ABSTRACT: Although 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.645 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-? (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 IL2R? (sIL2R?)-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.Similar 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 sIL2R?-levels (p?=?1.44×10(-3)); lower sIL2R?-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 sIL2R?-levels in one analysis, the HR for rs2104286 was 2.27 (95 % CI?=?1.06-4.84, p?=?0.034) and for sIL2R? 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).IL2RA-rs2104286 and sIL2R?-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.
