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Provided by Integrity Continuing Education, Inc.Supported by an educational grant from Sanofi Genzyme and Regeneron Pharmaceuticals.

The Role of the Physician Assistant in Achieving Optimal Outcomes in Moderate to Severe

Atopic Dermatitis

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Faculty and Affiliation

Anthony J. Mancini, MD, FAAP, FAADHead, Division of Dermatology

Ann & Robert H. Lurie Children’s Hospital of Chicago Professor of Pediatrics and Dermatology

Northwestern University Feinberg School of MedicineChicago, Illinois

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Faculty Disclosures

Anthony J. Mancini, MD, FAAP, FAAD

Consulting Fees:Pfizer Pharmaceuticals

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Learning Objectives

Utilize updated criteria and guidelines to accurately diagnose atopic dermatitis (AD)

Assess and document disease severity in individual patients

Review updated guidelines and evaluate available clinical data for therapies utilized in the treatment of AD

Describe indications for specialist referral of patients with AD and review best practices for co-management of moderate to severe disease with specialist physicians

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Burden of AD and Unmet Needs

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Prevalence of AD

AD in almost 32 million

Affects ~31.9 million in the US1

– 11%–20% of children2

– 7% of adults1,3

• 29% with moderate disease; 11% with severe disease3

AD often the first sign of long-term disease continuum4

– 60% eventually develop asthma or allergic rhinitis

– 30% develop food allergies

1 in 4 adults with AD report adult onset5

– 30% of childhood cases persist into adult years6

1. Silverberg JI. Dermatol Clin. 2017;35:283-289. 2. Shaw TE, et al. J Invest Dermatol. 2011;131:67-73. 3. Chiesa Fuxench ZC, et al. J Invest Dermatol. 2019;139:583-590. 4. NIH Genetics Home Reference. Atopic dermatitis. https://ghr.nlm.nih.gov/condition/atopic-dermatitis. 5. Lee HH, et al. J Am Acad Dermatol. 2019;80:1526-1532. 6. Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22.

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AD: Psychosocial/Health-Related Burden

HRQOL, health-related quality of life; QOL, quality of life.

1. Simpson EL. J Am Acad Dermatol. 2016;74:491-498. 2. Silverberg JI, et al. Ann Allergy Asthma Immunol. 2018;121:340-347. 3. Drucker AM. J Invest Dermatol. 2017;137:26-30. 4. Paller A, et al. Am J Clin Dermatol. 2018;19:821-838. 5. Patel KR, et al. J Am Acad Dermatol.2019;80:402-410. 6. Chang Y-S, Chiang B-L. Int J Mol Sci. 2016;174:462. 7. Simpson EL, et al. J Am Acad Dermatol. 2016;74:491-498. 8. Mollanazar NK, et al. Clin Rev Allergy Immunol. 2016;51:263-292.

Detrimental to QOL1-4

Heavy psychosocial impact– Due to stigma, embarrassment, isolation, unpredictability

of flares Associated with anxiety, depression, and suicidal ideation5

Negative impact on academic and job-related performance

Negative effect on sleep (mostly due to pruritus)6-8

87% experience itching daily Itching lasts ≥18 hours in ~42% of patients Leads to excessive daytime sleepiness, fatigue, and

reduced HRQOL

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AD: Psychosocial/Health-Related Burden (cont.)

1. Ong PY. Immunol Allergy Clin North Am. 2017;37:75-93. 2. Drucker AM, et al. J Invest Derm. 2017;137:26-30. 3. National Eczema Association 2016 Caregiver Survey. https://nationaleczema.org/in-your-words-survey-series/. 4. Zuberbier T. J Allergy Clin Immunol. 2006;118:226-232. 5. Ricci G, et al. J Pediatr Health Care. 2006;20:311-315.

