SpA non-radiografica: fase precoce di spondilite anchilosante o altro?

Rheumatology Department of Lucania, S. Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera SpA non-radiografica: fase precoce di spondilite anchilosante o altro? Ignazio Olivieri

Disclosures Consulting fees, research or institutional support and educational grants from: Abbott, Bristol Meyer Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Roche

The spondyloarthritis complex Undifferentiated SpA Juvenile SpA Psoriatic Arthritis Arthritis associated with Ulcerative colitis and Crohn s disease Ankylosing Spondylitis Reactive arthritis Acute anterior uveitis

Historical Look at Classification Criteria for Axial SpA Modified New York Criteria for AS 1 1984 Sacroiliitis (x-ray) (required) Plus 1 below: IBP/stiffness >3 months Limitation of Lumbar spine motion Limitation of chest expansion 1 van der Linden et al. Arthritis Rheum. 1984 Apr;27(4):361-8.

Historical Look at Classification Criteria for Axial SpA Modified New York Criteria for AS 1 1984 Amor Classification Criteria for Spondyloarthritis 2 1990 Sacroiliitis (x-ray) (required) Plus 1 below: Inflammatory LBP/stiffness >3 months Limitation of Lumbar spine motion Limitation of chest expansion Scoring 6/23 points Examples: Good response to NSAIDs Expanded pain description Articular & Extra-articular manifestations Genetic Background (HLA- B27, family hx) Sacroiliitis (x-ray) 1 van der Linden et al. Arthritis Rheum. 1984 Apr;27(4):361-8. 2 Amor et al. Rev Rhum Mal Osteoartic.1990 Feb;57(2):85-9.

Historical Look at Classification Criteria for Axial SpA Modified New York Criteria for AS 1 1984 Amor Classification Criteria for Spondyloarthritis 2 1990 European Spondyloarthropathy Study Group (ESSG) Criteria 3 1991 Sacroiliitis (x-ray) (required) Plus 1 below: Inflammatory LBP/stiffness >3 months Limitation of Lumbar spine motion Limitation of chest expansion Scoring 6/23 points Examples: Good response to NSAIDs Expanded pain description Articular & Extra-articular manifestations Genetic Background (HLA- B27, family hx) Sacroiliitis (x-ray) IBP or Synovitis (required) Plus 1 below: Enthesitis Family hx Psoriasis, CD, or UC Preceding infection Buttock pain Sacroiliitis (x-ray) No HLA-B27 1 van der Linden et al. Arthritis Rheum. 1984 Apr;27(4):361-8. 2 Amor et al. Rev Rhum Mal Osteoartic.1990 Feb;57(2):85-9. 3 Dougados et al, Arthritis Rheum. 1991 Oct;34(10):1218-27.

Historical Look at Classification Criteria for Axial SpA Modified New York Criteria for AS 1 1984 Amor Classification Criteria for Spondyloarthritis 2 1990 European Spondyloarthropathy Study Group (ESSG) Criteria 3 1991 Assessment of SpondyloArthritis (ASAS) Criteria for Axial Spondyloarthritis 4 2009 Sacroiliitis (x-ray) (required) Plus 1 below: Inflammatory LBP/stiffness >3 months Limitation of Lumbar spine motion Limitation of chest expansion Scoring 6/23 points Examples: Good response to NSAIDs Expanded pain description Articular & Extra-articular manifestations Genetic Background (HLA- B27, family hx) Sacroiliitis (x-ray) IBP or Synovitis (required) Plus 1 below: Enthesitis Family hx Psoriasis, CD, or UC Preceding infection Buttock pain Sacroiliitis (x-ray) Sacroiliitis (X-ray or MRI) Plus 1 SpA feature or HLA-B27 Plus 2 SpA features No HLA-B27 van der Linden et al. Arthritis Rheum. 1984 Apr;27(4):361-8. Amor et al. Rev Rhum Mal Osteoartic.1990 Feb;57(2):85-9. Dougados et al, Arthritis Rheum. 1991 Oct;34(10):1218-27. Rudwaleit M et al. Ann Rheum Dis 2009;68 777-83

Ankylosing Spondylitis Non-radiographic stage (axial undifferentiated SpA) Radiographic stage Modified New York Criteria 1984 Back pain MRI sacroiliitis Back pain Radiographic sacroiliitis Back pain Syndesmophytes Duration of symptoms (years) Rudwaleit M, et al. Arthritis Rheum. 2005;52:1000-8.

Definition of Positive MRI-SI Joint 13 13 ASAS handbook, Ann Rheum Dis 2009;68 (Suppl II) (with permission)

Age at First Symptoms and at First Diagnosis in Ankylosing Spondylitis Patients 14 1 Feldtkeller et al. Current Opinion in Rheum 2000;12:239-247 (with permission).

