Martin Rudwaleit

The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection

Objective: To validate and refine two sets of candidate criteria for the classification/diagnosis of axial spondyloarthritis (SpA). Methods: All Assessment of SpondyloArthritis international Society (ASAS) members were invited to include consecutively new patients with chronic (⩾3 months) back pain of unknown origin that began before 45 years of age. The candidate criteria were first tested in the entire cohort of 649 patients from 25 centres, and then refined in a random selection of 40% of cases and thereafter validated in the remaining 60%. Results: Upon diagnostic work-up, axial SpA was diagnosed in 60.2% of the cohort. Of these, 70% did not fulfil modified New York criteria and, therefore, were classified as having “non-radiographic” axial SpA. Refinement of the candidate criteria resulted in new ASAS classification criteria that are defined as: the presence of sacroiliitis by radiography or by magnetic resonance imaging (MRI) plus at least one SpA feature (“imaging arm”) or the presence of HLA-B27 plus at least two SpA features (“clinical arm”). The sensitivity and specificity of the entire set of the new criteria were 82.9% and 84.4%, and for the imaging arm alone 66.2% and 97.3%, respectively. The specificity of the new criteria was much better than that of the European Spondylarthropathy Study Group criteria modified for MRI (sensitivity 85.1%, specificity 65.1%) and slightly better than that of the modified Amor criteria (sensitivity 82.9, specificity 77.5%). Conclusion: The new ASAS classification criteria for axial SpA can reliably classify patients for clinical studies and may help rheumatologists in clinical practice in diagnosing axial SpA in those with chronic back pain. Trial registration number: NCT00328068.

Prevalence of spondylarthropathies in HLA‐B27 positive and negative blood donors

OBJECTIVE To determine the overall prevalence of spondylarthropathy (SpA) among whites. METHODS To screen for SpA symptoms, such as inflammatory back pain (IBP), joint swelling, psoriasis, and uveitis, or a specific family history, questionnaires were mailed to 348 blood donors (174 HLA-B27 positive and 174 HLA-B27 negative). From the responding 273 persons (78%; 140 B27 positive, 133 B27 negative), 126 were selected for further evaluation based on the symptoms reported. Of this group, 90 persons agreed to undergo physical examination (71.4%; 46 B27 positive, 44 B27 negative). There was no difference between the B27-positive and -negative groups in terms of age (mean +/- SD 38.4 +/- 10 versus 39.5 +/- 11 years) and sex ratio (67% versus 68% were men). In addition, 58 donors (32 B27 positive, 26 B27 negative) agreed to undergo magnetic resonance imaging (MRI) of the sacroiliac joints. A diagnosis of SpA and ankylosing spondylitis (AS) was made according to the European Spondylarthropathy Study Group criteria and the New York criteria. RESULTS SpA was diagnosed in 20 persons: 19 of 140 B27-positive (13.6%) and 1 of 133 B27-negative (0.7%) subjects (15 male and 5 female). AS was diagnosed in 9 persons (7 male and 2 female; 45%), undifferentiated SpA (USpA) in 7 (5 male and 2 female; 35%), psoriatic arthritis (PsA) in 3 (2 male and 1 female; 15%), and chronic reactive arthritis (ReA; Reiters syndrome) in 1 (male; 5%). On the basis of a B27 frequency of 9.3% among the population of Berlin (3.47 million persons), the estimated prevalence of SpA was 1.9%, AS was 0.86%, USpA was 0.67%, and PsA was 0.29%. The relative risk of developing SpA in B27-positive subjects was calculated as 20.7 (95% confidence interval 4.6-94.2; P = 0.001). Of 58 persons with IBP, sacroiliitis was detected by MRI in 15 of 32 B27-positive (46.9%) and 1 of 26 B27-negative (3.9%) subjects (P = 0.002). Four of these 16 donors did not fulfill diagnostic criteria for SpA. CONCLUSION With a calculated prevalence of 1.9%, spondylarthropathies are among the most frequent rheumatic diseases in the white population. HLA-B27 positive persons carry a 20-fold increased risk of developing SpA. AS and USpA are the most frequent SpA subtypes. Persons with IBP who are B27 positive have a 50% likelihood of having sacroiliitis.