Infection Increased risk of cutaneous and systemic

infections contribute to overuse of antibiotics1

Heavy care/financial burden for parents, caregivers2

Interrupted sleep >3×/week due to AD3

Patients average 9 flares/year, each lasting ~15 days4

Out-of-pocket expenses for families estimated to total ~10% of annual income5

AD superinfected with toxin-secreting S. aureus

Photo courtesy of Mark Boguniewicz, MD

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More Than Skin Deep: AD Comorbidities

Atopic

Allergic rhinitis

Asthma

Conjunctivitis

Food allergies

Eosinophilic esophagitis

Nonatopic

Cardiometabolic– Obesity– Diabetes– Hypertension

Autoimmune disease Neuropsychiatric

– ADHD– Anxiety– Depression

“Atopic march” concept says that for many, AD will start early and develop into extracutaneous nonatopic comorbidities

More recent understanding is that more-severe skin disease will manifest in a higher burden of multiple atopic and nonatopic comorbidities

Brunner PM, et al. J Invest Dermatol. 2017;137:18-25. Davidson WF, et al. J Allergy Clin Immunol. 2019;143:894-913. Paller A, et al. J Allergy Clin Immunol. 2019;143:46-55. Silverberg JI, et al. Ann Allergy Asthma Immunol. 201;121:604-612.

ADHD, attention deficit hyperactivity disorder.

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Unmet Needs in AD

Effective treatments that relieve symptoms

and improve long-term outcomes

Reliable biomarkers to guide treatment selection

Consistent guideline implementation

Effective strategies to ensure/encourage

medication adherence

Leung DYM. J Allergy Clin Immunol. 2017;139(4)(suppl):S47-S48. Patel N, Feldman SR. Adv Exp Med Biol. 2017;1027:139-159. Silverberg JI. Allergy Asthma Proc. 2017;38:243-249.

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Diagnosis, Severity Assessment & Available Guidelines

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Diagnostic Criteria for AD from the AAD

AD currently diagnosed based on history and clinical presentation (biomarkers not yet specific enough to confirm diagnosis or assess severity)

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. Eichenfield LF, et al. J Allergy Clin Immunol. 2017;139:S49-S57. Eichenfield LF, et al. J Am Acad Dermatol. 2014;70:338-351.

Essential (must be present)

• Pruritus• Eczema (acute, subacute,

chronic)• Morphology: typical or

atypical?• Age-specific patterns:

– Infants and children: facial, neck, extensor involvement

– Any age: current or previous flexural lesions; sparing of groin and axillary regions

• History: chronic or relapsing

Important(supports diagnosis)

• Early age of onset• Atopy• Personal and/or

family history• IgE reactivity• Xerosis

Differential/Exclusion Diagnoses

(alternate or concomitant)• Seborrheic dermatitis• Contact dermatitis

(allergic or irritant)• Scabies• Immunodeficiencies• Ichthyoses• Psoriasis• Photosensitivity dermatoses• Cutaneous T-cell lymphoma• Erythroderma of other causes

AAD, American Academy of Dermatology; IgE, immunoglobin E.

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Other Diseases Can Look Like AD

Contact Dermatitis (both photos) Scabies

AD

Photos courtesy of Sheila F. Friedlander, MD.

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Clinical Features in Darker Skin Types

Erythema may be difficult to see

Follicular accentuation

Hypopigmentation

Grayish-white skin discoloration (“ashy skin”)

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

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Distribution Patterns Vary with Age

InfantsForehead, cheeks,

and chin; trunk (except diaper area);

extensor surfaces

Young ChildrenFace, neck, antecubital/popliteal

fossae, wrists, ankles

Adolescents/AdultsPeriorbital area, neck, extensor

surfaces, antecubital/popliteal fossae, wrists, hands, ankles, feet

Simpson EL, et al. Semin Cutan Med Surg. 2016;35:S84-S88.

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Guidelines

1. Schneider L, et al. J Allergy Clin Immunol. 2013;131:295-299. 2. Eichenfield LF, et al. Pediatrics. 2015;136:554-565. 3. Eichenfield LF, et al. J Am Acad Dermatol. 2014;70:338-351. 4. Eichenfield LF, et al. J Am Acad Dermatol. 2014;71:116-132. 5. Sidbury R, et al. J Am Acad Dermatol. 2014;71:327-349. 6. Sidbury R, et al. J Am Acad Dermatol. 2014;71:1218-1233. 7. Eichenfield LF, et al. J Allergy Clin Immunol. 2017;139:S49-S57.

Guidelines for assessing and treating AD come from divergent clinical perspectives

AAAAI, American Academy of Allergy, Asthma, and Immunology; ACAAI, American College of Allergy, Asthma, and Immunology; PCPs, primary care providers.

