What's New in Eczema Management

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What’s New in Eczema Management: Practice Pearls for the Family Physician

This educational activity is jointly provided by the North Carolina Academy of Family Physicians (NCAFP) and Spire Learning.

This activity is supported by an educational grant from Pfizer Inc. What’s New in Eczema Management: Practice Pearls for the Family Physician

PROGRAM OVERVIEW This live meeting series will address the latest in the care and management of pediatric and adult dermatitis as well as strategies to individualize treatment.

TARGET AUDIENCE Family physicians

LEARNING OBJECTIVES At the conclusion of this live activity, family physicians should be better able to: • Recognize the clinical features and characteristic age distribution patterns of atopic dermatitis (AD) • Describe the role of skin barrier dysfunction, immune dysregulation, and environmental factors in the pathogenesis of AD • Individualize AD management regimens according to age, location, disease severity, response to treatment, and quality-of-life (QOL) concerns • Educate patients and families about the safe and appropriate use of skin-directed therapies for the treatment of AD

ACCREDITATION AND DISCLAIMER STATEMENTS This live activity, What’s New in Eczema Management: Practice Pearls for the Family Physician has been reviewed and is acceptable for up to 1.00 Prescribed credit(s) by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

AMA/AAFP Equivalency: AAFP Prescribed credit is accepted by the American Medical Association as equivalent to AMA PRA Category 1 Credit(s)™ toward the AMA Physician’s Recognition Award. When applying for the AMA PRA, Prescribed credit earned must be reported as Prescribed credit, not as Category 1. What’s New in Eczema Management: Practice Pearls for the Family Physician

HOW TO RECEIVE CREDIT To receive credit for your participation in this educational activity: • Read the objectives and other introductory CME information

• Complete the preassessment prior to the start of the activity • Participate in the atopic dermatitis (eczema) presentation

• Complete the postassessment and evaluation at the conclusion of the activity If you are seeking Prescribed credit, you must complete the postassessment and evaluation at the conclusion of the activity.

LEVELS OF EVIDENCE Levels of evidence are provided for any patient care recommendations made during this presentation.

Level A (randomized controlled trial/meta-analysis): High-quality, randomized controlled trial (RCT) that considers all important outcomes. High-quality meta-analysis (quantitative systematic review) using comprehensive search strategies

Level B (other evidence): A well-designed, nonrandomized clinical trial. A nonquantitative systematic review with appropriate search strategies and well-substantiated conclusions. Includes lower-quality RCTs, clinical cohort studies, and case-controlled studies with nonbiased selection of study participants and consistent findings. Other evidence, such as high-quality, historical, uncontrolled studies, or well-designed epidemiologic studies with compelling findings, is also included

Level C (consensus/expert opinion): Consensus viewpoint or expert opinion Each rating is applied to a single reference in the presentation, not the entire body of evidence on the topic.

OFF-LABEL STATEMENT The faculty will discuss non–FDA-approved or investigational agents for the treatment of AD (eczema), including anti-IL-31, apremilast, fezakinumab, lebrikizumab, OPA-154062, roflumilast, SB011, tofacitinib ointment, tralokinumab, and ustekinumab. Participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this activity. What’s New in Eczema Management: Practice Pearls for the Family Physician

FACULTY PRESENTERS Activity Chair: Anthony J. Mancini, MD, FAAP, FAAD Head, Division of Pediatric Dermatology Ann & Robert H. Lurie Children’s Hospital of Chicago Professor of Pediatrics and Dermatology Northwestern University Feinberg School of Medicine Chicago, IL Anthony J. Mancini, MD, FAAP, FAAD, is Professor of Pediatrics and Dermatology at Northwestern University Feinberg School of Medicine and Head of the Division of Pediatric Dermatology at Ann & Robert H. Lurie Children’s Hospital of Chicago, where he directs the division’s pediatric dermatology fellowship training program. Dr Mancini received his medical degree at the University of Arizona, and trained in pediatrics, pediatric dermatology, and dermatology at Stanford University, California. He is a Fellow of both the American Academy of Dermatology and the American Academy of Pediatrics (AAP). Dr Mancini’s clinical and research interests include infantile hemangiomas, atopic dermatitis, exanthems of childhood, and neonatal skin maturation and skin disorders. He has published 215 peer-reviewed articles, abstracts, books, and book chapters. He is coauthor of Hurwitz Clinical Pediatric Dermatology (3rd, 4th, 5th, and the upcoming 6th editions), coeditor of the AAP publication, Pediatric Dermatology – A Quick Reference Guide (1st, 2nd, and 3rd editions), and Pediatric Section Editor of Dermatology (1st, 2nd, and 3rd editions). Dr Mancini is the past President of the Society for Pediatric Dermatology, where he also served for 10 years as Secretary-Treasurer, and past Chair of the 2017 World Congress of Pediatric Dermatology. He previously served on the AAP Executive Committee of the Section on Dermatology, the AAP Super CME Planning Group, and the AAP PediaLink Pediatric Dermatology Project Team. Dr Mancini is an author of the upcoming AAP Clinical Practice Guidelines on Infantile Hemangiomas.

