Background/Purpose: Improved means to predict which RA patients will respond to methotrexate monotherapy, the preferred first line therapy in early RA, would allow patients to more quickly receive effective treatment, possibly preventing irreversible joint damage. Among the more than 100 risk loci so far identified as risk factors for RA, many tag genes in pathways targeted by current therapies and/or that are involved in general inflammatory response. Thus, it would not be unexpected if alleles influencing RA risk also have an effect on RA treatment response.

Methods: We linked recent onset RA patients from the EIRA study (genotyped with the Illumina Immunochip array) to prospectively recorded data on treatment and clinical characteristics in the nationwide Swedish Rheumatology register (SRQ). The cohort was defined as those who started methotrexate monotherapy as first DMARD treatment 2000-2012 (n=1390), and had at least one return visit with recorded DAS28 within 2-8 months after treatment start (92%, N=1278).Based on previous meta-GWAS data on risk factors for RA development, we identified 76 risk loci tagged by SNPs on the Immunochip (R²>0.6), and calculated a risk score by weighting alleles by their published log-odds, standardizing the sum against an RA-free population. The association of RA risk score, individual SNPs, and the shared epitope alleles, with DAS28-based EULAR response at the evaluation visit closest to 3 months after initiation, was estimated using logistic regression models.

Results: With respect to RA risk, the genetic risk score was a stronger predictor of onset of ACPA+ than ACPA- RA (odds ratio per stdev increase: 2.2 vs 1.2). With respect to response to methotrexate, the number of SNPs associated to EULAR response in individual analyses was not higher than expected by chance (3/76 SNPs had p<0.05 in ACPA+, 2/76 in ACPA-), and there was no association of the genetic risk score to methotrexate response in RA overall, nor in ACPA+ (Table). Higher genetic risk score was, however, associated with borderline significantly better response to methotrexate in ACPA- RA (odds ratio [95%CI]: 1.27 [1.01-1.60]).

Conclusion: We found no association between identified RA susceptibility loci and response to methotrexate monotherapy in RA overall nor in the ACPA-positive subgroup. The borderline increased EULAR response with higher genetic risk score among ACPA- RA patients may reflect individuals within this subset with a “correct” diagnosis of RA, and hence more likely to respond to this therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/do-ra-susceptibility-loci-predict-response-to-methotrexate-as-first-dmard-in-early-ra/