2013

2014

2015

2017

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“Yardstick” Guidelines Published in 2018*

Developed to merge and reconcile differing recommendations from multidisciplinary specialist guidelines

Incorporates many of the recommendations from the 4-part AAD guidelines

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22.

*Yardstick guidelines available as open-access PDF at https://www.annallergy.org/article/S1081-1206(17)31260-7/pdf

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Emphasis is on practical, step-by-step, “how-to” strategies to ensure clear or almost-clear skin from all levels of severity

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Don’t test for:

Testing Options

Do test for:

Secondary bacterial infections with disease

exacerbations

Food allergies for patients <5 years with refractory AD despite optimal treatment and/or clinical history of

allergic reaction to certain foods

Contact dermatitis for refractory AD despite optimal treatment, especially if involving the face

and/or feet

Food allergies on a routine basis

Testing recommendations from integrated guidelines1

1. Eichenfield LF, et al. J Allergy Clin Immunol. 2017;139:S49-S57. 2. Totte JE, et al. Br J Dermatol. 2016;175:687-695.

Serum IgE, patch testing, and/or genetic testing should be done if necessary, to rule out

differential diagnoses.

~70% of patients with AD will show

Staphylococcus aureus colonization with swab testing2

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Determining Clinically Relevant Infections

Systemic antibiotics are recommended only when there is clear evidence of infection (presence of purulent exudate and pustules)3

Some guidelines recommend dilute bleach baths for bacterial control; however, a systematic review of 5 published articles concluded bleach baths are no more effective than water baths, alone4

1. Totte JE, et al. Br J Dermatol. 2016;175:687-695. 2. Eichenfield LF, et al. J Am Acad Dermatol. 2014;71:116-132. 3. Sidbury R, et al. J Am Acad Dermatol. 2014;71:327-349. 4. Chopra R, et al. Ann Allergy Asthma Immunol. 2017;119:435-440.

S. aureus is resident on the skin of ≥70% of AD patients1

– This colonization does not indicate infection– However, S. aureus can exacerbate AD

AAD guidelines do not support the use of antimicrobial solutions nor topical antibiotics—even when infection is present2

– These do not improve outcomes or disease severity and are associated with contact dermatitis and antimicrobial drug resistance

S. aureus infectionPhoto courtesy of Eric L. Simpson, MD

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Severity Assessments

Accurate assessment of disease severity is important for optimal treatment

Nonspecialists can quickly and easily use the vIGA and NRS for itch

To use the NRS, ask your patient: “What’s your worst itch intensity over the last 24 hours on a scale of 0 to 10?” (0 = no itch; 10 = worst itch imaginable)

NRS, numerical rating scale.Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22.

Validated Investigator Global Assessment (vIGA)

Score Description

0 – Clear No inflammatory signs of AD (erythema, induration/papulation, lichenification, nor oozing/ crusting). Postinflammatory hyperpigmentation and/or hypopigmentation may be present.

1 – Almost Clear

Barely perceptible erythema, barely perceptible induration/papulation, and/or minimal lichenification. No oozing or crusting.

2 – Mild Slight but definite erythema (pink), slight but definite induration/papulation, and/or slight but definite lichenification. No oozing or crusting.

3 – Moderate Clearly perceptible erythema (dull red), clearly perceptible induration/papulation, and/or clearly perceptible lichenification. Oozing and crusting may be present.

4 – Severe Marked erythema (deep or bright red), marked induration/papulation, and/or marked lichenification. Disease is widespread in extent. Oozing or crusting may be present.

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AD Severity: Mild

Photos courtesy of Eric L. Simpson, MD

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AD Severity: Moderate

Photos courtesy of Eric L. Simpson, MD

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AD Severity: Severe

Photo courtesy of Eric L. Simpson, MD

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Severity Assessment in Clinical Practice

At each visit, ask about impact of AD on:

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. Eichenfield LF, et al. J Allergy Clin Immunol. 2017;139:S49-S57.

