborole.5 Crisaborole 2% ointment was approved by the US Food and Drug Administration (FDA) in late 2016 for the treatment of mild-to-moderate atopic dermatitis in patients ≥2 years of age.6

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ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

TABLE 1. Treatment Options for Atopic Dermatitis4 Over-the-Counter Options

Topical Agents

Systemic Therapies

Bathing practices and oils

Antimicrobials/ antiseptics

Antihistamines

Emollients

Antihistamines

Antimicrobials

Moisturizers

Calcineurin inhibitors

Dupilumab

Corticosteroids

Immunomodulatory agents

Crisaborole

Azathioprine Cyclosporine Corticosteroids Calcineurin inhibitors Interferon gamma Methotrexate Mycophenolate mofetil Other less frequently used agents

TRADITIONAL SYSTEMIC THERAPIES for ATOPIC DERMATITIS When topical treatments prove inadequate, as is often the case in moderate-to-severe atopic dermatitis, clinicians are faced with deciding how best to individualize step-up therapy based on symptoms and patient preferences. Phototherapy is widely recommended as a second-line option for patients who have failed to respond adequately to such topical agents as corticosteroids and calcineurin inhibitors.1 This modality can be burdensome for patients, who may need to visit the health care providerâ&#x20AC;&#x2122;s office several times each week to maximize benefits.1 If patients are unable to receive this modality in a health care facility, it may be considered in the home setting, but should remain under the direction of a physician.1

CHAPTER 3 Current and Emerging Therapies for Atopic Dermatitis

In addition to phototherapy, a number of systemic pharmacologic therapies are available for patients who are struggling to control symptoms or prevent outbreaks with nonpharmacologic therapies.4 These systemic therapies include immunomodulatory agents, antimicrobials, antihistamines, and a new FDA-approved biologic therapy, dupilumab.4 Although many of the more traditional systemic approaches are included in clinical practice guidelines, there is a paucity of high-level evidence for the relative efficacy and safety of these medication classes or individual agents within classes. Similarly, strong evidence is scant concerning dosing levels or treatment durations most likely to maximize benefits, and adverse events are frequently cited as reasons for treatment discontinuation.1 The published evidence for these traditional therapeutic options generally comes from short-term trials and includes little follow-up data to assess their risk-benefit profiles in ongoing maintenance regimens for patients with moderate-to-severe disease.7 Therefore, clinicians need to have a good understanding of the clinical profiles of these agents and remain vigilant about risks for adverse events, particularly when patients need to use them for extended periods (see Chapter 4). Moreover, even when evidencebased, severity-stratified guidelines are applied appropriately, notable interindividual variability in patient responses leaves a sizable percentage of patients with inadequately controlled disease.8 Thus, there is a significant need for new treatmentsâ&#x20AC;&#x201D;ideally targeted therapies that optimize efficacy and reduce risks for serious side effects.

NEWER TARGETED THERAPIES for MODERATE-to-SEVERE ATOPIC DERMATITIS The development of targeted medications, including biologics, holds great promise for patients with difficult-to-control atopic dermatitis. Proof-of-concept for these types of therapies have been shown in several other chronic inflammatory and immune-related disorders.9 Key signaling pathways involved in the immune dysfunction and cutaneous inflammation that contribute to atopic dermatitis pathophysiology continue to be characterized, revealing new treatment targets. The first targeted biologic therapy to receive approval from the FDA is dupilumab, a fully human monoclonal antibody that binds to the Îą subunit of the interleukin (IL)-4 receptor, thereby inhibiting signaling by both IL-4 and IL-13.10 Research has shown that IL-4 and IL-13 are T helper type 2 (Th2) cytokines that play a number of roles in atopic dermatitis development and persistence (see Chapter 1).10,11 Early

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

research demonstrated that skin samples from dupilumab-treated patients showed downregulated epidermal proliferation markers, upregulated expression of genes involved in skin-barrier function, and suppressed expression of genes related to the activation of T cells and associated inflammatory pathways.12 These histologic and biochemical results have also paralleled improvements in clinical trial endpoints for disease severity and other symptoms.12,13 Initial clinical studies showed impressive efficacy with no major safety concerns, prompting the FDA to designate dupilumab as a breakthrough drug, thereby allowing fast-track development.10 Larger randomized controlled trials also demonstrated the efficacy of dupilumab in patients with moderateto-severe atopic dermatitis. In two phase 3 clinical trials that included almost 1500 adults, dupilumab was superior to placebo at week 16 for a number of primary and key secondary endpoints.13 Treatment with dupilumab was associated with an improvement in disease severity as assessed by both Investigator’s Global Assessment (IGA) and Eczema Area and Severity Index (EASI) scores (Figure 1), disease-associated pruritus, anxiety and depression, and overall quality of life.13 Moreover, dupilumab has an acceptable safety profile. Injection-site reactions and conjunctivitis were the most notable adverse effects reported more frequently in both dupilumab treatment arms compared with placebo in both phase 3 studies (see link to supplementary VIDEO 5).13 In March 2017, the FDA approved dupilumab as the first biologic therapy for the treatment of moderate-to-severe atopic dermatitis in adult patients whose disease is not adequately controlled with topical prescription therapies or in whom those therapies are not advisable.14 Additional phase 3 trials are underway to assess the long-term efficacy and safety profiles of this drug, outcomes in children and adolescents with atopic dermatitis, and clinical effects in other atopic diseases, such as asthma. A number of other targeted therapies are in various stages of clinical development. For example, lebrikizumab and tralokinumab—monoclonal antibodies specific for the IL-13 cytokine—have produced positive results in phase 2 clinical trials.15,16 Another biologic, nemolizumab, is an anti–IL-31 receptor A monoclonal antibody that interferes with signaling by IL-31, a cytokine expressed by Th2 cells, keratinocytes, and mast cells in response to antimicrobial peptides.17 Research suggests that IL-31 increases epidermal basal-cell proliferation and thickening of the epidermal skin layer, resulting in transepidermal water loss.17,18 Several anti-IL-22 agents are also under investigation in early-mid phase clinical studies.17

