Kim Hørslev-Petersen

Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis.

At least 30% of patients with rheumatoid arthritis (RA) do not respond to biologic agents, which emphasizes the need of predictive biomarkers. We aimed to identify microRNAs (miRNAs) predictive of response to adalimumab in 180 treatment-naïve RA patients enrolled in the OPtimized treatment algorithm for patients with early RA (OPERA) Study, an investigator-initiated, prospective, double-blind placebo-controlled study. Patients were randomized to adalimumab 40 mg (n=89) or placebo–adalimumab (n=91) subcutaneously in combination with methotrexate. Expressions of 377 miRNAs were determined using TaqMan Human MicroRNA LDA, A Card v2.0 (Applied Biosystems). Associations between miRNAs and treatment response were tested using interaction analyses. MiRNAs with a P-value <0.05 using three different normalizations were included in a multivariate model. After backwards elimination, the combination of low expression of miR-22 and high expression of miR-886.3p was associated with EULAR good response. Future studies to assess the utility of these miRNAs as predictive biomarkers are needed.

Interactions between smoking, increased serum levels of anti-CCP antibodies, rheumatoid factors, and erosive joint disease in patients with early, untreated rheumatoid arthritis

Objectives: To determine to what extent shared epitopes, smoking, and anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with disease activity and erosive disease in patients with rheumatoid arthritis (RA) at disease onset. Method: RA patients not previously treated with disease-modifying anti-rheumatic drugs (DMARDs) and with a disease duration of < 6 months (CIMESTRA study) were examined for shared epitopes, anti-CCP antibodies, immunoglobulin M rheumatoid factor (IgM-RF) and IgA-RF, radiographic erosive changes in hands and feet, and clinical disease activity. Results: The study comprised 153 patients, of whom 104 (68%) were ever-smokers. The prevalence of patients with 0, 1, or 2 shared epitopes was 40 (48%), 71 (49%), and 33 (23%), respectively. Anti-CCP antibodies, IgM-RF, and IgA-RF were present in 89 (58%), 99 (65%), and 82 (54%) patients, respectively. Among smokers, erosive disease was associated with anti-CCP antibodies [odds ratio (OR) 3.9, 95% confidence interval (CI) 1.6–9.3], IgM-RF (OR 4.9, 95% CI 1.9–12), and IgA-RF (OR 2.8, 95% CI 1.2–6.4) but absent with regard to shared epitopes. Among never-smokers, erosive disease was not associated with either shared epitopes or antibodies. All antibody levels measured were associated with smoking and shared epitopes. Conclusions: Shared epitopes and smoking were associated with the production of anti-CCP antibodies and rheumatoid factors of IgM and IgA isotypes, which again were associated with erosive disease at presentation only in smokers. As shared epitopes and smoking were not directly associated with erosive disease, smoking may enhance the development of erosive disease in RA at different levels or through separate pathways.

Within-day variation and influence of physical exercise on circulating Galectin-3 in patients with rheumatoid arthritis and healthy individuals

Galectin‐3 has been suggested as a pro‐inflammatory mediator in rheumatoid arthritis (RA). Previous studies have reported overexpression of Galectin‐3 in RA synovitis and increased levels in synovial fluid and serum in long‐standing RA compared with osteoarthritis and healthy controls. Our objectives were to study whether serum Galectin‐3 (1) exhibits circadian variation and/or (2) responds to exercise in RA and controls. The study on circadian patterns (1) comprised eleven patients with newly diagnosed RA, disease duration less than 6 months (ERA), 10 patients with long‐standing RA [5–15 years (LRA)] and 16 self‐reportedly healthy control subjects. During 24 h, 7 blood samples were drawn at 3‐h intervals starting at 10 a.m. through 10 p.m. and at 7 and 10 a.m. on the following day. The study on the effect of physical activity (2) included 10 patients with ERA, 10 with LRA and 14 controls. The participants underwent a standardized exercise programme and four blood samples were drawn before, during and after exercise. Serum Galectin‐3 was quantified by ELISA (R&D systems). (1) Galectin‐3 was increased at baseline in both RA subsets (P = 0.08). There were no diurnal oscillations (P = 0.85). Day‐to‐day variation amounted to 3%. (2) Baseline Galectin‐3 was increased in LRA versus controls and ERA (P < 0.01 and 0.05). Physical exercise induced 10–15% Galectin‐3 increments in RA and controls (P < 0.001) peaking after 1–3 h. To conclude, Galectin‐3 did not exhibit circadian variation. Day‐to‐day variation was 3%. Exercise elicited comparable increments in patients with RA of short and long duration and controls, approaching normal after 1–3 h.

