1
Provided by Integrity Continuing Education, Inc.Supported by an educational grant from Sanofi Genzyme and Regeneron Pharmaceuticals.
Advances in Management of Moderate to Severe Atopic Dermatitis in Children and Adolescents
2
Faculty and Affiliation
Michael S. Blaiss, MDClinical Professor of
PediatricsMedical College of Georgia
Augusta UniversityAugusta, Georgia
3
Faculty Disclosures
Michael S. Blaiss, MDConsulting Fees:Sanofi Regeneron Pharmaceuticals Inc.
4
Learning Objectives
Accurately diagnose and assess severity of disease in children and adolescents with atopic dermatitis (AD)
Utilize guidelines to design treatment plans for patients with AD based on disease severity
Identify patients with AD who are inadequately controlled on topical therapy and are candidates for treatment with biologic therapy
Discuss efficacy and safety of biologic therapies for the management of patients with AD and considerations for their use
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Burden of Pediatric AD
6
Prevalence of AD in Children
9%–18% in the US1
~20% worldwide2
85% of cases present before 5 years of age3
30% of childhood cases persist into adult years3
AD often the first sign of long-term disease continuum4
– 60% develop asthma or allergic rhinitis later in life
– ~30% develop food allergies
1. Shaw TE, et al. Health J Invest Dermatol. 2011;131:67-73. 2. Nutten S. Ann Nutr Metab. 2015;66(Suppl 1):8-16. 3. Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. 4. Hill DA, Spergel JM. Ann Allergy Asthma Immunol. 2018;120:131-137.
The Atopic March
Dens
ity o
f Dis
ease
0 to 5 6 to 11 12 to 17 18 to 23 24 to 29 30 to 35 36 to 41 42 to 47 48 to 53 54 to 59
At a Diagnosis (mo)
0.8
0.6
0.4
0.2
0
Atopic dermatitisFood allergyAsthmaAllergic rhinitis
Figure adapted from: Ann Allergy Asthma Immunol. 2018;120:131-137.
7
AD: Psychosocial/Health-Related Burden
Detrimental to QOL1,2
• Heavy psychosocial impact– Due to stigma, isolation, embarrassment, bullying,
unpredictability of flares
• Suicidal ideation reported by ~20% with severe disease3
• Negative impact on academic performance2
Infections• AD leads to invasive infections, including
eczema herpeticum, septicemia, osteomyelitis, and skin abscesses4
QOL, quality of life.
AD patient infected with eczema herpeticum. Photo courtesy of Peck Y. Ong, MD
1. Simpson EL. J Am Acad Dermatol. 2016;74:491-498. 2. Drucker AM. J Invest Dermatol. 2017;137:26-30. 3. Kimata H. Suicide Life Threat Behav. 2006;36:120-124. 4. Sun D, Ong PY. Immunol Allergy Clin North Am. 2017;37:75-93.
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AD: Psychosocial/Health-Related Burden
Negative effect on QOL1• Negative impact on sleep (mostly due to pruritus) in 47%–60%
of children2• Itching lasts ≥18 hours in ~42% of patients2• Leads to excessive daytime sleepiness, fatigue, reduced HRQOL• Study of 92,642 children found those with AD had significantly
increased risk for ADHD, depression, anxiety, conduct disorder, and autism3
Heavy care/financial burden for parents, caregivers• ~40% of parents/caregivers report interrupted sleep
>3×/week due to child’s AD4• Patients average 9 flares/year, each lasting ~15 days5• Out-of-pocket expenses for families estimated to be
approximately 35% of expendable income in the month before an office visit6
ADHD, attention deficit hyperactivity disorder; HRQOL, health-related quality of life.1. Simpson EL, et al. J Am Acad Dermatol. 2016;74:491-498. 2. Chang YS, Chiang BL. Int J Mol Sci. 2016;174:462. 3. Yaghmaie P, et al. J Allergy Clin Immunol. 2013;131:428-433. 4. National Eczema Association Caregiver Survey. https://nationaleczema.org/in-your-words-survey-series/. 5. Zuberbier T. J Allergy Clin Immunol. 2006;118:226-232. 6. Filanovsky MG, et al. J Pediatr. 2016;169:284-290.
