Brian S. Kim, MD, MTR, FAAD

Transcription

1 What s New In the Pathophysiology of Itch? Brian S. Kim, MD, MTR, FAAD Assistant Professor of Dermatology, Anesthesiology, and Pathology and Immunology Co-Director, Center for the Study of Itch

2 Itch is a central feature of atopic dermatitis (AD) or eczema Chronic, relapsing skin disease High incidence, costly Therapeutic options limited Itch is the central symptom

3 The classical paradigm of AD pathogenesis T H 2 cell IL-4 IgE IL-13 B cell

4 The new paradigm of atopic itch Itch sensation T H 2 cell IL-31 Dillon et al. Nat Immunol 2004 Cevikbas et al. J Allergy Clin Immunol 2014

5 The emerging paradigm of AD pathogenesis T H 2 cell IL-33 and TSLP Basophil IL-4 IgE T H 2 cell Kim et al. Sci Transl Med 2013 Kim et al. J Immunol 2014 ILC2 IL-13 B cell

6 Innate type 2 cells promote AD-like disease

7 Dupilumab (anti-il-4/13r mab) demonstrates unprecedented efficacy in AD

8 Itch improves markedly when type 2 cytokines are disrupted

9 The emerging paradigm of AD pathogenesis Itch sensation IL-33 and TSLP Basophil IL-4? Kim et al. Sci Transl Med 2013 Kim et al. J Immunol 2014 ILC2 IL-13

10 Do sensory dorsal root ganglia (DRG) express type 2 cytokine receptors? Mouse Human 500 bp 500 bp Oetjen et al. Cell 2017

11 Do sensory neurons respond to IL-4? Harvest sensory ganglia Before IL-4 Load with Fura-2 IL-4 Calcium imaging After IL-4

12 Sensory neurons respond to type 2 cytokines Normalized Fluorescence IL-4 KCl Time (s) Normalized Fluorescence IL-13 KCl Time (s) Normalized Fluorescence IL-31 KCl Time (s) Oetjen et al. Cell 2017

13 Do human sensory neurons respond to IL-4? Human DRG Normalized Fluorescence 1.4 IL-4 Capsaicin KCl Time (s) Oetjen et al. Cell 2017

14 An experimental mouse model of AD Topical vehicle (EtOH) or MC903 WT Day 12 AD-like disease Oetjen et al. Cell 2017

15 Does neuronal deletion of IL-4Rα abate chronic itch? Topical MC903 Control Il4ra Δneuron Day 12 Scratching bouts Ear thickness Histopathology Oetjen et al. Cell 2017

16 How does IL-4 promote itch? IL-31 IL-31R TRPA1 TRPV1 Normalized Fluorescence Vehicle IL-31 IL-4 IL-31 KCl Time (s) Oetjen et al. Cell 2017

17 IL-4 promotes neural hypersensitivity Histamine Capsaicin H1R TRPV1 Oetjen et al. Cell 2017

18 Dupilumab (anti-il-4/13r mab) may have direct anti-itch properties

19 Dupuliumab demonstrates anti-pruritic effects in refractory AD patients Immunosuppression: Azathioprine Cyclosporine Mycophenolate mofetil Mack et al. (In Preparation)

20 How else can we therapeutically approach chronic itch?

21 Does neuronal deletion of JAK1 limit itch? Topical MC903 Control Jak1 Δneuron Day 7 Scratching bouts Disease Scratching Ear Thickness Littermate JAK1 Δneuron Bouts per 30 min 300 * % Change 30 N.S Oetjen et al. Cell 2017

22 Jakinibs may function as neuromodulators Itch sensation T H 2 cell IL-31 JAK inhibition JAK inhibition Basophil IL-4 Sensory neuron ILC2 IL-13 Dillon et al. Nat Immunol 2004 Cevikbas et al. J Allergy Clin Immunol 2014

23 Would Jakinibs work in itch without a rash? Atopic Dermatitis (AD) Chronic Idiopathic Pruritus (CIP) Oetjen et al. Cell 2017

24 Jakinibs demonstrate preliminary efficacy A Tofacitinib B Tofacitinib 10 ** 10 Cyclosporine Tofacitinib NRS Itch Score NRS Itch Score Day Oetjen et al. Cell 2017

25 Identification of a novel itch-regulatory pathway

26 Implications: Upadacitinib (JAK1-selective inhibitor) markedly improves pruritus

27 Implications: Anti-pruritic effect may outpace anti-inflammatory effect ( PRESSROOM (/) SEPTEMBER 7, 2017 once-daily dose of upadacitinib[1] AbbVie's Upadacitinib (ABT-494) Meets Primary Endpoint in Phase 2b Study in Atopic Dermatitis - Upadacitinib demonstrated reduction in pruritus (itch) within the first week and improvement in skin within the first two weeks for all doses[1] ( (/article_print.cfm? - Upadacitinib, an oral agent engineered by article_id=11530) AbbVie to selectively inhibit JAK1, is being studied as a once-a-day therapy in atopic dermatitis and across multiple - Study shows positive results for upadacitinib and no new safety signals detected[1] - All doses achieved the primary endpoint of greater mean percentage change from baseline in Eczema Area and Severity Index (EASI) score versus placebo at 16 weeks[1] - Clear or almost clear skin was achieved by 50 percent of patients receiving 30 mg once-daily dose of upadacitinib[1] - Upadacitinib demonstrated reduction in pruritus (itch) within the first week and improvement in skin within the first two weeks for all doses[1] - Upadacitinib, an oral agent engineered by AbbVie to selectively inhibit JAK1, is being studied as a once-a-day therapy in atopic dermatitis and across multiple immune-mediated diseases[2],[3],[4-9]

28 Implications: Topical Jakinibs demonstrate anti-pruritic effects by Day 1-2

29 Implications: Patients with JAK1 gain-offunction mutations exhibit severe pruritus Alanine to aspartate substitution at position 634 (A634D) Del Bel et al. J Allerg Clin Immunol 2017

30 Implications: JAK1 gain-of-function pruritus only responsive to JAK inhibitors Del Bel et al. J Allerg Clin Immunol 2017

31 Conclusions 1. IL-4Rα blockers and JAK1 inhibitors may function as neuromodulators 2. Jakinibs demonstrate efficacy for chronic idiopathic pruritus 3. These pathways are likely conserved across multiple barrier surfaces: asthma, conjunctivitis, eosinophilic GI disorders, IBS, IBD, etc.

32 Acknowledgements Kim Lab Landon Kyle Oetjen (MSTP Student) Madison Mack (PhD Student) Anna Trier (MSTP Student) Fang Wang (Postdoctoral Fellow) Timothy Whelan Nancy Bodet (Research Nurse) Joy Niu (Postdoctoral Fellow) Amy Xu (HHMI Med Fellow) Collaborators Qin Liu Hongzhen Hu Zhoufeng Chen Steve Davidson (U Cinn) Mark Miller Chyi-Song Hsieh Josh Milner (NIH) Robert Gereau Funding K08AR R01AR Doris Duke Charitable Foundation American Skin Association LEO Pharma Research Grant