Folate and global health review series, part 4: syntheses on folate and autoimmune diseases and skeletal outcomes

Background Autoimmune diseases and bone density loss (osteopenia and osteoporosis) are chronic conditions of complex aetiology that affect diverse populations. Folate may be associated with a higher risk of these disorders due to its essential role in one-carbon metabolism required for nucleotide synthesis, homocysteine metabolism, and methylation processes. However, the evidence on this association is inconclusive. Methods We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations between folate exposure (dietary intake, supplementation, or blood concentrations) and any autoimmune diseases or skeletal outcomes. Pairs of researchers screened the retrieved syntheses, extracted the relevant data, assessed their risk of bias using the ROBIS tool, and evaluated the credibility of the evidence using predefined criteria. Results We found 19 reviews reporting 25 unique associations: 15 on autoimmune diseases (multiple sclerosis, inflammatory bowel disease, psoriasis, human immunodeficiency virus, vitiligo, and systemic lupus erythematosus) and 10 on skeletal outcomes (fractures and bone mineral density loss). Most of the syntheses consisted of small-scale case-control studies. The risk of bias in the included syntheses was high. Owing to the small sample sizes, all the unique associations were assessed to be at a weak level of credibility. Conclusions The evidence on the relationship between folate status and autoimmune diseases or skeletal outcomes was limited in breadth and depth. Most of the 25 unique associations were reported by a single synthesis comprising small-scale studies. Subgroup analyses or dose-response analyses were severely limited or unavailable. More well-powered, prospective studies investigating the relationships between folate and autoimmune and skeletal conditions are warranted.