Disclosure Statement: Advisory Board: Pfizer Inc Consultant: Pfizer Inc

What’s New in Eczema Management: Practice Pearls for the Family Physician

FACULTY PRESENTERS (CONT’D) Jane Sanders Bellet, MD, FAAD Associate Professor of Dermatology Associate Professor of Pediatrics Duke University School of Medicine Durham, NC Jane Sanders Bellet, MD, FAAD, is an Associate Professor in the Departments of Dermatology and Pediatrics at Duke University School of Medicine in Durham, North Carolina. She is also Founder and Director of the Duke Nail Clinic. Dr Bellet received her medical degree from the University of Cincinnati College of Medicine in Cincinnati, Ohio. She trained in pediatrics and dermatology at Duke University School of Medicine, and completed a fellowship in pediatric dermatology at Children’s Memorial Hospital of Northwestern University in Chicago, Illinois. Dr Bellet cares for all pediatric skin conditions and specializes in the treatment of hemangiomas, port wine stains, vascular malformations, hyperhidrosis, and nail abnormalities. She is a frequent lecturer on these topics and has published widely, including peer-reviewed articles, invited reviews, and book chapters. Dr Bellet serves on committees for the Society for Pediatric Dermatology and the American Academy of Dermatology at Duke University Health System. She was presented with the Strength, Hope, and Caring Award in 2016. This annual award is presented to employees whose extraordinary care embodies the ideals of the Duke University Health System through compassionate support of patients, their families, and fellow employees.

Disclosure Statement: Advisory Board: Pfizer Inc

What’s New in Eczema Management: Practice Pearls for the Family Physician

FACULTY PRESENTERS (CONT’D) Lucia Z. Diaz, MD Chief of Pediatric and Adolescent Dermatology Dermatology Residency Associate Program Director Assistant Professor of Medicine and Pediatrics University of Texas Dell Medical School Austin, TX Lucia Z. Diaz, MD, is Chief of Pediatric and Adolescent Dermatology, Dermatology Residency Associate Program Director, and an Assistant Professor of Medicine and Pediatrics at the University of Texas Dell Medical School in Austin, Texas. She is also Co-director of the Dermatology-Rheumatology Combined Clinic at Dell Children’s Medical Center. Dr Diaz received her medical degree from the University of Texas Health Science Center in San Antonio, Texas, where she also completed a pediatric internship. She subsequently completed a dermatology residency at the University of Texas Medical School/MD Anderson Cancer Center in Houston, Texas, and a pediatric dermatology fellowship at the University of California, San Diego Medical School/Rady Children’s Hospital in San Diego, California. Dr Diaz’s clinical interests include birthmarks, rheumatologic conditions, severe inflammatory skin diseases, and procedural dermatology. She is a frequent lecturer on these topics and other areas of pediatric and general dermatology. Dr Diaz has numerous publications to her credit, including peer-reviewed articles, abstracts, and book chapters. She is an active and longstanding member of several professional societies, including the American Academy of Dermatology, the Pediatric Dermatology Research Alliance, the Society for Pediatric Dermatology, the Women’s Dermatology Society, and the American Society for Laser Medicine and Surgery. Dr Diaz enjoys working with children and discovering the long-lasting impact one can make on a child’s mental and physical health through patient education and advocacy, in addition to medical treatments. She has won multiple awards for teaching and clinical care and has been named “Super Doctor Rising Star” for the past 2 years.

Disclosure Statement: No relevant financial relationships with any commercial interests. What’s New in Eczema Management: Practice Pearls for the Family Physician

AGENDA 5 minutes Welcome and Introductions 5 minutes AD: Epidemiology and Burden of Disease 10 minutes Making the Diagnosis

5 minutes AD Pathogenesis Basics 10 minutes Management of AD 10 minutes Bringing It Together: AD Case Presentations 10 minutes Q&A 5 minutes Postassessment and Evaluation What’s New in Eczema Management: Practice Pearls for the Family Physician

Please complete the preassessment located in your meeting handout before the program begins .

Sponsorship and Support

This educational activity is jointly provided by the North Carolina Academy of Family Physicians (NCAFP) and Spire Learning.

This activity is supported by an educational grant from Pfizer Inc.

