MTHFR c.665C>T and c.1298A>C Polymorphisms in Tailoring Personalized Anti-TNF-α Therapy for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with a prevalence of 1%. Currently, RA treatment aims to achieve low disease activity or remission. Failure to achieve this goal causes disease progression with a poor prognosis. When treatment with first-line drugs fails, treatment with tumor necrosis factor-alpha (TNF-alpha) inhibitors may be prescribed to which many patients do not respond adequately, making the identification of response markers urgent. This study investigated the association of two RA-related genetic polymorphisms, c.665C > T (historically referred to as C677T) and c.1298A > C, in the MTHFR gene as response markers to an anti-TNF-alpha therapy. A total of 81 patients were enrolled, 60% of whom responded to the therapy. Analyses showed that both polymorphisms were associated with a response to therapy in an allele dose-dependent manner. The association for c.665C > T was significant for a rare genotype (p = 0.01). However, the observed opposite trend of association for c.1298A > C was not significant. An analysis revealed that c.1298A > C, unlike c.665C > T, was also significantly associated with the drug type (p = 0.032). Our preliminary results showed that the genetic polymorphisms in the MTHFR gene were associated with a response to anti-TNF-alpha therapy, with a potential significance for the anti-TNF-alpha drug type. This evidence suggests a role for one-carbon metabolism in anti-TNF-alpha drug efficacy and contributes to further personalized RA interventions.