CHAPTER 3 Current and Emerging Therapies for Atopic Dermatitis

Patients Achieving Primary Endpoint Based on IGA Score, %a

19 60

Placebo Dupilumab Q2W Dupilumab QW

50 38

30 20

10 0

n=224 n=224 n=223

n=236 n=233 n=239

SOLO 1

SOLO 2

Patients With EASI-75, %a

40 30 20

10 0

n=224 n=224 n=223

n=236 n=233 n=239

SOLO 1

SOLO 2

Primary Endpoint: IGA score at week 16 of 0 (clear) or 1 (almost clear) and ≥2-point reduction from baseline

FIGURE 1: Phase 3 data for the anti–IL-4 receptor α dupilumab in adult patients with atopic dermatitis.13 a

P<0.001 for all comparisons of dupilumab vs placebo.

EASI-75, improvement from baseline of ≥75% on the EASI; IGA, Investigator’s Global Assessment; IL-4Rα, IL-4 receptor α; QW, every week; Q2W, every two weeks. Patients ≥18 years of age with moderate-to-severe atopic dermatitis inadequately controlled with topical therapy were randomized to dupilumab 300 mg QW, dupilumab 300 mg Q2W, or placebo for 16 weeks (dupilumab-treated patients received a 600-mg loading dose on day 1).

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

Other targeted approaches to atopic dermatitis therapy include inhibition of the JAK/STAT pathway and κ-opioid receptor agonism.19-21 Baricitinib is a JAK1/JAK2 inhibitor that is in mid-to-late-stage clinical development as a therapy for various inflammatory and autoimmune diseases, including rheumatoid arthritis, psoriasis, and atopic dermatitis.19 Baricitinib’s oral, once-daily dosing would offer an alternative mode of administration for a targeted agent should this agent receive FDA-approval for atopic dermatitis in the future.15 Asimadoline is a κ-opioid receptor-specific agonist currently in phase 2 trials for treatment of pruritus associated with a broad spectrum of conditions, including atopic dermatitis.15,20 Clearly, expanding knowledge of atopic dermatitis pathogenesis has promoted the development of many new targeted therapies in various stages of clinical investigation, including the first biologic therapy FDA-approved for moderate-to-severe atopic dermatitis. Clinicians need to become familiar with the efficacy and safety profiles of dupilumab and begin to identify which patients are good candidates for this therapy (see Chapter 4). Moreover, clinicians will be increasingly tasked with staying abreast of the latest clinical study results, recommendations for patient selection, protocols for pretreatment screening, and strategies for ongoing surveillance of efficacy and safety.

KEY CLINICAL HIGHLIGHTS • Managing atopic dermatitis begins with trigger avoidance, nonprescription modalities, and often topical medications • Many traditional systemic approaches have little supportive high-level clinical trial data, and their use is often limited by side effects • A number of novel targeted systemic therapies are under development, including dupilumab, the first biologic medication approved by the FDA for moderate-to-severe atopic dermatitis

REFERENCES 1. Sidbury R, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71(2):327-349. 2. Sidbury R, et al. Guidelines of care for the management of atopic dermatitis: Section 4. Prevention of disease flares and use of adjunctive therapies and approaches. J Am Acad Dermatol. 2014;71(6):1218-1233.

CHAPTER 3 Initiating Intrathecal Therapy for Severe Chronic Pain

3. Eichenfield LF, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351. 4. Eichenfield LF, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116-132. 5. Paller AS, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494-503.e4. 6. US Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/index. cfm. Accessed May 1, 2017. 7. Roekevisch E, et al. Efficacy and safety of systemic treatments for moderate-to-severe atopic dermatitis: a systematic review. J Allergy Clin Immunol. 2014;133(2):429-438. 8. Montes-Torres A, et al. Biological treatments in atopic dermatitis. J Clin Med. 2015;4(4):593-613. 9. Kuek A, et al. Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad Med J. 2007;83(978):251-260. 10. Thaci D, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2016;387(10013):40-52. 11. Beck LA, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371(2):130-139. 12. Hamilton JD, et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2014;134(6):1293-1300. 13. Simpson EL, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348. 14. Dupilumab [prescribing information]. Initial US approval 2017. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; March 2017. 15. National Institutes of Health. https://clinicaltrials.gov. Accessed May 1, 2017. 16. Popovic B, et al. Structural characterisation reveals mechanism of IL-13-neutralising monoclonal antibody tralokinumab as inhibition of binding to IL-13Rα1 and IL-13Rα2. J Mol Biol. 2017;429(2):208-219. 17. Ruzicka T, et al. Anti-interleukin-31 receptor A antibody for atopic dermatitis. N Engl J Med. 2017;376(9):826-835. 18. Singh B, et al. IL-31-driven skin remodeling involves epidermal cell proliferation and thickening that lead to impaired skin-barrier function. PLoS One. 2016;11(8):e0161877. 19. Shreberk-Hassidim R, et al. Janus kinase inhibitors in dermatology: a systematic review. J Am Acad Dermatol. 2017;76(4):745-753. 20. Cowan A, et al. Targeting itch with ligands selective for κ opioid receptors. Handb Exp Pharmacol. 2015;226:291-314. 21. Lou H, et al. Expression of IL-22 in the skin causes Th2-biased immunity, epidermal barrier dysfunction, and pruritus via stimulating epithelial Th2 cytokines and the GRP pathway. J Immunol. 2017;198(7):2543-2555.