1 Faculty and Disclosures

Activity Chair Anthony J. Mancini, MD, FAAP, FAAD Head, Division of Pediatric Dermatology Ann & Robert H. Lurie Children’s Hospital of Chicago Professor of Pediatrics and Dermatology Northwestern University Feinberg School of Medicine Chicago, IL

Disclosure Statement: Dr Mancini has disclosed the following relationships: Advisory Board: Pfizer Inc Consultant: Pfizer Inc

Faculty and Disclosures (cont’d)

Faculty Presenter Jane Sanders Bellet, MD, FAAD Associate Professor of Dermatology Associate Professor of Pediatrics Duke University School of Medicine Durham, NC

Disclosure Statement: Dr Bellet has disclosed the following relationship: Advisory Board: Pfizer Inc

2 Faculty and Disclosures (cont’d)

Faculty Presenter Lucía Z. Diaz, MD Chief of Pediatric and Adolescent Dermatology Dermatology Residency Associate Program Director Assistant Professor of Medicine and Pediatrics University of Texas Dell Medical School Austin, TX

Disclosure Statement: Dr Diaz has no relevant financial relationships with any commercial interests.

Levels of Evidence

Levels of evidence are provided for any patient care recommendations made during this presentation. • Level A (randomized controlled trial/meta-analysis): High-quality, randomized controlled trial (RCT) that considers all important outcomes. High-quality meta-analysis (quantitative systematic review) using comprehensive search strategies • Level B (other evidence): A well-designed, nonrandomized clinical trial. A nonquantitative systematic review with appropriate search strategies and well-substantiated conclusions. Includes lower-quality RCTs, clinical cohort studies, and case-controlled studies with nonbiased selection of study participants and consistent findings. Other evidence, such as high-quality, historical, uncontrolled studies, or well-designed epidemiologic studies with compelling findings, is also included • Level C (consensus/expert opinion): Consensus viewpoint or expert opinion Each rating is applied to a single reference in the presentation, not the entire body of evidence on the topic.

3 Off-Label Statement

The faculty will discuss non–FDA-approved or investigational agents for the treatment of atopic dermatitis (eczema), including apremilast, anti-IL-31, fezakinumab, lebrikizumab, OPA-154062, roflumilast, SB011, tofacitinib ointment, tralokinumab, and ustekinumab.

Participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this activity.

Learning Objectives

At the conclusion of this live activity, family physicians should be better able to: Recognize the clinical features and characteristic age distribution patterns of AD Describe the role of skin barrier dysfunction, immune dysregulation, and environmental factors in the pathogenesis of AD Individualize AD management regimens according to age, location, disease severity, response to treatment, and QoL concerns Educate patients and families about the safe and appropriate use of skin-directed therapies for the treatment of AD

AD, atopic dermatitis; QoL, quality of life. 8

4 Worldwide Prevalence of AD

Figure not available for handout due to copyright restrictions. See reference below.

The Pharmaceutical Journal. https://www.pharmaceutical-journal.com/news-and-analysis/infographics/atopic-dermatitis-emerging-and-current- treatments/20202373.article. Accessed January 24, 2019. 9

Epidemiology of AD Lifetime prevalence of AD is > 50 million Americans suffer from 10 %-20 % 1%-3% allergic diseases 1 in children in adults 2

Onset Can persist into 60 % typically 85 %3 adulthood within 10 %-30 %4 First year Age 5

1. CDC. https://www.cdc.gov/healthcommunication/toolstemplates/entertainmented/tips/allergies.html. Accessed January 24, 2019. 2. Leung DY, et al. J Clin Invest . 2004;113:651-657. 3. Boguniewicz M, et al. Ann Allergy Asthma Immunol . 2018;120:10-22. 4. Ellis CN, et al. Semin Cutan Med Surg . 2012;31(3 Suppl):S18-S22. 10

5 Burden of Disease Itching 2 An average of 9 flares Itching lasts per year, each lasting 87 % ≥ 18 hours in 15 days 1 ~42% of experience itching daily patients

• Sleep disturbances 3 or more days a week , affecting the entire family’s sleep 3 Poor quality • Children with moderate disease wake up an average of of sleep 36 times per night , negatively impacting mental health and growth rates 4

1. Zuberbier T. J Allergy Clin Immunol. 2006;118:226-232. 2. Simpson EL, et al. J Am Acad Dermatol. 2016;74(3):491-498. 3. National Eczema Association 2016 Caregiver Survey. https://nationaleczema.org/in-your-words-survey-series/. Accessed January 24, 2019. 4. Kruse L. Paper presented at: 42nd Annual Society for Pediatric Dermatology Meeting; July 14-17, 2016; Minneapolis, MN. 11

Burden of Disease (cont’d)

• Mental health comorbidities 1-3 – Anxiety – Depression – Poor self-image – Attention-deficit/hyperactivity disorder (ADHD) – Behavioral or conduct problems • Of note, in the GINI-plus birth cohort study, even children whose eczema appeared to resolve in the first 1-2 years of life were shown to have persistent emotional and behavioral difficulties at 10 years of age 4

