Lawrence F. Eichenfield, M.D.

Transcription

1 What s New in Pediatric Dermatology Lawrence F. Eichenfield, M.D. Professor of Dermatology and Pediatrics Rady Children s Hospital, San Diego University of California, San Diego Disclosure Lawrence F. Eichenfield, M.D. Investigator/Consultant Anacor/Pfizer, Amgen, Genentech, Lilly, Regeneron/Sanofi; Medimetriks, Novan, Otsuka, Valeant Discussion is based on evidence-based recommendations and published, well designed studies 1

2 Inflammatory Skin Diseases tremendous impact over a lifetime for affected individuals insights into pathogenesis: driving new therapies Psoriasis Comorbidities appreciated, may be disease driver, should be screened; Therapies broaden Acne Work to improve pediatrician knowledge, treatment Evolving insights, therapies Emollient from birth: atopic dermatitis prevention Randomized controlled UA and UK: 124 neonates high risk. Full-body emollient therapy at least once per day starting within 3 weeks of birth. Parents in the control arm were asked to use no emollients Statistically significant protective effect Relative risk reduction of AD: 50% (relative risk, 0.50; 95% CI, ; P =.017). Simpson EL et al. J All Clin Immunol 2014;134:4:

3 Neonatal Moisturizer Intervention Prospective, RCT: emulsion-type moisturizer applied qd for 32 wks 59 of 118 high risk neonates for AD (parent or sib with AD) Onset of AD (eczematous symptoms lasting >4 weeks) and eczema (lasting >2 weeks) was assessed by a dermatology specialist modified Hanifin and Rajka criteria. Horimukai K et al. J Allergy Clin Immunol :

4 Neonatal Moisturizer Intervention 32% fewer moisturized neonates had AD by week 32 (P =.012, log-rank test) No impact on effect of emollient on allergic sensitization (IgE Ab to egg white) Daily moisturizer application during the first 32 weeks of life reduces the risk of AD Horimukai K et al. J Allergy Clin Immunol : Moisturizer as Intervention: Cost Effectiveness Average cost of total-body moisturization 7 common products: from birth to 6 months Assumed 50% reduction in relative risk from application, and used QALY (quality-adjusted life-years) impact over a 6 month time window Assumed equal efficacy Xu S et al. JAMA Pediatr 2016;Dec 5:e

5 Moisturizer as Intervention: Cost Effectiveness Birth: 3.6 grams (.12 ounce)/d; 6.6 grams/d at 6 mths Range of costs: ($0.13/oz-$2.96/oz) Cost per QALY: $353 petrolatum vs. $8386 Petroleum jelly, Vaniply Ointment, Aveeno Eczema Therapy Moisturizing Cream, Cetaphil Moisturizing Cream, CeraVe Moisturizing Cream, Sunflower seed oil UK NIHCE threshold for cost-effectivenesss: $38,000/QALY Xu S et al. JAMA Pediatr 2016;Dec 5:e Pathogenesis of AD Gittler JK and Guttman-Yassky E, JACI

6 SIMPLIFICATION AD is a disease of barrier dysfunction and Th2 driven inflammation Role of Phosphodiesterase (PDE) Hanifin et al. reported increased PDE activity and decreased intracellular camp levels in peripheral blood leukocytes of patients with atopic dermatitis PDE inhibitors increase intracellular camp levels and reduce cytokine and mediator release 6

7 Boron-based PDE4 Inhibitor Crisaborole Integration of boron ring into cyclic structure: stability, effective target binding capacity/selectivity, Found naturally in high concentrations in foods Low molecular weight facilitates penetration through human skin and access to target cells Boron-based topical PDE4 inhibitor Crisaborole Topical Ointment, 2%: PK Study Adolescents with : Open Label Phase 2a Study Tom WL et al. Pediatric Dermatology Volume 33, Issue 2, pages , 18 JAN 2016 DOI: /pde

