Dra. Rocío Maseda

DERMATOLOGÍA PEDIÁTRICA

ACNE

Acne

▪ Skin microbiome is a crucial target for treating inflammatory acne lesions

▪ Lost of diversity of phylotypes of C. acnes with predominant phylotype IAI

▪ Role of other bacteria as S. epidermidis has to be taken in count

▪ Intestinal microbiome is modified in acne and could influence the skin microbiome

▪ Chronic inflammation is associated with the destruction of sebaceous gland

▪ Explaining why atrophic scars are associated to acne

▪ Need to treat early acne lesions to block inflammation as soon as possible

▪ To inhibit hyperseborrhea remains a challenge in 2019 although some targeted therapiescould be promising

▪ Future of treatment in inflammatory acne

▪ Vaccination, pro/prebiotics, antimicrobial peptides, microbe transplantation

Brigitte Dréno

Acne

▪ TRIFAROTENE 50 mcg/g (Aklief®)

▪ New retinoic acid receptor gamma-selective topical retinoid cream formulation that is suitable for use on the face and trunk

▪ Indicated for the topical treatment of acne vulgaris in patients > 9 years of age

Tan et al. J Am Acad Dermatol 2019

Acne

▪ TRIFAROTENE 50 mcg/g (Aklief®)

▪ New retinoic acid receptor gamma-selective topical retinoid cream formulation that is suitable for use on the face and trunk

▪ Indicated for the topical treatment of acne vulgaris in patients > 9 years of age

Tan et al. J Am Acad Dermatol 2019

Acne

▪ Younger age < 15 is one of the top reasons for poor adherence

▪ Association of daily soft drink intake with sugar (>100 g per day) and

moderate-to-severe acne vulgaris in survey study in Chinese adolescents

Huang et al. J Pediatrics 2019

BIOLOGICS IN PEDIATRIC DERMATOLOGY

Biologics in pediatric dermatology

▪ Biologics are generally associated with less treatment relatedtoxicity tan conventional systemic agents

▪ Biologics in pediatric psoriasis and AD are effective and show reassuring safety profiles

▪ Further research and post-marketing registries are needed to collect long-term safety data and extend the use of biologics in pediatric patients

Phan et al. J Eur Dermatol Venereol 2019

Biologics in pediatric dermatology

▪ ETANERCEPT 2009

▪ 0.8 mg/Kg

▪ > 6 años

▪ ADALIMUMAB 2015

▪ 0.8 mg/Kg

▪ > 4 años

▪ USTEKINUMAB 2015

▪ 0.75 mg/Kg en < 60 Kg; 45 mg en > 60 Kg

▪ > 12 años

▪ DUPILUMAB 2019

▪ 200 mg en < 60 Kg; 300 mg en > 60 Kg

▪ 12-17 años

Marieke Seyger

Biologics in pediatric dermatology

A RETROSPECTIVE OBSERVATIONAL STUDY IN FRANCE

▪ 134 children with moderate to severe psoriasis in 30 centres

▪ 184 treatment episodes: 70 ETN, 68 ADA, 46 UKB

▪ Mean age at onset 7.2 years; mean age at biologic 13.2 years

▪ 7 SAEs:▪ 3 serious infections

▪ 2 weight gain

▪ 1 psoriasis flare

▪ 1 malaise

Phan et al. J Eur Dermatol Venereol 2019

Biologics in pediatric dermatology

▪ CURRENT PHASE 3 TRIALS IN PEDIATRIC PSORIASIS AND ATOPIC DERMATITIS

STUDY DRUG AGE (YEARS)

INTERVENTION ESTIMATED STUDY

COMPLETION

USTEKINUMAB 6-12 Open label Ustekinumab Dec 2020

IXEKIZUMAB 6-17 Ixekizumab/placebo June 2021

SECUKINUMAB 6-17 Secukinumab/placebo/Etanercept Sept 2023

GUSELKUMAB 6-17 Guselkumab/placebo/Etanercept June 2025

TRALOKINUMAB (AD) 12-17 Tralokinumab/placebo Feb 2021

Novel therapeutic approaches in atopic dermatitisDUPILUMAB

Novel therapeutic approaches in atopic dermatitis

▪ New topical treatments▪ Phosphodiesterase 4 inhibitors: CRISABOROL

▪ JAK inhibitors: TOFACITINIB

▪ New oral treatments▪ JAK inhibitors

▪ Biological drugs

▪ Inhibitors of the activation of lymphocyte populations TH2

▪ Inhibitors of activation of other TH lymphocyte populations

▪ Inhibitors of B lymphocyte activation

▪ Inhibitors of interleukins related to pruritus of atopicdermatitis

Novel therapeutic approaches in atopic dermatitis: DUPILUMAB▪ Ocular surface disease

▪ 10-30% patients

▪ Most cases are mild, but some patients can develop blepharoconjunctivitis

▪ Risk factors: AD severity and previous conjunctivitis

DUPILUMAB

Novel therapeutic approaches in atopic dermatitis: DUPILUMAB

▪ PREVENTION

▪ Emollients for eye lids

▪ Topical pimecrolimus/tacrolimus

▪ No effect of anti-histamines

▪ TREATMENT

▪ Mild:

