Pediatric Inflammatory Skin Disease Update. Inflammatory Skin Diseases. Factors influencing development of atopic dermatitis.

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1 Pediatric Inflammatory Skin Disease Update 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, Genentech, Regeneron/Sanofi; Medimetriks; Otsuka No equity interest Discussion is based on evidence-based recommendations and published, well designed studies Inflammatory Skin Diseases Inflammatory skin diseases have a tremendous impact over a lifetime for affected individuals Insights into pathogenesis are driving new therapies Clinical intervention studies provide the basis for improved disease management Comorbidities are being recognized and impact on approaches to patient care US prevalence by state: 2003 National Survey of Children's Health (n=102,353 children aged 0 17) Overall prevalence in children aged 0 17 years: 10.7%, ranging from % between regions Percent with Eczema Less than More than 11.5 Shaw TE et al. J Invest Dermatol. 2011;131(1): Factors influencing development of atopic dermatitis 1

2 Baby Skin: Leaky Skin Predicts AD! 1903 infants enrolled Skin barrier function at 2days; 2 mths 1300 infants genotyped FLG mutations AD at 6 mths: 18.7% AD at 12 mths: 15.53% INCREASED TEWL DAY 2: PREDICTIVE of AD Even independent of parent AD, FLG status Lowest quartile TEWL: Less risk of AD Kelleher M et al. J Allergy Clin Immunol 2015 Emollient from birth: atopic dermatitis prevention Randomized controlled UA and UK: 124 neonates at high risk for atopic dermatitis. 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. The primary feasibility outcome was the percentage of families willing to be randomized. The primary clinical outcome was the cumulative incidence of atopic dermatitis at 6 months, as assessed by a trained investigator. Simpson EL et al. J All Clin Immunol 2014;134:4: Emollient from birth: atopic dermatitis prevention 42% percent families agreed to be randomized Statistically significant protective effect Relative risk reduction of AD: 50% (relative risk, 0.50; 95% CI, ; P =.017). No emollient-related adverse events and no differences in adverse events between groups. If confirmed in larger trials, emollient therapy from: simple and low-cost intervention that could reduce the global burden of allergic diseases Wait. Is atopic dermatitis from barrier dysfunction, or altered immunologic responses? Simpson EL et al. J All Clin Immunol 2014;134:4: Good and Bad News: GET READY TO LEARN SOME IMMUNOLOGY! New therapeutic agents have novel targets and newer research techniques will dissect immune response to traditional and new agents SIMPLIFICATION AD is a disease of barrier dysfunction and Th2 driven inflammation 2

3 Therapies Targeting Type 2 Immune Pathways Allergens Itch/ Infection Scratch Cycle Therapies Targeting Type 2 Signaling Pathways expression of skin barrier proteins and AMPs Mediates pruritis Epidermis Key: 1 Anti-TSLP MEDI9929/AMG157 IL-4 2 TSLP 1 IL Dual Anti-IL-4/IL-13 Dupilumab IL-13 3 B-cell 3 Anti-IL-13 Lebrikizumab Tralokinumab DC ThO IL-4 * 2 IL-4 IL Anti-IgE Omalizumab Ligelitumab MEDI4212 XmAb7195 Th2 IgE 4 Eosinophil Basophil Mast cell Dermis 5 Anti-IL-31/Anti-IL-31 Nemolizumab BMS IL-4 IL-31 IL-13 IL-5 IL-5 6 CRTH2 Antagonist Fevipiprant OC 459 BB IL-4 2 PGD2 IL-13 3 Granule release PGD2 / granule release expression of endothelial adhesion molecules PGD2P 6 Blood vessel Definition of Abbreviations: AMP: Antimicrobial Peptide CRTH2: Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells, DP2 DC: Dendritic Cell IgE: Immunoglobulin E IL-: Interleukin PGD2: Prostaglandin D2 Th: T-Helper TSLP: Thymic Stromal Lymphopoeitin (Am J Clin Dermatol Oct;17(5):425) (Am J Clin Dermatol Oct;17(5):425) New Therapies 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 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 PDE-4 Inhibitor treated AD Atopic Dermatitis Associated Inflammation by Inhibiting PDE4 AMP, adenosine monophosphate; AD, atopic dermatitis; camp, cyclic adenosine monophosphate; PDE4, phosphodiesterase 4. Freund YR et al. FEBS Lett. 2012;586: Dastidar SG et al. Curr Opin Investig Drugs. 2007;8: Baumer W et al. Inflamm Allergy Drug Targets. 2007;6: Jimenez JL et al. J Pharmacol Exp Ther. 2001;299(2): Chan SC et al. J Invest Dermatol. 1993;100(5): Grewe S et al. J Allergy Clin Immunol. 1982;70(6): Heskel NS et al. J Am Acad Dermatol. 1984;11(3): Butler JM et al. J Allergy Clin Immunol. 1983;71(5): Hanifin JM. J Dermatol Sci. 1990;1(1): 1-6. Hanifin JM et al. J Invest Dermatol. 1996;107(1):

