Therapeutic Advances for the Management of Patients with Psoriatic Arthritis

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1 Therapeutic Advances for the Management of Patients with Psoriatic Arthritis Alan L. Epstein, MD Clinical Professor of Medicine Univ. of Penn. School of Medicine

2 Disclosure of Conflicts of Interest Alan L. Epstein, MD Disclosures: Speakers Bureau: AbbVie Inc.; Amgen Inc.; Bristol-Myers Squibb Company; Celgene Corporation; Crescendo Bioscience, Inc.; Genentech, Inc.; Janssen Global Services, LLC; Lilly USA, LLC; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Quest Pharmaceuticals, Inc.; Regeneron; Sanofi

3 Spectrum of the Spondyloarthritides Van der Linden S, et al. Kelley s Textbook of Rheumatology. 2008; 8: Zochling J, et al. Rheumatology (Oxford). 2005; 44(12):

4 Updated Concept of the Spondyloarthritides Predominantly Axial Disease Ankylosing Spondylitis (radiographic SpA) Nonradiographic Axial SpA Predominantly Peripheral Disease Psoriatic Arthritis Reactive Arthritis Enteropathic/Colitic Arthritis Undifferentiated SpA Rudwaleit M. Ann Rheum Dis. 2009; 68(6): Rudwaleit M. Ann Rheum Dis. 2011; 70(1): Zochling J, et al. Rheumatology (Oxford). 2005; 44(12):

5 Features Characteristic of the Spondylarthritides Sacroiliitis or spondylitis may be the dominant clinical feature HLA-B27+ / Rheumatoid Factor Negative Peripheral arthritis, often asymmetric Enthesopathy Extra-skeletal features include: Eye: Anterior Uveitis GI: Inflammatory Bowel Disease Skin: Psoriasis Van der Linden S, et al. Kelley s Textbook of Rheumatology. 2008; 8: Zochling J, et al. Rheumatology (Oxford). 2005; 44(12):

6 Definition Enthesopathy Normal tendon attachment to bone Inflamed tendon attachment to bone Ruhoy M, el al. In: Klippel J, Dieppe P. Rheumatology. Mosby, London (2): 2.

7 Enthesitis Inflammation of the enthesis typical feature attachment of ligament, tendon, joint capsule to bone. Common sites of enthesial inflammation: Achilles tendon Plantar fascia Pelvis Tibial tubercles Costochondral junctions Elbow epicondyles Relevance of enthesitis to synovitis, subchondral marrow inflammation, and osteitis no entirely clear Entheseal fibrocartilage felt to be a major target of immune response and primary site of immunopathology Sieper J, et al. Ann Rheum Dis. 2002; 61(3): Granfors K, et al. Arthritis Rheum. 2002; 46(3):

8 Anatomy of the Enthesis Specialized tissue composed of fibrocartilage Interface between tendon, ligament, capsule, and bone Anchored to an extended trabecular network Tendon Enthesis Bone

9 Normal Entheseal Histology Cormick, W. AJUM. 2010; 13(4): FC=Fibrocartilage

10 Synovio-entheseal Complex (Enthesis Organ-components share stress forces) Bursa Fat Pad Enthesis Calcaneus Achilles Tendon Heel Cross-Section Adapted from: McGonagle D, et al. Arthritis Rheum. 2007; 56(8):

11 Synovio-Entheseal Complex in Health McGonagle D, et al. Arthritis Rheum. 2007; 56(8):

12 Synovio-entheseal Complex in Disease/Enthesitis McGonagle D, et al. Arthritis Rheum. 2007; 56(8):

13 Enthesitis Achilles Tendon Right Heel

14 Enthesis Inflammation Fluid within retrocalcaneal bursa Swollen Achilles Tendon Calcaneal Edema Heel MRI Adapted from: Olivieri I, et al. Rheumatol. 2006; 45(10): 1315.

15 SpA and HLA-B27 Disease HLA-B27 Prevalence Ankylosing Spondylitis 90 Reactive Arthritis Juvenile Spondyloarthropathy 70 Enteropathic Spondyloarthropathy Psoriatic Arthritis Undifferentiated Spondyloarthropathy 70 Acute Anterior Uveitis 50 Aortic incompetence with heart block 80 Khan MA. Ann Intern Med. 2002;136(12):

