Systemic and Novel Management of Alopecia Areata in Children. Alopecia Areata: Prognosis. Alopecia Areata. Alopecia Areata: Pathogenesis

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1 Systemic ad Novel Maagemet of Alopecia Areata i Childre Kimberly Morel, MD, FAAD, FAAP Associate Professor of Dermatology & Pediatrics S006 - Treatig Severe Ski Disease i Childre 02/16/2018, 9:00 AM Room 28A Kimberly Morel, MD, FAAD, FAAP DISCLOSURES I do ot have ay relevat relatioships with idustry. *Off-label use of medicatios will be discussed Alopecia Areata Autoimmue o-scarrig alopecia US Lifetime risk: 2% Prevalece % of geeral populatio No geder predilectio?pediatric prevalece higher tha adults vs. peak i 2 d to 3 rd decade Most Alopecia Areata (AA) presets as localized patches of o-scarrig alopecia Progosis Course upredictable: Up to 50% improve spotaeously withi 1 year 8% for extesive disease (>50% scalp ivolvemet) 68% for limited disease (<25% scalp ivolvemet) 5% develop Alopecia Totalis (AT) or Alopecia Uiversalis (AU) or overlap Pathogeesis Exact trigger ot kow: Geetic ad evirometal factors play a role Collapse of immue privilege i hair follicle Cytotoxic NK T-cell ifiltratio Histologic Swarm of Bees Iflammatory attack o the hair bulb forces hair follicle out of aage ito catage Treatmet Algorithm Cosider age, extet of ivolvemet, years sice oset, effect o child ad family, respose to iitial therapies Address quality of life Address o treatmet, support groups/couselig, hair prosthesis Paus, Bertolii. J Ivest Dermatol Symp Proc 2013:16(1);S

2 Treatmet Topical steroids +/- mioxidil IL TAC 2.5 mg/ml TAC same beefit as 5 or 10 mg/ml 2.5mg/ml, adult max 8 ml, eyebrows <0.5ml each eyebrow Side effects: atrophy, HPA axis suppressio. Cautio eyebrows: small risk icreased itraocular pressure, glaucoma, cataracts. Topical immuotherapy Strazzulla et al, J Am Acad Dermatol 2018;78: Methylpredisoloe Pulse Therapy Retrospective review 18 childre with severe AA < 17 years (rage years) 2-3 cycles of IV methylpredisoloe pulse therapy (IV-MPPT) at mothly itervals (maximum 500 mg/day o 3 cosecutive days) Results: 10/18 good respose (>75% regrowth) 1 moderate respose (50-74% regrowth), 3 poor respose (1-49% regrowth), 4 (with AT or AU) had o respose. 7 of 10 good respoders relapsed with marked hair loss after last IV-MPPT sessio. Media time to relapse was 8 moths. Coclusio: IV-MPPT, eve early i the course of disease, did ot affect log-term outcome of alopecia areata i our group of severely affected patiets. Smith et al, Pediatric Dermatol 2015;32(4) Efficacy ad Tolerability of Methotrexate i Severe Childhood Alopecia Areata Retrospective review >50% hair regrowth i 5 out of 14 childre (age 8-18 yrs) with severe AA who were treated with MTX mg/week. No serious side effects were reported. Methotrexate for the Treatmet of Pediatric Alopecia Areata Retrospective review of 14 childre 8/14 (57%) good regrowth 3/14 could ot be assessed Coclusio: This review suggests that methotrexate is a geerally safe ad ofte effective medicatio i pediatric alopecia areata. Royer et al, BJD 2011;165: Ladis ad Pichardo-Geisiger. J Dermatol Treat 2017 Ju 30:1-4. Geetic Basis GWAS i Mahatta Plot 2010 Geome-Wide Associatio Study (GWAS) 1,054 patiets from Natioal Alopecia Areata Registry 8 regios of the geome idetified as sigificatly associated with AA Highest peak: HLA Secod highest peak: ULBP3/ULBP6 ULBP gee fuctio: NKG2D-activatig Ligad Stress-iduced dager sigals Attract NK, NKT, CD8+ T cells Petukhova et al. Nature (7302) Petukhova et al. Nature (7302)

3 Swarm of Bees: NKG2DL Dager sigal Killer CD8+ T cells attracted 2010 Swarm of Bees idetified GWAS: Gees with Sigificat Associatios to AA Shared mechaism: NK Ligad i the ed orga: Type 1 Diabetes Rheumatoid Arthritis Celiac Disease Petukhova et al. Nature 2010;466(7302) Betz RC et al. Nat Comm 2015(6)5966. Alopecia Areata Reversed by JAK Ihibitio Geetic studies led to traslatioal research ad ew cliical approaches to treatmet Pre-cliical studies: Cytotoxic CD8+NKG2D+ T cells are both ecessary ad sufficiet for the iductio of AA JAK ihibitio reverses AA, prevets AA Cliical study: 3 patiets Oral ruxolitiib, JAK1/JAK2 ihibitor Near-complete hair regrowth withi 5 moths of treatmet. Xig L et al. Nat Med. 2014;20(9): Breakig News: RA Drug Treats AA 25 year old with Psoriasis ad Alopecia Uiversalis Tofacitiib 5 mg po BID x 2 moths, the icreased to 10mg, 15 mg x 3 moths Complete hair regrowth What are JAKs? Jaus kiase (JAK) family of proteis: JAK1, JAK2, JAK3, JAK4, Tyk2 Ivolved i trascriptio of cytokie sigalig iside the cell IL-15 ad IFN-γ Craiglow ad Kig. J Ivest Dermatol (2014)134, O Shea, Immuity

