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

Abstract

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.

Figure 1.. Distribution of C-reactive Protein (CRP) Values in 313 Patients With Rheumatoid Arthritis by Serum Folate Tertile From the Third National Health and Nutrition Survey, 1988-1994

The χ² test value for the difference in the proportion of patients according to CRP was not statistically significant (P = .23). The mean CRP values were 1.32 mg/dL among patients in folate tertile 1 (ie, folate levels <4.3 ng/mL), 1.13 mg/dL among patients in folate tertile 2 (ie, folate levels 4.3-8.2 ng/mL), and 1.22 mg/dL among patients in folate tertile 3 (ie, folate levels >8.2 ng/mL). To convert C-reactive protein to nanomoles per liter, multiply by 9.524; to convert folate to nanomoles per liter, multiply by 2.266.

Figure 2.. Cumulative Incidence Curves for All-Cause and Cardiovascular Mortality Risk Among Patients With Rheumatoid Arthritis by Serum Folate Tertile From the Third National Health and Nutrition Survey, 1988-1994

Cumulative incidence curves were adjusted for age, sex, race, body mass index, C-reactive protein value, smoking status, disease-modifying antirheumatic drug use, steroid use, nonsteroidal anti-inflammatory drug use, and existing hypertension, diabetes, and cardiovascular disease diagnoses. Tertile 1 includes patients with folate levels less than 4.3 ng/mL; tertile 2, 4.3 to 8.2 ng/mL; and tertile 3, greater than 8.2 ng/mL. To convert folate to nanomoles per liter, multiply by 2.266.