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

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CHAPTER 4

Individualizing Maintenance Therapy for Moderate-to-Severe Atopic Dermatitis Jeffrey M. Weinberg, MD

o prevent flares and improve psychosocial outcomes for moderateto-severe atopic dermatitis, management recommendations should be personalized based on disease severity, comorbid conditions, treatment responses, and patient preferences. As discussed previously, all patients with atopic dermatitis should be counseled on bathing practices, moisturizer and emollient use, and trigger avoidance.1 Bathing in water can help hydrate the skin and remove scales, crust, irritants, and allergens that may be present.1,2 However, failing to quickly apply moisturizer allows water to evaporate from the skin after a bath and can increase transepidermal water loss and precipitate associated symptoms (see link to supplementary VIDEO 6).1,3 Although there is no strong evidence about the optimal bath frequency or duration, Joint Task Force (JTF) practice parameters from the American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma & Immunology state that baths should last for at least 10 minutes.4 JTF practice parameters and the 2014 American Academy of Dermatology (AAD) clinical practice guidelines also emphasize the importance of applying moisturizers soon after bathing to retain skin hydration.1,4 Furthermore, bleach baths as often as several times per week may be beneficial for patients with moderate-to-severe disease who experience frequent bacterial infections.1 During particularly problematic flares, AAD and JFT guidelines both note the potential benefits of wet-wrap therapy (with or without a topical corticosteroid) to reduce water loss and improve symptoms in patients with moderateto-severe disease.1,4 There are risks, however, including the potential for folliculitis, skin maceration, and secondary infections when wet wraps are used for prolonged periods.4 Clinicians also need to dialogue with their patients to identify disease triggers (eg, food, other allergens, environmental irritants, temperature changes) and develop strategies that lessen patientsâ&#x20AC;&#x2122; exposure to those triggers (Table 1).5-8 Despite Download this activity and additional tools at

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

these efforts and good adherence to topical regimens, some patients with atopic dermatitis will continue to experience frequent outbreaks and the associated psychological burdens, social isolation, and lost work/school productivity.9 In these cases, clinicians should stratify patients based on disease severity and functional/quality of life effects as a guide to weighing the potential benefits and risks of stepping up to systemic therapies.

TABLE 1. Common Triggers for Atopic Dermatitis Flares5-8 • Exposure to food or other allergens –– Dust mites

• Environmental exposures –– Chemical irritants –– Temperature/humidity

• Body soaps or laundry products • Wool or tight-fitting clothing • Stress

ADDRESSING COMORBID CONDITIONS Patients with comorbid conditions can be difficult to treat. In fact, national guidelines emphasize that individuals with moderate-tosevere disease and multiple comorbidities should be referred to atopic dermatitis specialists, who can coordinate integrated, multidisciplinary care.4,10 Epidemiologic analyses have demonstrated strong relationships between atopic dermatitis and other atopic conditions (eg, rhinitis, asthma, and allergies), a consequence of substantial overlap in the genetic factors and pathophysiologic mechanisms underlying these disorders.11-13 On the other hand, emerging evidence suggesting associations with cardiovascular, neuropsychiatric, and malignant diseases may reflect, in part, systemic effects of atopic dermatitis.11-13 AAD guidelines recommend that physicians educate patients and caregivers about these potential relationships as a component of ongoing management plans.14 Comorbidities should also play a role as clinicians individualize therapy. For instance, if systemic agents are required, providers can consider

CHAPTER 4 Individualizing Maintenance Therapy for Moderate-to-Severe Atopic Dermatitis

evidence for efficacy and safety both in atopic dermatitis and, if possible, in the comorbid condition as well. This recommendation may be especially useful for patients with multiple atopic disorders, in whom appropriate treatment choices can be used to target shared pathophysiologic processes. As an example, several T helper 2 (Th2) cytokines (eg, interleukin [IL]-4, IL-5, IL-13) play immunopathologic roles in atopic dermatitis, asthma, and rhinitis. Therapies targeting these signaling pathways could theoretically improve more than 1 of these disorders in a single patient. Although no single targeted agent is approved by the US Food and Drug Administration (FDA) for all of these atopic conditions, some biologics (but not all) have produced positive clinical trial results for more than one of these conditions.15,16 Similarly, if specific allergens are identified as flare and/or exacerbation triggers for more than 1 atopic disease, clinicians may want to consider whether sublingual or injectionbased allergen immunotherapy is appropriate to desensitize patients in the context of their overall atopy.17 Of note, however, there is need for additional evidence from well-designed clinical trials using standardized methodologies to better understand the strengths and weakness of this modality for individual and co-occurring atopic diseases.17 Management plans should also account for nonatopic comorbidities, with varying degrees of evidence suggesting patients are at increased risk for cardiovascular disease, major depression, and anxiety disorders, among others.11-13 Properly treating these disorders is essential not only to overall patient health, but often specifically to control of atopic dermatitis. For example, unaddressed major depressive disorder will likely interfere with patients’ adherence to self-management recommendations and medication use. Comprehensive management of the “whole patient” is essential, and may require referrals and open communication with primary care providers, especially if that provider is serving as the patient’s medical home.

