Methotrexate use, MTHFR polymorphisms and traditional risk factors in predicting cardiovascular events in elderly males with rheumatoid arthritis (RA)

Objective The enzyme methylenetetrahydrofolate reductase (MTHFR) has been implicated in the metabolism of methotrexate (MTX) – the most common disease modifying antirheumatic drug used to treat rheumatoid arthritis (RA). MTHFR C677T and A1298C polymorphisms have been associated with increased cardiovascular (CV) events in non-RA populations. We explored the potential associations of MTHFR C677T, A1298C and MTX with decreased time-to-CV event in the prospective Veterans Affairs Rheumatoid Arthritis (VARA) registry. Methods VARA participants were genotyped for MTHFR polymorphisms. Demographic information, RA duration and auto-antibody status were collected upon enrolment into the registry. Disease activity was recorded at baseline and at follow-up visits. Patients9 baseline comorbidities and the outcome variable were defined using ICD-9 and CPT codes recorded in inpatient and outpatient patient treatment files. The combined CV event outcome included: myocardial infarction (MI), percutaneous transluminal coronary angioplasty, coronary artery bypass graft and stroke. Multivariable Cox proportional-hazards regression was used to model the time-to-CV event. Results Data were available for 1047 subjects. Post-enrolment CV events occurred in 406 patients. Prior MI was strongly associated with time-to-CV event (HR 6.65 (CI 5.31 to 8.33)), as was hyperlipidaemia (HR 1.64 (CI 1.32 to 2.05)). Methotrexate use was associated with a substantial decline in first CV events (HR 0.76 (CI 0.62 to 0.92)). MTHFR polymorphisms were not associated with decreased time-to-CV event. Conclusions Although MTHFR polymorphisms have previously been associated with increased CV events, we found no evidence that MTHFR status was associated with VARA patients9 time-to-CV event. Traditional CV risk factors conferred substantial CV risk, while methotrexate use was protective.