The Assessment of SpondyloArthritis international Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general

Objective To evaluate new classification criteria for peripheral spondyloarthritis (SpA) in patients with SpA with peripheral manifestations only. Methods In this Assessment of SpondyloArthritis international Society (ASAS) study, two prespecified sets of criteria were compared against the European Spondylarthropathy Study Group (ESSG) and Amor criteria in newly referred consecutive patients with undiagnosed peripheral arthritis, and/or enthesitis, and/or dactylitis that usually began before 45 years of age. The clinical diagnosis (SpA vs no SpA) made by the ASAS rheumatologist served as reference standard. Results In all, 24 ASAS centres included 266 patients, with a final diagnosis of SpA being made in 66.2%. After adjustments a final set of criteria showed the best balance between sensitivity (77.8%) and specificity (82.9%): arthritis and/or enthesitis and/or dactylitis plus (A) one or more of the following parameters: psoriasis, inflammatory bowel disease, preceding infection, human leucocyte antigen B27, uveitis, sacroiliitis on imaging, or (B) two or more other parameters: arthritis, enthesitis, dactylitis, inflammatory back pain in the past, family history of SpA. The new criteria performed better than modified versions of the ESSG (sensitivity 62.5%, specificity 81.1%) and the Amor criteria (sensitivity 39.8%, specificity 97.8%), particularly regarding sensitivity. In the entire ASAS population of 975 patients the combined use of ASAS criteria for axial SpA and ASAS criteria for peripheral SpA also had a better balance (sensitivity 79.5%, specificity 83.3%) than the modified ESSG (sensitivity 79.1%, specificity 68.8%) and Amor criteria (sensitivity 67.5%, specificity 86.7%), respectively. Conclusions The new ASAS classification criteria for peripheral SpA performed well in patients presenting with peripheral arthritis, enthesitis and/or dactylitis.

The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis

The field of spondyloarthritis (SpA) has experienced major progress in the last decade, especially with regard to new treatments, earlier diagnosis, imaging technology and a better definition of outcome parameters for clinical trials. In the present work, the Assessment in SpondyloArthritis international Society (ASAS) provides a comprehensive handbook on the most relevant aspects for the assessments of spondyloarthritis, covering classification criteria, MRI and x rays for sacroiliac joints and the spine, a complete set of all measurements relevant for clinical trials and international recommendations for the management of SpA. The handbook focuses at this time on axial SpA, with ankylosing spondylitis (AS) being the prototype disease, for which recent progress has been faster than in peripheral SpA. The target audience includes rheumatologists, trial methodologists and any doctor and/or medical student interested in SpA. The focus of this handbook is on practicality, with many examples of MRI and x ray images, which will help to standardise not only patient care but also the design of clinical studies.

Defining active sacroiliitis on Magnetic Resonance Imaging (MRI) for classification of axial spondyloarthritis –a consensual approach by the ASAS/ OMERACT MRI Group

Background: Magnetic resonance imaging (MRI) of sacroiliac joints has evolved as the most relevant imaging modality for diagnosis and classification of early axial spondyloarthritis (SpA) including early ankylosing spondylitis. Objectives: To identify and describe MRI findings in sacroiliitis and to reach consensus on which MRI findings are essential for the definition of sacroiliitis. Methods: Ten doctors (two radiologists and eight rheumatologists) from the ASAS/OMERACT MRI working group reviewed and discussed in three workshops MR images depicting sacroiliitis associated with SpA and other conditions which may mimic SpA. Descriptions of the pathological findings and technical requirements for the appropriate acquisition were formulated. In a consensual approach MRI findings considered to be essential for sacroiliitis were defined. Results: Active inflammatory lesions such as bone marrow oedema (BMO)/osteitis, synovitis, enthesitis and capsulitis associated with SpA can be detected by MRI. Among these, the clear presence of BMO/osteitis was considered essential for defining active sacroiliitis. Structural damage lesions such as sclerosis, erosions, fat deposition and ankylosis can also be detected by MRI. At present, however, the exact place of structural damage lesions for diagnosis and classification is less clear, particularly if these findings are minor. The ASAS group formally approved these proposals by voting at the annual assembly. Conclusions: For the first time, MRI findings relevant for sacroiliitis have been defined by consensus by a group of rheumatologists and radiologists. These definitions should help in applying correctly the imaging feature “active sacroiliitis by MRI” in the new ASAS classification criteria for axial SpA.