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AD Mental Health Comorbidities
Common psychological comorbidities include1-3
– Anxiety– Depression– Poor self-image– ADHD– Behavioral/conduct problems
In GINIplus, children whose AD appeared to resolve in 1st or 2nd year of life still had emotional/behavioral difficulties by 10 years of age4
1. Brunner PM, et al. J Invest Dermatol. 2017;137:18-25. 2. Yaghmaie P, et al. J Allergy Clin Immunol. 2013;131:428-433. 3. Paller A, et al. Am J Clin Dermatol. 2018;19:821-838. 4. Schmitt J, et al. J Allergy Clin Immunol. 2010;125:404-410.
GINIplus, German Infant Nutrition Intervention plus.
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More Than Skin Deep: AD Comorbidities
Referred to as “atopic march,” comorbidities recognized as components of AD disease continuum usually begin early in life1
Systemic immune activation underlying AD correlates with common noncutaneous comorbidities2– Allergic rhinitis, asthma, conjunctivitis,
eosinophilic esophagitis The prevalence of food allergy increases
with AD severity in children– Approximately 40% of children with
moderate/severe AD have ≥1 food allergy compared with 8% in the general pediatric population3
1. Brunner PM, et al. J Invest Dermatol. 2017;137:18-25. 2. Vernon N, et al. Allergy Asthma Proc. 2014;35:409-414. 3. Silverberg NB, et al. Cutis. 2016;97:227-232.
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Diagnosis and Severity Assessment
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Diagnostic Criteria for AD
AD is currently diagnosed based on history and clinical presentation– Personal or family history of atopy is a risk factor– Biomarkers not specific enough to confirm diagnosis or assess severity
IgE, immunoglobin E.
Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22; Eichenfield LF, et al. J Allergy Clin Immunol. 2017;139:S49-S57.
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(dermatologic manifestations of
alternate or concomitant diagnoses)
• Seborrheic dermatitis• Contact dermatitis (allergic or
irritant)• Scabies• Immunodeficiencies• Ichthyoses• Psoriasis• Photosensitivity dermatoses• Cutaneous T-cell lymphoma• Erythroderma of other causes
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Visual Representations of Moderate to Severe Pediatric AD
Xerosis Ill-defined erythema Papules, edema Erosions,
excoriations Oozing, crusting Lichenification Generally spares axillae and groin
Eichenfield LF, et al. J Am Acad Dermatol. 2014;70:338-351.
Photos courtesy of Mark Boguniewicz, MD, and 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.
Photos courtesy of Mark Boguniewicz, MD, and Sheila F. Friedlander, MD.
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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
AdolescentsPeriorbital 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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Other Diseases Can Look Like AD
Photos courtesy of Sheila F. Friedlander, MD.
Contact Dermatitis (both photos) Scabies
AD
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Guidelines
Allergists: AAAAI/ACAAI
Joint Task Force published in
20131
Dermatologists: 4-part series
from AAD published in
20143-6
Simplified, integratedversion merging
recommendations published in 20177
1. Schneider L, et al. J Allergy Clin Immunol. 2013;131:295-299. 2. Eichenfeld 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; AAD, American Academy of Dermatology; ACAAI, American College of Allergy, Asthma, and Immunology; PCPs, primary care providers.
AD guidelines designed for
PCPs and pediatricians2
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Testing Options
Test for1:
Secondary bacterial infections with disease
exacerbations
Food allergies for patients
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Severity Assessments
Accurate assessment of disease severity important for optimal treatment
Validated clinical scoring systems are not recommended by guidelines for general clinical use
Disease categorized into “mild,” “moderate,” and “severe” based on clinician assessment– IGA and ISGA scores that rank lesion severity from 0 (clear)
to 4 (severe) are most often used– Validated IGA score (vIGA-AD) recently introduced by
International Eczema Council
IGA, Investigator Global Assessment; ISGA, Investigator Static Global Assessment; vIGA-AD, validated Investigator Global Assessment-Atopic Dermatitis. Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. Validated IGA for atopic dermatitis. http://www.eczemacouncil.org/research/investigator-global-assessment-scale/.