1. National Eczema Association 2016 Caregiver Survey. https://nationaleczema.org/in-your-words-survey-series/. Accessed January 24, 2019. 2. Simpson EL, et al. J Am Acad Dermatol . 2016;74(3):491-498. 3. Yaghmaie P, et al. J Allergy Clin Immunol . 2013;131(2):428-433. 4. Schmitt J, et al. J Allergy Clin Immunol . 2010;125(2):404-410. 12

6 Diagnostic Features of AD

• Pruritus (itching) • Chronic or relapsing dermatitis that exhibits: – Typical lesion morphology – Age-specific distribution • Other important features: – Early age of onset – Personal or family history of atopy – Xerosis

American Academy of Dermatology (AAD). J Am Acad Dermatol . 2014;70(2):338-351. 13

What Does AD Look Like?

• Erythematous papules and plaques • Excoriations • Xerosis • Erosions/crusting • Lichenification • Dyspigmentation • Generally spares axillae

and groin Photos courtesy of Anthony J. Mancini, MD

Eichenfield LF, et al. Pediatrics . 2015;136(3):554-565. Siegfried EC, et al. J Clin Med . 2015;4(5):884-917. 14

7 Clinical Features in Darker Skin Types

• Erythema may be difficult to see • Follicular accentuation • Hypo- or hyperpigmentation • Grayish-white skin discoloration (“ashy skin”)

Photos courtesy of Elaine C. Siegfried, MD; Adelaide A. Hebert, MD; and Anthony J. Mancini, MD. Simpson EL, et al. Semin Cutan Med Surg . 2016;35(5S):S84-S88. 15

Lesion Distribution Varies With Age

Figure not available for handout due to copyright restrictions. See reference to Simpson EL, et al. below.

Adapted from Simpson EL, et al . Semin Cutan Med Surg . 2016;35(5S):S84-S88. Eichenfield LF, et al. Semin Cutan Med Surg . 2017;36(supp2):S36-S38. Kapur S, et al. Allergy Asthma Clin Immunol . 2018;14(Suppl 2):52. 16

8 Differential Diagnoses (All Ages)

• Seborrheic dermatitis • Contact dermatitis (allergic and irritant) • Scabies • Psoriasis • Ichthyosis vulgaris • Tinea corporis • Keratosis pilaris • Nutritional deficiencies in young children • Immune disorders/immunodeficiency

Siegfried EC, et al. J Clin Med . 2015;4(5):884-917. 17

Differential Diagnoses: Considerations in Adolescents and Adults • Cutaneous T-cell lymphoma (mycosis fungoides or Sézary syndrome) • HIV-associated dermatoses • Dermatomyositis • Graft-versus-host disease • Lupus erythematosus • Pemphigus foliaceus • Drug eruptions

Siegfried EC, et al. J Clin Med . 2015;4(5):884-917. 18

9 Differential Dx Seborrheic Dermatitis (Infant)

Photos courtesy of Anthony J. Mancini, MD 19

Differential Dx Scabies

Photos courtesy of Anthony J. Mancini, MD 20

10 Differential Dx Psoriasis

Photos courtesy of Anthony J. Mancini, MD 21

Differential Dx Ichthyosis Vulgaris

Photos courtesy of Anthony J. Mancini, MD 22

11 Differential Dx Tinea Corporis

Photos courtesy of Anthony J. Mancini, MD 23

Differential Dx Keratosis Pilaris

Photos courtesy of Anthony J. Mancini, MD 24

12 Differential Dx Impetigo

Photos courtesy of Anthony J. Mancini, MD 25

AD Pathogenesis Basics

Epidermal Barrier Dysfunction 1-3 Immune Dysregulation 4-7 Aggravating Factors 7-8

• Filaggrin gene mutation • Decreased filaggrin • Sweat (in a subset) protein levels • Heat • ↑ Skin pH • Th2 cell activation • Seasonal change • ↓ Ceramides • ↑ IL-4, IL-5, IL-13 • Infection • ↑ TEWL (also IL-17, IL-22, IL-31, • Stress others) • ↓ Hydration • Harsh soaps, detergents, • ↑ S. aureus colonization • ↑ Serum IgE wool • ↑ Allergen sensitization • ↑ PDE-4 activation • Allergens • ↑ Allergen sensitization

Ig, immunoglobulin; IL, interleukin; PDE-4, phosphodiesterase type 4; TEWL, transepidermal water loss; Th2, T helper 2. 1. Eichenfield LF, et al. J Am Acad Dermatol. 2014;70(2):338-351. 2. Leung DY, et al. J Clin Invest . 2004;113(5):651-657. 3. Simpson EL, et al. Semin Cutan Med Surg . 2016;35(5S):S84-S88. 4. Egawa G, et al. J Allergy Clin Immunol . 2016;138(2)350-358. 5. Boguniewicz M, et al. Immunol Rev . 2011;242(1):233-246. 6. Hanifin JM, et al. J Invest Dermatol . 1996;107(1):51-56. 7. Irvine AD, et al. Semin Cutan Med Surg . 2016;35(5 Suppl):S89-S91. 8. Silverberg JI, et al. J Invest Dermatol . 2013;133(7):1752-1759. 26

