What s new in clinical assesment of ankylosing spondylitis? Désirée van der Heijde Professor of Rheumatology Leiden University Medical Center, the Netherlands Diakonhjemmet Hospital, Oslo, Norway
Content ASAS new criteria sets ASDAS
Spondyloarthritis (SpA) Undifferentiated SpA Juvenile SpA Ankylosing Spondylitis Psoriatic Arthritis Arthritis associated with Ulcerative Colitis / Crohn s Disease www.asas-group.org Reactive Arthritis Acute anterior Uveitis
Spondyloarthritis: Characteristic Parameters Used for Diagnosis-I Symptoms Inflammatory back pain Imaging Lab ESR/CRP Patient s history Good response to NSAIDs
Spondyloarthritis-Characteristic Parameters Used for Diagnosis II Spondyloarthritis: Characteristic Parameters Used for Diagnosis-II Genetics HLA-B27 positive family history Predisposing/concomitant diseases Infection* psoriasis Crohn s Uveitis *positive staining for Chlamydia in synovial membrane 1 1. Schumacher HR et al. Arthritis Rheum 1988; 31:937-46
Until 2009 - Criteria for AS and for SpA Focus on spine involvement modified New York criteria Focus on total concept AMOR, ESSG
Historical Look at Classification Criteria for Axial SpA (radiographic sacroiliitis is only REQUIRED for modified New York Criteria) 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 7 7 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 (radiographic sacroiliitis is only REQUIRED for modified New York Criteria) Modified New York Criteria for AS 1 Amor Classification Criteria for Spondyloarthritis 2 European Spondyloarthropathy Study Group (ESSG) Criteria 3 Assessment of SpondyloArthritis (ASAS) Criteria for Axial Spondyloarthritis 4 1984 1990 1991 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 8 8 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. 4 Rudwaleit M et al. Ann Rheum Dis 2009;68 777-83
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
Age at First Symptoms and at First Diagnosis in Ankylosing Spondylitis Patients Cumulated percentage of patients Age at first symptoms Age at first diagnosis 920 males 476 females Age in years Average delay in diagnosis: 9 years Feldtkeller E et al. Curr Opin Rheumatol 2000;12:239-247 (with permission)
Mean Disease Duration (years) Before Seeing a Rheumatologist the First Time German Core Documentation 1994 and 2004 1994 2004 RA 2.0 1.1 Psoriatic arthritis 2.9 1.3 SLE 3.0 1.6 AS 6.8 6.4 Courtesy of A. Zink, unpublished data.
Axial Spondyloarthritis Non-radiographic stage Radiographic stage Modified New York Criteria 1984 Back pain Sacroiliitis on MRI Back pain Radiographic sacroiliitis Back pain Syndesmophytes Time (years) Rudwaleit M et al. Arthritis Rheum. 2005;52:1000-8.
Axial SpA (%) Hypothetical Development of Radiographic Sacroiliitis in Patients With Axial SpA Chronic back pain Radiographic Non-radiographic 100 80 60 40 20 0 2 5 10 20 Time (years)
Burden of Disease is Similar in AS and Non-Radiographic Axial SpA Rudwaleit et al. Arthritis Rheum 2009; 60:717 727.
