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.

Associations of Serum Folate and Vitamin B12 Levels With Cardiovascular Disease Mortality Among Patients With Type 2 Diabetes

“…Among participants with rheumatoid arthritis in NHANES III (1988)(1989)(1990)(1991)(1992)(1993)(1994) and 2011, circulating folate levels were inversely associated with risk of all-cause mortality and CVD mortality, 25 whereas a U-shaped association between serum folate level and CVD mortality was observed among adults with hypertension. 26 However, among adults with T2D, the evidence regarding folate status and long-term health outcomes is limited and mixed.…”

Association Between Folate and Health Outcomes: An Umbrella Review of Meta-Analyses

“…The evidence on the association of folate with the all-cause mortality rate in the general population remains controversial. Several studies have demonstrated that folate supplementation could reduce the risk of CVD-related death, which might be attributable to serum homocysteine reduction (137). In contrast, Ebbing et al reported that folate treatment was associated with increased risks of cancer outcomes and allcause mortality in patients with ischemic heart disease (138).…”

Associations of Serum and Red Blood Cell Folate With All-Cause and Cardiovascular Mortality Among Hypertensive Patients With Elevated Homocysteine

“…Although the associations between folate levels and mortality have been previously investigated, the current evidence is not yet conclusive: some studies did not find any significant associations (18,19); among studies that did, J-or U-shaped associations (20)(21)(22)(23), positive linear associations (24), and inverse associations (17,25,26) have all been reported; additionally, two studies found that only low folate levels were significantly associated with increased risk of mortality (27,28). However, most of the previous studies used serum folate as the main exposure, and only two studies used RBC folate in the analysis (21,24).…”

“…The leading cause of death falls into 9 cause-specific death categories based on the International Classification of Diseases, 10th Revision (ICD-10) code on the participant's death certificate (16). We defined all-cause mortality as death because of any reason, while cardiovascular mortality included deaths reportedly due to disease of the heart (leading death code 001) or cerebrovascular diseases (leading death code 005) (17).…”