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Severity Scoring in Clinical Practice
Guidelines recommend clinicians ask patients or their parents/caregivers general questions about itch, sleep, impact of disease on daily life– Incorporate patient-friendly scales only when practical
Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. Eichenfield LF, et al. J Allergy Clin Immunol. 2017;139:S49-S57.
ItchSleep
Daily Life
At each visit, ask about impact of AD on:
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AD = Altered Epidermal Barrier + Immune Dysregulation
Nonlesional
CLA, cutaneous lymphocyte-associated; IDEC, inflammatory dendritic epidermal cells; IFN, interferon; IL, Interleukin; LC, Langerhans cells; MC, mast cell; MØ, macrophage; Th, T helper cell; TSLP, thymic stromal lymphopoietin. Adapted from: Boguniewicz M, et al. Immunol Rev. 2011;242:233-246.
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Treatment Approaches
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“Yardstick” Guidelines Published in 2018
Developed to reconcile differing recommendations from multidisciplinary guidelines
Emphasis is on practical, step-by-step, “how-to” strategies to ensure clear or almost-clear skin from all levels of severity
Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. 23
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Treatment Goals
Restore barrier integrity Control skin inflammation
and itch Decrease xerosis Treat secondary infection Recognize and prevent triggers Reduce frequency of flares Improve and maintain QOL
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Basic Management: bathing, moisturizers, avoid irritants
Soak for 20 minutes– With or without oatmeal or baking soda – Quickly clean with mild wash
Or Quick 10 min bath Apply occlusive emollient immediately
http://www.google.com/imgres?imgurl=http://common1.csnimages.com/lf/1/hash/1727/1673114/1/Fish+N+Fun+Bath+Toy.jpg&imgrefurl=http://www.csnstores.com/edushape-915018-EDS1086.html&usg=__-UT5Vs7r0N9z04a6m1gEzmpyuMA=&h=400&w=400&sz=31&hl=en&start=9&zoom=1&um=1&itbs=1&tbnid=LvGtWopyfWx1tM:&tbnh=124&tbnw=124&prev=/images?q=children+fun+bath&um=1&hl=en&sa=G&rlz=1T4ADRA_enUS357US359&tbs=isch:1&ei=qJNyTdK3JobNhAfy09Qu
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Basic management: Skin Hydration & Barrier Therapy
Emollients• Improve skin barrier function• Reduce susceptibility to irritants• Adding emollients strengthens skin by delaying intercellular filaggrin
uncoiling• Regular use of topical CS can inhibit epidermal fatty acids synthesis* &
disrupt barrier function• alleviated by application of mixture of ceramides, free fatty acids &
cholesterol**• Support regular use of appropriate emollients
Darsow et al. ETFAD/EADV eczema task force 2009 position paper on diagnosis and treatment of atopic dermatitis. Journal compilation @2009 European Academy of Dermatology and Venereology 2010, 24, 317-328* Jensen JM, Pfeiffer S, Witt M, et al. Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis.J Allergy Clin Immunol 2009;124(3 Suppl 2):R19–28.** Kao JS, Fluhr JW, Man MQ, et al. Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity:inhibition of epidermal lipid synthesis accounts for functional abnormalities.J Invest Dermatol 2003;120(3):456–64.