16 Psoriatic Arthritis

17 PsA/Psoriasis: Epidemiology Prevalence Psoriasis ~2% to 3% of white population 1 Rare in African Americans 2 PsA an inflammatory arthropathy 7% to 31% of patients with psoriasis 1 reports) Equal in males and females 3,4 Most PsA diagnosed in patients in their late 30s to 40s 3,4 (25-30% in recent 1. Mease P. In: Smolen J, Lipsky P. Targeted Therapies in Rheumatology. London: Stanley Dunitz; Koo J. Psychodermatology. 1996; 14: Gladman DD, et al. Q J Med. 1987; 62: Shbeeb M, et al. J Rheumatol. 2000; 27:

18 Epidemiology Psoriasis precedes the onset of PsA by as long as 10 years in 70% of patients Arthritis precedes psoriasis in 15% of cases (even more frequently in in children) Simultaneous onset in 15% Correlation between severity of psoriasis and psoriatic arthritis? 15% 15% Onset of PsA 70% Skin First Joints First Simultaneous Mease PJ, Goffe, BS. J Am Acad Dermatol. 2005; 52: 1. Gottleib A, et al. Dermatol Nurs. 2003; 15: 107. Pitzalis C. Br J Rheumatol. 1998; 37: 480.

19 Pathogenesis

20 Introduction Spondyloarthritis (SpA) Represents a group of immune-mediated inflammatory diseases that exhibit overlapping clinical features, genetic predisposition and pathogenic mechanisms Accumulating evidence implicates the IL-23/IL-17 axis in the pathogenesis of SpA Psoriatic Arthritis (PsA) Belongs to SpA and affects primarily the peripheral joints, spine and entheses Associated with psoriasis (PsO) Pathogenesis is not completely understood Considered by some to be an entheseal disease linking mechanical stress on the entheses to immunologically active tissue in the synovium Chimenti MS, et al. Autoimmun Rev. 2013; 12:

21 Psoriatic arthritis is not a benign rheumatoid variant. It is clinically, genetically, and immunologically distinct from RA. PsA PsO RA CLINICAL 1 Skin,Nails, Entheses,Joints,Bone CLINICAL 4 skin (elbows, knees, scalp), nails CLINICAL 5 Synovium, Joints, Bone GENETIC 2 IL-23R, CARD14, IL12B, IL-13, HLA-B,-C,-DRB1, TRAF3IP2 GENETIC 4 PSORS2, CARD14, IL36RN, HLA-Cw6, IL23 and others GENETIC 6 HLA-DRB1, PTPN22, TRAF1/C5, STAT4, PADI4, IRF5, FCGR, IL2RA,IL2RB, CD40,CCL21,CCR6 CELLULAR 1,3 neutrophils, osteocytes, osteoclasts, keratinocytes, T cells, macrophages, dendritic cells CELLULAR 4 keratinocytes, Langerhans cells, T cells, skin-homing T cells CELLULAR 5 synoviocytes, T cells, B cells macrophages, dendritic cells, chondrocytes, osteoclasts 1 Suzuki E, et al. Autoimmunity Rev. 2014; 13: Genetics Home Reference. Accessed on March 19, Smith JA. Arthritis and Rheumatology. 2014; 66: Lowes MA, et al. Annu Rev Immunol ;32: Choy E, Rheumatology 2012; 51: Kurko J, et al. Clinic Rev Allerg Immunol. 2013; 45 :

22 Overview of the Pathophysiology of Psoriatic Arthritis

23 Important Features Mechanical stress at the enthesis may precipitate PsA Immune response dominated by an autoinflammatory/innate immune response Cytokines generated by the innate immune response promote differentiation of both Th1 and Th17 lymphocytes Highly heritable, polygenic The number of IL-17 producing cells correlates with disease activity Cytokines in the IL-23/Th17 axis drive the multiple clinical features of the disease Barnas JL, et al. Rheum Dis Clin N Am. 2015; 41:

24 Proposed Model: Cytokine Pathways in the Immunopathology of Psoriatic Arthritis Dendritic Cell (DC) or other APC IL-17: Other sources: IL-12 Activated DC Naïve T cell CD4+ Th1 TNF-α IFN-γ IL-17A/F Proinflammatory Cytokine Production IL-17 IL-22 TNF-α IFN-γ IL-22 IL-17 TNF-α IL-17 Skin: keratinocyte proliferation Enthesis: enthesitis Synovium: synovitis Macrophage γδ cell Natural Killer T Cell IL-23 Regulatory cytokines Naïve T cell CD4+ Th17 IL-22 Effector cytokines IL-17 IL-22 TNF-α RANKL Other cytokines Bone and cartilage IL-17 1 Cauli A, et al. J Rheumatol. 2012; 39(Suppl 89): Raychaudhuri SP. Clin Rev Allergy Immunol. 2013; 44: Smith JA, et al. Arthritis Rheum. 2014; 66: Maeda S, et al. Int J Rheumatol. 2012; 2012: Nograles KE, et al. Nat Clin Pract Rheumatol. 2009; 5: Chimenti MS, et al. Autoimmunity Rev ;12: Farhey Y. Curr Rheumatol Rev. 2012; 8: Schett G. J Rheumatol. 2014; 41: Lories RJ, et al. Nat Med. 2012; 18: Cua DJ, et al. Nature Rev Immunol. 2010; 10: Song C, et al. J Immunol. 2008; 181:

25 Clinical Features of Psoriatic Arthritis Psoriasis Dactylitis Enthesitis DIP Joint Involvement Sacroiliitis Spondylitis Nail Dystrophy

26 PsA: Clinical Features Progressive and destructive 1-3 (not a benign variant of RA as previously thought) Joints are less tender than in rheumatoid arthritis (RA) 1,2 Joints are less swollen than in RA 1,2 Erosions, proliferative changes, and fusion can occur early and rapidly 2,3 1. Gladman DD. Rheum Dis Clin North Am. 1992; 18: Hanly JG, et al. Ann Rheum Dis. 1988; 47: Sege-Peterson K, Winchester R. In: Freedberg IM, et al. eds. Fitzpatrick s Dermatology in General Medicine. New York, NY: McGraw-Hill, 1998:

27 Morbidity and Mortality Associated With PsA 40% to 57% have deforming arthritis 1,2 17% have 5 deformed joints 2 11% to 19% are disabled 1,2 Mortality is increased compared with the general population 3 1. Torre Alonso JC, et al. Br J Rheumatol. 1991; 30: Gladman DD, et al. Q J Med. 1987; 62: Gladman DD, et al. Arthritis Rheum. 1998; 41:

28 Moll and Wright Criteria for the Classification of Psoriatic Arthritis Initial Inclusion Criteria Inflammatory Arthritis Peripheral Arthritis Spondylitis Sacroiliitis Presence of Psoriasis Absence of Rheumatoid Factor Once meeting these criteria, patients are divided into 5 subgroups of PsA: Moll JM, Wright V. Semi Arthritis Rheum. 1973; 3:

29 Moll and Wright Criteria for the Classification of Psoriatic Arthritis DIP joint only Asymmetric oligoarthritis Polyarthritis similar to rheumatoid arthritis Spondylitis Arthritis mutilans Moll JM, Wright V. Semi Arthritis Rheum. 1973; 3:

30 Diagnostic Criteria for PsA (CASPAR) Taylor WJ, et al. Presented at EULAR; June 8-11, Vienna, Austria. Abstract #OP0157. Specificity 98.7%, Sensitivity 91.4%

31 ASCR

32 Psoriatic Arthritis: DIP Synovitis

33 Psoriatic Arthritis: Asymmetric Oligoarthritis

34 Dactylitis and Enthesitis Why are They Important? Dactylitis associated with erosive disease 1 Enthesitis often first manifestation of peripheral disease in SpAs 2 1. Brockbank. Ann Rheum Dis. 2005; 62: McGonagle et al. The Lancet. 1998; 352.

35 Definition Dactylitis Combination of: Enthesitis Tenosynovitis Synovitis of the entire digit Asymmetric Distribution Associated with greater joint damage than nonaffected digits Hochberg M, et al. Rheumatology Brockbank J, et al. Ann Rheum Dis. 2005; 64: Gottlieb A, et al. J Am Acad Dermatol. 2008; 58:

36 Spondylitis 44 Estimated frequency of 5% 1 The axial spine may be involved in 20% 40% of PsA cases subject to rigorous clinical and radiographic examination 2-4 HLA-B27 is positive in 40% 50% of Caucasian spondylitic PsA patients 5 Male predominance Bruce IN. In: Hochberg M, et al., eds. Rheumatology. Edinburgh, Scotland: Mosby. 2003; 3: Available at: 2 Hanly JG, et al. Ann Rheum Dis. 1988; 47: Veale D, et al. Br J Rheumatol. 1994; 33: Torre-Alonso JC, et al. Br J Rheumatol. 1991; 30: IN05807

37 Psoriatic Arthritis: Arthritis Mutilans

38 Psoriatic Arthritis: Arthritis Mutilans Slide Reproduced with permission Courtesy of Evan Siegel MD

39 Psoriatic Arthritis: Radiographic Characteristics Erosive arthritis (usually asymmetric) Pencil-in-cup deformity Ray phenomenon Arthritis mutilans Bony ankylosis Spurs/periosteal reaction Non-marginal asymmetric syndesmophytes Asymmetric sacroiliitis

