F. van Gaalen

Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles

Objectives: To study the gene–environment interaction of tobacco exposure and shared epitope on autoantibodies in patients with rheumatoid arthritis and undifferentiated arthritis. Methods: From incident cases of arthritis (n = 1305), patients who did not fulfil any classification criteria (undifferentiated arthritis (n = 486)) and those who fulfilled the American College of Rheumatology criteria for rheumatoid arthritis (n = 407) were identified. IgM rheumatoid factor (RF), anti-cyclic-citrullinated peptide (CCP) antibodies, and HLA-DRB1 alleles were determined. Results: In rheumatoid arthritis, an interaction was found between tobacco exposure and shared epitope for the presence of anti-CCP antibodies, as the odds ratio for anti-CCP antibodies in patients having both tobacco exposure (TE) and shared epitope (SE) was higher than the summed odds ratios of patients having only tobacco exposure or shared epitope (odds ratios: TE+/SE−, 1.07; TE−/SE+, 2.49; and TE+/SE+, 5.27—all relative to TE−/SE−). A similar effect was found for RF, but stratification showed that the interaction primarily associated with the anti-CCP antibody response. In patients with undifferentiated arthritis at two weeks, or with persistent undifferentiated arthritis after one year, no interaction between tobacco exposure and shared epitope was observed for the presence of autoantibodies. Conclusions: Tobacco exposure increases the risk factor for anti-CCP antibodies only in shared epitope positive patients with rheumatoid arthritis. The gene–environment interaction between smoking and shared epitope leading to autoantibodies is specific for rheumatoid arthritis and is not observed in undifferentiated arthritis.

A comparison of the diagnostic accuracy and prognostic value of the first and second anti-cyclic citrullinated peptides (CCP1 and CCP2) autoantibody tests for rheumatoid arthritis

Objectives: To compare the diagnostic performance and prognostic value of the anti-cyclic citrullinated peptide (CCP1) and anti-CCP2 autoantibody tests in a clinical setting. Methods: Anti-CCP1 and anti-CCP2 antibody tests were performed on the same serum samples obtained from 467 patients with early arthritis from the Leiden Arthritis Cohort. The sensitivity, specificity, positive predictive value, and negative predictive value for discriminating between rheumatoid arthritis (RA) and non-RA at 1 year’s follow up were calculated for both tests. Results were graphically presented using receiver operating characteristic curves. Progression of radiological joint damage was assessed over 4 years in patients with RA and used to assess the prognostics values of the CCP tests. Results: At a similar specificity the CCP2 test had a higher sensitivity than the CCP1 test. Both tests identified a subgroup of patients with RA with an increased rate of joint damage progression. The anti-CCP2 test identified more patients with an increased rate of joint damage progression than the anti-CCP1 test, and in multiple regression analysis CCP2 was the better predictor of joint damage. Conclusions: The CCP2 test had better diagnostic and prognostic ability than the CCP1 test.

Classifying Back Pain and Peripheral Joint Complaints in Inflammatory Bowel Disease Patients: A Prospective Longitudinal Follow-up Study

BACKGROUND AND AIMS Peripheral joint complaints [pJTC] and chronic back pain [CBP] are the most common extra-intestinal manifestations in patients with inflammatory bowel disease [IBD]. This prospective study evaluates variables associated with joint/back pain, including IBD disease activity. METHODS IBD patients with back pain ≥ 3 months and/or peripheral joint pain/swelling [n = 155], and IBD patients without joint complaints [n = 100; controls], were followed for a period of 1 year. Patients were classified as having SpondyloArthritis [SpA] according to several sets of criteria. Statistical analysis included logistic regression models and linear mixed model analysis. RESULTS Of the 155 patients with joint/back pain, 13 had chronic back pain, 80 peripheral joint complaints, and 62 axial and peripheral joint complaints. Smoking, female gender, and IBD disease activity were independently associated with IBD joint/back pain. The Assessment in Spondyloarthritis International Society criteria for axial and peripheral SpA were fulfilled in 12.3% of patients, with 9.7% [n = 15] receiving a rheumatological diagnosis of arthritis. During the 12-month follow-up, the majority of the patients reporting joint/back pain remained stable. CONCLUSIONS In our cohort, the majority of IBD patients reported joint/back pain and SpA was relatively common. To facilitate effective care, gastroenterologists should be aware of the various features of SpA to classify joint complaints and, by making use of an efficient referral algorithm, to refer CBP patients to the rheumatologist.