13 Figure not available for handout due to copyright restrictions. See reference below.

Paller AS, et al. Allergy Clin Immunol . 2017;140:633-643. 27

Treatment Goals

Control itch and Improve skin barrier Reduce frequency skin inflammation and decrease xerosis of flares

Decrease risk Improve/maintain of/treat infection quality of life

14 Stepwise Management of AD

Systemic therapy (eg, CyA, MTX, Recalcitrant, severe AD Step 4 biologics) or UV therapy

Moderate to severe AD Step 3 Mid-high potency TCS and/or TCI,* TPDE-4*

Mild to moderate AD Step 2 Low-mid potency TCS and/or TCI,* TPDE-4*

Basic treatment: Dry skin only Step 1 Skin hydration, emollients, avoidance of irritants, identification and addressing of specific trigger factors

*Over the age of 2 years. CyA, cyclosporine A; MTX, methotrexate; TCI, topical calcineurin inhibitor; TCS, topical corticosteroid; TPDE-4, topical phosphodiesterase-4 inhibitor; UV, ultraviolet. Adapted from Akdis CA, et al. J Allergy Clin Immunol . 2006;118(1):152-169. 29

Water: Irritant or Therapeutic?

Water irritates skin IF: • Skin is frequently wet, without immediate application of effective moisturizer • Moisture evaporates, causing skin barrier to become dry, irritated

Water hydrates skin IF: • Effective moisturizer is applied and hydration is retained, keeping skin barrier intact and flexible

15 Skin Barrier Dysfunction Is Predictive of Future AD • Cork Babies After Scope Study 1,2 – 1903 infants – TEWL measured at day 2, 2/6 months – AD scored at 6/12 months – Day 2 TEWL, highly predictive of AD at 12 months – 2-month TEWL – highly predictive of AD • Infants in the Babies After Scope Study 1,3 – Day 2 TEWL predictive of food allergy at 2 years

Transcutaneous allergen sensitization?

1. Paller AS, et al. J Allergy Clin Immunol . 2017;140:633-643. 2. Kelleher MM, et al. J Allergy Clin Immunol . 2015;135(4):930-935. 3. Kelleher MM, et al. J Allergy Clin Immunol . 2016;137(4):1111-1116. 31

Is Early Emolliation Effective?

RCT Simpson EL, et al 1 Horimukai K, et al 2 # of neonates, high AD 124 110 risk Intervention Full-body emollient daily (starting Moisturizer applied daily for first 32 weeks of life 3 weeks of age) vs no emollient in 58 neonates

Primary outcome Cumulative AD incidence at • Cumulative AD/eczema incidence at week 32 6 months • Egg white IgE

Results 50% relative risk reduction in AD • 32% fewer neonates with AD in emollient arm (emollient arm) • No effect on allergic sensitization

Address barrier dysfunction in AD with good dry skin care: • Bathe daily (short bath or shower) • Apply emollient/barrier repair product immediately after bathing • Apply emollient after topical medications • May play a role in prevention as well

1. Simpson EL, et al. J Allergy Clin Immunol . 2014;134(4):818-823. 2. Horimukai K, et al. J Allergy Clin Immunol . 2014;134(4):824-830. 32

16 “Pathogenesis-Based Therapy” With Emollients/Barrier Repair Agents • Add to the skin “what is missing” • Restore the barrier, maintain hydration • Ceramide-based products: – Aveeno ® Eczema Therapy – CeraVe ® cream or lotion – EpiCeram ® (prescription only) – Mario Badescu A.H.A & Ceramide Moisturizer • Filaggrin-based products: – AFAs™ Moisturizer – Cetaphil RestoraDerm ® – Dr.G Filagrin™ Barrier cream or balm – pH Drop Filaggrin product line

Topical Corticosteroids (TCSs): Benefits and Limitations • Benefits: – Highly effective at treating inflammation – Rapid onset of action – Multiple potency and delivery vehicles • Varied potency frequently required per patient • Limitations: – Product-specific age limits (although often used off-label) – Potential for local and systemic side effects (but rare when used appropriately): • Local: striae, telangiectasias, skin atrophy, dyspigmentation, periorificial dermatitis, acne rosacea • Systemic: HPA axis suppression • Periorbital administration: cataracts, glaucoma

HPA, hypothalamic-pituitary-adrenal. Eichenfield LF, et al. J Am Acad Dermatol . 2014;71:116-132. Stein SL, et al. JAMA . 2016;315:1510-1511. 34