CONSIDERING DISEASE PHENOTYPES Although atopic dermatitis is a single clinical diagnosis, research over the last 2 decades has characterized multiple potential etiologies and underlying mechanistic processes, some of which may be identifiable clinically based on age at disease onset, symptom severity, demographic factors, biomarker testing, triggers, and treatment responses.18 As in many other areas of medicine, efforts are underway to detail various atopic dermatitis phenotypes with the goal of better predicting

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

disease courses and personalizing therapy for each patient. There is also considerable interest in defining endotypes—ie, phenotypic descriptions that have been matched to underlying pathophysiologic mechanisms—which will help improve clinical study designs and develop targeted mechanism-based therapies for particular cohorts.18 Among the disease’s most common incarnations is early-onset atopic dermatitis, which develops within the first 2 years of life in >60% of affected children. As many as two thirds of these children will experience remission by 11 years of age, although recurrences in adolescence and early adulthood are possible.19 Developing atopic dermatitis in early childhood appears to increase the potential for an “atopic march” to asthma and/or rhinitis.20,21 Additionally, moderateto-severe cases in adult patients often begin as suboptimally treated early-onset disease.22,23 Clinicians should consider these findings when managing older patients who first developed atopic dermatitis very early in life, including implications for risk-benefit analyses related to systemic therapies. Late-onset atopic dermatitis, on the other hand, mainly affects women and is associated with less immunoglobulin E (IgE) sensitization, suggesting that these patients may benefit from different therapeutic strategies.23 Other studies have classified atopic dermatitis cases as extrinsic vs intrinsic disease (80% vs 20% of patients, respectively).24 Patients with extrinsic atopic dermatitis have high overall serum levels of IgE, antibodies specific for food or airborne allergens, and often a personal or family atopic history.25 Treatment choices for patients with extrinsic disease should therefore reflect the key atopic mechanisms in these patients, including Th2 cell-driven processes.26 Conversely, patients with intrinsic disease often have total IgE levels within normal ranges, no other atopic diseases, and lower rates of filaggrin mutations.27 Intrinsic disease has also been tied to higher levels of Th17 and Th22 cytokines, such that emerging therapies targeting those signaling axes may eventually provide the best opportunity for good outcomes (see Chapter 3).24 By classifying patients based on disease phenotypes, clinicians can personalize therapeutic regimens to reflect a growing evidence base and their past clinical experiences. This will be facilitated in the future by better defined disease biomarkers and an expanded armamentarium of targeted therapies, now including the recently approved human monoclonal antibody dupilumab.

CHAPTER 4 Individualizing Maintenance Therapy for Moderate-to-Severe Atopic Dermatitis

MONITORING TREATMENT OUTCOMES With TOPICAL and SYSTEMIC THERAPIES By definition, patients with moderate-to-severe atopic dermatitis will almost certainly require pharmacologic therapy to control their symptoms and reduce flare risk. Depending on the agents included in therapeutic regimens, clinicians need to adjust ongoing monitoring plans to account for potential treatment-related adverse events both soon after a new medication is introduced and during long-term management. For example, topical corticosteroids are generally well-tolerated and clinicians need not specifically monitor patients for systemic side effects.1 However, cutaneous adverse events may occurâ&#x20AC;&#x201D;eg, purpura, telangiectasias, striae, focal hypertrichosis, and skin atrophyâ&#x20AC;&#x201D;particularly when high potency formulations are used for extended periods.28,29 Although many of these side effects resolve quickly when the medications are discontinued, they should be proactively considered when relatively long courses of topical corticosteroids are needed.1 The most common side effects of topical calcineurin inhibitors (TCIs) include local reactions (eg, stinging, burning), although these responses generally lessen over time.30 Of note, continuous treatment of infectious lesions with TCIs has not been well studied, and AAD clinical practice guidelines recommend against using these agents when acute infections are present.1 Prescribing information sheets for TCIs also include warnings about a risk of malignancies, which primarily are a result of observations related to high-dose oral calcineurin inhibitors in post-transplant patients and animal studies.31 Even though no strong evidence specifically links TCIs to treatment-emergent malignancies, clinicians should appropriately frame these risks and warnings with patients and be diligent during ongoing monitoring.1,31 Unlike many topical agents, traditional systemic medications used to treat atopic dermatitis have side-effect profiles that frequently lead patients to discontinue treatment.32 In addition to cancer, oral calcineurin inhibitors have been linked to nephrotoxicity and arterial hypertension.33,34 The risks of oral corticosteroids are well known to physicians (and often their patients as well). Examples include hypertension, glucose intolerance, gastritis, weight gain, decreased bone density, adrenal suppression, and emotional lability.32 When extended courses of oral corticosteroids are needed, clinicians should consider prophylactic

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

treatment to combat opportunistic infections, calcium and vitamin D supplementation, and potentially re-immunizations.32 Treating atopic dermatitis with the immunosuppressive drug cyclosporine places patients at increased risks for infection, nephrotoxicity, hypertension, tremor, skin cancer, and lymphoma, all of which should be considered during ongoing monitoring.32 These potential complications helped spur research into more specific treatment options with the goal of achieving desired efficacy, minimizing off-target activity, and narrowing immunosuppressive effects to dysregulated signaling pathways that drive disease development and persistence. Based on current phase 3 studies, the risk profile of the newly FDA-approved anti-IL-4 receptor α antibody dupilumab appears to meet these criteria, although long-term safety data are not yet available.35,36 The most prominent adverse events with this subcutaneously administered agent are injection-site reactions (a common problem for injected biologics), and a less well understood safety signal for conjunctivitis; patients should be advised to report worsening eye symptoms if they develop after dupilumab is initiated.36 In summary, therapies often used to treat moderate-to-severe atopic dermatitis are associated with varying risks of adverse events. Health care providers and their patients need to partner to determine the best treatment course and balance efficacy goals with tolerable side effects. Clinical studies will continue to provide information about safety issues related to available and emerging systemic therapies, highlighting that clinicians should continue to longitudinally monitor patients and be prepared to address any potential safety concerns that arise.