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Topical Treatments for Mild Disease
Corticosteroids• TCS usually the first line
of treatment to reduce local inflammation
• Can cause skin atrophy and thinning if used inappropriately (eg, chronic use of high-potency TCS)
• No consensus regarding optimal dosing or frequency
PDE4 Inhibitor
• Crisaborole• Nonsteroidal• FDA approved in 2016,
first new treatment approved for AD in >15 years
• Inhibits cAMP levels • No data yet on
long-term use
Calcineurin Inhibitors
• TCIs: tacrolimus and pimecrolimus
• Nonsteroidal • Approved in 2000–2001• Inhibit
calcineurin-dependent T-cell activation
• No risk of skin atrophy• Use may be impeded
by black-box warning about increased risk for malignancy, despite lack of evidence to date
cAMP, cyclic adenosine monophosphate; FDA Food and Drug Administration; PDE4, phosphodiesterase 4; TCIs, topical calcineurin inhibitors; TCS, topical corticosteroids.Ahmed A, et al. Br J Dermatol. 2018;178:659-662; Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22; Paller AS, et al. J Allergy Clin Immunol. 2017;140:633-643.
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TCIs
Can be applied to face, extremities, and genital area Little systemic absorption Stinging/burning at application site most frequently cited adverse event Not indicated for:
– Children
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PDE4 Inhibition
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 2 phase 3 studies
(N=1,522 patients >2 years old) with mild to moderate AD randomized 2:1 to crisaborole or placebo
Primary endpoint: ISGA score of clear (0) or almost clear (1) by day 29 with ≥2 grades improvement from baseline
Paller AS, et al. J Am Acad Dermatol. 2016;75:494-503.
51.748.5
40.6
29.7
0
10
20
30
40
50
60
AD-301 AD-302
Patie
nts w
ith IS
GA
of C
lear
(0)
or A
lmos
t Cle
ar (1
) at D
ay 2
9 (%
)
P=0.005 P
30
Step-Care Management: Mild ADAc
ute
Trea
tmen
t
Basic Management1. Skin Care
• Moisturizer, liberal and frequent• Warm baths or showers using non-soap
cleansers, usually 1x/day followed by moisturizer (even on clear areas)
2. Trigger Avoidance• Common allergens and irritants
Basic Management1. Skin Care
• Moisturizer, liberal and frequent • Warm baths or showers using non-soap
cleansers, usually 1x/day followed by moisturizer (even on clear areas)
2. Antiseptic Measures• Dilute bleach bath (or equivalent)
≤2x/week according to severity (especially with recurrent infections)
3. Trigger Avoidance • Patient-specific proven allergens and
irritants• Consider comorbidities
Apply TCS to Inflamed SkinLow-to-medium potency TCS 2x/day for 3-7 days beyond clearance
(consider TCI, crisaborole)
Mai
nten
ance
Tr
eatm
ent
Nonlesional
Mild
Adapted from: Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22.
31
Treatments for Moderate to Severe Disease
Systemic Immunosuppression
•Cyclosporine•Methotrexate•Mycophenolate mofetil•Azathioprine•Corticosteroids
Limitations:• All but corticosteroids are off-
label for AD• Not usable for long-term
maintenance because of multiple systemic adverse events
Phototherapy
•Primarily narrow-band UVB
Limitations:• Available only for patients ≥
12 years• Access/convenience (few
phototherapy centers)• Cost and travel time often not
covered by insurance• Very low risk for cutaneous
malignancies and cataracts
Biologics
•Dupilumab, only targeted biologic approved for moderate to severe AD
Limitations:• Currently approved only for
patients ≥12 years• Subcutaneous injection• Too new to be included
in guidelines• No data for optimal ways to
step down or discontinue after clear skin is achieved
UVB, ultraviolet B.
32
Moderate
Step-Care Management: Moderate-to-Severe ADAc
ute
Trea
tmen
tM
aint
enan
ce
Trea
tmen
t
Basic Management + Topical Anti-inflammatory Medication
Maintenance TCS• Low potency 1×-2×/day (including face)• Medium potency 1×-2×/day (except face)
OR Maintenance TCIa• 1×-2×/day • 2×-3×/week (not an indicated dose)
OR Crisaborole 2%a• 2×/day
Basic Management + Referral to Specialist
Phototherapy (Not approved for ≤12 years)Dupilumabb (Available for ages ≥12 years)Systemic Immunosuppressants
• Cyclosporine Ac• Methotrexatec• Mycophenolate mofetilc• Azathioprined
Consider acute treatment for some patients• Wet-wrap therapy or hospitalization
Apply TCS to Inflamed SkinMedium-to-high potency TCS 2×/day for 3-7
days beyond clearance (consider TCI, crisaborole)
Adapted from: Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22.