Itch

Sleep

Daily Life

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Case Study 1, Part 1

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Case Study 1: Nicholas, 17-Year-Old Male

Presents to family physician with eczema that has been present over past 6 months on flexural area of elbows, neck, and face

History of episodic eczema in early adolescence and childhood

Comorbidity of mild asthma Has had multiple allergy tests (all

negative) Has tried diets (gluten-free, probiotics) Now experiences stigma and

embarrassment in school Skin itch and appearance now

interrupting sleep, activities, and sports

Photo courtesy of Eric L. Simpson, MD

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Pathophysiology and Treatment Approaches

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AD Pathophysiology: Altered Epidermal Barrier + Immune Dysregulation

CLA, cutaneous lymphocyte-associated; IDEC, inflammatory dendritic epidermal cells; IFN, interferon; IL, Interleukin; LC, Langerhans cells; MC, mast cell; MØ, macrophage; Th2, T helper type 2 cell; ThO, native T cell; TSLP, thymic stromal lymphopoietin.

Adapted from: Boguniewicz M, et al. Immunol Rev. 2011;242:233-246.

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Treatment Goals

Control itch Control skin inflammation Restore barrier integrity Decrease xerosis Treat secondary infection Recognize and prevent triggers Reduce frequency of flares Improve and maintain QOL

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Step-Care Management: Non-Lesional/Basic

1. Skin Care• Moisturizer, liberal and frequent• Warm baths or showers using non-soap

cleansers, usually 1×/day followed by moisturizer (even on clear areas)

2. Trigger Avoidance• Common allergens and irritants

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22. van Zuuren EJ, et al. Cochrane Database Syst Rev. 2017 Feb 6:CD012119. Weber TM, et al. J Drugs Dermatol. 2015;14:478-485

Daily moisturizing can reduce incidence of flare and overall disease severity

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Step-Care Management: Mild Disease

Topical OTC hydrocortisone can temporarily relieve pruritus and inflammation due to mild AD

– Medical attention should be sought if symptoms worsen or last >7 days

– Not to be used on children <2 years

– OTC treatments should not contain ingredients known to be AD irritants

• eg, soaps, detergents, perfumes

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22. Weber TM, et al. J Drugs Dermatol. 2015;14:478-485.

1. Skin Care• Moisturizer, liberal and frequent • Warm baths or showers using non-

soap cleansers, usually 1×/day followed by moisturizer (even on clear areas)

2. Antiseptic Measures• Dilute bleach bath (or equivalent)

≤2×/week according to severity (especially with recurrent infections)

3. Trigger Avoidance • Patient-specific proven allergens

and irritants• Consider comorbidities

OTC, over the counter.

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Topicals: TCS

Available TCS Agents in Various Potencies and Vehicles

Potency Drugs

Least Potent • Hydrocortisone • Hydrocortisone acetate

Mild • Alclometasone dipropionate• Desonide

• Fluocinolone acetonide

Lower Mid-Strength

• Hydrocortisone butyrate• Hydrocortisone probutate

• Hydrocortisone valerate• Prednicarbate

Mid-Strength

• Betamethasone valerate• Clocortolone pivalate• Desoximetasone• Fluocinolone acetonide

• Flurandrenolide• Fluticasone propionate• Mometasone furoate• Triamcinolone acetonide

Potent

• Amcinonide• Betamethasone dipropionate• Desoximetasone• Diflorasone diacetate

• Fluocinonide• Halcinonide• Mometasone furoate• Triamcinolone acetonide

Most Potent • Betamethasone dipropionate• Clobetasol propionate

• Diflorasone diacetate• Halobetasol propionate

TCS usually the first line of treatment to reduce local inflammation Available in a wide variety of formulations (eg, cream, lotion, ointment, foam) Can cause skin

atrophy and thinning if used inappropriately (eg, long-term use of high-potency TCS)

No consensus regarding optimal dosing or frequency

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22. Eichenfield LF, et al. J Am Acad Dermatol. 2014;71:116-132. Paller AS, et al. J Allergy Clin Immunol. 2017;140:633-643.

TCS, topical corticosteroids.

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Topicals: TCIs

Nonsteroidal, can be applied to face, extremities, and genital area Stinging/burning at application site most frequent adverse event Inhibits calcineurin-dependent T-cell activation Not indicated for:

– Children <2 years of age

– Long-term, continuous treatment

Sun protection should be used as a precaution

Eichenfield LF, et al. J Am Acad Dermatol. 2014;71:116-132. Siegfried EC, et al. Am J Clin Dermatol. 2013;14:163-178. Stein SL, et al. JAMA. 2016;315:1510-1511.