4 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 Atopic Dermatitis: Open Label Phase 2a Study July/August 2016 Tom WL et al. Pediatric Dermatology Volume 33, Issue 2, pages , 18 JAN 2016 DOI: /pde Crisaborole Topical Ointment, 2% in Patients Ages 2 to 17 Years with Atopic Dermatitis: A Phase 1b Open Label Crisaborole 2% Ointment Phase 3 Tom Wl et al. Pediatric Dermatology Volume 33, Issue 4, pages , 18 MAY 2016 DOI: /pde Two multi-center, double-blind, vehicle-controlled U.S. studies Over 750 patients 2 years and older Mild-to-moderate atopic dermatitis affecting >5% body surface area Patients were randomized 2:1 (crisaborole:vehicle) and treated BID for 28 days OUTCOMES: ISGA (Investigator Static Global Assessment SUCCESS: Clear or Almost Clear with >2-grade improvement from baseline) at Day 29 CLEAR or ALMOST CLEAR (with or w/o> 2 grade improvement) TIME TO SUCCESS 4

5 Crisaborole 2% Ointment Phase 3 Primary Endpoint DAY 29 AD-301 (crisaborole / vehicle*) N=503 / 256 AD-302 (crisaborole / vehicle*) N=513 / 250 % 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) Crisaborole 2% Ointment Phase 3 * Crisaborole 2%: Long Term Safety Open-label 48 wk safety study (after phase 3) AD severity every 4 weeks ISGA scale Treated with 4-week cycles of crisaborole as needed Safety measures: local tolerability, adverse events (AEs), serious adverse events (SAEs), clinical laboratory results, vital signs, and physical examinations 517 patients: Treatment-emergent SAES: 10.2% AD, application-site pain, 1.2% AS-infection * 9 SAEs: Not considered treatment related No atrophy, telangiectasia, hypopigmentation Eichenfield LF et al ESPD 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) 5

6 OpA-15406: IGA Success Back to Basics : Successful response was defined as an IGA score of 0 or 1 with at least a 2-grade reduction from baseline.. Hanifin JM, Ellis CN et al. Journal of the American Academy of Dermatology, Volume 75, Issue 2, 2016, 297 European treatment of severe AE in children: TREAT survey Treatment of severe AE Taskforce Survey: collect data on current systemic agent prescribing practices First line agents Cyclosporin: 43% Oral Corticosteroids: 30.7% Azathioprine: 21.7% Second line agents: Cyclosporin: 33.6%; Third line agent: MTX: 26.2% Proudfoot LE et al. Br J Dermatol 2013:169: st Line 2 nd Line 3 rd Line RESULTS 86.5% Initiate Systemic Therapy for severe AD CYC MTX MYCO AZA CORT OTHER 45.2% 29.6% 13% 7% 5.2% % 31.3% 30.4% 20% % 19.1% 24.3% 33% 1.7% 4.5%* *Dapsone, referral, IVIG, either methotrexate or azathioprine, two week intensive topical therapy regimen Totri et al. TREATUS&Canada JAAD (in press) Factors that Discourage Use of Systemic Agents Side effect profile: (82.6%) Suspected risks of long term toxicity: (81.7%) ADVOCACY: A success story! Given the high unmet need for effective and safe therapies in atopic dermatitis in children, pediatric studies with systemic therapies should be initiated as soon as possible in the drug development process, as long as there are no safety signals that would raise particular concern in pediatric age patients. Endorsed by: PeDRA, AAD, SPD, SID, AAD-ERG AD, NEA-SAC, IEC, ACDS * n(% 6