40 PsA Clinical Features: Radiologic Images Pencil in cup joint erosions Sacroiliitis ACR Slide Collection on the Rheumatic Diseases; 3 rd edition

41 PsA Extra-articular Manifestations Acute and chronic inflammation have been reported in the bowel 15% of psoriasis patients 30% of psoriatic arthritis patients Lesions range from asymptomatic focal microscopic inflammation to florid inflammatory bowel disease indistinguishable from Crohn s disease Ritchlin C. Nat Clin Pract Rheumatol. 2007; 3(12):

42 PsA Extra-articular Manifestations Uveitis Present in 15-18% of patients with PsA Usually in patients who are HLA B27 positive Differs from uveitis seen in ankylosing spondylitis More often bilateral May involve posterior pole of eye Often requires NSAIDs to control pain Ritchlin C. Nat Clin Pract Rheumatol. 2007; 3(12):

43 PsA Extra-articular Manifestations Cardiovascular issues Psoriasis patients have a significantly higher rate of obesity, insulin resistance, type 2 diabetes and metabolic syndrome Increased incidence of hypertension, hyperlipidemia and cardiovascular disease compared to age matched controls Psoriasis is an independent risk factor for myocardial infarction Ritchlin C. Nat Clin Pract Rheumatol. 2007; 3(12):

44 Treatment Options Topical agents and NSAID/ Cox 2 inhibitors Traditional DMARDS Apremilast TNF alpha inhibitors IL-12/23 inhibitors IL-17 inhibitors JAK-STAT inhibitors

45 Lie E, et al. ARD. 2013; 72. Traditional DMARD s in PSA

46 Gossec L, et al. Ann Rheum Dis. 2015; 0: 1

47 Recommendation - 3 In patients with peripheral arthritis, particularly in those with many swollen joints, structural damage in the presence of inflammation, high ESR/CRP and/or clinically relevant extraarticular manifestations (1), csdmards should be considered (2) at an early stage (1), with methotrexate preferred in those with relevant skin involvement (2). csdmards= conventional synthetic disease-modifying anti-rheumatic drugs, such as methotrexate, sulfasalazine, or leflunomide

48 Evidence for PsA Evidence for RA Ash Z, Gaujoux-Viala C, et al. Ann Rheum Dis Mar; 71(3):

49 Methotrexate in PsA What s New? RCT: 2012, MIPA trial 6-month randomised controlled trial MTX 15 mg/week versus placebo, n=221 patients No significant differences for PsARC, ACR20, DAS28 Significant effect on skin Observational data Methotrexate widely used in cohorts and registries High treatment maintenance, around 65% at 3 years (similar to RA) MTX arm in TICOPA did very well Efficacious on skin psoriasis: preferred if skin involvement Lie E, et al. Ann Rheum Dis ; Gladman D, et al. Arthr Res Ther Creswell L et al. Ann Rheum Dis ; Simon P, et al. Clin Exp Rheumatol Theander E, et al. Ann Rheum Dis ; Gladman D, et al. Ann Rheum Dis Tillett W, et al. Ann Rheum Dis ; Ash Z, Gaujoux-Viala C, et al. Ann Rheum Dis Kingsley GH, et al. Rheumatology ; Coates L, et al. Lancet

50 Apremilast in PsA Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Ann Rheum Dis. 2014; 73(6):

51 TNF Inhibitors Approved to Treat Psoriatic Arthritis and Psoriasis Etanercept Infliximab Adalimumab Golimumab Certolizumab

52 TNFi Response Rates for Treating PsA 100 ACR20 Response After 24 Wks* 80 ACR20 (%) Mease PJ, et al. N Engl J Med. 2015; 373: McInnes IB, et al. Lancet. 2015; 386: Antoni C, et al. Ann Rheum Dis. 2005; 64: Mease PJ, et al. Arthritis Rheum. 2004; 50: Mease PJ, et al. Arthritis Rheum. 2005; 52: Kavanaugh A, et al. Arthritis Rheum. 2009; 60: *Independent trials; no head-to-head comparisons. Results for PI-recommended PsA doses of each agent shown. P <.001. P < Data given for Wk 12; results were sustained at Wk 24.