ASAS Classification Criteria for Axial Spondyloarthritis (SpA) In patients with 3 months back pain and age at onset <45 years Sacroiliitis on imaging* plus 1 SpA feature # OR HLA-B27 plus 2 other SpA features # # SpA features inflammatory back pain arthritis enthesitis (heel) uveitis dactylitis psoriasis Crohn s/colitis good response to NSAIDs family history for SpA HLA-B27 elevated CRP Rudwaleit M et al. Ann Rheum Dis 2009;68 777-83 *Sacroiliitis on imaging active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA definite radiographic sacroiliitis according to mod NY criteria n=649 patients with back pain; Sensitivity: 82.9%, Specificity: 84.4% Imaging alone: Sensitivity: 66.2%, Specificity: 97.3% Clinical arm alone: Sensitivity: 56.6%, Specificity: 83.3%
ASAS Inflammatory Back Pain Criteria by Experts (Chronic Back Pain; n=648) age at onset < 40 years insidious onset improvement with exercise no improvement with rest pain at night (with improvement upon getting up) Sensitivity: 79.6%; Specificity: 72.4% Inflammatory back pain present if at least 4 out of 5 parameters are fulfilled. Sieper J et al. Ann Rheum Dis. 2009;68:784-8
Chronic low back pain >3 months, onset <45 years Presence of other SpA-features: IBP, heel pain (enthesitis), dactylitis, uveitis, positive family history, IBD, alternating buttock pain, psoriasis, asymmetrical arthritis, positive response to NSAIDs, acute phase reactants (raised ESR/CRP) 4 SpA-features 2-3 SpA-features 0-1 SpA-features HLA-B27 HLA-B27 x-rays Pos Neg Pos Neg Pos Neg Consider other diagnosis MRI AS SpA Pos Neg Consider other diagnosis SpA van den Berg R, et al. Ann Rheum Dis 2011;70(Suppl3):512
Specification of the Variables Used for the ASAS-Criteria for Classification of Axial Spondyloarthritis I Clinical feature Inflammatory back pain (IBP) Arthritis Definition IBP according to experts: 4 out of 5 of the following parameters present: 1.age at onset <40 years 2.insidious onset 3.improvement with exercise 4.no improvement with rest 5.pain at night (with improvement upon getting up) Past or present active synovitis diagnosed by a physician Rudwaleit M et al. Ann Rheum Dis. 2009;68:777 783 Rudwaleit M et al. Ann Rheum Dis 2009;68 777-83
Specification of the Variables Used for the ASAS-Criteria for Classification of Axial Spondyloarthritis II Clinical feature Positive Family History Definition Presence in first-degree or second-degree relatives of any of the following: 1.Ankylosing spondylitis 2.Psoriasis 3.Uveitis 4.Reactive arthritis 5.Inflammatory bowel disease Rudwaleit M et al. Ann Rheum Dis. 2009;68:777 783 Rudwaleit M et al. Ann Rheum Dis 2009;68 777-83
Specification of the Variables Used for the ASAS-Criteria for Classification of Axial Spondyloarthritis III Clinical feature Psoriasis Inflammatory bowel disease Dactylitis Enthesitis Uveitis anterior Good response to NSAIDs Definition Past or present psoriasis diagnosed by a physician Past or present Crohn s disease or ulcerative colitis diagnosed by a physician Past or present dactylitis diagnosed by a physician Heel enthesitis: past or present spontaneous pain or tenderness at examination of the site of the insertion of the Achilles tendon or plantar fascia at the calcaneus Past or present uveitis anterior, confirmed by an ophthalmologist 24-48 hours after a full dose of a non-steroidal antiinflammatory drug (NSAID) the back pain is not present anymore or much better Rudwaleit M et al. Ann Rheum Dis. 2009;68:777 783 Rudwaleit M et al. Ann Rheum Dis 2009;68 777-83
Specification of the Variables Used for the ASAS-Criteria for Classification of Axial Spondyloarthritis IV Lab or imaging feature HLA-B27 elevated CRP Sacroiliitis by X-rays Sacroiliitis by MRI Definition Positive testing according to standard laboratory techniques C-reactive protein above upper normal limit in the presence of back pain, after exclusion of other causes for elevated CRP concentration Bilateral grade 2-4 or unilateral grade 3-4, according to the modified New York criteria Active inflammatory lesions of sacroiliac joints with definite bone marrow edema/ostiitis suggestive of sacroiliitis associated with spondyloarthritis Rudwaleit M et al. Ann Rheum Dis. 2009;68:777 783 Rudwaleit M et al. Ann Rheum Dis 2009;68 777-83