8 Summary of Phase 3 Study Designs and Patient Demographics AD-301 and AD-302 Double-blind, vehicle-controlled, safety and efficacy studies (4 weeks) 1 Enrollment AD-301 (N = 759) NCT AD-302 (N = 763) NCT BID treatment for 28 days Crisaborole Topical Ointment, 2% Vehicle a Crisaborole Topical Ointment, 2% Vehicle a AD-303 Long-term, open-label, single-arm safety study (48 weeks) Enrollment AD-303 Screening/ Enrolment (N = 517) Treatment received in parent study: Crisaborole (n = 357) Vehicle (n = 160) 12 cycles of BID treatment for 28-day intervals ISGA 2 Patient Evaluation ISGA 1 On-treatment Crisaborole Topical Ointment, 2% Re-evaluation every 28 days Off-treatment No Study Drug End of Study Patients analysed: N = Key Inclusion Criteria 2 years of age Clinical diagnosis of mild (ISGA 2) or moderate AD (ISGA 3) AD involvement 5% BSA Key Exclusion Criteria Use of TCS or TCI within 14 days Significant active infection Any previous use of biologic therapy AD, atopic dermatitis; ISGA, Investigator s Static Global Assessment; TCI, topical calcineurin inhibitor; TCS, topical corticosteroid. a Proprietary vehicle developed by Anacor Pharmaceuticals, Inc. 1. Paller A et al. J Am Acad Dermatol. 2016;74(2):

9 Treatment-related TEAEs by Age Group, % Lawrence F. Eichenfield, M.D. Crisaborole 2% Ointment Phase 3 AD-301 (crisaborole / vehicle*) N=503 / 256 AD-302 (crisaborole / vehicle*) N=513 / 250 Primary Endpoint DAY 29 % in ISGA Success (score of 0 (clear) or 1 (almost clear) with a minimum 2- grade improvement) Secondary Endpoints % in ISGA Clear/Almost Clear (0 or 1) 32.8% / 25.4% (p=0.038) 51.7% / 40.6% (p=0.005) 31.4% / 18% (p<0.001) 48.5% / 29.7% (p<0.001) Time to success in ISGA: Crisaborole achieved success earlier than vehicle-treated patients (p<0.001) Atopic dermatitis refers to atopic dermatitis flares. Pooled Treatment-related Adverse Events Pooled analysis by age group: reports by 1% of patients in studies (regardless of treatment) and extension study a b Atopic dermatitis Application site infection Application site pain Ages 2-11 (n = 308) Ages (n = 146) Age 18 (n = 63) Total (N = 517) Cutaneous adverse reactions, such as application site atrophy and telangiectasia, did not occur Application site pain refers to skin sensations such as burning or stinging c 9

10 What don t we know Comparative efficacy Neither head to head, nor by objective scores Cost-efficiency Effect on regions (eg face) Under age 2 Long term safety (but oral PDE-4 s exist) Therapy: Approach Stepped Therapy: Excellent Skin Care TCS for flares; Alternatives: TCIs, TPDE-4? Intermittent TCS or TCI: Maintenance regimens For more severe dx: Phototherapy; Systemic Therapy 10

11 Systemic Therapy in Atopic Dermatitis Get ready for the revolution Dupilumab Anti-interleukin-4receptor (IL-4R) α antibody Inhibits IL-4 and IL-13 singalling by inhibiting both IL-4 type 1 and 2 receptors on various immune cells Administered subcutaneously 11

12 Patients (%) Lawrence F. Eichenfield, M.D. SOLO-1 and SOLO-2: Efficacy of dupilumab in moderate to severe AD at Week 16 Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw IGA 0 or 1 and 2 points reduction from baseline * * * * SOLO-1 SOLO * * SOLO-1 EASI-75 a * * SOLO-2 *P< vs placebo For binary outcomes, patients were categorized as nonresponders from the time rescue medication was used; NRI a Coprimary endpoint in EU and Japan; key secondary endpoint in other regions. 12

13 Other Agents in Trials Oral PDE4 Inhibitor Nemolizumab : IL-31 JAK Inhibitors: Tofacitinib PF Baracitinib ABT-494 H4 Blockers Anti IL-13: Lebrikizumab; Tralokinumab Anti-leukotrienes LXR-Antagonists Peanut Consumption: Prevents Allergy! Negative skin-prick baseline Prevalence of peanut allergy at 60 mths: 13.7% in the avoidance group 1.9% in the consumption group (P<0.001) Initially positive skin prick at baseline: 35.3% avoidance group 10.6% consumption group Du Toit G, et al. N Engl J Med 2015;372:

14 New Guideline in the Works: NIAID 2016 Addendum to the 2010 guidelines for Diagnosis and Management of Food Allergy Identifies infants with severe AD (and/or egg allergy) as group at risk for peanut allergy Severe eczema is defined as persistent or frequently recurring eczema with typical morphology and distribution, assessed as severe by a health care provider and requiring frequent need for prescriptionstrength topical corticosteroids, calcineurin inhibitors or other antiinflammatory agents despite appropriate use of emollients. New NIAID Food Allergy Guidelines Recommends that infants with severe eczema, egg allergy or both have introduction of age-appropriate peanut-containing food as early as 4-6 months of age to reduce the risk of peanut allergy Direct referral to allergy or Serum IgE screen (if negative, feed); if + referral to allergy 14

15 Fig 1 Journal of Allergy and Clinical Immunology , 29-44DOI: ( /j.jaci ) Copyright 2016 Terms and Conditions Pediatric Psoriasis: Cardiovascular Risks? Case-control: 50 ped psor/50 age-matched controls Obesity or overweight: 50% (vs 32% of controls) Fasting insulin levels: statistically higher! Psoriasis pts: More ALT, AST, fasting lipid abnormalities than controls At least one marker CV risk: 44 % vs 28% ctrls DIFFERENCES: HDL size; Cholesterol buffering capacity (Independent of obesity) Tom WL et al. JID 2015 Sep30 15

16 Characterization of Lipoprotein Composition and Function in Pediatric Psoriasis Reveals a More Atherogenic Profile DECREASED Cholesterol efflux capacity (proportionate to severity) 73 HDL: smaller size (p=0.06) with decreased number of large, beneficial HDL particles (5.3 +/- 3.0 vs /- 2.7; p=0.02) Tom WL et al. J Invest Dermatol 2016:136:67-73 Pediatric Psoriasis: Comorbidity Screening Guidelines Cardiovascular risks ASHD, dyslipidemia, metabolic syndrome Obesity Arthritis Psychologic/psychiatric disorders Depression, anxiety National Psoriasis Foundation/PeDRA Pediatric Psoriasis CSI Project: Comorbidity Screening 16

17 Psoriasis in Children: Systemic Therapy Finally approval of systemic agents! Etanercept receives Pediatric Approval!! Not new Process ready to begin again Influential but Still much work to implement Pediatrics May;131 Suppl 3:S doi: /peds B 17

18 New Guidelines from the AAD New Guidelines from the AAD Topical antibiotics (eg, erythromycin and clindamycin): not recommended as monotherapy because of risk of bacterial resistance Zaenglein AL et al. J Am Acad Dermatol 2016 (Online) 18

19 New AAD Acne Guidelines: Systemic Antibiotics Systemic antibiotic use should be limited to the shortest possible duration, typically 3 months Monotherapy with systemic antibiotics is not recommended Use of systemic antibiotics, other than the tetracyclines and macrolides, is discouraged (due to limited data) Zaenglein AL et al. J Am Acad Dermatol 2016 (Online) What s New in Topical Agents Adapalene Gel 0.1%: OTC Status May rewrite algorithms Other retinoids: Access is an issue! New retinoids New topical retinoid (in the works) New formulations 19

20 Methods: Cases Choose the next best step for treating Cases designed, modified for clarity, relevance. Responses categorized as correct, c/w AARS/AAP Guidelines Feldstein S et al. Filling in Pediatric Acne Practice Gaps: A Prospective Multicenter Study of Case-Based Education. J Adolesc Health Nov;59(5): Skim Milk? Thin data thickening Multiple acne studie that differentiated milk type found association with skim milk biological effects in consumers Other data: Total dairy consumption beneficial re: metabolic syndrome, insulin resistance, cardiovascular risk, stroke Higher dairy fat = lower risk obesity/ CVD Adebamowo et al. J Am Acad Dermatol Feb;52(2) Adebamowo et al. J Amer Acad Dermatol 2008; 58: Adebamowo et al. Dermatol Online J May 30;12(4):1. DiLandro et. al. J Amer Acad Dermatol 2012;67(6:

21 Skim Milk? Hershey Data 226 teenagers 121 with moderate acne (IGA) 105 controls with no acne No dietary restriction or on medications influencing diet 24-hour dietary recall on 3 occasions Statistically significant difference in total servings of skim milk between the acne and control groups with a p- value after adjusting for age, gender, and BMI. CONCLUSIONS: Consumption of low-fat/skim milk, but not full-fat milk, was positively associated with acne LIMITATIONS: Limitations include self-report of diet and portion size, and association does not determine causation 21

22 Thank you for allowing me to participate in your learning! Come visit us in San Diego! 22