Currently Available TCIs

TCI Vehicle Indications

Pimecrolimus (1%) cream Mild to moderate AD (2 years and older)

Tacrolimus (0.03% and 0.1%) ointment Moderate to severe AD (2 years and older: 0.03%; 15 years and older: 0.1%)

Note: Despite black-box warnings, postmarketing registry studies have shown virtually no risk for malignancy.

TCIs, topical calcineurin inhibitors.

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Topical: PDE4 Inhibitor

PDE4 is a key regulator of inflammatory cytokines

Crisaborole 2% ointment, only PDE4 inhibitor approved for AD

– Approved for mild to moderate AD in adults and children ≥2 years

Efficacy proven in two phase 3 studies (N=1,522 patients >2 years) with mild to moderate AD randomized 2:1 to crisaborole or placebo

In both studies, crisaborole shown to be more effective than placebo at achieving clear or almost-clear skin

Stinging/burning at application site most frequent adverse event

Positive long-term data on safety recently published, but no long-term data on efficacy*

*Eichenfield LF, et al. J Am Acad Dermatol. 2017;77:641-649. Ahmed A, et al. Br J Dermatol. 2018;178:659-662. Paller AS, et al. J Am Acad Dermatol. 2016;75:494-503.

PDE4, phosphodiesterase 4.

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Case Study 1, Part 2

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Nicholas, Part 2

The family physician recommended that Nicholas avoid triggers and apply topical anti-inflammatory– Prescribed 2×/day for 2 weeks, then 2×/weekly as needed

Within a few weeks, patient reports dissatisfaction with this treatment– Complains that the treatment “never worked”

After careful questioning, Nicholas reveals he didn’t use it as instructed– Couldn’t remember to apply 2×/day

– Didn’t like the “greasy” feel

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Moderate to Severe Disease and Systemic Treatments

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Step-Care Management: Moderate Disease

Maintenance TCS• Low potency 1×-2×/day (including face)• Medium potency 1×-2×/day (except face)

OR Maintenance TCI• 1×-2×/day • 2×-3×/week (not an indicated dose)

OR PDE4 Inhibitor*• 2×/day

Inflamed Skin• Medium to high potency TCS 2x/day for 3–7

days beyond clearance (can consider TCI or PDE4 inhibitor)

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22.

*Indicated for patients at least 2 years old.

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When to Use Systemic Treatment

Many patients

effectively managed

with topical medications

If condition worsens despite

topicals, consider alternate or concomitant

diagnoses

If adherence is good, the treatment may have failed

—not the patient!Consider systemic

treatment

Simpson EL, et al. J Am Acad Dermatol. 2017;4:623-633.

Determine if adherence and

patient education has been optimal

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• Dupilumab, only targeted biologic approved for moderate to severe AD in patients ≥12 years

Limitation:• No data for optimal ways to step down or discontinue after clear skin is achieved

• Azathioprine*

• Corticosteroids†

• Cyclosporine*

• Methotrexate*

• Mycophenolate*

Limitation:• Not usable long-term because of multiple systemic adverse events

Types of Treatments for Moderate to Severe Disease

Systemic Immunosuppression

*Not approved by FDA to treat AD. †Not recommended for long-term maintenance.

Biologic

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Pros and Cons of 5 Most Frequently Used Oral Systemics

Agent Advantages Disadvantages

AZA • Demonstrated efficacy in 3 RCTs• Can be used as monotherapy in

refractory AD

• Nausea and other GI system AEs common• Delayed efficacy (may need ≥12 weeks)• Can cause myelosuppression• Increased risk for cutaneous cancer and lymphoma

CSA • Modest efficacy demonstrated in 14 RCTs• Rapid efficacy (2–6 weeks)

• Long-term use (≥1 year) associated with renal toxicity• Risk for cutaneous cancer and lymphoma

MMF • Modest effect in refractory AD• Generally well tolerated

• Efficacy inconsistent• Nausea most common AE (reduced with enteric-coated

formulation)

MTX • Can show efficacy in low doses• Can be taken long term• Risk for toxicities reduced with folic acid

supplementation

• Nausea and other GI system AEs common• Delayed efficacy (~10 weeks)• Chronic use increases risk for liver toxicity

SCS • Provides rapid response• Only systemic approved for AD

• High rates of toxicity/poor drug survival• Use discouraged by all guidelines because of unfavorable

risk-benefit profile

Drucker AM, et al. Br J Dermatol. 2018;178:768-775. Sidbury R, et al. J Am Acad Dermatol. 2014;71:327-349.