FRI0514 Adding Mri of The Spine To The Asas Classification Criteria for Axial Spondyloarthritis, Redundant or Beneficial? Data from The Spondyloarthritis Caught Early (Space)-Cohort

Background The ASAS definition of a positive MRI is solely based on inflammation in the sacroiliac joints (SIJ), although spinal inflammatory lesions on MRI suggestive of axial Spondyloarthritis (axSpA) may also occur. It is not well known how often inflammation in the spine occurs in absence of inflammation in the SIJ and consequently what the utility is of including inflammation in the spine in the definition of a positive MRI. Objectives To analyze the prevalence of spinal inflammation on MRI in patients with chronic back pain (CBP) at baseline and one-year follow-up, and to evaluate the yield of adding MRI-spine as imaging criterion to the ASAS classification criteria for axial SpA. Methods The SPACE-cohort includes patients with CBP (≥3 months, ≤2 years, onset <45 years) from five participating centres in Europe. All available baseline (BL) and one-year follow-up (FU) MRI of SIJ and spine were scored by 2 well-calibrated readers. MRI-SI were scored according to the ASAS definition. Bone marrow oedema suggestive of axSpA was assessed in the entire spine and only counted if visible on ≥2 consecutive slices. To define a positive MRI-spine, two cut-off values were used: ≥3 inflammatory lesions (ASAS consensus definition) and ≥5 inflammatory lesions (defined as the best cut-off in earlier analyses). Adjudication for the ASAS definition by an experienced reader was performed in case of disagreement and all modalities were considered positive if 2/3 readers agreed. Results All patients with both MRI-spine and MRI-SIJ available at BL (n=329) and FU (n=168) were included in the analyses. At BL 43/329 (13.1%) of patients had a positive MRI-SIJ, of which 7/43 (16.3%) patients had a positive MRI-spine (ASAS consensus definition, ≥3 inflammatory lesions) and 2/43 (4.7%) if defined by ≥5 inflammatory lesions. Positive MRI-SIJ at FU was seen in 28/168 (16.7%) patients, 14 of which were also positive at BL; MRI-spine positivity was identified in 2/28 (7.1%) and 1/28 (3.6%) patients for the ASAS definition defined by ≥3 and ≥5 inflammatory lesions, respectively. In total, 4 patients had a positive MRI-spine and a negative MRI-SIJ: at BL 2 patients according to the ASAS definition of whom 1 also fulfilled the alternative definition. At FU this was 2 (different patients than at baseline) and 0 patients, respectively. Addition of MRI-spine to the classification criteria by the ASAS definition of ≥3 inflammatory lesions would lead to classification of 3 additional patients via imaging arm, with 1 patient already fulfilling the clinical arm. Conclusions In this cohort, a positive MRI-spine in the absence of sacroiliitis on MRI was rarely seen Addition of MRI-spine as an imaging criterion to the ASAS criteria had a low yield in number of classifications. Therefore, performing MRI of the spine at either baseline or one-year follow-up is of little value in patients with short duration of CBP and suspicion of axial SpA. Disclosure of Interest None declared

THU0013 Interaction between two common HLA antigens defines a subset of individuals at a very high risk for ankylosing spondylitis