▪ Hyaluronic acid containing eye drops

▪ Topical pimecrolimus/tacrolimus

▪ Severe:

▪ Fluorometholon 0.1% eye drops

▪ Ciclosporin containing 1 mg/ml eyedrops

DUPILUMAB

HAIR DISORDERS IN CHILDREN

Alopecia areata

▪ Most common cause of non-cicatricial alopecia in children

▪ Pediatric onset: more severe, worse prognosis than adultonset

▪ Significant negative impact on HRQoL among affectedchildren/parents

▪ Increase rates of comorbid psychiatric conditions

Alopecia areata

▪ 125 patients with initial presentation < 4 years

▪ Most children had mild disease severity and continued mild disease over the next 2 years

▪ Children with more than 50% of hair loss at presentation were much more likely to have worsening SALT scores over time and remain more severe

▪ Concomitant AD: 41%

▪ Concomitant AI disorder: 4% (vitiligo, celiac disease, DM1)

▪ 28% had a family member with AA, and 27% had a first-degree family member with one or more autoimmune diseases

Alopecia areata

▪ SCREENING▪ Complete blood count

▪ Vitamin B12

▪ Ferritin

▪ Zinc

▪ Vitamin D

▪ TSH, fT4, TPO-Abs, Tg-Abs: only if AD, Down or family history of thyroiddisease

▪ Others if symptoms: ANA, parietal cell Abs…

Alopecia areata

▪ ORAL JAK INHIBITORS FOR PEDIATRIC ALOPECIA▪ 7 publications describing systemic therapy:

▪ 2 adolescent case series (19 patients 12-17 yo)

▪ 2 preadolescent case series (7 patients 4-11 yo)

▪ 3 case reports (8, 14, 17 yo)

▪ Tofacitinib 5 mg BID over 2-18 months

▪ 24/29 responders

▪ No SAEs

▪ No data on relapse after cessation of therapy

Alopecia areata

▪ TOPICAL JAK INHIBITORS FOR PEDIATRIC ALOPECIA▪ 3 publications describing treatment of children:

▪ 18 patients ages 3-17 yo

▪ Ruxolitinib and tofacitinib compounded in 0.6-2%

▪ Some response in 6/18 patients

▪ Only 6/18 with cosmetically aceptable regrowth

▪ No SAEs

Putterman et al. JAAD 2018Phan et al. JEADV 2019

BLISTERING DISEASES

Blistering diseases

▪ 63 patients included from 1993 to 2015. Mean aye: 4.7 years

▪ 27 linear IgA disease, 12 bullous pemphigoid, 12 pemphigus, 8 herpetiformdermatitis, 4 epidermolysis bullosa aquisita

▪ Mean treatment duration: 30.6 months

▪ Topical corticosteroids were used alone, effectively, for 7 patients, and in association with other treatments in 19 patients in complete remission

▪ Complete remission was noted in 34/38 children with a follow-up of 4.4. years

▪ The mean duration to complete remission was 30.5 months

• Childhood AIBDs appear to be of good overall prognosis but a long-term follow-up is mandatory, as relapses can be late, except

for BP

• The use of topical corticosteroids is frequently effective alone or in association

SYSTEMIC THERAPIES LOCALIZED THERAPIES

Epidermolysis bullosa

Leena K. Bruckner-Tuderman

OCTOBER 2019

▪ 81 clinical trials on EB

▪ 6 of them recruiting

▪ 5 of them gene therapy trials

EB THERAPEUTIC APPROACHES

Epidermolysis bullosa

▪ 2006 therapy breakthrough: gene therapy of JEB

De Luca et al. Nat Med 2006;

EX VIVO GENE THERAPY IN EB

Laminin restored

grafting 8 days post-graft

10 months post-graft

Epidermolysis bullosa

FIRST-IN-MAN GENE THERAPY STRATEGIES FOR Eby

▪ Keratinocyte gene therapy using retroviral vector▪ JEB: De Luca et al. Nat Med 2006; Hirsch et al. Nature 2017; Bauer et al.

JID 2017

▪ DEB: Siprashvili et al. JAMA 2016

▪ Keratinocyte gene therapy using gene editing withCRISPR/Cas9▪ DEB: Takashima et al. JID 2019

▪ A novel approach: topical application▪ HSV-1-based gene delivery targets keratinocytes/epidermis topical

application (Krystal Biotech)

▪ JEB, DEB: PTC-readthrough:

▪ Woodley et al. JCI 2017

▪ Lincoln et al. PNAS 2018

▪ DEB: anti-oligonucleotides:

▪ Turczynski et al. JID 2016

▪ Bornert et al. Mol Ther 2016

PRECLINICAL DEVELOPMENT OF FURTHER CURATIVE APPROACHES FOR EB:

“IGNORE MUTATION”

A first in human, double-blind, randomized, intra-subject placebo-controlled, multiple dose study of QR-313

evaluating safety, proof of mechanism, preliminary efficacy and systemic exposure in subjects wih Recessive

Dystrophic Epidermolysis Bullosa (RDEB) due to mutation(s) in exon 73 of the COL7A1 gene

Epidermolysis bullosa