53 Osteoclast Precursors in PsA OC per 10 6 PBMC p<2.12x PsA Control Ritchlin CT, et al. J Clin Invest. 2003;111(6):

54 Circulating Osteoclast Precursors Following Anti-TNF-α Therapy OCP Number OCP per 106 PBMC Pre-Rx 12 wks Rx Ritchlin CT, et al. J Clin Invest. 2003;111(6):

55 Ustekinumab

56 Mechanism of Action Extracelluar binding Intracellular signalling p40 IL12Rβ1 IL-23R p19 JAK 2 TYK 2 STAT3 Human monoclonal antibody Binds with specificity to the p40 protein subunit P40 subunit shared by IL-12 and IL-23 In vitro models demonstrate that ustekinumab disrupts the binding of IL-12 and IL-23 to their shared cell surface receptor Adapted from Toussirot E. Inflamm Allergy Drug Targets. 2012;11:

57 Primary Endpoint: ACR20 Responders at Week Percent of Patients * 42.4 * 49.5 * ACR20 *p<0.001 PBO (n=206) UST 90 mg (n=204) UST 45 mg (n=205) UST Combined (n=409) McInnes I.B, Kavanaugh W, et al. Lancet. 2013; 382:

58 Proportion of Patients Achieving ACR20 Responses Over Time Through Week 100 Proportion of Patients % 62.7% 56.7% Weeks PBO n= mg n= mg n= = Injection of UST or PBO Kavanaugh A, et al. Presented at ACR; October 25-30, San Diego, California. Abstract LB10.

59 Proportion of Patients Proportion of Patients Achieving ACR50 Responses Over Time Through Week % 38.8 % Weeks PBO n= mg n= mg n= = Injection of UST or PBO Kavanaugh A, et al. Presented at ACR; October 25-30, San Diego, California. Abstract LB10.

60 Median Improvement From Baseline in Patients With Dactylitis and Enthesitis at Week 24 Enthesitis** Dactylitis* Percent of Patients p=0.005 p= p= Percent of Patients p= p= p= n= 70/92 n= 56/99 n= 53/95 n= 109/194 0 n= 111/137 n= 96/140 n= 90/148 n= 186/288 *In patients with dactylitis in one digit or more at baseline. **In patients with psoriatic-arthritis-modified Maastricht ankylosing spondylitis enthesitis score 1 at baseline. McInnes IB, Kavanaugh W, et al. Lancet. 2013; 382:

61 Mechanism of Action of IL-17A Inhibitors in Treating PsA Secukinumab and Ixekizumab Monoclonal antibodies targeting IL-17A Brodalumab Monoclonal antibody targeting IL-17A receptor IL-17A Psoriatic plaques Dendritic cell Naive T-cell IL-23 Th17 IL-17R Pannus formation Joint erosion Bone formation Cartilage damage Enthesitis Coates LC, et al. Sem Arth Rheum

62 Secukinumab Human monoclonal antibody to IL-17A FDA approved for adults with: Active PsA Moderate to severe plaque psoriasis who are eligible for systemic therapy or phototherapy Active ankylosing spondylitis FUTURE 1 and 2 randomized phase III studies assessed secukinumab efficacy and safety in pts with PsA Ritchlin CT, et al. Curr Opin Rhematol. 2016; 28: Secukinumab [package insert]

63 FUTURE 1 and 2: Improved ACR20 Responses With Secukinumab vs PBO Pts With ACR20 Response (%) FUTURE 1 [1] FUTURE 2 [2] Secukinumab 75 mg (n = 202) Secukinumab 150 mg (n = 202) Placebo (n = 202) Wk Pts With ACR20 Response (%) Secukinumab 75 mg (n = 100) Secukinumab 150 mg (n = 100) Secukinumab 300 mg (n = 99) Placebo (n = 98) Wk 1. Mease PJ, et al. N Engl J Med. 2015; 373: McInnes IB, et al. Lancet. 2015; 386:

64 FUTURE 1 and 2: Additional Efficacy Findings Outcome, Wk 24 SECU 150 mg (n = 202) FUTURE 1 [1] FUTURE 2 [2] SECU 75 mg (n = 202) PBO (n = 202) SECU 300 mg (n = 100) SECU 150 mg (n = 100) SECU 75 mg (n = 99) PBO (n = 98) ACR20, %* ǁ 51 ǁ ACR50, % PASI 75, % ǁ PASI 90, % DAS28-CRP, Δ fr. BL Dactylitis resolved, % 52.4 # Enthesitis resolved, % 47.5 ** *Primary endpoint. P vs PBO: P <.001; P <.05; P <.01; ǁ P <.0001; P =.055. # Pooled data, n/n = 109/208. **Pooled data, n/n = 121/255. Pooled data, n/n = 52/111. Pooled data, n/n = 76/188. In both trials, ACR20 at Wk 24 higher for SECU vs PBO regardless of previous TNFi exposure; however, trend toward higher ACR20 for TNFi-naive vs TNFi-IR pts. 1. Mease PJ, et al. N Engl J Med. 2015; 373: McInnes IB, et al. Lancet. 2015; 386:

65 Ixekizumab Human monoclonal antibody to IL-17A FDA approved for adults with: [1] Moderate to severe plaque psoriasis who are eligible for systemic therapy or phototherapy UNCOVER-1, -2, and -3: randomized phase III studies assessing ixekizumab efficacy and safety in pts with psoriasis (N = 3866) [2,3] Ixekizumab treatment for 12 wks significantly improved proportion of pts with PASI 75 response or spga score of 0 or 1 vs PBO (all trials) and vs etanercept (UNCOVER-2 and -3) SPIRIT-P1: randomized phase III study assessing ixekizumab efficacy and safety in biologic-naïve pts with PsA [4] 1. Ixekizumab [package insert] Gordon KB, et al. N Engl J Med. 2016; 375: Griffiths CE, et al. Lancet. 2015; 386: Mease PJ, et al. Ann Rheum Dis. 2016; [Epub ahead of print].

66 SPIRIT-P1: Efficacy In biologic-naive pts with active PsA, IXE treatment improved both joint and skin symptoms Wk 24 Outcomes IXE Q2W IXE Q4W ADA PBO (n = 103) (n = 107) (n = 101) (n = 106) ACR20,* % ACR50, % ACR70, % PASI 75, % PASI 100, % HAQ-DI, from BL mtss, from BL LEI score 0, % LDI-B score 0, # % *Primary endpoint (IXE vs PBO). P.001 vs PBO; P.01 vs PBO. Only pts with 3% BSA at BL: IXE Q2W/Q4W/ADA/PBO, n = 59/73/68/67. Only pts with BL LEI score > 0: IXE Q2W/Q4W/ADA/PBO, n = 57/68/54/57. # Only pts with BL LDI-B score > 0: IXE Q2W/Q4W/ADA/PBO, n = 26/39/18/28. Mease PJ, et al. Ann Rheum Dis. 2016; [Epub ahead of print].

67 SPIRIT-P1: Safety Outcome, n (%) IXE Q2W (n = 102) IXE Q4W (n = 107) ADA (n = 101) PBO (n = 106) TEAEs 67 (65.7)* 71 (66.4)* 65 (64.4) 50 (47.2) Severe 5 (4.9) 4 (3.7) 1 (1.0) 2 (1.9) SAEs 3 (2.9) 6 (5.6) 5 (5.0) 2 (1.9) D/c due to AE 4 (3.9) 2 (1.9) 2 (2.0) 2 (1.9) Infections of special interest Herpes zoster (n = 1) Esophageal candida (n = 1) Oral candida (n = 1) Any infection 24 (23.5) 30 (28.0) 26 (25.7) 27 (25.5) Any Candida infection 1 (1.0) 1 (0.9) 0 0 Active or reactivated TB Depression 1 (1.0) 2 (1.9) 1 (1.0) 0 Cytopenias 4 (3.9) 1 (0.9) 4 (4.0) 6 (5.7) Neutropenia 1 (1.0) Cerebro-cardiovascular event (3.0) 0 Malignancy (1.0) 1 (0.9) Crohn s disease or UC *P.01 vs PBO. NR NR Mease PJ, et al. Ann Rheum Dis. 2016; [Epub ahead of print].

68 SPIRIT-P2 Ixekizumab in TNF-IR Patients ACR-20 for IXE 80 mg q4wks=53% ACR-20 for IXE 40 mg q2wks=48% Serious adverse events were low

69 Brodalumab for Pts With Active PsA Randomized, double-blind, placebo-controlled phase II trial [1] Wk 12 Adult pts with active PsA and no prior rituximab or IL-17 therapy; washout required for previous TNFi or IL-12/23 therapy (N = 168) Brodalumab 140 mg SC* (n = 57) Brodalumab 280 mg SC* (n = 56) Placebo* (n = 55) Pts remaining on study offered open-label brodalumab Q2W *Administered QW at Wks 1, 2, 4, 6, 8 and 10. All pts on methotrexate ( 25 mg/wk), leflunomide ( 20 mg/day), and glucosteroids ( 10 mg/day) for 4 wks prior to study initiation. At Wk 12, both 140-mg and 280-mg brodalumab significantly improved ACR20 and ACR50 vs placebo regardless of prior biologic therapy 1. Mease PJ, et al. N Engl J Med. 2014; 370: Ritchlin CT, et al. Curr Opin Rhematol. 2016; 28:

70 Guselkumab IL-12 IL-23 p35 p40 p19 p40 Ustekinumab Ustekinumab A fully human monoclonal antibody targeting the p19 subunit of ll-23 thus specifically inhibits the biological activity of IL-23. Demonstrated robust efficacy in psoriasis patients in 3 phase 3 trials. We report the efficacy and safety of guselkumab through Week 24 in patients with active psoriatic arthritis in a phase 2 study. DeodharA, et al. Presented at ACR; November 11-16, 2016 Washington, D.C. Abstract #4L.