AE(s), adverse event(s); AZA, azathioprine; CSA, cyclosporine A; GI, gastrointestinal; MMF, mycophenolate mofetil; MTX, methotrexate; RCTs, randomized clinical trials; SCS, systemic corticosteroids.

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Step-Care Management: Severe Disease

Systemic Immunosuppressants• Cyclosporine A‡

• Methotrexate‡

• Mycophenolate mofetil‡• Azathioprine§

Dupilumab†

• Approved for ages ≥12 years

If not resolved in 7 days, consider• Nonadherence, misdiagnosis, referral

Consider acute treatment for some patients• Wet-wrap therapy or hospitalization

Adapted from: Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22.

†Indicated for patients at least 12 years old. ‡Not approved by FDA to treat AD. §Not recommended for long-term maintenance.

Rarely used in children

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Case Study 2, Part 1

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Case Study 2, Brianna, 21-Year-Old Female

Presents to primary care physician with complaints of eczema and severe itching– Reports life-long history of mild to moderate disease that has

worsened over the past 2 years

Lesions recently appear on forehead and cheeks– Brianna contends that topical steroids “don’t help” and the lesions go

away only when she takes oral corticosteroids

– Has involvement of 15% of body surface area

Brianna is a newly licensed real estate agent– Complains that it’s difficult at her age to gain credibility in this field;

believes facial involvement worsens this

– Has difficulty sleeping, which makes her more anxious

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Approved Biologic

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AD Etiology: Interrelated Dysfunction Between Immune System and Skin

Immune System Skin

Dry skin and Eczematous Lesions

Cycle of Itching/Scratching

Epidermal Barrier Breakdown

Cellular Damage and Secondary Infections

Immune Dysregulation

Activated Inflammatory

Cascade

Overproduction of Cytokines

IL-4, IL-13, IL-31

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. Irvine AD, et al. N Engl J Med. 2011;365:1315-1327.

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One Approved Biologic Agent for AD

Dupilumab

Approved as second-line treatment for moderate to severe AD not controlled

by topical treatments

Anti-IL-4Rα targets IL-4 and IL-13 receptors

Subcutaneous injectable given every other

week after initial dose

Approved March 2019 for ages 12–17

with moderate to severe AD

mAb, monoclonal antibody. Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22. Dupilumab (Dupixent®) PI 03/2019.

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IGA Reduction at Week 16

12% (n=315)

8% (n=236)

10% (n=224)

39% (n=319)

36% (n=233)

38% (n=224)

39% (n=106)

36% (n=239)

37% (n=223)

0 5 10 15 20 25 30 35 40 45

LIBERTY AD CHRONOS (N=740)*

SOLO 2 (N=708)

SOLO 1 (N=671)

% Achieving IGA Endpoint from Baseline

Patients Achieving IGA Score of 0/1 and Reduction of ≥2 Points at Week 16 in SOLO 1, SOLO 2, and CHRONOS Trials

Dupilumab 300 mg QW Dupilumab 300 mg Q2W Placebo

*CHRONOS combined dupilumab with concomitant topical corticosteroid.IGA, Investigator’s Global Assessment; Q2W, every other week; QW, every week.

Simpson EL, et al. N Engl J Med. 2016;375:2335-2348.

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EASI Reduction at Week 16 and 52

Adapted from: Blauvelt A, et al. Lancet. 2017;389:2287-2303.

CHRONOS Trial Reduction in EASI Scores Over Time*

*Least squares mean percent change in EASI score over time. EASI, Eczema Area and Severity Index.