If not resolved in 7 days, considernonadherence, misdiagnosis,
contact allergy to prescription, referral
aIndicated for patients at least 2 years old; bIndicated for patients at least 12 years old; cNot approved by FDA to treat AD; dNot recommended for long-term maintenance.
Severe
Rarely used in children
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Causes for Treatment Failure
Poor understanding of disease– Clinicians, caregivers, patients often 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 Incorrect diagnosis Disease is severe
1. Li AW, et al. JAMA Dermatol. 2017;153:1036-1042.
34
Biologic Therapy
35
One Approved Biologic Agent: Dupilumab
Fully Human mAb Anti-IL-4Rα targets IL-4 and IL-13 receptor, blocking Th2 cytokine
signaling pathways
Approved as second-line treatment for moderate to severe AD after
topical treatments
Subcutaneous injection approved for patients ≥12 years
Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22. Dupilumab (Dupixent®) PI June 2019.
mAb, monoclonal antibody.
Granted FDA approval in March 2017 based on short-term results in SOLO 1 and SOLO 2 trials and long-term
results in CHRONOS AD LIBERTY trial. Approved for adolescents ages 12–17 in March 2019
36
Dupilumab Phase 3 Clinical Trials
Safety and efficacy demonstrated in 3 placebo-controlled clinical trials
SOLO 1, SOLO 2Evaluated dupilumab as monotherapy for
16 weeks
LIBERTY AD CHRONOSEvaluated dupilumab in
combination with TCS for 52 weeks
Blauvelt A, et al. Lancet. 2017;389:2287-2303. Simpson EL, et al. N Engl J Med. 2016;375:2335-2348.
Total of 2,119 adults with moderate to severe AD
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Efficacy in Global Assessment
Improvement in IGA Score (primary endpoint)
Adapted from: Simpson EL, et al. N Engl J Med. 2016;375:2335-2348.
0
10
20
30
40
50
60
70
80
SOLO 1 SOLO 2
Perc
enta
ge o
f Pat
ient
s with
Q
ualif
ying
IGA
Scor
e (%
)
Placebo Dupilumab Q2W Dupilumab QW
Investigator Global
Assessment (IGA) scoring system ranks
lesion severity from 0 (clear) to
4 (severe)
Q2W, every other week; QW, every week.
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Efficacy in Reducing Disease Severity
Improvement in EASI-75 Score (secondary endpoint)
Adapted from: Simpson EL, et al. N Engl J Med. 2016;375:2335-2348.
0
10
20
30
40
50
60
70
80
SOLO 1 SOLO 2
Perc
enta
ge o
f Pat
ient
s
Achi
evin
g E
ASI-7
5 (%
)
Placebo Dupilumab Q2W Dupilumab QW
Eczema Area and Severity Index-75
(EASI-75) measures a 75% reduction from
baseline in extent and severity of erythema,
induration, papulation, edema, excoriations,
and lichenification
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Efficacy in Pruritus
Adapted from: Awosika O, et al. Clin Cosmet Investig Dermatol. 2018;11:41-49. Blauvelt A, et al. Lancet. 2017;389:2287-2303.
Patients (%) in phase 3 trials who achievedimprovement of ≥4 points on pruritus NRS
0 10 20 30 40 50 60 70
Week 16 Phase 3 CHRONOS trial
Week 52 Phase 3 CHRONOS trial
Week 16 Phase 3 SOLO 1 trial
Week 16 Phase 3 SOLO 2 trial
Dupilumab Q2W
Dupilumab QW
Placebo
Dupilumab + TCS Q2W
Dupilumab + TCS QW
Placebo + TCS
NRS, numerical rating scale.
