Background The first-line treatment of rheumatoid arthritis (RA) involves the introduction of one or more disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) or more historically sulphasalazine (SSA). Many patients only achieve a partial response to these therapies, ultimately requiring biological therapy. There are currently no predictive biomarkers that are sufficiently robust to inform treatment decisions in routine clinical practice.
Objectives To investigate RA genetic susceptibility variants in the context of treatment outcomes in the initial 6 months of conventional DMARD therapy in RA.
Methods Clinical data from early RA patients recruited into a multi-centre observational cohort were used, consisting of matched clinical and genotyping data on 608 patients with 6 month follow-up. A multivariate analysis of each of 41 single nucleotide polymorphisms (SNPs) across 34 genomic loci previously associated with susceptibility to RA were investigated for association with primary and secondary treatment outcomes; the primary outcome of improvement in DAS28 (ΔDAS28; baseline DAS28 minus 6month DAS28) after adjustment for baseline DAS28 and baseline HAQ, and the secondary outcome of achieving a low-disease activity state at 6 months (DAS28≤3.2) adjusted for baseline HAQ only. A threshold for nominal association was set at p<0.05, with a Bonferroni adjusted p<1.47×10-3 for 34 tests based on the number of loci tested for association.
Results The 608 patients with 6 month follow-up data included in this analysis had a mean age at baseline of 59.4 years (SD 12.9), mean symptom duration of 8.59 months (SD 9.6), (70.7%) were female, 70.8% were seropositive for RF and/or ACPA (RF 70.5%, ACPA 61.4%) and 38.7% achieved a low disease activity state (DAS28≤3.2 at 6months). No differences were observed in treatment outcomes between patients on MTX or SSA (ΔDAS28 p=0.858, DAS28≤3.2 p=0.728). SNPs mapping to the FCGR2A, TRAF1/C5 and UBASH3A loci (rs12746613, rs10760130 and rs3788013 respectively) showed nominal association with ΔDAS28 at 6months follow up (p=0.028, p=0.035, p=0.034, respectively). Two SNPs were found to show nominal association with DAS28≤3.2 at 6months at the STAT4 (rs10181656) and UBASH3A (rs3788013) loci (p=0.004 and p=0.045, respectively). No SNPs were found to be associated with treatment outcomes at the Bonferroni adjusted threshold.
Conclusions Genetic variants associated with modulating susceptibility to RA may also have a role in determining treatment outcomes in early RA patients following conventional DMARD treatment. Replication studies in comparable populations are needed in order to interpret these findings robustly.
Disclosure of Interest None Declared
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