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100% M

ean

Chan

ge in

EAS

ISco

re fr

om B

asel

ine* Placebo + TCS

Dupilumab 300 mg QW + TCS

Dupilumab 300 mg Q2W + TCS

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52Study Week

-43%

-77%

-77%

-46%

-78%

-80%

53

Pruritus NRS Reduction at Week 16 and 52

-29 (n=315)

-27 (n=264)

-55 (n=319)

-55 (n=270)

-56 (n=106)

-56 (n=89)

-60

-50

-40

-30

-20

-10

0

% R

educ

tion

in P

rurit

us N

RS

Placebo + TCS Dupilumab 300 mg QW + TCS Dupilumab 300 Q2W + TCS

Week 16 Week 52

CHRONOS Trial Reductions in Pruritus*

Blauvelt A, et al. Lancet. 2017;389:2287-2303.

*Percentages are rounded.

54

Common AEs and Other Effects of Dupilumab

Incr

ease

d Ri

sk

Redu

ced

Risk Skin infection

(RR 0.54; 95% CI 0.42–0.69)

AD exacerbation (RR 0.44; 95% CI 0.34–0.59)

Injection-site reaction (RR 2.24; 95% CI 1.68–2.99)

Headache (RR 1.47; 95% CI 1.05–2.06)

Conjunctivitis (RR 2.64; 95% CI 1.79–3.89)

A meta-analysis of 8 dupilumab RCTs assessed common drug-related AEs in adults with moderate to severe AD

Ou Z, et al. Int Immunopharmacol. 2018;54:303-310.

CI, confidence interval; RR, risk ratio.

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Phase 3 Trial of Dupilumab in Adolescents

First biologic study of AD in ages 12–17 years (NCT03054428)– 251 patients with moderate to severe disease randomized to dosing

every 4 weeks, every 2 weeks, or placebo– Coprimary endpoints EASI response and IGA score of 0 (clear) or

1 (almost clear)– Secondary endpoint reduction in pruritus NRS

Preliminary phase 3 results presented September 2018 at EADV showed statistically significant improvement in skin, pruritus, and QOL by week 16– Approval granted for use in ages 12–17 in March 2019

Clinicaltrials.gov. NCT03054428 https://clinicaltrials.gov/ct2/show/NCT03054428. Simpson EL, et al. EADV abstract D3T01.1L. Presented September 15, 2018.

EADV, European Academy of Dermatology and Venereology.

56

Phase 3 Dupilumab Trial in Adolescents

18

38

46

24

4248

2.4 8.2

19

0

10

20

30

40

50

60

IGA EASI-75 Pruritus NRS

Perc

enta

ge

16 Weeks

Dupilumab 300 mg Q4W Dupilumab 200/300 Q2W Placebo

Simpson EL, et al. EADV abstract D3T01.1L. Presented September 15, 2018.

Patients Achieving Trial Endpoints of IGA 0/1,Improvement of ≥75% and Reductions in Pruritus*

*Percentages are rounded. Q4W, every 4 weeks.

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Phase 3 Dupilumab Trial in Adolescents: Safety

1311

6

11 10 9

20

5 5

0

5

10

15

20

25

Skin Infections Conjunctivitis Injection-Site Reactions

Perc

enta

ge

16 Weeks

Dupilumab 300 mg Q4W Dupilumab 200/300 Q2W Placebo

Most Common Adverse Events*

Simpson EL, et al. EADV abstract D3T01.1L. Presented September 15, 2018.*Percentages are rounded.

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Case Study 2, Part 2

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Brianna, Part 2

Brianna was prescribed a mid-strength topical corticosteroid– Instructed to apply once daily for 2 weeks

Begins to flare upon topical corticosteroid taper and daily TCI

Brianna reports struggling with anxiety and depression because of itching and appearance

It’s important to employ shared decision-making regarding treatment for this patient– Patient says she’s too busy to undergo phototherapy

– She says she wants a course of oral corticosteroids because they have always worked before

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Considerations in Managing AD

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Identifying Treatment Failure

No validated biomarkers to assess treatment response

No standard definition for treatment failure

Boguniewicz M, et al. J Allergy Clin Immunol Pract. 2017;5:1519-1531. Spergel JM. UpToDate. Last Updated: August 15, 2018.