Background Susceptibility to spondyloarthritis (SpA) is largely genetically determined. To understand increasingly complex genetic associations, one can look for interaction between genetic risk factors. Objectives In this study, we investigated interaction between common HLA class I risk antigens in ankylosing spondylitis (AS) the most typical form of SpA. Methods In 155 patients with AS and 5584 controls, common HLA class I antigens were analyzed for association with AS. Biologic interaction was analyzed by investigating whether the effects of the risk factors combined departed from additivity. Results Apart from an association with HLA-B27, we found an association between HLA-B60 and AS (OR 2,0; 95%CI 1.3-2.9; p<0.001). This was confirmed in meta-analysis of published studies (OR 2.3; CI 1.8 – 2.8). While 21.3% of AS patients had both HLA-B27 and HLA-B60, this combination was found in only 0.4% of controls. With HLA-B27-/HLA-B60- AS patients as the reference, the relative risk (RR) for HLA-B27-/HLA-B60+ patients was 2.3 (CI 0.9-5.8). For HLA-B27+/HLA-B60- the RR was 66 (CI 40-111) but increased to 342 (CI 167- 703) in HLA-B27+/HLA-B60+ patients. For the interaction, the relative excess risk (RERI) was 310 (95% CI 130-490), the attributable proportion (AP) was 0.8 (CI 0.7-0.9), and the synergy index (S) 5.7 (CI 3.8 -8.5). The interaction was confirmed in an independent cohort. Conclusions We report a strong interaction between HLA-B60 and HLA-B27 in AS susceptibility. As a result, individuals with the HLA-B27+/HLA-B60+ genotype are at a very high risk of developing AS. Disclosure of Interest None Declared

Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCP) affects severity of rheumatoid arthritis

Objective. The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of highaffinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies). Methods. High-resolution HLA–DR and DQ typing and anti–CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method. Results. Carriership of the individual alleles HLA–DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of antiCCP antibodies. Carriers of DQ–DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA–DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8–6.0 and OR 13.3, 95% CI 4.6–40.4, respectively). An increased rate of joint destruction was observed in SE, anti-CCP patients (mean Sharp score 7.6 points per year) compared with that in SE, anti-CCP patients (2.4 points per year) (P 0.04), SE, anti-CCP patients (1.6 points per year) (P < 0.001), and SE, anti-CCP patients (1.6 points per year) (P < 0.001). Conclusion. HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles.

FRI0475 ANTI-CD74 antibodies as diagnostic biomarker for early axial spondyloarthritis: data from the spondyloarthritis caught early (SPACE) cohort study

