Julie S. Johansen

Plasma IL‐6, plasma VEGF, and serum YKL‐40: relationship with disease activity and radiographic progression in rheumatoid arthritis patients treated with infliximab and methotrexate

Department of Rheumatology, Herlev Hospital, University of Copenhagen, Department of Rheumatology, H:S Hvidovre Hospital, University of Copenhagen, Department of Rheumatology, H:S Rigshospitalet, University of Copenhagen, Department of Radiology, H:S Rigshospitalet, University of Copenhagen, and Department of Surgical Gastroenterology, H:S Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark

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 40u2009mg (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.

Drug concentrations and anti-drug antibodies during treatment with biosimilar infliximab (CT-P13) in routine care

The Danish Rheumatologic Biobank, the DANBIO Registry and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark Department of Rheumatology, Gentofte and Herlev Hospital, Copenhagen University Hospital, Gentofte, Denmark The Danish Rheumatologic Biobank, Department of Pathology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Oslo, Norway Department of Rheumatology, Zealand University Hospital, Køge, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark King Christian X’s Hospital for Rheumatic Diseases, Graasten, Denmark Department of Rheumatology, Odense University Hospital, Svendborg Hospital, Svendborg, Denmark Department of Rheumatology, North Denmark Regional Hospital, Hjørring, Denmark Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark Department of Rheumatology, Odense University Hospital, Odense, Denmark Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway The Danish Rheumatologic Biobank, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Norway Center for Rheumatology and Spine Diseases, Institute for Inflammation Research (IIR), Rigshospitalet, Copenhagen University Hospital, Glostrup, Denmark Zitelab, Copenhagen, Denmark Department of Medicine and Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

Circulating serum interleukin-6, serum chitinase-3-like protein-1, and plasma vascular endothelial growth factor are not predictive for remission and radiographic progression in patients with early rheumatoid arthritis: post-hoc explorative and validation studies based on the CIMESTRA and OPERA trials

Objective: To investigate serum interleukin-6 (IL-6), serum chitinase-3-like protein-1 (YKL-40), and plasma vascular endothelial growth factor (VEGF) as measures of disease activity and predictors of clinical remission and radiographic progression in two early rheumatoid arthritis (RA) randomized controlled trials (RCTs). Method: Treatment-naïve patients with early RA (< 6 months’ duration) and active disease, participating in two investigator-initiated RCTs, were treated according to a predefined treat-to-target algorithm aiming at inflammatory control, using methotrexate (MTX) + cyclosporine versus MTX + placebo (CIMESTRA study, n = 150, 5 year follow-up) or MTX + adalimumab versus MTX + placebo (OPERA study, n = 180, 2 year follow-up). The 28-joint Disease Activity Score (DAS28) and conventional radiography [bilateral hands and feet at baseline, 2 years and 5 years (only CIMESTRA)] were obtained at baseline and during follow-up. Serum IL-6, serum YKL-40, and plasma VEGF were measured in baseline blood samples and during follow-up. Hypotheses regarding the biomarkers’ relation with DAS28 and ability to predict clinical remission (DAS28 < 2.6) and radiographic progression (change in total Sharp van der Heijde score ≥ 2) were generated in CIMESTRA and validated in OPERA, by Spearman’s correlation and logistic regression analyses. Results: Baseline IL-6, YKL-40, and VEGF correlated significantly with DAS28 in CIMESTRA (r = 0.50, r = 0.36, r = 0.36, respectively, all p < 0.01) and these results were confirmed in OPERA patients (r = 0.52, p < 0.01; r = 0.18, p = 0.01; r = 0.23, p = 0.002, respectively). None of the biomarkers (absolute values or change) was predictive of clinical remission or radiographic progression at 2 or 5 years in either study. Conclusion: Serum IL-6, serum YKL-40, and plasma VEGF were significantly correlated with DAS28 at baseline, but did not have consistent predictive value for clinical remission or radiographic progression in two early RA RCTs.

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