Definitions Proposed by

Expert Panel in 2017

No relief from impairment

(particularly in QOL)

Unacceptable AEs leading to treatment

discontinuation

Lack of stable, long-term control (flares continue)

Inadequate clinical

improvement

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Causes for Treatment Failure

Poor understanding of disease– Clinicians, caregivers, patients unaware AD is systemic,

inflammatory disorder

Poor adherence/incorrect medication use– TCS phobia affects up to 80% of patients and

caregivers1

Exacerbating factors/environmental triggers Secondary infection

– Bacterial, viral, dermatophyte

Hypersensitivity reactions to treatments Incorrect diagnosis

1. Li AW, et al. JAMA Dermatol. 2017;153:1036-1042. 2. Simpson EL, J Am Acad Dermatol. 2016;74:491-498.

“Misdiagnosis of atopic dermatitis is a

concern … it can contribute to making the disease worse.”2

–Dirk M. Elson, MD Past President, AAD

2013–2014

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Considerations for Dupilumab

Cost and coverage are important considerations Method of administration

– Subcutaneous injection may be difficult for some

Patients with moderate to severe AD have increased risk for infection– Dupilumab reduces risk for infection vs placebo

Insurance requires prior authorization for immunomodulators or biologics– Forms and requirements different for each company

For insurance to cover, clinicians must document– Diagnosis of AD (not just “eczema”)– Condition severity– Prior treatments and failures

• Specify the type of failure: inadequate response to medium- or high-potency TCS, suboptimal improvement, failure to achieve long-term control, unacceptable AEs

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. Eichenfield LF, et al. Am J Clin Dermatol. 2019;20:443-456. Kuznik A, et al. Dermatol Ther (Heidelb). 2017;7:493-505. Ou Z, et al. Int Immunopharmacol. 2018;54:303-310.

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Who Should Be Referred to Specialists?

Phototherapy‡

Stepping up from Moderate to Severe AD: If patient is still symptomatic* despite optimal

therapy and conservative management, options include the following†

Dupilumab§ Systemic immunosuppressantsǁ

*Poorly or inadequately controlled signs and symptoms of AD. †Before stepping up therapy, patient should be assessed for nonadherence, comorbidities, other factors that could mitigate against treatment response. ‡Patient should be willing and able to commit to phototherapy’s cost and understand its limited access. §Indicated for patients ≥12 years with moderate to severe AD. ǁNone are approved for AD, except for systemic corticosteroids, which are not typically recommended.

For some, consider acute treatment:• Wet-wrap

therapy• Hospitalization

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22. Eichenfield LF, et al. J Allergy Clin Immunol. 2017;139:S49-S57.

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Multidisciplinary Collaboration

AD specialists are usually dermatologists or allergists Patients with moderate to severe AD are good

candidates for multidisciplinary management which can include immunosuppressive or biologic therapy as well as additional specialist care

PCPs (family medicine, pediatricians, NPs, PAs) are the center of this team

Comorbid atopic diseases, sleep problems and mental health impacts should be addressed and appropriate specialists used if needed

Utilizing this multi-disciplinary team ensures that patients with AD get a more global approach to care to achieve optimal outcomes and give patients back their life

NPs, nurse practitioners; PAs, physician assistants.LeBovidge JS, et al. J Allergy Clin Immunol. 2016;138:325-334.

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Strategies for Adherence and Patient Education

Written eczema “action plans”

Nurse-led eczema workshops

Providing psychological support

Caring for comorbidities (eg, asthma, cardiovascular, allergies, obesity)

Multidisciplinary patient education

Discussing patients’ fears about treatment

Asking patients to choose preferred treatment vehicle (especially with topicals)

Bass AM, et al. J Clin Med. 2015;4:231-242. Borok J. Dermatology News. June 27, 2017. Patel NU, et al. Am J Clin Dermatol. 2017;18:323-332. Snyder, et al. Cutis. 2015;96:397-401.

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Summary

AD is an inflammatory disease involving immune dysregulation and epidermal barrier breakdown

Disease negatively affects QOL of children and adults, as well as their family members

Diagnosis based on clinical presentation

AD associated with multiple comorbidities—even later in life

Severity assessments are necessary to determine treatment

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Summary (cont)

Multiple treatments available depending on disease severity

Systemic immunosuppression not suitable for long-term maintenance and none approved in children

Dupilumab the only biologic thus far available

– Trials show long-term efficacy

– Recent phase 3 trial in adolescents yielded positive results

– Approved by FDA in March 2019 for adolescents 12–17 with moderate to severe AD

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Thank You!