How to Define Active Inflammatory Lesions ( positive MRI ) of the Sacroiliac Joint The presence of definite subchondral bone marrow edema/osteitis highly suggestive of sacroiliitis is mandatory. The presence of synovitis, capsulitis, or enthesitis only without subchondral bone marrow edema/ osteitis is compatible with but not sufficient for making a diagnosis of active sacroiliitis. Rudwaleit M et al, Ann Rheum Dis 2009;68:1520-27
Active Inflammatory Lesions: General Remarks Technical aspects: STIR images are usually sufficient to detect active (acute) inflammatory lesions; exception: synovitis (not detectable with STIR only). Amount of signal required If there is 1 signal (lesion) only, this should be present on at least 2 slices. If there is more than 1 signal on a single slice, 1 slice may be enough. Rudwaleit M et al, Ann Rheum Dis 2009;68:1520-27
Definition of Positive MRI-SI Joint subchondral bone marrow edema acute (bilateral) sacroiliitis STIR Rudwaleit M et al, Ann Rheum Dis 2009;68:1520-27
MRI spine does not add much information to MRI SI joints for making a diagnosis Rudwaleit M et al. Ann Rheum Dis 2009;68 777-83
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
Specification of the Variables Used for the ASAS-Criteria for Classification of Peripheral Spondyloarthritis I SpA feature Definition Entry criteria Arthritis Enthesitis Dactylitis Current peripheral arthritis compatible with SpA (usually asymmetric and/ or predominant involvement of the lower limb), diagnosed clinically by a physician. Current enthesitis, diagnosed clinically by a physician. Current dactylitis, diagnosed clinically by a physician. Rudwaleit M et al. Ann Rheum Dis. 2011:70:25 31
Specification of the Variables Used for the ASAS-Criteria for Classification of Peripheral Spondyloarthritis II Additional SpA features Dactylitis Past or present dactylitis, diagnosed by a physician. Arthritis Enthesitis Past or present peripheral arthritis compatible with SpA (usually asymmetric and/ or predominant involvement of the lower limb), diagnosed clinically by a physician. Enthesitis: past or present spontaneous pain or tenderness at examination of an enthesis. Any site of enthesitis can be affected whereas in the ASAS classification criteria for axial SpA only enthesitis of the heel is considered. Rudwaleit M et al. Ann Rheum Dis. 2011:70:25 31
Specification of the Variables Used for the ASAS-Criteria for Classification of Peripheral Spondyloarthritis III Additional SpA features Uveitis Psoriasis Inflammatory bowel disease Inflammatory back pain (IBP) in the past Past or present uveitis anterior, confirmed by an ophthalmologist. Past or present psoriasis, diagnosed by a physician. Past or present Crohn s disease or ulcerative colitis diagnosed by a physician. IBP in the past according to the rheumatologist s judgement. Here, only IBP in the past is considered. In patients with current IBP (and concomitant peripheral manifestations), the ASAS classification criteria for axial SpA should be applied. Rudwaleit M et al. Ann Rheum Dis. 2011:70:25 31
Specification of the Variables Used for the ASAS-Criteria for Classification of Peripheral Spondyloarthritis IV Additional SpA features Preceding infection Family history HLA-B27 Sacroiliitis by imaging Urethritis / cervicitis or diarrhoea within one month before the onset of arthritis / enthesitis / dactylitis. Presence in first-degree (mother, father, sisters, brothers, children) or second-degree (maternal and paternal grandparents, aunts, uncles, nieces, and nephews) relatives of any of the following: (a) ankylosing spondylitis, (b) psoriasis, (c) acute uveitis, (d) reactive arthritis, (e) inflammatory bowel disease. Positive testing according to standard laboratory techniques. Bilateral grade 2-4 or unilateral grade 3-4 sacroiliitis on plain radiographs, according to the modified New York criteria, or active sacroiliitis on MRI according to the ASAS consensus definition. Rudwaleit M et al. Ann Rheum Dis. 2011:70:25 31
Symptoms at presentation determine which pathway Axial ± peripheral symptoms at time of presentation Purely peripheral symptoms at time of presentation* Apply ASAS Criteria for Axial SpA 1 Apply ASAS Criteria for Peripheral SpA 2 *Past inflammatory back pain allowed 1 Rudwaleit et al. Ann Rheum Dis 2009;68:777-783. 2 Rudwaleit et al. Ann Rheum Dis 2011;70:25-31.
