Manouk de Hooge

Percentage of patients with spondyloarthritis in patients referred because of chronic back pain and performance of classification criteria: experience from the Spondyloarthritis Caught Early (SPACE) cohort

Objectives. The objectives of the study are to describe the Spondyloarthritis Caught Early (SPACE) cohort, present the performance of various SpA classification criteria and compare patients fulfilling the imaging arm with patients fulfilling the clinical arm of the Assessment of Spondyloarthritis international Society (ASAS) axSpA criteria on demographics, presence of SpA features and level of disease activity. Methods. Patients with back pain (53 months but 42 years, onset <45 years) visiting the rheumatology outpatient clinic of the Leiden University Medical Center were included in the SPACE cohort. Patients were classified according to the modified New York (mNY), ESSG, Amor and ASAS axSpA criteria. The sensitivity and specificity of criteria were tested against a rheumatologist’s diagnosis. Results. In total, 157 patients were included; 92 patients fulfilled any criteria, 11 fulfilled the mNY (sensitivity 16.9%, specificity 100%), 68 the ESSG (sensitivity 64.6%, specificity 71.7%), 48 the Amor (sensitivity 47.7%, specificity 81.5%) and 60 the ASAS axSpA criteria (sensitivity 84.6%, specificity 94.6%). Of those 60 patients, 30 fulfilled the imaging arm and 30 the clinical arm. Patients in the imaging arm are statistically significantly more often male, have a longer symptom duration and less often a positive family history for SpA than patients fulfilling the clinical arm. Patients in both arms are very similar regarding all other SpA features and level of disease activity. Conclusion. The inclusion criteria of the SPACE cohort yield the same high numbers of SpA patients compared with referral strategies like inflammatory back pain, HLA-B27+ or sacroiliitis, yet are easier to apply. The ASAS axSpA criteria outperformed the other criteria; 38.2% fulfilled the ASAS axSpA criteria. Patients fulfilling the clinical arm of the ASAS axSpA reflect a group of patients similar to those fulfilling the imaging arm.

ASAS modification of the Berlin algorithm for diagnosing axial spondyloarthritis: results from the SPondyloArthritis Caught Early (SPACE)-cohort and from the Assessment of SpondyloArthritis international Society (ASAS)-cohort

Objective To compare the original Berlin algorithm for diagnosing axial Spondyloarthritis (axSpA) with two modifications in the SPondyloArthritis Caught Early (SPACE)-cohort and the Assessment of SpondyloArthritis international Society (ASAS) axSpA criteria validation (ASAS)-cohort. Methods Patients in the SPACE-cohort (back pain ≥3 months, ≤2 years, onset <45 years) and the ASAS-cohort (undiagnosed chronic back pain) were diagnosed according to three algorithms: original (inflammatory back pain (IBP) mandatory), modification 1 (IBP defined by ≥3/5 IBP-features instead of ≥4/5) and modification 2 (IBP deleted as obligatory entry criterion, added as SpA-feature). Diagnosis by rheumatologist, ASAS axSpA criteria and likelihood ratio product were used as external standards to test the performance of the algorithms. Results SPACE-cohort: Compared to the diagnosis by rheumatologist (either axSpA or no-axSpA), the original algorithm agreed in 120 patients (76.4%). Agreement decreased using modification 1 (119 patients; 75.8%), increased using modification 2 (125 patients; 79.6%). Sensitivity increased from 66.2% (original) to 72.3% (modification 1) and 78.5% (modification 2). Specificity decreased more using modification 1 (83.7% to 78.3%) than when using modification 2 (83.7% to 79.6%). ASAS-cohort: Compared to the diagnosis by rheumatologist (either axSpA or no-axSpA), the original algorithm agreed in 484 patients (70.7%). Agreement increased using modification 1 (520 patients; 75.9%) and modification 2 (548 patients; 80.0%). Sensitivity increased from 65.3% (original) to 77.9% (modification 1) and 79.6% (modification 2). Specificity decreased more using modification 1 (79.2% to 72.2%) than when using modification 2 (79.2% to 75.6%). Conclusions ASAS accepted a modified algorithm for diagnosing axSpA in which IBP is excluded as obligatory entry criterion and added as SpA-feature.