Background Diagnosis of axSpA is often delayed with 5–10 years. A robust biological disease marker is lacking and could decrease the current diagnostic delay. Two studies showed that serum anti-CD74 IgG antibodies are increased in SpA1,2. Objectives To explore the value of anti-CD74 antibodies as diagnostic biomarker for axSpA in patients with early, chronic back pain. Methods We tested the prevalence of anti-CD74 IgG and IgA antibodies in patients from the SPondyloArthritis Caught Early (SPACE) cohort by enzyme-linked immunosorbent assay (ELISA). Patients from the SPACE cohort have chronic back pain for >3 months and ≤2 years with an onset <45 years. Results We included 560 patients of the SPACE cohort, of whom 274 patients were diagnosed with axSpA by a rheumatologist at baseline. Anti-CD74 IgG levels did not differ between patients with and without axSpA (p=0.152, Table 1). Median anti-CD74 IgA levels (tested with either casein or BSA as a blocking buffer) were higher in patients with axSpA (both p<0.0001). Despite these differences at the group level, the diagnostic value of the anti-CD74 IgA antibodies was limited as shown by ROC analysis. The optimal cut off according to ROC analysis was an optical density (OD) of 0.875, providing a sensitivity of 38.3% and a specificity of 77.6%. In line with previous reports, further analysis revealed that total IgA levels were elevated in early axSpA patients vs. non-SpA early back pain patients (p=0.008). When correcting the level of anti-CD74 IgA for the level of total IgA, the differentiating capacity of anti-CD74 disappeared for casein but remained intact for BSA (casein: p=0.731, BSA: p=0.038). Additional analyses using the ASAS classification criteria rather than a clinical diagnosis of axSpA, a strict combination of clinical diagnosis and ASAS classification criteria (excluding patients fulfilling the ASAS axSpA criteria without a clinical diagnosis and vice versa) (Table 1) and using the clinical diagnosis at 1 year of follow-up yielded similar results. Conclusions Serum anti-CD74 IgA antibody levels, but not serum anti-CD74 IgG levels, are elevated in patients with axSpA versus non-SpA with back pain of <2 years duration. However, ROC analyses revealed that these numerical differences are of limited diagnostic value in these patients with early back pain. References Baraliakos, X. et al. High prevalence of anti-CD74 antibodies specific for the HLA class II-associated invariant chain peptide (CLIP) in patients with axial spondyloarthritis. Ann. Rheum. Dis. 1–5 (2013). Baerlecken, N. T. et al. Autoantibodies against CD74 in spondyloarthritis. Ann. Rheum. Dis. 73, 1211–4 (2014). Disclosure of Interest J. de Winter: None declared, M. van de Sande Grant/research support from: Novartis, Eli Lilly, Boehringer Ingelheim, Benecke, Takeda, Tillotts, MSD, Cellgene, N. Baerlecken: None declared, I. Berg: None declared, R. Ramonda: None declared, D. van der Heijde: None declared, F. van Gaalen: None declared, T. Witte: None declared, D. Baeten Grant/research support from: Pfizer, MSD, AbbVie, UCB, Novartis, Janssen, Boehringer Ingelheim., Consultant for: Pfizer, MSD, AbbVie, UCB, Novartis, Janssen, Boehringer Ingelheim, Eli Lilly, Roche, BMS, Glenmark, Employee of: UCB

OP0085 Does The Presence of Multiple SpA-Features in Patients with Chronic Back Pain Always Lead To Diagnosis of Axial Spondyloarthritis?

Background The number of clinical SpA-features plays an important role in the Assessment of SpondyloArthritis international Society (ASAS) modified Berlin algorithm for the diagnostic work-up of patients (pts) with a suspicion of axial SpA (axSpA). Objectives To investigate whether all pts with short duration chronic back pain (CBP) and multiple SpA-features are always diagnosed as axSpA by the rheumatologist and to describe the features of these patients. Methods The SPondyloArthritis Caught Early (SPACE)-cohort includes CBP pts (≥3 months, ≤2 years, onset <45 years) from various European rheumatology centres. Baseline data were used for the analyses. Following a fixed protocol all pts underwent a full diagnostic work-up consisting of performance of MRI and radiographs of sacroiliac joints (MRI-SI and X-SI), acute phase reactants, HLA-B27 testing, and assessment of other SpA-features (inflammatory back pain (IBP), good response to NSAIDs, family history for SpA, peripheral arthritis, dactylitis, enthesitis, uveitis, inflammatory bowel disease (IBD), and psoriasis). Local radiologists or rheumatologists from the different centres interpreted MRI-SI and X-SI on presence of sacroiliitis (yes/no) using global assessment as part of routine clinical practice. Total number of SpA-features was calculated excluding sacroiliac imaging and HLA-B27 status. The treating rheumatologist provided clinical diagnosis of pts and the ASAS-criteria for axSpA were used for classification. Results A total of 522 pts were analysed in this study: before sacroiliac imaging and HLA-B27 testing 164/522 (31.4%) pts had no or 1 SpA-feature, 148/522 (28.4%) pts had 2 SpA-features, 85/522 (16.3%) pts had 3 SpA-features, and 125/522 (23.9%) pts had ≥4 SpA-features respectively. IBP, good response to NSAIDs, and positive family history for SpA were most common in all subgroups (0 or 1 feature: 26.8%, 8.5%, and 16.5% of pts; 2 features: 72.3%, 34.5%, 39.9%; 3 features: 87.1%, 60.0%, 54.1%; ≥4 features: 94.4%, 83.2%, 68.0% respectively). Of the pts with 2 and 3 SpA-features with negative X-SI 20/132 (15.2%) and 9/78 (11.5%) did not have axSpA diagnosis despite being HLA-B27+ (Figure 1). All pts with ≥4 SpA-features and X-SI+ (n=28) were diagnosed with axSpA. In contrast to what would be expected by following the modified Berlin algorithm for pts with ≥4 SpA-features, 18/94 pts (19.1%) with negative imaging (of which 4 HLA-B27+), were not diagnosed with axSpA by their rheumatologist. Multivariate regression analysis of presence of SpA-features identified MRI-SI+ (OR 41.7;95%CI 17.3.1–100.5), X-SI+ (OR 31.5;95%CI 3.1–321.0), HLA-B27+ (OR 4.7;95%CI 2.5–8.6), uveitis (OR 4.3;95%CI 1.5–12.7), IBP (OR 2.5;95%CI 1.4–4.7), heel enthesitis (OR 5.5;95%CI 2.7–11.4), IBD (OR 3.2;95%CI 1.2–8.8), elevated CRP/ESR (OR 2.7;95%CI 1.4–5.3), and psoriasis (OR 2.5;95%CI 1.0–6.0) as significant independent predictors of axSpA diagnosis. Conclusions In this cohort of pts with CBP having numerous SpA-features did not automatically lead to a clinical axSpA diagnosis but positive imaging was the main driving factor to diagnosis of axSpA. Disclosure of Interest None declared

