Therapeutic Advances for the Management of Patients with

Slide 1Univ. of Penn. School of Medicine
Therapeutic Advances for the Management of Patients with Psoriatic Arthritis
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
Spectrum of the Spondyloarthritides
Van der Linden S, et al. Kelley’s Textbook of Rheumatology. 2008; 8: 1169-1189. Zochling J, et al. Rheumatology (Oxford). 2005; 44(12): 1483-1491.
Updated Concept of the Spondyloarthritides
Rudwaleit M. Ann Rheum Dis. 2009; 68(6): 777-783. Rudwaleit M. Ann Rheum Dis. 2011; 70(1): 25-31. Zochling J, et al. Rheumatology (Oxford). 2005; 44(12): 1483-1491.
Predominantly Axial Disease ___________ Ankylosing Spondylitis (radiographic SpA)
Nonradiographic Axial SpA
Enteropathic/Colitic Arthritis
Undifferentiated SpA
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: 1169-1189. Zochling J, et al. Rheumatology (Oxford). 2005; 44(12): 1483-1491.
Definition Enthesopathy
Normal tendon attachment to bone
Inflamed tendon attachment to bone
Ruhoy M, el al. In: Klippel J, Dieppe P. Rheumatology. Mosby, London. 2008. (2): 2.
Enthesitis
Sieper J, et al. Ann Rheum Dis. 2002; 61(3): 8-18. Granfors K, et al. Arthritis Rheum. 2002; 46(3): 606-613.
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
Anatomy of the Enthesis
Interface between tendon, ligament, capsule, and bone
Anchored to an extended trabecular network
Normal Entheseal Histology
FC=Fibrocartilage
Heel Cross-Section
Fat Pad
Adapted from: McGonagle D, et al. Arthritis Rheum. 2007; 56(8): 2482-91.
Synovio-Entheseal Complex in Health
Synovio-entheseal Complex in Disease/Enthesitis
Enthesitis Achilles Tendon Right Heel
Enthesis Inflammation
Calcaneal Edema
Adapted from: Olivieri I, et al. Rheumatol. 2006; 45(10): 1315.
SpA and HLA-B27
Disease HLA-B27 Prevalence
Khan MA. Ann Intern Med. 2002;136(12):896-907.
Psoriatic Arthritis
PsA/Psoriasis: Epidemiology Prevalence
– Psoriasis • ~2% to 3% of white population1 • Rare in African Americans2
– PsA—an inflammatory arthropathy • 7% to 31% of patients with psoriasis1 (25-30% in recent
reports) • Equal in males and females3,4
Most PsA diagnosed in patients in their late 30s to 40s3,4
1. Mease P. In: Smolen J, Lipsky P. Targeted Therapies in Rheumatology. London: Stanley Dunitz; 2003. 2. Koo J. Psychodermatology. 1996; 14: 485-496. 3. Gladman DD, et al. Q J Med. 1987; 62: 127-141. 4. Shbeeb M, et al. J Rheumatol. 2000; 27: 1247-1250.
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%
Onset of PsA
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.
Pathogenesis
– 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: 599-606.
Psoriatic arthritis is not a “benign rheumatoid variant”. It is clinically, genetically, and immunologically distinct from RA.
1Suzuki E, et al. Autoimmunity Rev. 2014; 13: 496-502. 2Genetics Home Reference. http://ghr.nlm.nih.gov/condition/psoriatic-arthritis/show/Related+Gene(s). Accessed on March 19, 2015. 3Smith JA. Arthritis and Rheumatology. 2014; 66: 231-241. 4Lowes MA, et al. Annu Rev Immunol. 2014 ;32: 227-255. 5Choy E, Rheumatology 2012; 51: 3-11. 6Kurko J, et al. Clinic Rev Allerg Immunol. 2013; 45 :170-179.
PsA CLINICAL1 Skin,Nails,
TRAF3IP2
dendritic cells
PsO CLINICAL4
GENETIC4
T cells
CD40,CCL21,CCR6
CELLULAR5
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: 643-663.