KEY CLINICAL HIGHLIGHTS • Comprehensive management plans for patients with atopic dermatitis should be shaped by identifiable disease phenotypes and a full review of any atopic and nonatopic comorbidities • Using traditional systemic medications to treat moderate-tosevere atopic dermatitis requires detailed knowledge about their side-effect profiles and vigilance during ongoing patient monitoring • Newer targeted therapies are being designed to provide increased specificity with the goal of achieving good efficacy and minimizing adverse events

CHAPTER 4 Individualizing Maintenance Therapy for Moderate-to-Severe Atopic Dermatitis

REFERENCES 1. Eichenfield LF, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116-132. 2. Gutman AB, et al. Soak and smear: a standard technique revisited. Arch Dermatol. 2005;141(12):1556-1559. 3. Chiang C, Eichenfield LF. Quantitative assessment of combination bathing and moisturizing regimens on skin hydration in atopic dermatitis. Pediatr Dermatol. 2009;26(3):273-278. 4. Schneider L, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol. 2013; 131(2):295-299. 5. Forbes LR, et al. Food allergies and atopic dermatitis: differentiating myth from reality. Pediatr Ann. 2009;38(2):84-90. 6. Eichenfield LF, et al. Translating atopic dermatitis management guidelines into practice for primary care providers. Pediatrics. 2015;136(3):554-565. 7. Sidbury R, et al. Guidelines of care for the management of atopic dermatitis: Section 4. Prevention of disease flares and use of adjunctive therapies and approaches. J Am Acad Dermatol. 2014;71(6):1218-1233. 8. Wittkowski A, Richards HL. How beneficial is cognitive behaviour therapy in the treatment of atopic dermatitis? A single-case study. Psychol Health Med. 2007;12(4):445-449. 9. Whiteley J, et al. The burden of atopic dermatitis in US adults: results from the 2013 National Health and Wellness Survey. Curr Med Res Opin. 2016:32(10):1645-1651. 10. Boguniewicz M, et al. A multidisciplinary approach to evaluation and treatment of atopic dermatitis. Semin Cutan Med Surg. 2008;27(2):115-127. 11. Brunner PM, et al. Increasing comorbidities suggest that atopic dermatitis is a systemic disorder. J Invest Dermatol. 2017;137(1):18-25. 12. Muraro A, et al. Precision medicine in patients with allergic diseases: airway diseases and atopic dermatitis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2016;137(5):1347-1358. 13. Strom MA, et al. Association between atopic dermatitis and attention deficit hyperactivity disorder in U.S. children and adults. Br J Dermatol. 2016;175(5):920-929. 14. Eichenfield LF, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351. 15. Wenzel S, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting Î˛2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44. 16. Bagnasco D, et al. A critical evaluation of anti-IL-13 and anti-IL-4 strategies in severe asthma. Int Arch Allergy Immunol. 2016;170(2):122-131. 17. Eichenfield LF, et al. Current guidelines for the evaluation and management of atopic dermatitis: a comparison of the Joint Task Force Practice Parameter and American Academy of Dermatology guidelines. J Allergy Clin Immunol. 2017;139(4S):S49-S57. 18. Leung DY, Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol. 2014;134(4):769-779. 19. Williams HC, Strachan DP. The natural history of childhood eczema: observations from the British 1958 birth cohort study. Br J Dermatol 1998;139(5):834-839. 20. von Kobyletzki LB, et al. Eczema in early childhood is strongly associated with the development of asthma and rhinitis in a prospective cohort. BMC Dermatol. 2012;12:11. 21. Illi S, et al. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol. 2004;113(5):925-931. 22. Watson W, Kapur S. Atopic dermatitis. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S4. 23. Bieber T. Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy. 2012;67(12):1475-1482.

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

24. Suárez-Fariñas M, et al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol. 2013;132(2):361370. 25. Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. J Dermatol Sci. 2010;58(1):1-7. 26. Guttman-Yassky E, et al. Systemic immune mechanisms in atopic dermatitis and psoriasis with implications for treatment. Exp Dermatol. 2017. [Epub ahead of print]. 27. Kabashima-Kubo R, et al. A group of atopic dermatitis without IgE elevation or barrier impairment shows a high Th1 frequency: possible immunological state of the intrinsic type. J Dermatol Sci. 2012;67(1):37-43. 28. Callen J, et al. A systematic review of the safety of topical therapies for atopic dermatitis. Br J Dermatol. 2007;156(2):203-221. 29. Pariser D. Topical corticosteroids and topical calcineurin inhibitors in the treatment of atopic dermatitis: focus on percutaneous absorption. Am J Ther. 2009;16(3):264-273. 30. Frankel HC, Qureshi AA. Comparative effectiveness of topical calcineurin inhibitors in adult patients with atopic dermatitis. Am J Clin Dermatol. 2012;13(2):113-123. 31. Margolis DJ, et al. Association between malignancy and topical use of pimecrolimus. JAMA Dermatol. 2015;151(6):594-599. 32. Sidbury R, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71(2):327-349. 33. Hošková L, et al. Pathophysiological mechanisms of calcineurin inhibitor-induced nephrotoxicity and arterial hypertension. Physiol Res. 2017;66(2):167-180. 34. Naesens M, et al. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009;4(2):481508. 35. Simpson EL, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2017;376(11):1090-1091. 36. Dupilumab [prescribing information]. Initial US approval 2017. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; March 2017.