71 Guselkumab 100 Primary Endpoint % of Patients p< p=0.002 p=0.023 (post hoc) ACR20 ACR50 ACR70 Placebo (n=49) Guselkumab (n=100) DeodharA, et al. Presented at ACR; November 11-16, 2016 Washington, D.C. Abstract #4L.

72 Percent of Patients with Complete Resolution of Enthesitis at Week 24 % of Patients Placebo (n=31) p= Guselkumab (n=76) in Patients with Enthesitis at Baseline DeodharA, et al. Presented at ACR; November 11-16, 2016 Washington, D.C. Abstract #4L.

73 Percent of Patients with Complete Resolution of Dactylitis at Week 24 % of Patients Placebo (n=23) p= Guselkumab (n=58) in Patients with Dactylitis at Baseline DeodharA, et al. Presented at ACR; November 11-16, 2016 Washington, D.C. Abstract #4L.

74 PASI Responders at Week 24 % of Patients * 78.6 *p<0.001 * 66.3 * PASI 75 PASI 90 PASI 100 Placebo (n=48) Guselkumab (n=98) DeodharA, et al. Presented at ACR; November 11-16, 2016 Washington, D.C. Abstract #4L.

75 Efficacy and Safety of Tofacitinib, an Oral Janus Kinase Inhibitor, or Adalimumab in Patients with Active Psoriatic Arthritis and an Inadequate Response to Conventional Synthetic DMARDs: A Randomized, Placebo-Controlled, Phase 3 Trial PJ Mease, 1 S Hall, 2 O FitzGerald, 3 D van der Heijde, 4 JF Merola, 5 F Avila-Zapata, 6 D Cieślak, 7 D Graham, 8 C Wang, 9 S Menon, 9 T Hendrikx,

76 Study Design (12 months) Tofacitinib 5 mg BID (N=107) Tofacitinib 5 mg BID Randomization: 2:2:2:1:1 Tofacitinib 10 mg BID (N=104) Adalimumab 40 mg SC Q2W (active control arm) (N=106) Placebo (N=52) Tofacitinib 10 mg BID Adalimumab 40 mg SC Q2W (active control arm) Tofacitinib 5 mg BID Placebo (N=53) Tofacitinib 10 mg BID Month Primary endpoints ACR20 HAQ-DI Secondary endpoints ACR50; ACR70 PASI75; LEI; DSS; FACIT-F; MDA; Pain Radiographic progression (mtss) NCT ; Safety assessments and adverse events were reported throughout the study BID, twice daily; DSS, Dactylitis Severity Score; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; LEI, Leeds Enthesitis Index; MDA, minimal disease activity; mtss, modified Total Sharp Score; Q2W, once every two weeks; PASI75, 75% improvement from baseline Psoriasis Area and Severity Index; SC, subcutaneous 8

77 Primary Endpoints: ACR20 and HAQ-DI with Tofacitinib vs Placebo at Month 3 HAQ-DI 100 ACR20 0 Place bo Tofacitinib 5 mg BID Tofacitinib 10 mg BID Adalimumab 40 mg SC Q2W % of patients with ACR20 response ± SE * LS mean ΔHAQ-DI ± SE *p 0.05 for comparing tofacitinib vs placebo; nominal *p 0.05 for comparing adalimumab vs placebo; N for HAQ-DI is the number of 4 unique patients in the repeated measures model Full analysis set; missing ACR20 values were imputed as non-response; no imputation for missing HAQ-DI values, change from baseline; LS, least squares; SE, standard error Place bo Tofacitinib 5 mg BID Tofacitinib 10 mg BID Adalim umab 40 mg SC Q2W * * * 1 0 6

78 Radiographic Non-progression at Month Non-progressors (defined as an increase from baseline in mtss 0.5) % of patients with mtss increase 0.5 ± SE Placebo tofacitinib 5 mg BID Placebo tofacitinib 10 mg BID Tofacitinib 5 mg BID Tofacitinib 10 mg BID Adalimumab 40 mg SC Q2W mtss reported for evaluable patients in the full analysis set; missing values imputed by linear extrapolation mtss, modified Total Sharp Score; SE, standard error