Proposed Model: Cytokine Pathways in the Immunopathology of Psoriatic Arthritis
1Cauli A, et al. J Rheumatol. 2012; 39(Suppl 89): 15-18. 2Raychaudhuri SP. Clin Rev Allergy Immunol. 2013; 44: 183-193. 3Smith JA, et al. Arthritis Rheum. 2014; 66: 231-241. 4Maeda S, et al. Int J Rheumatol. 2012; 2012: 539683. 5Nograles KE, et al. Nat Clin Pract Rheumatol. 2009; 5: 83-91. 6Chimenti MS, et al. Autoimmunity Rev. 2013 ;12: 599-606. 7Farhey Y. Curr Rheumatol Rev. 2012; 8: 66-76. 8Schett G. J Rheumatol. 2014; 41: 1218-1219. 9Lories RJ, et al. Nat Med. 2012; 18: 1018-1019. 10Cua DJ, et al. Nature Rev Immunol. 2010; 10: 479-489. 11Song C, et al. J Immunol. 2008; 181: 6117-6124.
Th1
TNF-α
IFN-γ
IL-22
IL-17A/F
IL-12
Bone and cartilage IL-17 IL-22
TNF-α RANKL
Other cytokines
Regulatory cytokines
CD4+
IL-17: Other sources:
Psoriasis Dactylitis Enthesitis DIP Joint Involvement Sacroiliitis Spondylitis Nail Dystrophy
1. Gladman DD. Rheum Dis Clin North Am. 1992; 18: 247-256. 2. Hanly JG, et al. Ann Rheum Dis. 1988; 47: 386-393. 3. Sege-Peterson K, Winchester R. In: Freedberg IM, et al. eds. Fitzpatrick’s Dermatology in General Medicine. New York,
NY: McGraw-Hill, 1998: 522-533.
PsA: Clinical Features
Progressive and destructive1-3 (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 RA1,2 Erosions, proliferative changes, and fusion
can occur early and rapidly 2,3
Morbidity and Mortality Associated With PsA
40% to 57% have deforming arthritis1,2
17% have ≥5 deformed joints2
11% to 19% are disabled1,2
Mortality is increased compared with the general population3
1. Torre Alonso JC, et al. Br J Rheumatol. 1991; 30: 245-250. 2. Gladman DD, et al. Q J Med. 1987; 62: 127-141. 3. Gladman DD, et al. Arthritis Rheum. 1998; 41: 1103-1110.
Moll and Wright Criteria for the Classification of Psoriatic Arthritis
Initial Inclusion Criteria
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: 55-78.
DIP joint only Asymmetric oligoarthritis Polyarthritis similar to rheumatoid
arthritis Spondylitis Arthritis mutilans
Moll JM, Wright V. Semi Arthritis Rheum. 1973; 3: 55-78.
Diagnostic Criteria for PsA (CASPAR)
Taylor WJ, et al. Presented at EULAR; June 8-11, 2005. Vienna, Austria. Abstract #OP0157.
Specificity 98.7%, Sensitivity 91.4%
Enthesitis often first manifestation of peripheral
disease in SpAs2
Dactylitis associated with erosive disease1
1. Brockbank. Ann Rheum Dis. 2005; 62: 188-90. 2. McGonagle et al. The Lancet. 1998; 352.
Definition Dactylitis
digit Asymmetric Distribution Associated with greater
joint damage than non- affected digits
Hochberg M, et al. Rheumatology. 5. 2011. Brockbank J, et al. Ann Rheum Dis. 2005; 64: 189-90. Gottlieb A, et al. J Am Acad Dermatol. 2008; 58: 851-63.
Spondylitis • Estimated frequency of 5%1 • The axial spine may be
involved in 20%–40% of PsA cases subject to rigorous clinical and radiographic examination2-4
• HLA-B27 is positive in 40%– 50% of Caucasian spondylitic PsA patients5
• Male predominance2-4 1Bruce IN. In: Hochberg M, et al., eds. Rheumatology. Edinburgh, Scotland: Mosby. 2003; 3: 1241-1252. Available at: www.rheumtext.com. 2Hanly JG, et al. Ann Rheum Dis. 1988; 47: 386–393. 3Veale D, et al. Br J Rheumatol. 1994; 33: 133–138. 4Torre-Alonso JC, et al. Br J Rheumatol. 1991; 30: 245–250.
44
Psoriatic Arthritis: Arthritis Mutilans
Psoriatic Arthritis: Radiographic Characteristics
PsA Clinical Features: Radiologic Images
ACR Slide Collection on the Rheumatic Diseases; 3rd edition. 1994.
Pencil in cup joint erosions Sacroiliitis
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): 698-706.
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): 698-706.
– 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
•Traditional DMARDS
Lie E, et al. ARD. 2013; 72.