The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal

Objective: Non-radiographic axial spondyloarthritis (SpA) is characterised by a lack of definitive radiographic sacroiliitis and is considered an early stage of ankylosing spondylitis. The objective of this study was to develop candidate classification criteria for axial SpA that include patients with but also without radiographic sacroiliitis. Methods: Seventy-one patients with possible axial SpA, most of whom were lacking definite radiographic sacroiliitis, were reviewed as “paper patients” by 20 experts from the Assessment of SpondyloArthritis international Society (ASAS). Unequivocally classifiable patients were identified based on the aggregate expert opinion in conjunction with the expert-reported level of certainty of their judgement. Draft criteria for axial SpA were formulated and tested using classifiable patients. Results: Active sacroiliitis on magnetic resonance imaging (MRI) (odds ratio 45, 95% CI 5.3 to 383; p<0.001) was strongly associated with the classification of axial SpA. The knowledge of MRI findings led to a change in the classification of 21.1% of patients. According to the first set of candidate criteria (sensitivity 97.1%; specificity 94.7%) a patient with chronic back pain is classified as axial SpA in the presence of sacroiliitis by MRI or x rays in conjunction with one SpA feature or, if sacroilitiis is absent, in the presence of at least three SpA features. In a second set of candidate criteria, inflammatory back pain is obligatory in the clinical arm (sensitivity 86.1%; specificity 94.7%). Conclusion: The ASAS group has developed candidate criteria for the classification of axial SpA that include patients without radiographic sacroiliitis. The candidate criteria need to be validated in an independent international study.

The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort.

OBJECTIVE Ankylosing spondylitis (AS) is diagnosed late, because radiographs of the sacroiliac joints often do not show definite sacroiliitis at the time of disease onset. The aim of this study was to investigate whether patients without definite radiographically defined sacroiliitis, referred to as nonradiographic axial spondylarthritis (SpA), are different from patients with AS with regard to clinical manifestations and disease activity measures. Moreover, we sought to identify determinants of the development of radiographic sacroiliitis. METHODS In a cross-sectional analysis of 462 patients, we compared 226 patients with nonradiographic axial SpA (symptom duration < or =5 years) and 236 patients with AS (symptom duration < or =10 years) who are participants in the German Spondyloarthritis Inception Cohort. Radiographs of the sacroiliac joints and the spine were assessed by 2 readers in a blinded manner. Logistic regression analysis was applied to identify parameters associated with structural damage. RESULTS The 2 groups did not differ in the frequency of HLA-B27 positivity, inflammatory back pain, arthritis, enthesitis, and uveitis and had similar levels of disease activity, using measures such as the Bath Ankylosing Spondylitis Disease Activity Index. In both groups, HLA-B27 positivity determined the age at disease onset. Male sex (adjusted odds ratio [OR] 2.38, 95% confidence interval [95% CI] 1.19-4.73 [P = 0.014]) and an elevated C-reactive protein (CRP) level (adjusted OR 1.85, 95% CI 0.96-3.56 [P = 0.066]) were associated with radiographic sacroiliitis. In patients with AS, male sex and an elevated CRP level were also associated with the presence of syndesmophytes. CONCLUSION Clinical manifestations and disease activity measures are highly comparable between patients with early nonradiographic axial SpA and those with early AS, suggesting that these 2 entities are part of the same disease. Male sex and an elevated CRP level are associated with structural damage on radiographs, whereas HLA-B27 positivity determines the age at disease onset.