Magnetic resonance imaging of the sacroiliac joints in the early detection of spondyloarthritis: no added value of gadolinium compared with short tau inversion recovery sequence

OBJECTIVES To investigate the additional value of T1 fat-saturated after gadolinium (T1/Gd) compared with T1 and short tau inversion recovery (STIR) sequence in detecting active lesions of the SI joints typical of axial SpA (axSpA) in a prospective cohort study, the SpondyloArthritis Caught Early (SPACE) cohort, and to assess its influence on final MRI diagnosis of the SI joint (MRI-SIJ) based on the Assessment of Spondyloarthritis International Society (ASAS) definition of active sacroiliitis. METHODS Patients in the SPACE cohort received baseline and 3-month follow-up MRI-SIJ with coronal oblique T1, STIR and T1/Gd sequences. Bone marrow oedema (BME), capsulitis/enthesitis and synovitis and active sacroiliitis according to the ASAS definition were evaluated by three blinded readers. RESULTS A total of 127 patients received an MRI-SIJ at baseline and 67 patients also received an MRI-SIJ at 3 months follow-up since the Gd protocol was added some months after the start of the SPACE project. Twenty-five of the 127 patients (19.7%) with a baseline MRI-SIJ and 14 of 67 patients (20.6%) with a follow-up MRI-SIJ presented BME on the STIR sequence sufficient to fulfill the ASAS definition for a positive MRI-SIJ. In eight patients, additional synovitis and/or capsulitis/enthesitis was observed; however, no additional BME was visualized on T1/Gd. One patient, without clinical diagnosis of axSpA, showed synovitis as an isolated finding. CONCLUSION Synovitis and capsulitis/enthesitis are detectable with the administration of Gd. However, they are always observed in the presence of BME. Therefore T1 and STIR sequence alone are sufficient in the MRI assessment that, among others, is used for diagnosing patients with early axSpA.

Patients with chronic back pain of short duration from the SPACE cohort: which MRI structural lesions in the sacroiliac joints and inflammatory and structural lesions in the spine are most specific for axial spondyloarthritis?

Objectives To investigate the extent and performance of MRI lesions in the sacroiliac joint (MRI-SI) and spine (MRI-spine) in patients with suspected axial spondyloarthritis (axSpA). Methods MRI-SI/spine of patients with chronic back pain (onset <45 years) in the SPondyloArthritis Caught Early (SPACE) cohort were scored by two well-trained readers for inflammation, fatty lesions, erosions, sclerosis/ankylosis and syndesmophytes. MRI performances were tested against the Assessment of Spondyloarthritis international Society (ASAS) axSpA criteria (positive: imaging-arm+ or clinical-arm+; negative: possible axSpA (few spondyloarthritis (SpA) features present) or no SpA). Arbitrary cut-off levels for MRI lesions were set to assure at least 95% specificity (tested in the no SpA group). Results In total 126 patients were ASAS criteria positive (73 imaging-arm+ (22 by modified New York criteria (mNY)+; 51 by MRI+mNY−); 53 clinical-arm+) and 161 were ASAS criteria negative (89 possible axSpA and 72 no SpA). On MRI-SI (n=287), at least three fatty lesions (or at least three erosions) were seen in 45.5 (63.6)% of mNY+ patients, 15.7 (47.1)% of MRI+mNY− patients and 15.1 (13.2)% of clinical-arm+ patients versus 3.4 (6.7)% of possible axSpA patients and 2.8 (4.2)% of no SpA patients. A combined rule (at least five fatty lesions and/or erosions) performed equally well. Sclerosis and ankylosis were too rare to analyse. On MRI-spine (n=284), at least five inflammatory lesions (or at least five fatty lesions) were seen in 27.3 (18.2)% of mNY+ patients, 13.7 (21.6)% of MRI+mNY− patients and 3.8 (1.9)% of clinical-arm+ patients versus 4.5 (6.7)% of possible SpA patients and 2.9 (4.3)% of no SpA patients. Conclusions The presence of (1) at least five fatty lesions and/or erosions on MRI-SI, (2) at least five inflammatory lesions or (3) at least five fatty lesions on MRI-spine allows an acceptable discrimination of axSpA and no SpA, while assuring >95% specificity.

TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort

Objectives To analyse the impact of tumour necrosis factor inhibitors (TNFis) on spinal radiographic progression in ankylosing spondylitis (AS). Methods Patients with AS in the Swiss Clinical Quality Management cohort with up to 10 years of follow-up and radiographic assessments every 2 years were included. Radiographs were scored by two readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with known chronology. The relationship between TNFi use before a 2-year radiographic interval and progression within the interval was investigated using binomial generalised estimating equation models with adjustment for potential confounding and multiple imputation of missing values. Ankylosing Spondylitis Disease Activity Score (ASDAS) was regarded as mediating the effect of TNFi on progression and added to the model in a sensitivity analysis. Results A total of 432 patients with AS contributed to data for 616 radiographic intervals. Radiographic progression was defined as an increase in ≥2 mSASSS units in 2 years. Mean (SD) mSASSS increase was 0.9 (2.6) units in 2 years. Prior use of TNFi reduced the odds of progression by 50% (OR 0.50, 95% CI 0.28 to 0.88) in the multivariable analysis. While no direct effect of TNFi on progression was present in an analysis including time-varying ASDAS (OR 0.61, 95% CI 0.34 to 1.08), the indirect effect, via a reduction in ASDAS, was statistically significant (OR 0.75, 95% CI 0.59 to 0.97). Conclusion TNFis are associated with a reduction of spinal radiographic progression in patients with AS. This effect seems mediated through the inhibiting effect of TNFi on disease activity.

Sacroiliac radiographic progression in recent onset axial spondyloarthritis: the 5-year data of the DESIR cohort

Objective To estimate sacroiliac joint radiographic (X-SIJ) progression in patients with axial spondyloarthritis (axSpA) and to evaluate the effects of inflammation on MRI (MRI-SIJ) on X-SIJ progression. Methods X-SIJ and MRI-SIJ at baseline and after 2 and 5 years in patients with recent onset axSpA from the DESIR cohort were scored by three central readers. Progression was defined as (1) the shift from non-radiographic (nr) to radiographic (r) sacroiliitis (by modified New York (mNY) criteria) or alternative criteria, (2) a change of at least one grade or (3) a change of at least one grade but ignoring a change from grade 0 to 1. The effects of baseline inflammation on MRI-SIJ on 5-year X-SIJ damage (mNY) were tested by generalised estimating equations. Results In 416 patients with pairs of baseline and 5-year X-SIJ present, net progression occurred in 5.1% (1), 13.0% (2) and 10.3% (3) respectively, regarding a shift from nr-axSpA to r-axSpA (1), a change of at least one grade (2) or a change of at least one grade but ignoring a change from grade 0 to 1 (3). Baseline MRI-SIJ predicted structural damage after 5 years in human leukocyte antigen-B27 (HLA-B27) positive (OR 5.39 (95% CI 3.25 to 8.94)) and in HLA-B27 negative (OR 2.16 (95% CI 1.04 to 4.51)) patients. Conclusions Five-year progression of X-SIJ damage in patients with recent onset axSpA is limited but present beyond measurement error. Baseline MRI-SIJ inflammation drives 5-year radiographic changes.

Metric Properties of the SPARCC Score of the Sacroiliac Joints — Data from Baseline, 3-month, and 12-month Followup in the SPACE Cohort

Objective. To evaluate metric properties of the SpondyloArthritis Research Consortium of Canada (SPARCC) score of the sacroiliac (SI) joints. Methods. Patients with back pain (≥ 3 months, ≤ 2 years, onset < 45 years) were included in the SPACE cohort (SpondyloArthritis Caught Early). Patients with (possible) axial spondyloarthritis had followup visits after 3 and 12 months and were treated according to clinical practice. Magnetic resonance imaging (MRI) of the SI joints (MRI-SI) was scored in 2 independent campaigns (campaign 1: at baseline and 3 months; campaign 2: at baseline, 3 months, and 12 months) by 2 different blinded reader pairs, applying the Assessment of Spondyloarthritis International Society (ASAS) definition (MRI-SI+ vs MRI-SI−; discordant cases were adjudicated by a third reader) and SPARCC score (mean of 2 agreeing readers). Calculations were made for agreement between SPARCC score cutoff values and a consensus judgment of MRI-SI+ (ASAS definition) as external standard, change in SPARCC score, and smallest detectable changes (SDC) over 3 and 12 months. Results. SPARCC score ≥ 2 showed best agreement with MRI-SI+ in both campaigns. Regarding observed changes in relation to SDC, SPARCC score changed in 70/151 patients; 26/70 patients changed > SDC (3.4), of whom 20 patients received stable treatment over 3 months in campaign 1. Over 3 months, 20/68 patients showed changes in SPARCC score; 11/20 > SDC (2.1), of whom 8 patients received stable treatment. Over 1 year, 23/74 patients changed their SPARCC score; 14/23 changed > SDC (2.4), of whom 7 received stable treatment in campaign 2. Conclusion. SPARCC score ≥ 2 can be used as surrogate for a consensus judgment of MRI-SI+ (ASAS definition) in clinical trials. The SDC ranged from 2.1–3.4 dependent on reader pair and were close to the proposed minimum important change of 2.5.