17 Best Practices When Using TCSs

• Examples of location-appropriate corticosteroids: – Face/fold areas: low potency (eg, hydrocortisone 2.5%, desonide, alclometasone) – Trunk/extremities: mid potency (eg, fluocinolone, triamcinolone) – Severe flares (trunk/extremities): high potency (eg, mometasone, fluocinonide) • Apply twice daily to actively inflamed areas • Oral corticosteroids (eg, prednisone) rarely indicated in the treatment of AD; risks of rebound, side effects

C, cream; F, foam; G, gel; L, lotion; Oi, oil; O, ointment; S, solution. Adapted from Eichenfield LF, et al. J Am Acad Dermatol . 2014;71:116-132. 35

Topical Calcineurin Inhibitors (TCIs) – Benefits • Extensive clinical trials experience • Nonsteroid alternative • Good efficacy for mild, moderate, and severe AD • Used for acute AD and maintenance therapy • Little systemic absorption • Can be applied to face, fold areas, periorbital region, genitals

Eichenfield LF, et al. J Am Acad Dermatol . 2014;71:116-132. Stein SL, et al. JAMA . 2016.315:1510-1511. 36

18 TCIs: Limitations and Potential AEs

• Second-line agents 1,2 • Not approved for use in children < 2 years of age 1,2 • Limited range of vehicles available vs TCS • Stinging and burning in a subset of patients 1,2 • FDA-mandated boxed warning and medication guide – No evidence to date of increased cancer risk in majority of studies, post-marketing surveillance registries – Recent study of European population databases (JOELLE): increased IRR for lymphoma (Hodgkin’s in children, CTCL in adults) with tacrolimus vs TCS, and for CTCL with pimecrolimus vs TCS in adults; if low IRs causal small excess risk for individual patients 3

AEs, adverse events; CTCL, cutaneous T-cell lymphoma; IR, incidence rate; IRR, incidence rate ratio. 1. Eichenfield LF, et al. J Am Acad Dermatol . 2014;71:116-132. 2. Stein SL, et al. JAMA . 2016;315:1510-1511. 3. Castellsague J, et al. Clin Epidemiol. 2018;10:299-310. 37

Available TCIs

TCI Vehicle Indications Pimecrolimus Cream Approved for mild to moderate AD (1%) 1 (2 years and older) Tacrolimus Ointment Approved for moderate to severe AD (0.03% and 0.1%) 2 (0.03%: 2 years and older; 0.1%: 15 years and older)

• Both TCIs were shown to be more effective than vehicle in short-term (3-12 weeks) and long-term studies (up to 12 months) in adults and children with active disease 3-8 – Decline in Eczema Area and Severity Index (EASI) score – Decrease in percentage of body surface involved – Reduction in patient-evaluated symptoms and signs of disease

1. US FDA. CDER. Pimecrolimus NDA 021302. Label 03/28/2014. 5. Ho VC, et al. J Pediatr . 2003;142:155-162. 2. US FDA CDER. Tacrolimus NDA 050777. Label 11/04/2011. 6. Kang S, et al. J Am Acad Dermatol . 2001;44(Suppl):S58-S64. 3. Boguniewicz M, et al. J Allergy Clin Immunol . 1998;102:637-644. 7. Paller A, et al. J Am Acad Dermatol . 2001;44(Suppl):S47-S57. 4. Eichenfield LF, et al. J Am Acad Dermatol . 2002;46:495-504. 8. El-Batawy MM, et al. J Dermatol Sci . 2009;54:76-87. 38

19 Crisaborole 2% Ointment

• A nonsteroidal, boron-based PDE-4 inhibitor 1,2 • Indicated for mild to moderate AD in adults and children ≥ 2 years 3 • Benefits 3,4 Figure not available due to copyright restrictions. See reference to Jarnagin K et al. below. – Reduces inflammation and itching – Maintains skin barrier – Low molecular weight enhances skin penetration – Limited systemic exposure – Favorable safety profile over 48-week study 5 • Limitations – Stinging and burning at application site

1. Hanifin JM, et al. J Invest Dermatol. 1996;107:51-56. 2. Jarnagin K et al. J Drugs Dermatol . 2016;15(4):390-396. 3. US FDA. CDER. Crisaborole NDA 207695. Label 10/16/2017. 4. Tom WL, et al. Pediatr Dermatol . 2016;33(2):150-159. 5. Eichenfield LF, et al. Presented at: Winter Clinical Dermatology Conference; January 15-20, 2016; Koloa, HI. 39

Dupilumab

• Human monoclonal IgG antibody targets IL-4R α; blocks IL-4 and IL-13 signaling 1 • Indicated for patients ≥ 12 years with moderate-to-severe AD; subQ injection every 2 weeks 1 • Phase III trials: > 33% of patients achieved significant improvement in AD severity 2 • Topical therapies can be combined with dupilumab for additional benefit in adults with refractory AD 3 • Associated with potentially serious side effects, requires close monitoring 1,4 – Conjunctivitis – Injection-site reactions