40
Efficacy in QOL Improvements
Patients in phase 3 trials who demonstrated improvements in QOL (eg, sleep, anxiety, depression) as indicated by least squares* mean change in dermatology life quality index (DLQI) score
Adapted from: Awosika O, et al. Clin Cosmet Investig Dermatol. 2018;11:41-49; Blauvelt A, et al. Lancet. 2017;389:2287-2303.
-12-10-8-6-4-20
Week 16 Phase 3 CHRONOS trial
Week 52 Phase 3 CHRONOS trial
Week 16 Phase 3 SOLO 1 trial
Week 16 Phase 3 SOLO 2 trial
*Least squares incorporate percent change over time, primary analysis, and sensitivity analysis.
Dupilumab Q2W
Dupilumab QW
Placebo
Dupilumab + TCS Q2W
Dupilumab + TCS QW
Placebo + TCS
41
Dupilumab: Trial Findings in Safety
Dupilumab found to be highly tolerable in both SOLO 1 and SOLO 2 – Only SAE was exacerbation of AD, reported in 2 patients
in SOLO 1 and 1 patient in SOLO 2• Same SAE experienced by patients taking placebo: 3 in SOLO 1,
5 in SOLO 2
– Other adverse events included infections: ~35% in both trials (non-skin infections: upper respiratory or oral) vs ~30% for those taking placebo
– Injection-site reactions also common: 13%–19% for those injecting the drug weekly vs 6% for placebo
Simpson EL, et al. N Engl J Med. 2016;375:2335-2348.
SAE, serious adverse event.
42
Long-Term Efficacy
CHRONOS Study: Patients (%) showing sustained improvement over time in pruritus scores
Adapted from: Blauvelt A, et al. Lancet. 2017;389:2287-2303.
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
100
90
80
70
60
50
40
30
20
10
0
18%
37%
59%54%
51%
27%
16%20%
16%
39%
13%8%
Perc
enta
geAc
hiev
ing
≥4 P
oint
s Im
prov
emen
t in
Peak
Pru
ritus
51%
44%
43
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 not controlled by
topicals randomized to dosing every 4 weeks, every 2 weeks, or placebo
– Coprimary endpoints EASI-75 response and IGA score of 0 (clear) or 1 (almost clear)
– Secondary endpoint improvement 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
Simpson EL, et al. EADV abstract D3T01.1L. Presented September 15, 2018.
EADV, European Academy of Dermatology and Venereology.
44
Phase 3 Dupilumab Trial in Adolescents: Results
17.9
38.1
45.5
24.4
41.5
47.9
2.4 8.2
19
0
10
20
30
40
50
60
IGA EASI-75 Pruritus NRS
Perc
enta
ge
16 Weeks
Q4W Q2W Placebo
Simpson EL, et al. EADV abstract D3T01.1L. Presented September 15, 2018.
Patients Achieving Trial Endpoints
Q4W, every 4 weeks.
45
Phase 3 Dupilumab Trial in Adolescents: Safety
1311
6
11 108.5
20
5 5
0
5
10
15
20
25
Skin Infections Conjunctivitis Injection-Site Reactions
Perc
enta
ge
16 Weeks
Q4W Q2W Placebo
Simpson EL, et al. EADV abstract D3T01.1L. Presented September 15, 2018.
Most Common Adverse Events
46
Ongoing/Recruiting Clinical Trials of Dupilumab in Children
Trial Name*/ Number Focus # Pts/Ages Phase
Estimated Completion
NCT02612454† Long-term safety 765
≥6 mos to
47
Considerations in Prescribing Dupilumab
Cost and coverage important considerations Method of administration (subcutaneous may be particularly
difficult for children) 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 adverse events
– Impact of disease on QOL
Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22.