Gossec L, et al. Ann Rheum Dis. 2015; 0: 1– 12
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 extra- articular 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
Ash Z, Gaujoux-Viala C, et al. Ann Rheum Dis. 2012 Mar; 71(3): 319-26.
Evidence for RA
Evidence for PsA
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. 2010.; Gladman D, et al. Arthr Res Ther. 2010. Creswell L et al. Ann Rheum Dis. 2011.; Simon P, et al. Clin Exp Rheumatol. 2012. Theander E, et al. Ann Rheum Dis. 2013.; Gladman D, et al. Ann Rheum Dis. 2011. Tillett W, et al. Ann Rheum Dis. 2013.; Ash Z, Gaujoux-Viala C, et al. Ann Rheum Dis. 2012. Kingsley GH, et al. Rheumatology. 2012.; Coates L, et al. Lancet. 2015.
Apremilast in PsA
Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Ann Rheum Dis. 2014; 73(6): 1020–1026.
TNF Inhibitors Approved to Treat Psoriatic Arthritis and Psoriasis
• Etanercept
• Infliximab
• Adalimumab
• Golimumab
• Certolizumab
TNFi Response Rates for Treating PsA
1. Mease PJ, et al. N Engl J Med. 2015; 373: 1329-1339. 2. McInnes IB, et al. Lancet. 2015; 386: 1137-1146. 3. Antoni C, et al. Ann Rheum Dis. 2005; 64: 1150-1157. 4. Mease PJ, et al. Arthritis Rheum. 2004; 50: 2264-2272. 5. Mease PJ, et al. Arthritis Rheum. 2005; 52: 3279-3289. 6. Kavanaugh A, et al. Arthritis Rheum. 2009; 60: 976-986.
*Independent trials; no head-to-head comparisons. Results for PI-recommended PsA doses of each agent shown. †P < .001. ‡P < .0001. §Data given for Wk 12; results were sustained at Wk 24.
100 ACR20 Response After 24 Wks*
80
60
40
20
0
0
20
40
60
80
100
120
Ritchlin CT, et al. J Clin Invest. 2003;111(6):821-31.
Chart1
Pre-Rx
Pre-Rx
Pre-Rx
Pre-Rx
Pre-Rx
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;11:159-168.
p40 p19
22.8
s
ACR20
PBO (n=206) UST 45 mg (n=205) UST 90 mg (n=204) UST Combined (n=409)
*p<0.001
* * *
McInnes I.B, Kavanaugh W, et al. Lancet. 2013; 382: 780–789.
Proportion of Patients Achieving ACR20 Responses Over Time Through Week 100
62.7%
56.7%
63.6%
0
20
40
60
80
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100
Pr op
or tio
n of
P at
ie nt
= Injection of UST or PBO
PBO n= 206 206 185 177 45 mg n= 205 205 195 178 90 mg n= 204 204 189 176
Kavanaugh A, et al. Presented at ACR; October 25-30, 2013. San Diego, California. Abstract LB10.
38.8 46.0
0
20
40
60
80
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100
Pr op
or tio
n of
P at
ie nt
= Injection of UST or PBO
PBO n= 206 206 185 177 45 mg n= 205 205 195 178 90 mg n= 204 204 189 176
Kavanaugh A, et al. Presented at ACR; October 25-30, 2013. San Diego, California. Abstract LB10.
Median Improvement From Baseline in Patients With Dactylitis and Enthesitis at Week 24
Enthesitis**
76.1
*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.
p=0.005 p=0.0001 p=0.0001
p=0.0179 p=0.0002 p=0.0006
McInnes IB, Kavanaugh W, et al. Lancet. 2013; 382: 780–789.
n= 111/137
n= 96/140
n= 90/148
n= 186/288
n= 70/92
n= 56/99
n= 53/95
n= 109/194
Psoriatic plaques
IL-17A
Coates LC, et al. Sem Arth Rheum. 2016.
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: 204-210. Secukinumab [package insert]. 2016.
FUTURE 1 and 2: Improved ACR20 Responses With Secukinumab vs PBO
1. Mease PJ, et al. N Engl J Med. 2015; 373: 1329-1339. 2. McInnes IB, et al. Lancet. 2015; 386: 1137-1146.
FUTURE 1[1] FUTURE 2[2]
Wk
)
0 4 8 12 16 20 28 32 40 44 48 52
100
80
60
40
20
0
Wk
e (%
) 0 4 8 12 16 20 28 32 40 44 48 52
100
80
60
40
20
0
Secukinumab 75 mg (n = 202) Secukinumab 150 mg (n = 202) Placebo (n = 202)
Secukinumab 75 mg (n = 100) Secukinumab 150 mg (n = 100) Secukinumab 300 mg (n = 99) Placebo (n = 98)
FUTURE 1 and 2: Additional Efficacy Findings
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.