FRI0404 Illness Perceptions and Health-Related Quality of Life in Patients with Axial Spondyloarthritis and Other Forms of Chronic Back Pain in The Space-Cohort

Background Knowledge about the impact of illness perceptions on Health-Related Quality of Life (HRQoL) in patients (pts) with axial Spondyloarthritis (axSpA) and other forms of chronic back pain (CBP) is lacking. Objectives To explore the association between illness perceptions and HRQoL in pts with short symptom duration of axSpA and other forms of CBP at baseline. Methods The Spondyloarthritis Caught Early (SPACE) study includes pts with CBP (≥3 months, ≤2 years, onset <45 years) recruited from 5 European centres. The Revised Illness Perception Questionnaire (IPQ-R) was completed at baseline. In the illness identity dimension, pts reported if they have experienced and believed that a certain symptom is CBP related. Other illness perceptions and causal dimensions used 5-point Likert scales (1 strongly disagree, 5 strongly agree). HRQoL was assessed by 36-item Short-Form (SF-36). Scale scores ranged from 0 (worst) to 100 (best). Physical (PCS) and Mental Component Summary (MCS) scores were calculated. Univariable regression models were built for each IPQ-R subscale as independent and PCS or MCS as dependent variable. The models were adjusted for age and gender and stratified in case of effect modification by gender (p<0.10). Results 315 pts were included; 123 fulfilled axSpA ASAS criteria and 192 did not fulfil the criteria. Mean age was 31.3 (SD 8.3) years, mean duration of CBP was 13.2 (SD 7.2) months and 36.5% was male. Mean PCS was 28.0 (SD 16.3) for axSpA pts and 24.9 (SD 14.4) for CBP. As the MCS was only slightly decreased compared to the general population (48.0 (SD 13.3) axSpA and 49.7 (SD 11.5) CBP pts), analyses focused on PCS. Pts reported a mean of 4.3 (axSpA) and 4.8 (CBP) symptoms to be associated with back pain. Most reported symptoms were pain and joint stiffness. All other subscales showed a mean of approximately 3, except psychological attributions, risk factors, immunity and accident (mean approximately 2). All pts attributed their complaints mostly to genetic factors. In both pts groups attribution of multiple symptoms to CBP (Figure 1;-1.8 axSpA, -2.1 CBP) was associated with lower PCS. However more dimensions showed association with PCS in axSpA (8) than CBP pts (6). In male axSpA pts belief in severe consequences (-12.1), more negative emotions towards their complaints (-9.3), and stronger belief of psychological attributions as a cause (-8.8) were associated with lower PCS. Whereas in male CBP pts stronger belief in risk factors (-8.1) and immunity as a cause (-10.0) were associated with lower PCS. More illness coherence was associated with higher PCS in male axSpA (6.2) and all CBP pts (2.8). In women consequences (-6.3, axSpA) and strong emotional representations (-4.0, CBP) were statistically significant. No gender differences were found for risk factors (-6.0) or immunity (-5.7) in axSpA and consequences (-7.9) in CBP pts. Conclusions Negative illness perceptions are associated with lower PCS of HRQoL in pts with axSpA and other forms of CBP. The impact of negative illness perceptions on PCS was more pronounced in men than in women. Disclosure of Interest None declared

