2011 National Meeting

3013 — Methotrexate Use, MTHFR Polymorphisms, and Traditional Risk Factors in Predicting Cardiovascular Events in Rheumatoid Arthritis (RA)

Caplan L (Denver VAMC) , Davis LA (Denver VAMC), Cannon GW (Salt Lake VAMC), Pointer LM (Denver VAMC), Wolff RK (Salt Lake VAMC), Mikuls TR (Omaha VAMC), Reimold AM (Dallas VAMC), Kerr GS (Washington DC VAMC), Richards JS (Washington DC VAMC), Johnson DS (Jackson VAMC)

The enzyme methylenetetrahydrofolate reductase (MTHFR) has been implicated in the metabolism of methotrexate—the most common disease modifying anti-rheumatic drug in RA. MTHFR A1298C and C677T polymorphisms have been associated with increased cardiovascular (CV) events in non-RA populations. Whether these findings affect our ability to predict CV events in comparison to established clinical risk factors remains unclear. Thus, we explored the potential association between methotrexate use, MTHFR A1298C or C677T genetic status, and time to first CV event in a prospective registry of patients with RA—a condition associated with accelerated CV disease.

Veterans Affairs Rheumatoid Arthritis (VARA) registry participants were genotyped for MTHFR polymorphisms. Numerous variables (including demographic information, RA duration, and auto-antibody status) were collected from patients by investigators on enrollment into the registry; disease activity was recorded at baseline and at follow-up visits. These data were used to control for disease severity. Patients’ baseline comorbidities and the outcome variable were defined using ICD-9 and CPT codes recorded in the inpatient and outpatient patient treatment records. The combined CV event outcome included: myocardial infarction (MI), percutaneous transluminal coronary angioplasty, coronary artery bypass graft, and stroke. Cox proportional-hazards regression was used to model the time to first CV event.

Data were available for 1047 subjects. CV events occurred in 406 patients post-enrollment. Prior MI was strongly associated with time to first CV event (H.R. 6.65 [CI 5.31-8.33]), as was hyperlipidemia (H.R. 1.64 [CI 1.32-2.05]). Methotrexate use was associated with a substantial decline in first CV events (H.R. 0.76 [CI 0.53-0.94]). MTHFR polymorphisms were not associated with decreased time-to-CV event.

Although MTHFR polymorphisms have previously been associated with increased CV events, we found no evidence that MTHFR status was associated with VARA patients’ time to first CV event. Traditional CV risk factors conferred substantial CV risk, while methotrexate use was protective.

Patients with RA may benefit from methotrexate treatment to prevent CV events—the primary cause of death in patients with RA. For the polymorphisms studied, genetic data do not add additional value to traditional risk factors in predicting CV events. We recommend against the clinical use of MTHFR polymorphisms in assessing RA patients for CV risk.