Prevalence of degenerative changes of the spine on magnetic resonance images and radiographs in patients aged 16–45 years with chronic back pain of short duration in the Spondyloarthritis Caught Early (SPACE) cohort

OBJECTIVES To determine the prevalence of degenerative changes (DCs) in the spine of young patients with back pain without axial spondyloarthritis (no-axSpA), with possible axSpA (poss-axSpA) and with definite axSpA (axSpA), as shown on MRI and radiographs. METHODS Whole-spine MRI and cervical and lumbar radiography were performed in patients ≥16 years of age with chronic back pain (≥3 months, ≤2 years, onset <45 years) and potential axSpA (Spondyloarthritis Caught Early cohort). Patients were classified as no-axSpA, poss-axSpA [not fulfilling the Assessment of Spondyloarthritis International Society (ASAS) axSpA criteria] or axSpA (fulfilling ASAS axSpA criteria). Images (MRI and X-rays) were evaluated on the presence of DCs by two independent readers, blinded to clinical and laboratory information as well as to the results of the other imaging modality. In cases of disagreement, a third reader served as adjudicator. A Chi-square test was used to analyse differences between patient groups according to various selected cut-off points (1-3) of individual DCs. RESULTS Of 274 patients (38% male, mean age: 29 years), 25 (9%) were classified as no-axSpA, 134 (48.9%) as poss-axSpA and 115 (42.0%) as axSpA. Two hundred and forty-five (89%) patients had DCs on MRI [21/25 (84%) no-axSpA, 121/134 (90%) poss-axSpA, 103/115 (90%) axSpA, P = 0.792], range 1-29 (median 5.5), and 121 (44%) patients had DCs on radiographs [13/25 (52%) no-axSpA, 62/134 (46%) poss-axSpA, 48/115 (42%) axSpA, P = 0.261], range 1-11 (median 2). Prevalence of DCs was similar between patient groups. DCs were predominantly found in the lumbar spine. CONCLUSION Prevalence of DCs was high in this cohort of young patients with short-term chronic back pain, in accordance with the literature. Prevalence of DCs in no-axSpA patients, poss-axSpA patients and axSpA patients was found to be similar.

Evaluation of the change in structural radiographic sacroiliac joint damage after 2 years of etanercept therapy (EMBARK trial) in comparison to a contemporary control cohort (DESIR cohort) in recent onset axial spondyloarthritis

Objective To compare 2 years of radiographic sacroiliac joint (SIJ) changes in patients with recent onset axial spondyloarthritis (axSpA) receiving etanercept in a clinical trial (EMBARK) to similar patients not receiving biologics in a cohort study (DESIR). Methods Endpoints were changes at week 104 per the modified New York (mNY) grading system in total SIJ score (primary endpoint) and net percentage of patients with progression defined three ways. Treatment effect was analysed with and without adjustment for baseline covariates. Results At 104 weeks, total SIJ score improved in the etanercept group (n=154, adjusted least-squares mean change: –0.14) and worsened in the control group (n=182, change: 0.08). The adjusted difference between groups (etanercept minus control) was –0.22 (95% CI –0.38 to –0.06), p=0.008. The net percentage of patients with progression was significantly lower in the etanercept versus the control group for two of three binary endpoints: –1.9% versus 1.6% (adjusted difference for etanercept minus control: –4.7%,95% CI –9.9 to 0.5, p=0.07) for change in mNY criteria; –1.9% versus 7.8% (adjusted difference: –18.2%,95% CI –30.9 to –5.6, p=0.005) for change ≥1 grade in ≥1 SIJ; and –0.6% versus 6.7% (adjusted difference: –16.4%,95% CI –27.9 to –5.0, p=0.005) for change ≥1 grade in ≥1 SIJ, with shift from 0 to 1 or 1 to 0 considered no change. Conclusion Despite the slow radiographic SIJ progression rate over 2 years in axSpA, this study suggests a lower rate of progression in the SIJ with etanercept than without anti-tumour necrosis factor therapy. Trial registration numbers NCT01258738, NCT01648907; Post-results.

Is the Site of Back Pain Related to the Location of Magnetic Resonance Imaging Lesions in Patients With Chronic Back Pain? Results From the Spondyloarthritis Caught Early Cohort

To determine associations between magnetic resonance imaging (MRI) lesions originating from either axial spondyloarthritis (SpA) or from degeneration and pain in patients with chronic back pain of <2 years duration.