48
Emerging Biologics Being Studied in Adolescents
Agent Name(s)Study ID # (Acronym)
Phase/StatusNo. Pts
Age Range, Study PopulationPrimary Endpoint(s)
IL-13 Inhibitor (subcutaneous)
Tralokinumab NCT03526861ECZTRA 63/Recruiting
29412–17 with moderate/severe ADIGA and EASI-75, baseline to week 16
IL-23 Inhibitor (subcutaneous)
Risankizumab NCT03706040 2/Recruiting155≥12 years with moderate/severe ADEASI-75, baseline to week 16
IL-31 RA (subcutaneous)
Nemolizumab
NCT03985943 3/Recruiting750
≥12 years with moderate/severe ADIGA ≥2 point reduction and EASI-75, baseline to week 16
NCT03989349 3/Recruiting750
≥12 years with moderate/severe ADIGA ≥2 point reduction and EASI-75, baseline to week 16
Source: ClinicalTrials.gov, using filters for “atopic dermatitis eczema,” “phase 2,” “phase 3,” “recruiting,” “active, not recruiting,” and “child (birth‒17)”.
IL, interleukin; RA, receptor antagonist.
49
Emerging Small-Molecule Agents Being Studied in Children/Adolescents
Agent Name(s)Study ID # (Acronym)
Phase/StatusNo. Pts
Age Range, Study PopulationPrimary Endpoint(s)
JAK Inhibitors (Oral)
Abrocitinib (PF-04965842)
NCT03575871JADE Mono-2
3/Recruiting375
≥12 years with moderate/severe ADIGA and EASI-75, baseline to week 12
NCT03796676 JADE TEEN
3/Recruiting225
12–17 years with moderate/severe ADIGA and EASI-75, baseline to week 12
NCT03627767 3/Recruiting1,370≥12 years with moderate/severe ADLOR requiring rescue Tx, week 12 to week 52
NCT03422822 JADE EXTEND
3/Recruiting2,300
≥12 years with moderate/severe ADTEAEs, SAEs, and ∆ from baseline in lab values, ECG, and vital signs, up to 96 weeks
Baricitinib(LY3009104)
NCT03952559 BREEZE-AD-PEDS
3/Recruiting465
2–17 years with moderate/severe AD% achieving ≥2 point IGA improvement, up to 16 weeks; AUC and Cmax, baseline to 2 weeks
∆, change; AUC, area under curve; Cmax, maximum concentration; ECG, electrocardiogram; LOR, loss of response; SAEs, serious adverse events; TEAEs, treatment-emergent adverse events; Tx, treatment.
Source: ClinicalTrials.gov, using filters for “atopic dermatitis eczema,” “phase 2,” “phase 3,” “recruiting,” “active, not recruiting,” and “child (birth‒17)”.
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Emerging Small-Molecule Agents Being Studied in Adolescents (cont)
Agent Name(s)Study ID # (Acronym)
Phase/StatusNo. Pts
Age Range, Study PopulationPrimary Endpoint(s)
JAK Inhibitors (Oral)
Ruxolitinib NCT03745638
TRuE AD13/Recruiting
600≥12 years with ADIGA-TS, baseline to week 8
NCT03745651 TRuE AD2
3/Recruiting600
≥12 years with ADIGA-TS, baseline to week 8
Upadacitinib
NCT03661138 3/Active272≥12 years with moderate/severe AD% experiencing AEs up to 141 weeks
NCT03569293Measure Up 1
3/Recruiting810
≥12 years with moderate/severe ADEASI-75 and vIGA with ≥2 grades of reduction, up to 16 weeks
NCT03607422 3/Recruiting810≥12 years with moderate/severe ADEASI-75 and vIGA with ≥2 grades of reduction, up to 16 weeks
NCT03568318AD Up
3/Recruiting810
≥12 years with moderate/severe ADEASI-75 and vIGA with ≥2 grades of reduction, up to 16 weeks
IGA-TS, Investigator Global Assessment Treatment Success.
Source: ClinicalTrials.gov, using filters for “atopic dermatitis eczema,” “phase 2,” “phase 3,” “recruiting,” “active, not recruiting,” and “child (birth‒17)”.
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Considerations in AD Management
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Improving Patient Satisfaction
Results from National Eczema Association’s “In Your Words” patient satisfaction survey (N=192) in 2016
Treatment Satisfaction:Overall, are you satisfied with the
treatment of AD?