Axial spondyloarthritis Non-radiographic stage (axial undifferentiated SpA) Radiographic stage Modified New York Criteria 1984 Back pain MRI sacroiliitis Back pain Radiographic sacroiliitis Back pain Syndesmophytes Duration of symptoms (years) Rudwaleit M, et al. Arthritis Rheum. 2005;52:1000-8.

Concept of Spondyloarthritides (SpA) Reactive arthritis Non-radiographic axial SpA Ankylosing Spondylitis Psoriatic Arthritis Arthritis with inflammatory bowel disease Undifferentiated SpA Predominantly Axial SpA Predominantly Peripheral SpA

Disease course of axial spondyloarthritis New Nomenclature (1) Spondyloarthritis Axial Peripheral SIJ structural damage (plain pelvic X-Rays) Yes No Ankylosing Spondylitis Axial non radiographic spondyloarthritis Axial radiographic Spondyloarthritis (1) Claudepierre P.et al. Joint Bone Spine 2012,79:534-

Disease course of axial spondyloarthritis Labelling of biologics in axial SpA 2004 2012: Ankylosing Spondylitis 2012 ongoing: [ Ankylosing Spondylitis] OR Axial non-radiographic spondyloarthritis and - SIJ inflammation at MRI OR Abnormal CRP axial spondyloarthritis with at least one of the following: - Presence of SIJ structural damage at pelvic X-Rays - Presence of SIJ inflammation at MRI or Abnormal CRP

Percent Female in Non-Radiographic Axial SpA Cohorts % 100 90 80 70 60 50 40 30 20 10 0 Female sex generally >50% of nr-axspa cohort 68,2 57,1 54 54,6 47,6 1 GESPIC* Haibel ABILITY-I Kiltz ASAS Validation 2 3 4 5 *GESPIC combines patients with primarily axial and primarily peripheral symptoms Rudwaleit. Arthritis Rheum. 2009:60(3)717 727. Haibel et al. Arthritis Rheum 2008;58(7):1981-91. Sieper et al. ACR 2011. Tues2486A. 4 Kiltz et al. EULAR 2011 FRI 0529. Rudwaleit et al.ann Rheum Dis 2009;68:777-783.

Disease course of axial spondyloarthritis Structural damage in axial Spondyloarthritis * Dougados M. et al. Joint Bone Spine 2011;78:598-603

Disease course of axial spondyloarthritis Cross sectional analysis of familial SpA* 86% Radiographic Sacroiliitis (%) 40% 70% <10 n = 99 10-19 n = 110 20 n = 120 Disease duration (years) *Saïd-Nahal R, Amor B, Dougados M, Breban M. Arthritis Rheum 2000;43:1356-1365

Disease course of axial spondyloarthritis The GESPIC cohort Baseline radiographic sacroiliitis 2 year Radiographic sacroiliitis yes no Yes no 112 11 3 84 11.6% 2.6% (115) (95)

Disease course of axial spondyloarthritis 2 year Radiographic sacroiliitis yes no 5.7% Baseline radiographic sacroiliitis Yes no 116 16 7 310 (123) (326) 4.9%

Progression from non-radiographic axial SpA to AS: Longitudinal Studies Includes² only patients age 17 0-2 years 1-2 2-9 years 1,3-7 10 years 1,5 % progression 8-12% 20-45% 36-59% Variable methodology and disease definitions were used in the studies reported Most studies included report mixed axial and peripheral disease at baseline No study used ASAS criteria for axial SpA Reported range represents data from different sources, study N range 23-119 1 Sampaio-Barros et al, J Rheumatol 2010; 37:1195-9. 2 Poddubnyy et al, Ann Rheum Dis 2011; 70: 1369-74. 3 Schattenkirchner et al, Clin Rheumnatol 32 1987; 6 (Suppl 2): 83-6. 4 Sany et al. Arthritis Rheum 1980;23(2):258-9. 5 Mau et al. J Rheumatol. 1988;15:1109 14. 6 Oostveen et al, J Rheumatol 1999; 26:1953-8. 7 Bennett et al. Arthritis Rheum 2008; 58(11):3413-18.

Hypothetical Development of Radiographic Sacroiliitis in Patients With Axial SpA Chronic back pain Radiographic Non-radiographic 100 Axial SpA (%) 80 60 40 20 0 2 5 10 20 Time (years)

Disease course of axial spondyloarthritis Natural history of the disease Clinical features of Spa CDER, FDA 2013. Regulatory considerations for the potential novel indication axial spondyloarthritis. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/arthritisadvisorycommittee/ucm366488.pdf. Accessed 20 February 2014.