4 Tofacitiib JAK1/3 ihibitor (pa JAK) FDA approved i 2012 for Rheumatoid Arthritis treatmet i adults 5 mg po BID, or 11 mg XR Cliical trial ope for Pediatric JIA age 2-17 yrs Black box warig: Lymphoma Immuosuppressio: r/o TB, hepatitis prior to treatmet JAK Ihibitor Tofacitiib for AA 66 adults, AA >50%, AT, AU Tofacitiib 5 mg po BID x 3 moths 32 experieced >50% improved SALT score AA ad ophiasis subtypes respoded better tha AT/AU Keedy Crispi et al, JCI Isight. 2016;1(15):e JAK Ihibitor Tofacitiib for AA 90 adult patiets, retrospective review Tofacitiib 5 mg BID x 2-3 moths The 57% wet o to 5mg BID +/- pulsed predisoe (300 mg mothly x 3 moths) Observatios: 58% >50% SALT score improvemet over 4-18 mos Duratio of AT/AU > 10 years less likely to respod Ruxolitiib JAK1/JAK2 ihibitor FDA Approved Idicatios: Myelofibrosis (approved i 2011) Polycythemia Vera (approved i 2014) Warigs iclude: Ifectios Progressive Multifocal Leukoecephalopathy (PML) Liu et al. J Am Acad Dermatol 2017;76:22-8. JAK Ihibitor Ruxolitiib for AA 9/12 patiets experieced sigificat regrowth Post-treatmet follow up: hairloss recurred i the moths followig therapy Mackay-Wigga J et al. JCI Isight 2016:1(15);e89790 Alopecia Areata Disease Activity Idex: ALADIN Biomarker tool for trackig disease severity ad respose to treatmet 3 dimesioal quatitative composite gee expressio score Ca you predict o-respoders prior to therapy? No-respoders marked similar to cotrol patiets without AA 3 Axes: x) Cytotoxic T lymphocyte ifiltratio (CTL) y) IFN-associated markers (IFN) z) Hair kerati pael (KRT) Xig et al. Nat Med 2014(20);

5 Tofacitiib for Severe Alopecia Areata i Adolescets Pediatric Off-label Use of Jak Ihibitors 13 adolescet patiets with AA, AT, AU Age years Retrospective review Tofacitiib 5 mg po BID oe icreased to 10mg/5 mg 9 experieced sigificat hair regrowth Adverse evets were mild Craiglow et al. J Am Acad Dermatol 2017;76: Tofacitiib for Alopecia Uiversalis i Adolescets 8 adolescet patiets with AU Age yrs Tofacitiib 5 mg po BID x 5-18 moths All had slow but sigificat regrowth first 3 moths, followed by more rapid regrowth Mea 58% improvemet i SALT score at 6 mos 52-79% percet improvemet i SALT score at 12 mos Topical JAK Ihibitors Cliical trials i adults Psoriasis: topical tofacitiib 1% Ports et al. Br J Dermatol. 2013;169(1): Atopic Dermatitis: topical tofacitiib 2% Bissoette et al. Br J Dermatol 2016;175, Vitiligo: INCB cream topical tofacitiib, topical ruxolitiib Castelo-Soccio L. J Amer Acad Dermatol 2017; 76(4): Topical JAK Ihibitor: Alopecia Areata Case report Teeage girl with AU Ruxolitiib 0.6% cream Compouded Sigificat hair regrowth of eyebrows Regrowth 10% of scalp hairs Small decrease i WBC cout 3,800/μL over 12 weeks of treatmet Craiglow et al. JAMA Dermatol. 2016;152(4):490-49) Topical JAK Ihibitors 6 pediatric AA, AU, AT patiets Age 3-17 years Topical Tofacitiib 2% liposomal base Oe pt o respose Versabase, respoded to liposomal base Topical Ruxolitiib 1-2% liposomal base 4/6 experieced some hair regrowth 2 pts had 80-95% regrowth Bayart et al. J Am Acad Dermatol. 2017;77(1):

6 JAK Ihibitor Cost? Tofacitiib $3,800/moth Ruxolitiib $10,000/moth Take Home Poits: Kowledge regardig the geetic basis of alopecia areata is icreasig ad leadig to traslatio cliical research Jak ihibitors show promise i the treatmet of off-label treatmet of alopecia areata We eed more cliical trials for safe ad effective treatmets for our pediatric patiets with AA! 6