Physician Satisfaction:Overall, do you think doctors know
how to treat AD?
National Eczema Association Caregiver Survey. https://nationaleczema.org/in-your-words-surveyseries/.
NO(91%)
YES(9%)
NO(86%)
YES(14%)
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Improving Patient Satisfaction (cont)
Participant recommendations from “In Your Words” survey to improve satisfaction– Pay attention to the mental health/QOL impact of AD– Demonstrate understanding that AD is more than just a
skin condition– Treat root cause, not just symptoms– Convey an attitude of caring about the patient– Don’t rely too heavily only on corticosteroids– Quickly recognize when patients should be referred for
more advanced treatments
National Eczema Association Caregiver Survey. https://nationaleczema.org/in-your-words-surveyseries/.
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Shared Decision Making
Expertise
Shared Decision
Healthcare Provider(pediatrician, nurse, NP, PA,
other clinicians)Patient/Caregiver
Diagnosis Treatment options Potential benefits Potential adverse events Treatment expectations
Values Lifestyle preferences
(may include schedule, socioeconomic factors)
Previous experience
Adapted from: Blaiss MS, et al. Ann Allergy Asthma Immunol. 2019;122:463-470.
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Important Patient Education Points
Written treatment
plan increases likelihood of adherence
Moisturize frequently throughout
the day
Topical medications do not take the place of moisturizers
Continue maintenance
therapies even when
skin appearshealthy
AD treatments will not work if they aren’t
used!
Eichenfield LF, et al. Pediatrics. 2015;136:554-565.
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Summary
AD is an inflammatory disease involving immune dysregulation and epidermal barrier breakdown
Disease negatively affects QOL of children and parents/caregivers Diagnosis based on clinical presentation AD leads to multiple comorbidities—even later in life Severity assessments are necessary to determine treatment 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
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Thank You!
Advances in Management of Moderate to Severe Atopic Dermatitis in Children and AdolescentsFaculty and AffiliationFaculty DisclosuresLearning ObjectivesBurden of Pediatric AD Prevalence of AD in ChildrenAD: Psychosocial/Health-Related Burden AD: Psychosocial/Health-Related Burden AD Mental Health ComorbiditiesMore Than Skin Deep: AD Comorbidities Diagnosis and Severity AssessmentDiagnostic Criteria for ADVisual Representations of Moderate to Severe Pediatric ADClinical Features in Darker Skin TypesDistribution Patterns Vary with AgeOther Diseases Can Look Like ADGuidelinesTesting OptionsSeverity AssessmentsSeverity Scoring in Clinical PracticeAD = Altered Epidermal Barrier + Immune Dysregulation Treatment Approaches��“Yardstick” Guidelines Published in 2018Treatment GoalsBasic Management: bathing, moisturizers, avoid irritantsBasic management: Skin Hydration & Barrier Therapy�Topical Treatments for Mild DiseaseTCIs PDE4 InhibitionStep-Care Management: Mild ADTreatments for Moderate to Severe DiseaseStep-Care Management: Moderate-to-Severe ADCauses for Treatment FailureBiologic Therapy��One Approved Biologic Agent: Dupilumab Dupilumab Phase 3 Clinical TrialsEfficacy in Global AssessmentEfficacy in Reducing Disease SeverityEfficacy in PruritusEfficacy in QOL ImprovementsDupilumab: Trial Findings in SafetyLong-Term EfficacyPhase 3 Trial of Dupilumab in AdolescentsPhase 3 Dupilumab Trial in Adolescents: ResultsPhase 3 Dupilumab Trial in Adolescents: SafetyOngoing/Recruiting Clinical Trials of Dupilumab in ChildrenConsiderations in Prescribing DupilumabEmerging Biologics Being Studied in AdolescentsEmerging Small-Molecule Agents Being Studied in Children/Adolescents Emerging Small-Molecule Agents Being Studied in Adolescents (cont)Considerations in �AD ManagementImproving Patient SatisfactionImproving Patient Satisfaction (cont)Shared Decision Making Important Patient Education PointsSummaryThank You!