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CHAPTER 5

Educating Patients and Improving Adherence Robert E. Kalb, MD

stablishing trusting relationships with patients who have atopic dermatitis and, if necessary, their caregivers is essential to engage in shared decision-making and improve therapeutic outcomes. These relationships are also the foundation for ongoing dialogue aimed at activating patients to participate in long-term treatment planning, which has been shown to promote a sense of control over healthrelated challenges and increase the likelihood of favorable outcomes.1,2 Good patient-clinician partnerships are particularly important in the setting of moderate-to-severe disease, in which treatment decisions can be complex and patient education especially critical. American Academy of Dermatology (AAD) guidelines and Joint Task Force (JTF) practice parameters agree that providing patients and caregivers with evidence-based education matched to their degree of health literacy is itself an important therapeutic intervention and necessary for positive long-term outcomes.3-5 The education should explain the chronic relapsingâ&#x20AC;&#x201C;remitting nature of atopic dermatitis, underlying disease mechanisms, trigger avoidance, and skin care techniques (see link to supplementary VIDEO 7).3-5 Ideally, this information can be conveyed during multidisciplinary training programs, although national guidelines also suggest that video-based interventions and nurse-led teaching sessions can be effective in expanding and reinforcing initial educational messages from physicians.3-5 AAD and JTF recommendations also encourage clinicians to provide written action plans that detail how to respond quickly to acute disease flares and strategies to improve environmental control (see link to supplementary VIDEO 8).3-5 Understanding that cliniciansâ&#x20AC;&#x2122; time with patients is often limited, a number of well-respected organizations have developed patient education resources that clinicians and patients can access online (Table 1).

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TABLE 1. Online Resources for Patient Education Materials American Academy of Dermatology

www.aad.org/public/ diseases/eczema/ atopic-dermatitis

International Eczema Council

www.eczemacouncil.org

National Eczema Association

www.nationaleczema.org/

National Institute of Arthritis and Musculoskeletal and Skin Disease

www.aad.org/public/ diseases/eczema/ atopic-dermatitis

ENCOURAGING SHARED DECISION-MAKING Individualizing atopic dermatitis management plans requires a good understanding of patient and caregiver preferences, their burdens of care, and any fears related to prescribed therapies. For example, studies have shown that many patients with atopic dermatitis have “steroid phobia,” the consequences of which can range from poor adherence to outright refusal to use steroid-containing therapies because of side-effect concerns.6,7 Providers should be alert for patients who are skeptical about steroid-based regimens, especially when these agents are likely to be prescribed for extended periods. Clinicians can also provide information about differences in the potential benefits and risks of various steroid medications, including topical and oral formulations. Similarly, the “black box” warnings from calcineurin inhibitor prescribing information sheets need to be explained to patients, in the context of expected treatment duration and the risks of oral vs topical therapies.7,8 As discussed in Chapter 4, the side effects of many traditional systemic therapies often lead patients to discontinue treatment. Openly discussing these risks allows patients to make informed decisions about modifying therapy, while increasing awareness of signs and symptoms of potential treatment-emergent adverse effects to facilitate ongoing monitoring efforts (see link to supplementary VIDEO 9). In addition to education provided by their clinicians, some patients and caregivers will proactively research disease-related topics

CHAPTER 5 Educating Patients and Improving Adherence

that they feel are pertinent to their situations.4 This often includes online information about allergen screening, dietary interventions, environmental issues, and complementary and alternative medicine (CAM).4 Of note, reviews of CAM in atopic dermatitis have observed at least some published level I evidence that supports the use of acupuncture, stress-reducing hypnosis, balneotherapy, and certain herbal preparations or botanical oils (with important caveats).9 On the other hand, a number of CAM modalities have been shown to be ineffective in clinical trials, whereas others have not yet been sufficiently evaluated to make any evidence-based recommendations.9 Clinicians should be prepared to discuss the utility (or lack thereof) of these strategies, preferably using results from randomized controlled trials but at times based on their own clinical experience.

ENHANCING TREATMENT ADHERENCE Because the patient population with atopic dermatitis is heterogeneous, clinicians are likely to encounter a diverse set of life circumstances that can impair communication with affected individuals, interfere with acceptance of the diagnosis, or reduce treatment adherence. In fact, studies have shown that adherence to prescribed regimens is commonly poor among patients with atopic dermatitis.10 Not surprisingly, it is clear that closely following therapeutic recommendations is essential to maximize outcomes, particularly for cases of relatively severe disease. A number of factors can interfere with treatment adherence or persistence (Table 2).11 For example, patients may not obtain prescription refills or follow recommended dosing schedules because of potential side effects, treatment-related toxicities or medication costs.11 Clinicians are presumably aware that poor adherence is a barrier to good outcomes for patients with atopic dermatitis. However, many providers underestimate how many of their patients are not following the prescribed management plans.1 Research has shown that general clinical judgment about a patient is not a reliable indicator of treatment adherence.12,13 In fact, some evidence suggests that clinicians are more likely to overestimate adherence by patients with whom they have the strongest relationships.13,14 A number of other strategies to assess adherence have been described, including medication bottles with electronic monitors and reviews of pharmacy records. Some studies, however, have reported that this information is often inaccurate or