7 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 Randomized, double-blind, placebo-controlled phase 3 studies of dupilumab in adults with moderate to severe AD Primary endpoint: % achieving IGA of 0/1 at 16 weeks n=1,379 adults with moderate-severe AD Trial Dose % % change achieving EASI IGA SOLO-1 SOLO-2 300mg q1wk 300mg q2wk 300mg q1wk 37% vs. 10%; 38% vs. 10%; 36% vs. 8.5%; 36% vs. 8.5%; 72% vs. 38%; 72% vs. 38%; 69% vs. 31%; 67% vs. 31%; EASI % vs. 15% 51% vs. 15% 48% vs. 12% 300mg 44% vs. 12% q2wk Accessed 31 August Dupilimab: Phase 3 Data 37 and 36 % dupilumab 300 mg q wk 38 and 36 % dupilumab 300 mg q 2 weeks, achieved clearing or near-clear (IGA 0 or 1) 10 and 8.5 % with placebo (p <0.0001). EASI improvement: 72 and 69 % 300 mg q wk 72 and 67 percent 300 mg q 2 weeks, 38 and 31 percent for placebo (p =<0.0001) EASI 75: 52.5;48 % 300 mg weekly, 51; 44 % 300 q every 2 weeks 15; 12 percent with placebo (p <0.0001) NOTE: Released online (not peer reviewed) How common is food allergy in children with AD? Older figures: 30-50% Mild to moderate AD: ABOUT 15-16% Spergel JM et al. Pediatrics 2015(Dec)136:e Spergel JM et al. Pediatrics 2015(Dec)136:e

8 Peanut Consumption and Allergy 640 infants 4 mths-11 mths, with: severe eczema, egg allergy or both Randomized based on preexisting sensitivity to peanut extract (skin-prick test) to: CONSUME or AVOID Peanuts Du Toit G., Roberts G, et al. N Engl J Med 2015;372: Peanut Consumption and Allergy Negative skin-prick test Prevalence of peanut allergy at 60 mths: 13.7% in the avoidance group 1.9% in the consumption group (P<0.001) Initially positive test results: 35.3% avoidance group 10.6% consumption group Du Toit G, et al. N Engl J Med 2015;372: 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 prescription-strength topical corticosteroids, calcineurin inhibitors or other antiinflammatory agents despite appropriate use of emollients. 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. Consider referral to allergy for skin prick testing for peanut, or IgE screen, with referral if positive Skin prick testing: Negative, low level: EARLY FEEDING Medium positive: OBSERVED FEEDING ACNE: New Treatments! Novel nitric oxide based therapy Topical hormonal therapy (cortexalone) New topical retinoid Lipid-changing topicals (targeting sebum) Recently approved: Dapsone 7.5% gel q day Lortscher D, Admani S Eichenfield LF. J Drugs Dermatol 2016;15:670 8

9 Hormonal Contraceptives and Acne At the time of initial on line consultation for acne, each of 2147 consecutive patients using hormonal contraception provided assessment contraceptive affect on acne Depot injections, subdermal implants, and hormonal intrauterine devices worsened acne COC hierarchy: drospirenone (most helpful)>norgestimate & desogestrel> levonorgestrel & norethrindone Triphasic progestin dosage had positive effect No distinct effect from estrogen dosage variation Lortscher D, Admani S, Satur N, Eichenfield LF. JDD 2016;15:670 PSORIASIS INFLAMMATION MATTERS, IN WAYS WE ARE JUST FIGURING OUT 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 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 9

10 Psoriasis in Children: Systemic Therapy Finally some movement towards approval of systemic agents! Summary: Evolving perspectives on atopic dermatitis, acne and psoriasis Rapidly evolving therapy But it is a long and arduous route to approval of new therapies! And then.we have to figure out how they work in practice! 10