Outcome, Wk 24
SECU 150 mg
PASI 75, % 61.1† 64.8† 8.3 63 48§ 28 16
PASI 90, % 45.4† 49.1† 3.7 49§ 33§ 12 9
DAS28-CRP, Δ fr. BL -1.62† -1.67† -0.77 -1.61§ -1.58§ -1.12 -0.96
Dactylitis resolved, % 52.4‡# 15.5 47†† 15
Enthesitis resolved, % 47.5‡** 12.8 40‡‡ 22
*Primary endpoint. P vs PBO: † P < .001; ‡P < .05; §P < .01; 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.
1. Mease PJ, et al. N Engl J Med. 2015; 373: 1329-1339. 2. McInnes IB, et al. Lancet. 2015; 386: 1137-1146.
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)

1. Ixekizumab [package insert]. 2016. 2. Gordon KB, et al. N Engl J Med. 2016; 375: 345-356. 3. Griffiths CE, et al. Lancet. 2015; 386: 541-551. 4. Mease PJ, et al. Ann Rheum Dis. 2016; [Epub ahead of print].
SPIRIT-P1: Efficacy In biologic-naive pts with active PsA, IXE treatment improved
both joint and skin symptoms
Wk 24 Outcomes IXE Q2W (n = 103)
IXE Q4W (n = 107)
ADA (n = 101)
PBO (n = 106)
ACR20,* % 62† 58† 57† 30 ACR50, % 47† 40† 39† 15 ACR70, % 34† 23† 26† 6 PASI 75, % 80† 71† 54† 10 PASI 100, % 53† 43† 24‡ 3 HAQ-DI, from BL -0.50† -0.44† -0.37‡ -0.18 mTSS, from BL 0.08† 0.17‡ 0.10† 0.49 LEI score 0,¶ % 39† 43† 33 19 LDI-B score 0,# % 77† 80† 78 25 *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].
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) NR NR
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 0 0 0 0
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) 0 0 0
Cerebro-cardiovascular event 0 0 3 (3.0) 0 Malignancy 0 0 1 (1.0) 1 (0.9) Crohn’s disease or UC 0 0 0 0
*P ≤ .01 vs PBO.
SPIRIT-P1: Safety
Mease PJ, et al. Ann Rheum Dis. 2016; [Epub ahead of print].
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
Brodalumab for Pts With Active PsA Randomized, double-blind, placebo-controlled phase II trial[1]
1. Mease PJ, et al. N Engl J Med. 2014; 370: 2295-2306. 2. Ritchlin CT, et al. Curr Opin Rhematol. 2016; 28: 204-210.
Pts remaining on study offered open-label brodalumab Q2W
Brodalumab 140 mg SC* (n = 57)
Brodalumab 280 mg SC*
(n = 55)
Wk 12
*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
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)
Guselkumab
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.
p40 p19
IL-12
Ustekinumab
DeodharA, et al. Presented at ACR; November 11-16, 2016 Washington, D.C. Abstract #4L.