Issues with assessment of disease activity in AS Single-variable parameters (pain, CRP etc.) and indices (BASDAI etc.) cover only a part of disease activity Disease activity as defined by the patient and physician global assessment is completely different
Construct of disease activity All different assessments try to measure the construct disease activity All the assessments measure a part of the construct Combining several assessments in one score will increase the truth (validity) of the score and enhance discriminative capacity and sensitivity to change Providing that the assessments measure a different aspect (are not redundant)
Construct of disease activity
ASDAS scores 0.08 x Back Pain + 0.07 x Duration + Morning Stiffness 0.11 x Patient Global 0.07 x Peripheral Pain/Swelling + 0.58 x Ln (CRP+1) 0.12 x Back Pain + 0.06 x Duration + Morning Stiffness 0.11 x Patient Global 0.09 x Peripheral Pain/Swelling + 0.29 x SQR (ESR)
www.asas-group.org
3 2 3 4 0,4 0,1 0,3 0,3 15 1,6 2,7 15
NORDMARD - Pearson Correlations Patient s global assessment Physician s global assessment ASDAS with CRP 0.74 0.47 ASDAS with ESR 0.71 0.54 BASDAI 0.77 0.29 Physician global 0.30 - BASDAI 1 fatigue (0-10) 0.56 0.10 BASDAI 2 back pain (0-10) 0.66 0.28 BASDAI 3 pain/swel periph joints (0-10) 0.49 0.24 BASDAI 4 enthesitis (0-10) 0.57 0.26 BASDAI 5 severity morning stiffness (0-10) 0.58 0.22 BASDAI 6 duration morning stiffness (0-10) 0.41 0.14 BASDAI 5/6 morning stiffness (0-10) 0.53 0.19 ESR (mm/hr) 0.15 0.36 CRP (mg/l) 0.18 0.38
Trial - Discrimination between TNF and placebo (change over 3 months) Standardised Mean Difference t-score Guyatt s Effect Size ASDAS with CRP 1.50 9.7 2.4 ASDAS with ESR 1.51 9.9 2.2 BASDAI 1.09 7.2 1.5 BASDAI 1 fatigue (0-10) 0.77 4.8 1.1 BASDAI 2 back pain (0-10) 0.99 6.2 1.6 BASDAI 3 pain/swel periph joints (0-10) 0.63 4.0 0.8 BASDAI 4 enthesitis (0-10) 0.75 4.7 1.0 BASDAI 5 severity morning stiffness (0-10) 1.04 6.5 1.6 BASDAI 6 duration morning stiffness (0-10) 0.82 5.1 1.5 BASDAI 5/6 morning stiffness (0-10) 1.03 6.4 1.7 Patient global 1.09 7.2 1.6 Physician global 1.24 8.2 1.8 ESR (mm/hr) 1.17 7.6 1.5 CRP (mg/l) 0.83 5.2 1.5
Trial - Discrimination between TNF and placebo according to baseline CRP and peripheral arthritis Baseline CRP<5 Baseline CRP 5 Peripheral Arthritis Absent Peripheral Arthritis Present SMD SMD SMD SMD ASDAS with CRP 1.55 1.57 1.49 1.49 ASDAS with ESR 2.01 1.53 1.50 1.50 BASDAI 1.50 1.04 1.05 1.12 BASDAI 1 fatigue (0-10) 1.05 0.70 0.76 0.76 BASDAI 2 back pain (0-10) 1.24 0.94 0.99 0.98 BASDAI 3 pain/swel periph joints (0-10) 1.18 0.55 0.57 0.73 BASDAI 4 enthesitis (0-10) 0.71 0.76 0.67 0.89 BASDAI 5 severity morning stiffness (0-10) 1.17 1.02 0.97 1.16 BASDAI 6 duration morning stiffness (0-10) 0.67 0.85 0.91 0.67 BASDAI 5/6 morning stiffness (0-10) 1.15 1.05 1.04 1.01 Patient global 1.13 1.08 0.98 1.24 Physician global 1.22 1.25 1.22 1.24 ESR (mm/hr) 1.07 1.27 1.09 1.26 CRP (mg/l) 0.01 0.97 0.67 1.06
ASSERT Improvements at 3M Change criteria 3 months (INF vs PL) Chi 2 (p-value) n per group (80% power, 2-sided) ASDAS 1.1 71.3 vs 19.6 45.9 (<.001) n=15 BASDAI 2 60.4 vs 23.2 23.1 (<.001) n=28 BASDAI 50 50.6 vs 10.7 27.6 (<.001) n=29 ASAS 20 64.0 vs 25.0 25.6 (<.001) n=24
ASSERT Improvements at 3M Change criteria 3 months (INF vs PL) Chi 2 (p-value) n per group (80% power, 2-sided) ASDAS 2.0 43.9 vs 3.6 30.4 (<.001) n=16 ASAS 40 50.6 vs 16.1 20.5 (<.001) n=30
ASDAS Well balanced index covering the underlying construct of disease activity without too much redundancy Highly discriminatory tool Opportunity to reduce the sample size in RCTs by about 50% while preserving the same statistical power to detect a treatment effect Lukas et al. Ann Rheum Dis 2009;68:18-24 van der Heijde D et al. Ann Rheum Dis 2009;68:1811-8
Conclusions New concepts SpA (nonradiographic) axial Spa vs peripheral SpA ASAS new criteria sets ASDAS is a useful combined disease activity index
Thank you!