SubQ, subcutaneous. 1. US FDA. CDER. Dupilumab NDA 761055. Label 03/11/2019. 3. Blauvelt A, et al. Lancet . 2017;389(10086):2287-2303. 2. Simpson EL, et al. N Engl J Med . 2016;375(24):2335-2348. 4. Yang EJ, et al. Pediatrics . 2018;142(4):e20181102. 40

20 Dupilumab: Pediatric Studies Underway…

Emerging Treatments for AD

• Topical therapies – PDE-4 inhibitors (eg, roflumilast, 1 OPA-15406 2) – Janus kinase inhibitors: tofacitinib ointment 3 – Calcineurin inhibitor: SB011 4 • Systemic therapies – Apremilast: an oral PDE-4 inhibitor 5 – Anti-IL-31 6 – Ustekinumab, lebrikizumab, tralokinumab, fezakinumab (IL inhibitors) 7 • Numerous other potential targets in development

IL, interleukin. 1. ClinicalTrials.gov Identifier: NCT01856764. 2. Hanifin JM, et al. J Am Acad Dermatol . 2016;75(2):297-305. 3. ClinicalTrials.gov Identifier: NCT02001181. 4. ClinicalTrials.gov Identifier: NCT02079688. 5. ClinicalTrials.gov Identifier: NCT02087943. 6. ClinicalTrials.gov Identifier: NCT01614756. 7. Yang EJ, et al. Pediatrics . 2018;142(4):e20181102. 42

21 Wet Wraps

• Wet wraps prevent scratching and promote moisture retention • Use with emollients or a TCS • Taper from TCS to Vaseline ® • Sporadically or frequently (during acute flares) • Extensive or localized • Absorption toxicity risk is minimal

Sladden MJ, et al. Clin Exp Dermatol . 2005;30(4):454-455. Krakowski AC, et al. Pediatrics . 2008;122(4):812-824. Hindley D, et al. Arch Dis Child . 2006;91(2):164-168. Dabade TS, et al. J Am Acad Dermatol . 2012;67(1):100-106. 43

Colonization With Staphylococcus aureus

• Carriage common in nares/subungual areas • Worsens disease status • Renders disease harder to control • Patients do not have to be infected to be adversely impacted by S. aureus • Skin that is colonized: a trigger for disease flares

Boguniewicz M, et al. J Allergy Clin Immunol . 2010;125:4-13. 44

22 Bleach Therapy

• Sodium hypochlorite has disinfectant and antimicrobial properties • Bleach baths/intranasal mupirocin shown to: – Improve disease severity in patients with moderate to severe AD – Minimize antibiotic use • When is bleach therapy indicated? – Moderate to severe AD – Frequent infection/antibiotic use

Huang JT, et al. Pediatrics . 2009;123:e808-e814. Eichenfield LF, et al. J Am Acad Dermatol . 2014;71:116-132. Kedzierska A, et al. Br J Dermatol. 2008;159(6):1290-1299. Lever R, et al. Br J Dermatol . 1988;119(2):189-196. 45

Bleach Therapy Delivery Options

• Clorox ® bleach, 6% sodium hypochlorite (newer formulas 8.25%) – 1/8-1/2 cup bleach in full tub; soak 10-15 min, TIW • CLn ® wash – OTC cleanser with sodium hypochlorite (0.006%); good option for older kids and teens (www.clnwash.com) • Levicyn™ – Rx antipruritic gel and spray gel with hypochlorous acid/water – Broad antimicrobial activity – Indicated for burning and itching of dermatoses, pain of burns

Rx, prescription; TIW, three times a week. 46

23 Oral Antihistamines in AD

Agent Vehicle Properties

Diphenhydramine* Oral Sedating antihistamine

Hydroxyzine Oral Sedating antihistamine

Doxepin Oral Sedating antihistamine Cetirizine* Oral Nonsedating antihistamine

• Some controversy, but many use them, especially for sleep • Hydroxyzine most commonly used sedating antihistamine at bedtime

*Available over-the-counter. Sidbury R, et al. J Am Acad Dermatol . 2014;71:116-132. 47

Maintenance Therapies for AD

• Liberal and frequent application of moisturizers to reduce dryness and itching, prevent flares • Warm baths/showers (< 5 min) using non-soap cleansers or mild soaps • Antiseptic measures – Dilute bleach baths, if indicated • Trigger avoidance, when feasible • Intermittent application of TCSs or TCIs to prevent flares (“hot zones”)

Eichenfield LF, et al. J Am Acad Dermatol . 2014;71:116-132. Boguniewicz M, et al. Ann Allergy Asthma Immunol . 2018;120:10-22. Kirkup ME, et al . J Dermatolog Treat . 2003;14(3):141-148. Breneman D, et al. J Am Acad Dermatol . 2008;58(6):990-999. 48