18.4 10.2
p<0.001
Primary Endpoint
Guselkumab
Percent of Patients with Complete Resolution of Enthesitis at Week 24
29.0
56.6
0 10 20 30 40 50 60 70 80 90
100
% o
p=0.012
in Patients with Enthesitis at Baseline
Percent of Patients with Complete Resolution of Dactylitis at Week 24
17.4
55.2
0 10 20 30 40 50 60 70 80 90
100
% o
p=0.001
in Patients with Dactylitis at Baseline
PASI Responders at Week 24
12.5 6.3 6.3
% o
*p<0.001
* *
*
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 Cielak,7 D Graham,8
C Wang,9 S Menon,9 T Hendrikx,
Study Design (12 months)
NCT01877668; 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
Secondary endpoints
Adalimumab 40 mg SC Q2W (active control arm) (N=106)
Tofacitinib 5 mg BID (N=107)
Tofacitinib 10 mg BID (N=104)
Placebo (N=52)
Placebo (N=53)
Tofacitinib 5 mg BID
8 6
Primary endpoints
ACR20 HAQ-DI
± SE
**p≤0.05 for comparing tofacitinib vs ppllaacceebboo;; nominal *p≤0.05 for comparing adalimumab vs placebo; N for HAQ-DI is the number of unique patients in the repeated measures model
ACR20
*
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 1
2
Primary Endpoints: ACR20 and HAQ-DI with Tofacitinib vs Placebo at Month 3
-0.18
LS m
1 0 4
1 0 6
95.8
mTSS reported for evaluable patients in the full analysis set; missing values imputed by linear extrapolation mTSS, modified Total Sharp Score; SE, standard error
91.1 95.9 95.0 97.9
Adalimumab 40 mg SC
Non-progressors (defined as an increase from baseline in mTSS ≤0.5)
% o
* * *
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
8
-0.4 -0.8
-1.5 -1.1
aamong 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
9
Tofac itinib 10 mg BID
Adalim umab 40 mg Q2W
Baseline enthesitis (LEI>0), n (%)
65 (61.9) 75 (70.1) 64 (61.5) 76 (71.7)
Baseline LEI score,a mean (SD)
2.8 (1.5) 2.5 (1.4) 3.0 (1.6) 2.3 (1.2)
Change from Baseline for Dactylitis
-2.0
-3.5
-5.5
aamong 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
Placebo Tofaci tinib 5 mg BID
Tofac itinib 10 mg BID
Adalim umab 40 mg Q2W
Baseline dactylitis (DSS>0), n (%)
58 (55.2) 61 (57.0) 60 (57.7) 58 (54.7)
Baseline DSS,a mean (SD) 9.9 (8.4) 9.1 (8.0) 8.5 (8.2) 8.0 (7.4)
GRAPPA 2015 Treatment Guidance
Domain Setting Recommendation*
Peripheral arthritis
First line 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)†
Axial disease
Enthesitis First line Physiotherapy or NSAIDs
Second line/switch PDE-4i or biologics (TNFi, IL-12/23i, IL-17i)
Dactylitis
Second line DMARDs or PDE-4i†
Third line/switch Biologics: first TNFi, IL-12/23i,† then PDE-4i, IL-17i (switch)
Skin
Second line Phototherapy or DMARDs or PDE-4i
Third line/switch PDE-4i or biologics (TNFi, IL-12/23i, IL-17i)†
Nails First line Topical or procedural or DMARDs or PDE-4i or biologics (TNFi, IL-
12/23i, IL-17i) Second line/switch PDE-4i or biologics (TNFi, IL-12/23i, IL-17i)
Conditional recommendations in italics. *Second line. †Expedited therapeutic route.
ASCR
Questions?
Therapeutic Advances for the Management of Patients with Psoriatic Arthritis
Slide Number 4
Definition Enthesopathy
Synovio-Entheseal Complex in Health
Synovio-entheseal Complex in Disease/Enthesitis
Epidemiology
Pathogenesis
Introduction
Psoriatic arthritis is not a “benign rheumatoid variant”.It is clinically, genetically, and immunologically distinct from RA.
Overview of the Pathophysiology of Psoriatic Arthritis
Important Features
Proposed Model: Cytokine Pathways in the Immunopathology of Psoriatic Arthritis
Clinical Features of Psoriatic Arthritis
PsA: Clinical Features
Diagnostic Criteria for PsA (CASPAR)
Slide Number 39
Definition Dactylitis
Slide Number 56
Apremilast in PsA
TNFi Response Rates for Treating PsA
Osteoclast Precursors in PsA
Ustekinumab
Primary Endpoint: ACR20 Responders at Week 24
Median Improvement From Baseline in Patients With Dactylitis and Enthesitis at Week 24
Mechanism of Action of IL-17A Inhibitors in Treating PsA
Secukinumab
FUTURE 1 and 2: Improved ACR20 Responses With Secukinumab vs PBO
FUTURE 1 and 2: Additional Efficacy Findings
Ixekizumab
Brodalumab for Pts With Active PsA
Slide Number 80
Slide Number 81
Slide Number 82
Slide Number 83
Slide Number 84
Slide Number 85
PASI75 with Tofacitinib vs Placebo (MR=NR)
Change from Baseline for Enthesitis
Change from Baseline for Dactylitis
GRAPPA 2015 Treatment Guidance

Documents

Therapeutic Advances for the Management of Patients with