Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.

1. Translating Advances in Therapeutics
to Pediatrics
Amy S. Paller, MS, MD
Professor of Dermatology and Pediatrics
Northwestern Univ. Feinberg School of
Medicine, Chicago
Leslie Castelo-Soccio, MD, PhD
Assistant Professor of Pediatrics and
Dermatology
University of Pennsylvania, Philadelphia
Dr. Castelo-Soccio has no conflicts to discloseDr. Paller (related to AD or AA) has been an investigator for
Galderma, Incyte, Leo, and Regeneron, and a consultant for
AbbVie, Asana, Dermavant, Dermira, Galderma, Eli Lilly, Forte,
Leo, Matrisys, Menlo, Morphosys/Galapagos, Novartis, Pfizer,
and Sanofi-Regeneron

2. Children are not just little adults
Different clinical features, differential diagnosis,
course, and responses/tolerance of therapy

3. Children are not just little adults
• Diagnosis largely clinical and more straightforward than adults
3
• Distribution in young child
- Diaper area sparing
- More cheek, chin, trunk
- More exudation
Atopic Dermatitis
• In older child, adolescent
- More periorbital, perioral,
neck, flexural, hands, feet
- More lichenification with
chronicity
• Environmental exposure (saliva,
food, friction), microbiome effects,
or inherent differences in skin at
different sites at different ages?

4. Children are not just little adults
• Similarly clinical diagnosis and resembles adult alopecia
• Different needs based on age of patient/ developmental stage ….As
in atopic dermatitis…..
• Treatment is family oriented and care must be taken to treat child
and not the care taker
• Different tolerance for therapies (injections, irritants)
• Consideration of weight based therapies and potential absorption
due to high head surface area to body surface area
4
Alopecia areata/totalis/universalis

5. Differential diagnosis in children
Alopecia areata
• Tinea capitis
• Telogen effluvium
• Trichotillomania
• Loose anagen syndrome
• Temporal triangular alopecia
• Genodermatoses with sparse, fragile
hair
Atopic Dermatitis
• Immunodeficiencies (HIES, WAS)
• Ichthyoses, esp Netherton
• Seborrheic dermatitis
• Psoriasis
• Scabies
• Allergic/ irritant contact dermatitis
• Widespread tinea
• Cutaneous T-cell lymphoma

6. Epidemiology / Natural History
Alopecia areata
• <20 y/o’s 2nd largest group presenting for care
• 40% with AA experience 1st episode by age 20
• Younger age may predict more severe disease
• Onset in childhood more frequent in girls (1.5:1)
• Severe alopecia and early age higher in boys
Atopic Dermatitis
• Primarily in infants and young children
- 10-20% of children overall
- 90% start under 5 years of age
- 60% by 1 year of age
- Girls = boys
Prevalence by age:
Atopic Dermatitis
Caldwell et al. JAAD 2017
Augustin et al. Dermatology 2015

7. Atopic Dermatitis
 Percentage of children with mod-
severe AD increases with age, esp.
after 3 years (p<.0002)
Disease Severity in Children
Silverberg, Simpson. Pedi Allergy Immunol. 2013;24:476
Alopecia areata
SALT 0-24%
(17.9%)
SALT 24-49%
(11.6%)
SALT 50-74%
(9.2%)
SALT 75-99%
(15.8%)
SALT 100%
(45.6%)
Wohlmuth-Wieser et al. Pediatr Dermatol. 2018;35:164
• Percentage within NAAF Registry
• NAAF Registry is a skewed population
• Population studies (eg, in Asian and middle
Eastern populations) were mainly mild

8. Immune Pathways in Skin and Blood
8
Atopic Dermatitis
• Skin phenotypes early AD vs. adult AD
- <5 year olds with AD for < 6 months
- Strong Th2 skewing in skin
- Th2 skewing in nonlesional skin much higher early vs. adult
Esaki et al. JACI
2016;138:1639
Alopecia areata: Not investigated in children
• More Th17 activation
than adults
• Persistently low Th1/Th2
ratios in AD vs. control
children (skin and blood)
Esaki et al. JACI 2016;138:1437
Czarnowicki et al. JACI 2015;136:941