2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis

This paper presents the second update of the Assessment in SpondyloArthritis international Society (ASAS) consensus statement on the use of anti-tumour necrosis factor (anti-TNF) agents in patients with axial spondyloarthritis (SpA). A major change from the previous recommendations is that patients fulfilling the ASAS axial SpA criteria, which also include patients fulfilling the modified New York criteria for ankylosing spondylitis, can be treated with anti-TNF agents. This makes an earlier start in the disease process possible. A second major change is the mandatory pretreatment before anti-TNF agents can be started. All patients should have tried a minimum of two non-steroidal anti-inflammatory drugs for a minimum of 4 weeks in total. This is significantly shorter than the previous requirement of 3 months. As previously, patients with axial symptoms require no further pretreatment. Patients with symptomatic peripheral symptoms should normally have had an adequate therapeutic trial of a disease-modifying antirheumatic drug, preferably sulfasalazine. Sulfasalazine is no longer mandatory in this group of patients. Finally, efficacy should be evaluated after at least 12 weeks. The remaining recommendations stayed largely unchanged.

New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis international Society (ASAS)

Objective: Inflammatory back pain (IBP) is an important clinical symptom in patients with axial spondyloarthritis (SpA), and relevant for classification and diagnosis. In the present report, a new approach for the development of IBP classification criteria is discussed. Methods: Rheumatologists (n = 13) who are experts in SpA took part in a 2-day international workshop to investigate 20 patients with back pain and possible SpA. Each expert documented the presence/absence of clinical parameters typical for IBP, and judged whether IBP was considered present or absent based on the received information. This expert judgement was used as the dependent variable in a logistic regression analysis in order to identify those individual IBP parameters that contributed best to a diagnosis of IBP. The new set of IBP criteria was validated in a separate cohort of patients (n = 648). Results: Five parameters best explained IBP according to the experts. These were: (1) improvement with exercise (odds ratio (OR) 23.1); (2) pain at night (OR 20.4); (3) insidious onset (OR 12.7); (4) age at onset <40 years (OR 9.9); and (5) no improvement with rest (OR 7.7). If at least four out of these five parameters were fulfilled, the criteria had a sensitivity of 77.0% and specificity of 91.7% in the patients participating in the workshop, and 79.6% and 72.4%, respectively, in the validation cohort. Conclusion: This new approach with real patients defines a set of IBP definition criteria using overall expert judgement on IBP as the gold standard. The IBP experts’ criteria are robust, easy to apply and have good face validity.

Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week fifty-two.

OBJECTIVE To evaluate the efficacy and safety of the tumor necrosis factor (TNF) antagonist adalimumab in patients with axial spondylarthritis (SpA) without radiographically defined sacroiliitis refractory to conventional treatment. METHODS Patients with active axial SpA (n = 46) were randomized to receive placebo or adalimumab at a dosage of 40 mg subcutaneously every other week for 12 weeks, followed by an open-label extension that continued up to week 52. The diagnosis of axial SpA required the presence of 3 of 6 diagnostic criteria, including 2 of the following 3 criteria: inflammatory back pain, HLA-B27 positivity, or acute inflammation of the spine or sacroiliac joints on magnetic resonance imaging, in the absence of radiographic evidence of sacroiliitis. The primary end point was a 40% response according to the improvement criteria of the Assessment of SpondyloArthritis international Society (ASAS40). RESULTS All 46 patients (22 receiving adalimumab and 24 receiving placebo) completed the 12-week trial; 38 patients completed the extension period to week 52. At week 12, an ASAS40 response was achieved by 54.5% of the adalimumab-treated patients, as compared with 12.5% of the placebo-treated patients (P = 0.004). After switching to adalimumab, a similar degree of efficacy was also achieved by the patients who were initially treated with placebo. Efficacy was maintained in all patients until week 52. Young age at study entry and an elevated C-reactive protein concentration were the best predictors of achieving an ASAS40 response. Serious adverse events occurred in 5 patients, none of which was related to the study drug. CONCLUSION Adalimumab is the first TNF antagonist to demonstrate good clinical efficacy and safety in patients with axial SpA without radiographically defined sacroiliitis.