Association of Serum Folate Levels With Cardiovascular Mortality Among Adults With Rheumatoid Arthritis

Importance Patients with rheumatoid arthritis (RA) are at high risk for cardiovascular (CV) mortality, attributed to chronic inflammation coupled with elevated circulatory homocysteine levels. Increasing the serum folate level reduces homocysteine, but the association of serum folate concentration with CV mortality in patients with RA has not been previously examined. Objective To examine the association of serum folate concentration and CV mortality risk among patients with RA. Design, Setting, and Participants A cohort study of the third National Health and Nutrition Examination Survey (1988-1994) and 2011 Linked Mortality File was performed. Adults aged 18 years or older with self-reported physician-diagnosed RA were included. Data analysis was performed between April 2019 and June 2019. Exposure Serum folate level. Main Outcomes and Measures All-cause and CV mortality risk estimated using Cox proportional hazards models, adjusted for the complex survey design and patient characteristics, including demographic characteristics, body mass index, C-reactive protein level, smoking, RA medication use, and comorbid conditions. Results A total of 683 patients with RA (mean [SE] age, 55.9 [1.0] years; 225 [30.2%] men; 478 [87.0%] white) were classified into tertiles based on serum folate levels, as follows: tertile 1, folate levels less than 4.3 ng/mL (n = 239); tertile 2, folate levels 4.3 ng/mL to 8.2 ng/mL (n = 234); and tertile 3, folate levels greater than 8.2 ng/mL (n = 210). During a median (interquartile range) follow-up of 17.4 (10.0-19.4) years, a total of 392 all-cause deaths and 258 CV deaths occurred. Compared with tertile 1, patients in tertile 2 had lower all-cause mortality risk (hazard ratio [HR], 0.63; 95% CI, 0.47-0.85). The risk of CV mortality was lower among patients in tertile 2 (HR, 0.52; 95% CI, 0.30-0.92) and tertile 3 (HR, 0.44; 95% CI, 0.26-0.75) compared with those in tertile 1 (P for trend = .01). Findings for CV mortality were consistent in a sensitivity analysis that estimated 10-year risk; patients in tertile 2 (HR, 0.31; 95% CI, 0.17-0.57) and tertile 3 (HR, 0.39; 95% CI, 0.22-0.69) had lower CV mortality risk compared with those in tertile 1 (P for trend = .04). Conclusions and Relevance Among patients with RA, a serum folate level of at least 4.3 ng/mL was associated with lower CV mortality risk. Further research is needed to examine whether a causal relationship exists between serum folate and CV risk among patients with RA. This cohort study examines the association of serum folate concentration with cardiovascular mortality risk among patients with rheumatoid arthritis. Question Are serum folate levels associated with cardiovascular mortality risk among adults with rheumatoid arthritis (RA)? Findings In this cohort study including 683 patients with RA, those with serum folate levels between 4.3 and 8.2 ng/mL and greater than 8.2 ng/mL had 48% and 56% lower cardiovascular mortality risk, respectively, compared with patients who had serum folate levels less than 4.3 ng/mL after adjusting for demographic characteristics, body mass index, C-reactive protein level, smoking, RA medication use, and comorbid conditions. Meaning In this study, serum folate levels of at least 4.3 ng/mL were associated with lower cardiovascular mortality risk among patients with RA.