Circadian pattern and the effect of standardized physical exercise on procollagen IIA N-peptide (PIIANP) in rheumatoid arthritis at different stages and in healthy individuals

Background: Variant collagen IIA is re-expressed in diseased cartilage. Low procollagen IIA N-peptide (PIIANP) levels in serum have recently been reported in rheumatoid arthritis (RA). We investigated circadian rhythmicity and effect of physical activity on PIIANP in early and longstanding RA and in healthy subjects. Methods: Patients with early and longstanding RA and controls were included. Fasting and serial blood samples were collected during 24 h. PIIANP response to physical activity was studied before and serially after standardized exercise. Results and conclusion: In RA at different stages and healthy individuals, PIIANP exhibited no circadian rhythmicity, and PIIANP in serum was not influenced by physical activity.

FRI0607 Effect of Methotrexate and Intra-Articular Betamethasone with or Without Additional Cyclosporine on Magnetic Resonance Imaging (MRI)-Determined Inflammatory and Destructive Changes in Very Early Rheumatoid Arthritis – Results from a 24-Months' Randomised Double Blind Placebo Controlled Trial

Background MRI has been shown to be more sensitive than clinical examination and x-ray for detection of inflammatory and destructive joint changes in early rheumatoid arthritis (RA) and to discriminate between treatment arms in clinical trials using the semi-quantitative Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA MRI scoring (RAMRIS) system. Objectives To investigate whether MRI-determined measures of disease activity and joint destruction were suppressed in very early RA patients following a treat-to-target strategy with methotrexate (MTX) and intraarticular (i.a.) betamethasone and to investigate whether concomitant cyclosporine (CYA) had an additional effect on MRI determined inflammatory and destructive findings over 2 years. Methods In the 2-year randomised, double-blind, multicentre, clinical, treat-to-target trial, CIMESTRA, 160 patients with early (<6 months) RA were treated with MTX, i.a. betamethasone and CYA/placebo CYA. 129 patients participated in the MRI substudy, and had contrast-enhanced MRIs at months 0, 6, 12 and 24 that covered the non-dominant wrist (wrist-only group) and if technically possible both wrist and metacarpophalangeal (MCP) joints (wrist+MCP group). MRIs were evaluated by an experienced radiologist blinded to patient identity, clinical and biochemical data but not to chronology, using the RAMRIS scoring system assessing inflammatory (osteitis, synovitis, tenosynovisits) and destructive (erosions, joint space narrowing) changes. Observed data, without any data imputations, are reported. Non-parametric statistics were used. A value of p<0.05 was considered statistically significant. Results MRI-results from the wrist-only group are shown in table 1. The data in the wrist+MCP group were overall similar (data not shown). No statistically significant differences between the treatment groups were observed in any MRI characteristics at baseline or at any follow-up time point. Both the wrist-only group and the wrist+MCP group showed significant reductions compared to baseline in osteitis, synovitis and tenosynovitis at 6 months (all parameters) and 12 and 24 months (synovitis and tenosynovitis). Statistically significant, but numerically low, increases in erosion and JSN scores from baseline to 6, 12 and 24 months were seen. Conclusions A treat-to-target strategy with MTX and i.a. betamethasone reduced MRI inflammatory findings significantly, with no additional effect of CYA, but minor structural damage progression was still observed. References Hetland ML, et al. 2006. Arthritis Rheum 54:1401-1409. Hetland ML, et al. 2009. Ann Rheum Dis 68:384-390. Disclosure of Interest None declared