9. Barrier Issues in Pediatric vs. Adult Skin
9
Atopic Dermatitis
• Reduction in barrier proteins, such as filaggrin, in biopsies is reflective
of chronicity and not in first 6 months (gene arrays, qRT-PCR, IHC)
Brunner et al. JACI 2018;141:2094
Alopecia areata: Not investigated in children
• Lipid and tight junction abnormalities present
early on and likely major cause of barrier defects
Esaki et al. JACI
2016;138:1639
Pedi AD Pedi control
Adult controlAdult AD

10. QoL and Neuropsychiatric Comorbidities
Atopic Dermatitis
• Depression
• Anxiety
• Conduct disorder
• Autism
• ADHD
- Esp. if severe/poor sleep
• Children with AD and AA both have a poorer quality of life
Alopecia areata
• Depression
• Anxiety
• More prolonged disease
duration or later disease
onset = positive effects
• Greater severity =
negative effects
• Study of impact of pediatric AD and AA on stigmatization, depression,
anxiety and peer relationships ongoing [PeDRA Big Study]

11. Shared comorbidities in children
Atopic Dermatitis
• Atopic
– Asthma, allergies (food, seasonal),
urticaria
• Infections of skin (S. aureus, herpes,
molluscum) and other sites
Alopecia areata
• Atopic
– AD (32.7%), asthma (20.7%), seasonal
allergies (20.0%), other allergies
(14.2%), urticaria (4.7%)
• Autoimmune
– Thyroid disease (1.4%) (Hashimoto’s;
hypothyroid)
– Vitiligo (1.5%)
– Psoriasis (1.5%)
– Diabetes
– JIA
– IBD
• Emerging: Autoimmune
– Alopecia areata
– Vitiligo
– IBD
– Celiac disease
– SLE
Cipriano et al. JACI 2018;141:2094
National AA Registry; Wohlmuth-
Wieser et al. Pedi Derm
2018;35:164

12. Alopecia areata
• Case report of two people with AA
improved after fecal transplant
• Interest in compromised central
and peripheral tolerance, and
increased intestinal inflammation
with enhanced gut permeability
• Ongoing studies looking at fecal
microbiome in children and adults
with AA
Microbiome
Atopic Dermatitis
• Increase in S. aureus and reduced
diversity associated with flares
• Interest in relationship between
microbiome, barrier dysfunction
and immunity
• Emerging topical therapy with
commensal organisms with anti-S.
aureus activity (eg, Staphylococcus
hominis and Roseomonas mucosa),
including promising early studies in
children

13. Therapy: shared pediatric responses
to topical therapies
• Topical steroids: Main topical treatment of AD and AA
- More potent steroids required for treating AA vs. AD
- Intralesional most effective is in adolescent AA
- TCIs for sensitive areas, but more effective in AD than AA
• Topical JAK inhibitors in adolescents to date
- AD, adolescent (phase 3): ruxolitinib cream (NCT03745638 and
NCT03745651)
– AA: NCT 02812342, 02561585, 03800979- completed in 18years+
NCT 03354637 recruiting 18 years+; none recruiting for children
currently
• Disease-specific topicals: Crisaborole for AD; Minoxidil and topical
immunotherapy for AA

14. Use of systemic therapies for pediatric AD
• Most commonly used agents for pediatric atopic dermatitis in US
• 1st-line choices are cyclosporine (45%), methotrexate (30%) and MMF
(13%)
- Most popular 2nd-line choice: Methotrexate and mycophenolate
mofetil
- Most popular 3rd-line choice: Azathioprine
• Concerns: Side effect profiles and perceived risks of long-term toxicity
• Use of systemic steroids rare (by pediatric dermatologists) because of
toxicity and rebound issues
14
Totri et al. JAAD 2017;76:281