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

TABLE 2. Factors That May Interfere With Adherence to Treatment Regimens11 • Lack of awareness regarding how to apply the medication or dosing frequency • Failure to accept the atopic dermatitis diagnosis • Forgetfulness or poorly organized daily schedules • Belief that therapy is not adequately effective • Fear of unacceptable or intolerable side effects • Cosmetic concerns about therapies (eg, shiny ointment applied to the face) • Belief that a medication worsens symptoms • Pain following application of a medication • Concerns over medication costs • Reduced motivation during temporary periods of remission

incomplete, and busy community-based practices commonly do not have the time or other resources needed to obtain and review the available data.1,2 Nevertheless, all patients should be specifically and repeatedly evaluated for their understanding of treatment instructions and adherence. The fundamental practice of providing clear, concrete, and accessible patient education and action plans is central to improving adherence rates.1 Additional recommended communication strategies include using the “teach-back” confirmation method (asking patients or caretakers to accurately repeat instructions to a health care provider) and asking open nonleading questions about medication use: “Tell me how you are taking your medications” instead of “Are you taking that medication twice each day?” Other factors that can improve adherence include reducing pill burden, if possible. Of note, current and emerging biologic options are dosed less frequently than other systemic and topical therapies, which may translate to better overall adherence rates and improved patient satisfaction.15

CHAPTER 5 Educating Patients and Improving Adherence

KEY CLINICAL HIGHLIGHTS • The foundation of management plans for atopic dermatitis is open and trusting relationships between patients and their clinicians • All patients (and caregivers when appropriate) should receive evidence-based atopic dermatitis education that addresses disease mechanisms, trigger avoidance, and skin care strategies • Assessing treatment adherence in atopic dermatitis requires specific evaluations of patients’ understanding of therapeutic instructions and queries about their use of prescribed medications

REFERENCES 1. Gilliam AE, et al. Use of Eczema Action Plans (EAPs) to improve parental understanding of treatment regimens in pediatric atopic dermatitis (AD): A randomized controlled trial. J Am Acad Dermatol. 2016;74(2):375-377. 2. Bass AM, et al. Interventions to increase treatment adherence in pediatric atopic dermatitis: a systematic review. J Clin Med. 2015;4(2):231-242. 3. Eichenfield LF, et al. Translating atopic dermatitis management guidelines Into practice for primary care providers. Pediatrics. 2015;136(3):554-565. 4. Sidbury R, et al. Guidelines of care for the management of atopic dermatitis: Section 4. Prevention of disease flares and use of adjunctive therapies and approaches. J Am Acad Dermatol. 2014;71(6):1218-1233. 5. Schneider L, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol. 2013;131(2):295-299. 6. Charman CR, et al. Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol. 2000;142(5):931-936. 7. Eichenfield LF, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116-132. 8. Ring J, et al. The US FDA ‘black box’ warning for topical calcineurin inhibitors: an ongoing controversy. Drug Saf. 2008;31(3):185-198. 9. Vieira BL, et al. Complementary and alternative medicine for atopic dermatitis: an evidencebased review. Am J Clin Dermatol. 2016;17(6):557-581. 10. Snyder A, et al. A review of patient adherence to topical therapies for treatment of atopic dermatitis. Cutis. 2015;96(6):397-401. 11. Arkwright PD, et al. Management of difficult-to-treat atopic dermatitis. J Allergy Clin Immunol Pract. 2013;1(2):142-151. 12. Gilbert JR, et al. Predicting compliance with a regimen of digoxin therapy in family practice. Can Med Assoc J. 1980;123(2):119-212. 13. Miller LG, et al. How well do clinicians estimate patients’ adherence to combination antiretroviral therapy? J Gen Intern Med. 2002;17(1):1-11.

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

14. Velligan DI, et al. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70(suppl 4):1-46. 15. Dupilumab [prescribing information]. Initial US approval 2017. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; March 2017.

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ATOPIC DERMATITIS

CLINICAL RESOURCE CENTER™ GUIDELINES

Guidelines of care for the management of atopic dermatitis: part 1. Diagnosis and assessment of atopic dermatitis. Eichenfield LF, et al. J Am Acad Dermatol. 2014;70(2):338-351. »» https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4410183/pdf/nihms598033.pdf

Guidelines of care for the management of atopic dermatitis: part 2. Management and treatment of atopic dermatitis with topical therapies. Eichenfield LF, et al. J Am Acad Dermatol. 2014;71(1):116-132. »» https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4326095/pdf/nihms598590.pdf

Guidelines of care for the management of atopic dermatitis: part 3. Management and treatment with phototherapy and systemic agents. Sidbury R, et al. J Am Acad Dermatol. 2014;71(2):327-349. »» https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4410179/pdf/nihms-598620.pdf

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ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

Guidelines of care for the management of atopic dermatitis: part 4. Prevention of disease flares and use of adjunctive therapies and approaches. Sidbury R, et al. J Am Acad Dermatol. 2014;71(6):1218-1233. »» https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4430554/pdf/nihms685688.pdf

PATIENT RESOURCES International Eczema Council Founded in late 2014, the International Eczema Council (IEC) is a global nonprofit organization led by dermatology experts on atopic dermatitis. The IEC is dedicated to increasing the understanding of atopic dermatitis and promoting its optimal management through research, education, and patient/family care. »» http://www.eczemacouncil.org/