AB0001 Genotype and Haplotype Effects of 7 Single-Nucleotide Polymorphisms in the CRP Gene on Levels of C-Reactive Protein and DAS28 in Two Cohorts of Treatment NaÏVe, Recent Onset Rheumatoid Arthritis Patients

Background Single nucleotide polymorphisms (SNPs) in the C-reactive protein (CRP) gene are implicated in the regulation of the constitutional CRP expression and its response to pro-inflammatory stimuli. Previous reports suggest that these effects may influence instruments for clinical decision-making based on CRP, e.g. DAS28. Objectives To investigate the associations between 7 CRP SNPs, their haplotypes, the serum level of CRP and DAS28 in recent onset, treatment naïve RA (rheumatoid arthritis) patients. Methods 315 DMARD and steroid naïve RA patients with disease duration <6 months were included from two randomized controlled trials (CIMESTRA (n=135), OPERA (n=180)). The genotype and haplotype associations to CRP and DAS28 at baseline and after one year of active treatment were evaluated using linear regression analysis adjusted for age, sex and treatment. Genotyping were analyzed by the TaqMan OpenArray system. The results from the combined cohorts are presented. Results Table 1. Genotype associations to CRP and DAS28 Rs-no. CRP [β (P)] DAS28 [β (P)] Baseline Year 1 Baseline Year 1 rs11265257 −0.14 (0.19) −0.01 (0.91) −0.09 (0.31) −0.06 (0.49) rs1130864 0.15 (0.21) 0.03 (0.78) 0.16 (0.10) 0.14 (0.12) rs1205 −0.26 (0.03) −0.09 (0.38) −0.08 (0.39) −0.09 (0.32) rs1800947 −0.34 (0.14) −0.12 (0.57) 0.02 (0.91) 0.23 (0.21) rs2808632 0.18 (0.15) −0.04 (0.73) −0.04 (0.71) −0.08 (0.40) rs3093077 −0.10 (0.69) 0.30 (0.16) −0.26 (0.21) −0.02 (0.90) rs876538 0.15 (0.28) −0.05 (0.66) 0.02 (0.86) −0.02 (0.87) β, β coefficient; P, P-value. Table 2. CRP haplotype build, frequency and effect on CRP and DAS28 Haplotype Frequency CRP [Effect (CI)] DAS28 [Effect (CI)] Baseline Year 1 Baseline Year 1 H1 (CACT) 30.5% 96% (73;126) 99% (77;126) 102% (98;107) 105% (97;113) H2 (TGCT) 25.7% 74% (55;99) 91% (70;118) 99% (94;103) 97% (89;106) H3 (CGCG) 31.4% 100% 100% 100% 100% H4 (CGCT) 6.2% 66% (41;107) 121% (80;184) 95% (88;103) 102% (89;116) H5 (TGGT) 5.5% 64% (40;103) 86% (56;134) 101% (93;108) 110% (95;124) Haplotype defining SNPs (rs1205, rs1130864, rs1800947, rs2808632). Effects are stated relative to the most frequent Haplotype H3 (= reference, 100.) The minor allele of rs1205 C>T was associated with decreased CRP levels at baseline (p=0.03). The TT genotype showed a 50% reduction in CRP from 16.7 to 8.4 mg/l (p=0.005) compared to the CC genotype. This association was not observed after one year of active treatment (p=0.38) (Table 1). The common H2 haplotype, characterized by the T allele of rs1205, was associated with a 26% reduction in CRP at baseline (p=0.04), but no effect was observed at year 1 (p=0.47) (Table 2). No other SNP or haplotype were associated with CRP at baseline or year 1 (p≥0.09). We observed no associations between SNPs or haplotypes and DAS28 scores at baseline or year 1 (p≥0.10) Conclusions This study shows that DAS28 can be used for clinical decision-making without adjustment for CRP gene variants, as CRP genotypes and haplotypes were only marginally associated with CRP levels and without any association to the DAS28 score. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1357