15. Q2 Week
(200/300mg
based on wt)
Q4 week
(300mg)
Placebo
Adverse
Events (%)
72% 64% 69%
Injection site
reactions (%)
8.5% 6% 3.5%
Conjunctivitis (%) 10% 11% 5%
Skin Infections (%) 11% 13% 20%
Q2 Week
(200/300mg
based on wt)
Q4 week
(300mg)
Placebo
IGA 0 or 1 24%* 18%** 2%
EASI-75 41.5%* 38%* 8%
EASI – mean %
change from
baseline
66%* 65%* 24%
Itch NRS – mean
% change from
baseline
48%* 45.5%* 19%
* p< 0.0001
**p<0.001
Placebo SC q2w
Dupilumab 300mg SC q4w
(no weight limit, 600mg load) Post-treatment
options
• Safety follow-up
through Week 28
• Open-label
extension
enrollment
Screening
(5 weeks)
Dupilumab 200 mg SC q2w <60Kg (400mg load)
Dupilumab 300mg SC q2w >60Kg (600mg load)
Day –35 to Day –1 Baseline Week 28Week 16
R
251 children >12 years old with IGA 3 or 4 (phase 3)AD: Dupilumab
Press release, www.news.sanofi.us, May 16, 2018
Ongoing
trials in
children 6
months to 11
years of age
Long-term
risks
unknown

16. Other emerging systemic therapies for pediatric AD
16
• Ongoing trial of tralokinumab for adolescents
• Moderate to severe AD, adolescent (phase 3) NCT03526861
• Ongoing trials of systemic JAK1 inhibitors
• Moderate-severe AD, adolescent (phase 3)
– Abrocitinib/ PF-04965842, NCT03796676
– Upadacitinib/ ABT-494, NCT03569293
• Moderate-severe AD, 6-<12 years, 2-<6 years, phase 1 pharmacokinetic
– Upadacitinib/ ABT-494: NCT03646604, NCT03568318, NCT03607422

17. Use of systemic therapy for pediatric AA
• Systemic steroids for acute alopecia areata flares- mixed
• Methotrexate
• JAK inhibitors (off-label for children and adolescents)
– NCT03732807 oral JAK inhibitor study recruiting 12+ years
– Concerns about hematologic issues, coagulation/ thromboembolic events,
malignancy with long-term use, especially aggressive B-cell lymphomas
• Dupilumab
• Two case reports: 13 y/o with totalis since age 2 and 28 y/o - treated for AD
• Two reports of new AA within a few weeks after start of dupilumab
17
Landis and Pichardo-Geisenger. J Dermatol Treatment 2018;29:145; Lucas et al. Acta Derm
2016;96:102; Phan et al. JAAD 2019;80:120; Browne et al. Br J Dermatol 2018;179:609
Smogorzewski et al, 2019 JAAD Case Rep 2019;5:116; Darrigade et al. Br J Dermatol 2018;179:534
Flanagan et al. JAAD Case Rep 2018;5:54; Barroso-Garcia, 2018 J Invest Allergol Clin Immunol 2018;28:420

18. Unmet needs in pediatric AD and AA
• Establishment of a prospective registry/ standardized patient data
collection for both AD and AA
• Better understanding of comorbidities
– Impact on QoL and psychiatric issues for both disorders
– Autoimmune associations with AA and AD
– Risk factors for development of comorbidities

19. Unmet needs in pediatric AD and AA
• Better understanding of mechanistic differences vs. adults
– Overlap and differences between AD and AA
– Underlying genetic factors that predispose to disease, affect natural
history, or alter response to medications
– Immune biomarker differences
– Role of the microbiome
– Sub-phenotypes and their differential response to intervention
• Translating Advances in Therapeutics to Pediatrics
– More therapeutic trials of JAK inhibitors, including attention to safety and
best strategies for maintenance
– Beyond JAK inhibition: More targeted approaches

20. ….Thanks for
your attention
Thanks for
your attention!
Philadelphia
Chicago