79 PASI75 with Tofacitinib vs Placebo (MR=NR) 100 PASI75 Response Rate % of patients with PASI75 response ± SE * 43 * 44 * Month Placebo Tofacitinib 5 mg BID Placebo tofacitinib 5 mg BID Tofacitinib 10 mg BID Placebo tofacitinib 10 mg BID Adalimumab 40 mg SC Q2W *p 0.05 for comparing tofacitinib vs placebo; nominal *p 0.05 for comparing adalimumab vs placebo; statistical significance was declared for both tofacitinib doses as per the pre-specified step-down testing procedure; PASI75 reported for patients in the full analysis set with baseline BSA 3% and baseline PASI >0 MR=NR, missing response as non-response; PASI75, 75% improvement from baseline Psoriasis Area and Severity Index; SE, standard error 1

80 Change from Baseline for Enthesitis Leeds Enthesitis Index 3 Month 6 12 LS mean ΔLEI ± SE * * -1.1 Baseline enthesitis (LEI>0), n (%) Baseline LEI score, a mean (SD) Placebo Tofaci Tofac Adalim tinib itinib umab 5 mg mg BID mg Q2W BID 65 (61.9) 75 (70.1) 64 (61.5) 76 (71.7) 2.8 (1.5) 2.5 (1.4) 3.0 (1.6) 2.3 (1.2) Placebo Tofacitinib 5 mg BID Placebo tofacitinib 5 mg BID Tofacitinib 10 mg BID Placebo tofacitinib 10 mg BID Adalimumab 40 mg SC Q2W a among patients with baseline score >0; *p 0.05 for comparing tofacitinib vs placebo; nominal *p 0.05 for comparing adalimumab vs placebo; statistical significance was declared for tofacitinib 10 mg BID per the pre-specified step-down testing procedure; LEI reported for patients in the full analysis set with baseline score >0; no imputation for missing values Δ, change from baseline; LEI, Leeds Enthesitis Index; LS, least squares; SD, standard deviation; SE, standard error 1

81 Change from Baseline for Dactylitis Dactylitis Severity Score 3 Month 6 12 LS mean ΔDSS ± SE * Placebo Tofaci Tofac Adalim tinib itinib umab 5 mg mg BID mg Q2W BID Baseline dactylitis (DSS>0), 58 (55.2) 61 (57.0) 60 (57.7) 58 (54.7) n (%) Baseline DSS, a mean (SD) 9.9 (8.4) 9.1 (8.0) 8.5 (8.2) 8.0 (7.4) Placebo Tofacitinib 5 mg BID Placebo tofacitinib 5 mg BID Tofacitinib 10 mg BID Placebo tofacitinib 10 mg BID Adalimumab 40 mg SC Q2W a among patients with baseline score >0; nominal *p 0.05 vs placebo; statistical significance was declared for secondary endpoints if a comparison passed the test as per the pre-specified step-down testing procedure; otherwise a nominal p value was used to guide interpretation of results; DSS reported for patients in the full analysis set with baseline score >0; no imputation for missing values Δ, change from baseline; DSS, Dactylitis Severity Score; LS, least squares; SD, standard deviation; SE, standard error

82 GRAPPA 2015 Treatment Guidance Domain Setting Recommendation* Peripheral arthritis Axial disease Enthesitis Dactylitis Skin Nails First line Coates LC, et al. Arthritis Rheumatol. 2016; 68: NSAIDs and IA CSs as indicated or DMARDs or PDE-4i or TNFi Second line/switch PDE-4i* or biologics (TNFi, IL-12/23i, IL-17i) First line Physiotherapy and/or NSAIDs Second-line/switch Biologics (TNFi, IL-12/23i, IL-17i) First line Second line/switch First line Physiotherapy or NSAIDs PDE-4i or biologics (TNFi, IL-12/23i, IL-17i) CS injection as indicated or NSAIDs Second line DMARDs or PDE-4i Third line/switch First line Second line Biologics: first TNFi, IL-12/23i, then PDE-4i, IL-17i (switch) Topicals as indicated Phototherapy or DMARDs or PDE-4i Third line/switch PDE-4i or biologics (TNFi, IL-12/23i, IL-17i) First line Second line/switch Topical or procedural or DMARDs or PDE-4i or biologics (TNFi, IL- 12/23i, IL-17i) PDE-4i or biologics (TNFi, IL-12/23i, IL-17i) Conditional recommendations in italics. *Second line. Expedited therapeutic route.

83 ASCR Questions?