Background Chronic inflammation is a hallmark of rheumatoid arthritis (RA). Thus far, the biologic mechanisms underlying disease persistence are largely unknown. A proportion of RA-patients achieve DMARD-free sustained remission (persistent absence of arthritis after cessation of DMARD-therapy) over time, reflecting loss of disease persistence. To identify genetic variants indicative for processes underlying disease persistence we performed a candidate gene study. We hypothesized that variants associating with lack of radiographic progression also associate with DMARD-free sustained remission.
Methods 645 Dutch RA-patients were studied on achieving DMARD-free sustained remission during a maximal follow-up of 10-years. Variants replicated to be associated with radiographic progression under an additive model (HLA-DRB1-shared epitope (SE), DKK1-rs1896368, DKK1-rs1896367, DKK1-rs1528873, C5Orf30-rs26232, IL2RA-rs2104286, MMP-9-rs11908352, rs451066 and OPG-rs1485305) were studied. Cox-regression analyses were performed and Bonferroni correction applied. Soluble IL2RA (sIL2Ra)-levels were studied in relation to remission. For replication, 622 RA-patients included in the ESPOIR cohort were studied. Results were combined in inverse-variance weighted meta-analysis.
Results 119 patients achieved DMARD-free sustained remission after median disease duration of 4.3 years. The SE-alleles associated with a lower chance on remission, similar as previously reported (hazard ratio (HR)=0.57 95% confidence interval (95%CI)=0.42-0.77 p=2.72x10-4). 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=2.44x10-3), also after additional adjustment for anti-citrullinated peptide antibody status (HR=1.47, 95%CI=1.12-1.93, p=5.78x10-3). The rs2104286 minor allele associated with lower sIL2Ra-levels (p=1.43x10-3) and lower sIL2Ra-levels associated with a higher chance on remission (HR=0.81 per 100 pg/L 95%CI=0.68-0.95 p=0.012). When including both rs2104286 and sIL2Ra-levels in one analysis the HR for rs2104286 was 2.27 (95%CI=1.06-4.84 p=0.034) and for sIL2Ra 0.83 per 100 pg/L (95%CI=0.70-0.98 p=0.026). Within ESPOIR, the HR of rs2104286 was 1.31 (95%CI=0.90-1.90). Meta-analysis of the two cohorts revealed a p-value of 1.01x10-3.
Conclusions IL2RA-rs2104286 and sIL2Ra-level associated with loss of disease persistence in RA. Variants in IL2RA are known to protect against development of multiple sclerosis, diabetes and RA. Present data revealed that IL2RA-rs2104286, in addition to HLA-SE, is the only genetic factor that is associated with both radiographic joint destruction and RA-persistence. This underlines the relevance of IL2RA for RA.
Disclosure of Interest None declared