National Eczema Association The National Eczema Association is a nonprofit organization founded in 1988 to improve the health and quality of life for individuals with eczema through research, support, and education. »» www.nationaleczema.org

CLINICAL ASSESSMENT TOOLS Eczema Area and Severity Index (EASI) EASI is a clinician assessment tool designed to measure clinical severity of atopic dermatitis. Severity scores can range from 0 (clear) to 72 (very severe). Hanifin JM, et al. Exp Dermatol. 2001;10(1):11-18. »» http://www.homeforeczema.org/documents/easi-casereport-form-for-age-8-years-and-over.pdf

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Atopic Dermatitis CLINICAL RESOURCE CENTER™

Investigator Global Assessment (IGA) The IGA is a clinician assessment strategy designed to provide a snapshot of overall disease severity in dermatologic clinical trials. Futamura M, et al. J Am Acad Dermatol. 2016;74(2):288-294. »» http://www.pubmed.gov/26685719

Scoring Atopic Dermatitis (SCORAD) SCORAD is a clinical tool used to assess the extent and severity of eczema. (Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31.) »» http://adserver.sante.univ-nantes.fr/Compute.html

SUGGESTED READING Management of difficult-to-treat atopic dermatitis. Arkwright PD, et al. J Allergy Clin Immunol Pract. 2013;1(2):142-151. »» www.pubmed.gov/24565453

Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Blauvelt A, et al. Lancet. May 2017. [Epub ahead of print]. »» https://www.ncbi.nlm.nih.gov/pubmed/28478972

Translating atopic dermatitis management guidelines into practice for primary care providers. Eichenfield LF, et al. Pediatrics. 2015;136(3):554-565. »» http://pediatrics.aappublications.org/content/pediatrics/136/3/554.full.pdf

Persistence of mild to moderate atopic dermatitis. Margolis JS, et al. JAMA Dermatol. 2014;150(6):593-600. »» https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352328/pdf/ nihms665922.pdf Download this activity and additional tools at

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. Paller AS, et al. J Am Acad Dermatol. 2016;75(3):494-503. »» http://www.jaad.org/article/S0190-9622(16)30330-9/pdf

Serious complications from Staphylococcal aureus in atopic dermatitis. Patel D, Jahnke MN. Pediatr Dermatol. 2015;32(6):792-796. »» www.pubmed.gov/26337792

Anti-interleukin-31 receptor A antibody for atopic dermatitis. Ruzicka T, et al. N Engl J Med. 2017;376(9):826-835. »» https://www.ncbi.nlm.nih.gov/pubmed/?term=28249150

Patient burden of moderate to severe atopic dermatitis (AD): insights from a phase 2b clinical trial of dupilumab in adults. Simpson EL, et al. J Am Acad Dermatol. 2016;74(3):491-498. »» http://www.jaad.org/article/S0190-9622(15)02471-8/pdf

Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. Simpson EL, et al. N Engl J Med. 2016;375(24):2335-2348. »» www.pubmed.gov/27690741

Eczema and cardiovascular risk factors in 2 US adult population studies. Silverberg JI, Greenland P. J Allergy Clin Immunol. 2015;135(3):721-728. »» http://www.jacionline.org/article/S0091-6749(14)01677-7/pdf

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Atopic Dermatitis CLINICAL RESOURCE CENTER™

Childhood atopic dermatitis and warts are associated with increased risk of infection: a US population-based study. Silverberg JI, Silverberg NB. J Allergy Clin Immunol. 2014;133(4):1041-1047. »» http://www.jacionline.org/article/S0091-6749(13)01294-3/pdf

The burden of atopic dermatitis in US adults: results from the 2013 National Health and Wellness Survey. Whiteley J, et al. Curr Med Res Opin. 2016;32(10):1645-1651. »» https://www.ncbi.nlm.nih.gov/pubmed/?term=27240604

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ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

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ATOPIC DERMATITIS

SUPPLEMENTAL VIDEO LIBRARY VIDEO 1: The Burden of Atopic Dermatitis Jeffrey M. Weinberg, MD »» http://www.exchangecme.com/project/advideos

VIDEO 2: Clinical Insights Into Atopic Dermatitis Pathogenesis Jeffrey M. Weinberg, MD »» http://www.exchangecme.com/project/advideos

VIDEO 3: Identification of Atopic Dermatitis Triggers Robert E. Kalb, MD »» http://www.exchangecme.com/project/advideos

VIDEO 4: Optimizing Topical and Nonpharmacologic Treatments in Atopic Dermatitis Jeffrey M. Weinberg, MD »» http://www.exchangecme.com/project/advideos

VIDEO 5: Efficacy of Dupilumab for Moderate-to-Severe Atopic Dermatitis Jeffrey M. Weinberg, MD »» http://www.exchangecme.com/project/advideos Download this activity and additional tools at

ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE

VIDEO 6: Insights into Optimal Bathing Practices Robert E. Kalb, MD »» http://www.exchangecme.com/project/advideos

VIDEO 7: Importance of Patient Education Robert E. Kalb, MD »» http://www.exchangecme.com/project/advideos

VIDEO 8: Educational Resources for Patients and Caregivers Jeffrey M. Weinberg, MD »» http://www.exchangecme.com/project/advideos

VIDEO 9: Atopic Dermatitis: The Patient’s Perspective »» http://www.exchangecme.com/project/advideos

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ATOPIC DERMATITIS: NEW PERSPECTIVES on MANAGING a CHRONIC INFLAMMATORY DISEASE