24 Customizing Patient Treatment Plans

• Written treatment plan increases likelihood of adherence • Tailor treatment plan based on: – Age – Locations of disease – Previous treatment success/failures – Patient/caregiver preferences • Identify/eliminate triggers, if possible • Address quality-of-life issues (eg, sleep disruption, co-sleeping) • Provide basic skin care instructions (eg, bathing, emollients) – Moisturize frequently throughout the day – Topical medications do not take the place of moisturizers – Continue maintenance therapies, even if skin “appears” healthy

When to Test for Food Allergies

• Food allergy testing should be considered when: – Moderate to severe AD is persistent despite optimal management – Reliable history of anaphylaxis or immediate reaction after ingestion of a specific food

Specialist Referral

• Early referral in the case of severe, persistent disease • Otherwise, refer if the patient is not responding to conservative measures and standard treatment modalities

25 Case Presentation

• 5-month-old female who developed an eczematous rash on her cheeks at about 3 months of age, and more recently has had involvement of her neck and outer aspects of upper extremities. She has not had any open or weeping lesions. • Her pediatrician prescribed hydrocortisone 2.5% cream, but her parents are concerned about using a topical steroid. They are wondering about allergic triggers.

Photo courtesy of Anthony J. Mancini, MD 51

Treatment Guidelines Mild Atopic Dermatitis

• Basic skin care (hydration and moisturizer) • Avoid irritants (and known allergens) • TCSs – Use lower strength in thin-skin areas (face, axillae, genital areas) and for mild eczema anywhere on the body Clinical Pearl: Choose correct vehicle and dispense correct amount • TCIs – Pimecrolimus cream indicated for ages 2 years and older for mild to moderate AD; if parents concerned about TCSs can consider, but disclose that it is off-label • Crisaborole ointment indicated for mild to moderate AD in children 2 years and older; another steroid-free option, also off-label in this patient • Sedating antihistamine may help with itch and sleep disruption • Discuss atopic diathesis and possible allergies but appropriate to treat first and assess response to therapies (unless clear-cut indication for allergy referral) 52

26 Case Presentation

• 12-year-old female with onset of eczema in early childhood. Over the years, it has involved her head and neck, trunk, and flexural aspects of her upper and lower extremities. She has had infrequent superficial skin infections. • On exam: moderate patches of eczema involving face (including eyelids), neck, and flexural aspects of all 4 extremities with lichenification. Several areas with crusting. • Parents want to discuss TCI options

Photo courtesy of Anthony J. Mancini, MD 53

Treatment Guidelines Moderate Atopic Dermatitis • Basic skin care (hydration and moisturizer) • Avoid irritants (and known allergens) • TCSs – Use lower strength in thin-skin areas (face, axillae, genital areas) – Use mid-potency for trunk and extremities – Caution with TCSs in periorbital locations • TCIs – Pimecrolimus indicated for ages 2 years and older for mild to moderate AD – Tacrolimus ointment indicated for ages 2 years and older for moderate to severe AD (0.03% for ages 2-15 years; 0.1% for > 15 years) – Discuss potential indications (especially around eyes), boxed warning • Crisaborole ointment indicated for mild to moderate AD in ages 2 years and older • Sedating antihistamine for sleep disruption/nocturnal pruritus • Nonsedating antihistamine may help in patients with allergic triggers, better for daytime (school) • Dilute bleach baths – 1/8-1/2 cup of bleach in a full bathtub (about 40 gallons) of water – Soak 5 to 10 minutes 2-3 times/weekly • Oral antibiotic for bacterial infection (usually MSSA; consider MRSA if history or suggestive clinical findings)

MRSA, methicillin-resistant Staphylococcus aureus ; MSSA, methicillin-susceptible Staphylococcus aureus . 54

27 Patient/Parent Education

• Chronic disease, prone to flares and remissions • Importance of dry skin care and maintenance use of emollients/barrier- repair agents • Treat acute flares aggressively • Recognize/treat infection, and attempt to prevent (bleach) when indicated • Optimize sleep, consider antihistamines for this and control of pruritus • Escalate therapy if response suboptimal (and good adherence)

Take-Home Messages

• Most patients with mild to moderate AD can be managed by the primary care physician • AD impacts the entire family’s QoL, not just the patient’s • Need to educate patients and caregivers about the disease, provide a written action plan, and review/modify PRN at follow-up • Address itch-scratch cycle, sleep disturbance, behavioral associations • Underlying skin inflammation is always present, even when the skin appears normal – treat with the appropriate agents and consider maintenance anti-inflammatory therapy • Patient adherence is critical to AD management • Consistent skin care can reduce flare-ups

28 Questions?

Thank You Please complete the postassessment and evaluation located in your meeting handout.