Disease course of axial spondyloarthritis Natural history of the disease Clinical features of Spa Sacroiliitis on imaging CDER, FDA 2013. Regulatory considerations for the potential novel indication axial spondyloarthritis. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/arthritisadvisorycommittee/ucm366488.pdf. Accessed 20 February 2014.

Disease course of axial spondyloarthritis Natural history of the disease Clinical features of Spa Radiographic sacroiliitis MRI sacroiliitis CDER, FDA 2013. Regulatory considerations for the potential novel indication axial spondyloarthritis. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/arthritisadvisorycommittee/ucm366488.pdf. Accessed 20 February 2014.

Disease course of axial spondyloarthritis Natural history of the disease PROGRESSION Clinical features of Spa Radiographic sacroiliitis RESOLUTION STABILITY RESOLUTION CDER, FDA 2013. Regulatory considerations for the potential novel indication axial spondyloarthritis. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/arthritisadvisorycommittee/ucm366488.pdf. Accessed 20 February 2014.

Disease course of axial spondyloarthritis Validity of the ASAS criteria Burden of the disease: BASFI* 43,8 BASFI (mean) 27,5 31,7 29,4 27,4 X-RAY + MRI + n = 132 X-RAY + MRI - n = 55 Imaging X-RAY - MRI + n = 99 X-RAY - MRI - CRP + n = 33 clinical X-RAY - MRI - CRP - n = 154 *Molto A Dougados M. Ann Rheum Dis 2014, jan, Epub ahead of print

Burden of disease in pre-radiographic axial SpA and established AS is similar 6 5 AS 5-10 yrs. (n=120) AS <5 yrs. (n=105) Pre-radiogr. AS <5 yrs. (n=196) 4 3 2 1 0 BASDAI Pain BASFI BASMI Rudwaleit M, et al. Arthritis Rheum. 2004;50:S211.

ADALIMUMAB IN RHEUMATIC DISEASES Adalimumab in non-radiographic axial spondyloarthritis Efficacy (% ASAS40 response) % patients 80 60 40 20 p<.001 Whole population * treatment 15 36 * % patients 80 60 40 20 baseline CRP * treatment p=.03 55 27 18 11 % patients 80 60 40 20 baseline sacroiliitis by MRI * treatment p=.65 38 35 14 16 0 Placebo (n=94) Whole population Adalimumab (n=91) 0 n/n: 10/57 17/62 4/37 16/29 Normal Abnormal Baseline CRP 0 n/n: 7/51 17/45 7/45 16/46 Negative Positive Sacroiliitis on Baseline MRI Placebo Adalimumab Sieper J, et al. Ann Rheum Dis 2013; 72:815-822

111 65 46

Pfizer 1031 study proportion of patients achieving ASAS40 response at week 12 and 24 ASAS40 response at week 12 and 24 (mitt, LOCF) 60 Double blind Open label 51,9 50 41,4 Patients (%) 40 30 20 15,2 * 20 28,6 33,3 15,7 14,8 * 38,5 44 ETN/ETN PBO/ETN (n = 105) (n = 108) 10 0 3,8 14,8 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Weeks In this population of patients with early, active nr-axspa who had an inadequate response to 2 NSAIDs, ETN was more effective than PBO in decreasing disease activity *p<0.05; p<0.01 vs placebo. ASAS, Assessment of SpondyloArthritis international Society; ETN, etanercept; LOCF, last observation carried forward; mitt, modified intention to treat; nr-axspa, non-radiographic axial spondyloarthritis; NSAID, non-steroidal anti-inflammatory drug; PBO, placebo. Dougados M, et al. Arth Rheum 2014;66:2091 2102.

Treatment of AS and nr-axspa with Golimumab GO-RAISE Study GO-AHEAD Study In Ankylosing Spondylitis In non-radiographic axial spondyloarthritis 50 mg golimumab every four weeks vs 100 mg golimumab every four weeks vs placebo 50 mg golimumab every four weeks vs placebo Response Rate (% Patients) 80 60 40 20 0 ASAS40 at Weeks 14 and 24 * * 49,3 44,9 15,4 15,4 43,5 Week 14 Week 24 * * 54,3 * p<0.001 PBO GLM 50 mg GLM 100 mg Abstracts with data from GO-AHEAD are presented during the scientific sessions Posters THU0218 & THU0238 Abstract AB0757 CHMP positive opinion for nr-axspa indication received May 2015 n= 78 138 140 Inman R et al. A&R 2008; 58:3402-12

Take home messages

CONCLUSIONS Non-radiographic/Non-imaging axial spondyloarthritis DOES EXIST The natural history of axial spondyloarthritis requires further investigations Non-radiographic/Non-imaging axial spondyloarthritis deserves to have access to all the therapies available for radiographic axial spondyloarthritis

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