Abstract
IntroductionAlthough rheumatoid arthritis (RA) is generally a chronic disease, a proportion of RA-patients achieve disease-modifying antirheumatic drug (DMARD)-free sustained remission, reflecting loss of disease-persistence. To explore mechanisms underlying RA-persistence, we performed a candidate gene study. We hypothesized that variants associating with lack of radiographic progression also associate with DMARD-free sustained remission.Methods645 Dutch RA-patients were studied on DMARD-free sustained remission during a maximal follow-up duration of 10-years. Variants associated with radiographic progression under an additive model in the total RA-population (Human Leukocyte Antigens (HLA)-DRB1-shared epitope (SE), Dickkopf-1 (DKK1)-rs1896368, DKK1-rs1896367, DKK1-rs1528873, C5Orf30-rs26232, Interleukin-2 receptor-α (IL2RA)-rs2104286, Matrix metalloproteinase-9 (MMP-9)-rs11908352, rs451066 and Osteoprotegerin (OPG)-rs1485305) were studied. Cox-regression analyses were performed and Bonferroni correction applied. Soluble IL2Rα (sIL2Rα)-levels were studied. For replication, 622 RA-patients included in the French Evaluation et Suivi de POlyarthrites Indifférenciées Récentes cohort (ESPOIR)-cohort were investigated. Results were combined in inverse-variance weighted meta-analysis.ResultsSimilar as previously reported, the SE-alleles associated with less remission (hazard ratio (HR) = 0.57, 95 % confidence interval (95 % CI) = 0.42-0.77, p = 2.72×10−4). Variants in DKK-1, C5orf30, MMP-9 and OPG were not associated with remission. The IL2RA-rs2104286 minor allele associated with a higher chance on remission (HR = 1.52, 95 % CI = 1.16-1.99, p = 2.44×10−3). The rs2104286 minor allele associated with lower sIL2Rα-levels (p = 1.44×10−3); lower sIL2Rα-levels associated with a higher chance on remission (HR per 100 pg/L = 0.81, 95 % CI = 0.68-0.95, p = 0.012). When including rs2104286 and sIL2Rα-levels in one analysis, the HR for rs2104286 was 2.27 (95 % CI = 1.06-4.84, p = 0.034) and for sIL2Rα 0.83 (95 % CI = 0.70-0.98, p = 0.026). Within ESPOIR, the HR of rs2104286 was 1.31 (95 % CI = 0.90-1.90). The meta-analysis revealed a p-value of 1.01×10−3.ConclusionIL2RA-rs2104286 and sIL2Rα-level associated with RA-persistence. IL2RA variants are known to protect against multiple sclerosis, diabetes mellitus and RA. Besides HLA-SE, IL2RA-rs2104286 is thus far the only known genetic variant associated with both joint destruction and RA-persistence. This underlines the relevance of IL2RA for RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0739-6) contains supplementary material, which is available to authorized users.
Highlights
Rheumatoid arthritis (RA) is generally a chronic disease, a proportion of rheumatoid arthritis (RA)-patients achieve disease-modifying antirheumatic drug (DMARD)-free sustained remission, reflecting loss of disease-persistence
The initial treatment strategy was different for patients included and diagnosed during different inclusion periods: patients included in 1993–1995 were initially treated with nonsteroidal antiinflammatory drugs (NSAIDs) and DMARDs were initiated with delay; patients included in 1996–1998 were treated early with rather mild DMARDs such as hydroxychloroquine or sulfasalazine; and patients included in 1999–2008 were treated promptly with methotrexate [2]
The hazard ratio (HR) per shared epitope (SE) allele on achieving DMARD-free sustained remission was 0.57 (95 % confidence interval = 0.42–0.77) compared with patients without SE alleles (Table 2; Additional file 1); this finding is in line with previous reports
Summary
Rheumatoid arthritis (RA) is generally a chronic disease, a proportion of RA-patients achieve disease-modifying antirheumatic drug (DMARD)-free sustained remission, reflecting loss of disease-persistence. A few risk factors for RA persistence (absence of achieving DMARD-free sustained remission) have been van Steenbergen et al Arthritis Research & Therapy (2015) 17:244 reported and replicated. One of these factors is prolonged symptom duration at treatment start [1, 4, 6, 7]. One genetic risk factor has been found associated with arthritis persistence in two European cohorts: the presence of human leukocyte antigen (HLA)-DRB1 shared epitope (SE) alleles This risk factor presumably acts in the same pathway as ACPA [1, 2]
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