AB1096 Local Radiologists Score More Abnormalities in Comparison to Central Readers Leading to More Patients Fulfilling the Classification Criteria of Axial Spa: Data from the Space-Cohort

Background The interpretation of findings on MRI and radiographs of the sacroiliac joints (MRI-SI and X-SI respectively) is known to vary amongst radiologists and trained readers as recently shown in the DESIR-cohort in France1. Since imaging is used in the ASAS axial spondyloarthritis (axSpA) criteria for the classification of patients, different findings can result in a different SpA classification. Objectives To objectify if classification (ASAS axSpA criteria) of patients (pts) in the SPACE-cohort differed based on evaluation of MRI-SI and X-SI by radiologists (local evaluation) and two blinded readers (central reading). Methods The SpondyloArthritis Caught Early (SPACE)-cohort includes pts with chronic back pain (≥3 months, ≤2 years, onset <45 years) visiting the rheumatology outpatient clinics of five participating centres in the Netherlands, Norway and Italy. Local radiologists provided information on bone marrow oedema compatible with sacroiliitis and signs of radiographic sacroiliitis compatible with axSpA without formal scoring. MRI-SI were scored by the central readers according to the ASAS definition and X-SI were scored according to the mNY criteria. In case of disagreement, an experienced reader served as adjudicator. MRI-SI and X-SI were considered positive if 2/3 readers agreed. Pts were classified according to the ASAS axSpA criteria using the scores of local evaluation and again using the scores of central reading. Results In total, 143/395 pts (36.2%) fulfilled the ASAS axSpA criteria based on central reading and 170/395 pts (43,0%) based on local evaluation. MRI-SI was rated discordant in 34 pts (8.4%) and concordant in 27 pts (6.8%); these figures were 19 pts (4.8%) and 12 pts (3.0%) for X-SI. In 43 pts (10.9%) a different reading resulted in a different rating of presence of axSpA; 35 pts (8.9%) classified no SpA by central reading were identified as axSpA by local evaluation; 8 pts (2.0%) classified axSpA by central reading were no SpA by local evaluation. Furthermore, discrepancies were observed when interested in whether pts fulfilled the imaging and clinical arm within the ASAS axSpA criteria (see table). Twenty-two pts (5.6%) fulfilled the imaging arm by local evaluation, but fulfilled the clinical arm only based on central reading. In contrast only 4 pts (1.0%), who fulfilled only the clinical arm based on local evaluation, were reclassified into the imaging arm by central reading. Conclusions In pts with chronic back pain 10.9% of pts were classified differently based on scores of trained central readers and local evaluation of radiologists. This was due to difference in reading in both MRI-SI and X-SI. However, in a greater proportion of pts the classification did not change even with discrepant reading because of the clinical arm of the ASAS classification criteria. References van den Berg. Ann Rheum Dis 2014. Disclosure of Interest None declared