BOSTON — Rheumatoid arthritis tends to develop slowly over years. To better understand the process, a study looked at metabolic changes prior to RA onset using a large nontargeted metabolomics platform to identify novel pathways.

The goal of the research, published in Rheumatology (Oxford), was to advance understanding of RA development.1

Brigham and Women’s Hospital-led researchers matched 254 incident RA cases with plasma samples drawn pre-RA onset in the Nurses’ Health Study (NHS) with 501 controls on age, race, menopause/post-menopausal hormone use and blood collection features. In addition, the researchers, including representatives from Walter Reed National Military Medical Center, measured 360 unique, known metabolites. Associations between metabolites and incidence of RA, adjusted for age, smoking and BMI, were assessed using conditional logistic regression. After subgroup analyses investigated seropositive (sero+) RA and RA within five years of sample collection, significant metabolites were then tested in a 290 female military pre-RA case-control study.

Results indicated that, In the NHS, metabolites associated with RA and sero+RA in multivariable models included 4-acetamidobutanoate (odds ratio (OR) = 0.80/S.d., 95% CI: 0.66, 0.95), N-acetylputrescine (OR = 0.82, 95% CI: 0.69, 0.96), C5 carnitine (OR = 0.84, 95% CI: 0.71, 0.99) and C5:1 carnitine (OR = 0.81, 95% CI: 0.68, 0.95). Those were found to be involved primarily in polyamine and leucine, isoleucine and valine metabolism. Researchers reported that several metabolites associated with sero+RA within five years of diagnosis were replicated in the independent military cohort: C5 carnitine (OR = 0.55, 95% CI: 0.33, 0.92), C5:1 carnitine (OR = 0.62, 95% CI: 0.39, 0.99) and C3 carnitine (OR = 0.57, 95% CI: 0.36, 0.91).

“Several metabolites were inversely associated with incidence of RA among women,” the authors wrote. “Three short-chain acylcarnitines replicated in a smaller dataset and may reflect inflammation in the five-year period prior to sero+RA diagnosis.”


  1. Chu SH, Cui J, Sparks JA, Lu B, et. Al. Circulating plasma metabolites and risk of rheumatoid arthritis in the Nurses’ Health Study. Rheumatology (Oxford). 2020 Nov 1;59(11):3369-3379. doi: 10.1093/rheumatology/keaa125. PMID: 32310291; PMCID: PMC7590418.