Metabolic Perturbations Identified Before RA Diagnosis, May Be Useful in Biomarker Development

blood sample for clinical test
blood sample for clinical test
Researchers identified metabolic changes related to rheumatoid arthritis pathogenesis occurring in the blood before disease diagnosis.

Certain metabolic perturbations have been identified prior to a diagnosis of rheumatoid arthritis (RA) that may have the potential to serve as biomarkers and/or therapeutic targets, according to study results published in Annals of the Rheumatic Diseases.

Researchers sought to describe the trajectory of changes in metabolite concentrations among pre-RA participants compared with matched control participants who did not develop RA.

The independent pre-RA case-control study was conducted among military personnel in the US Department of Defense Serum Biorepository. Serum samples were obtained from 2 separate timepoints, both within several years of an actual RA diagnosis, which might be related to RA pathogenesis. Metabolomics that use liquid chromatography and tandem mass spectrometry can detect biological perturbations that lead to disease. Researchers evaluated whether pre-RA case vs control status predicted differences in metabolite concentration and those differences over time (ie, trajectories), using linear mixed models.

A total of 1142 serum samples that had been collected from 291 pre-RA participants and 292 matched control participants were included in the current analysis. Each RA case (80.8% seropositive; 51.9% women) had 2 blood samples selected during the pre-RA period (first mean, 2.7±1.6 years; second mean, 1.0±0.9 years prior to onset of clinical RA). The matched case-control group included 52% women with a mean age of 31.2 years at the first blood draw; 33.9 years at the second blood draw; and 35.3 years at an RA diagnosis.

A history of smoking was reported more commonly among the pre-RA vs control group (31.3% vs 25.3%, respectively). In addition, being overweight or obese was more common among pre-RA individuals compared with control participants (48.5% vs 26.0%, respectively, and 17.9% vs 8.9%, respectively). Among study participants with pre-RA, 58.1% were seropositive at the first blood draw; 72.5% were seropositive at the second blood draw; and 80.8% were ultimately diagnosed with seropositive RA.

Researchers identified a total of 14 metabolites that showed evidence of significantly altered trajectories over time among the pre-RA vs control group (P <.005). These metabolites were grouped into 4 main super class categories, including steroids, lipids, amino acids, and xenobiotics. Negative interaction effects, indicative of a more rapid decline in the metabolite over time, were seen in the pre-RA vs control group for several steroids, lipids, and some of the xenobiotics. Further, a significant increase over time was reported in the pre-RA vs control group for amino acids and naproxen.

A limitation of the current analysis was the fact that smoking data were not available for all participants and body mass index data were missing for participants in the control vs pre-RA group. Other potential confounders, including diet, physical activity, and alcohol use, were not available. Moreover, sample sizes were inadequate for subgroup analyses.

Researchers concluded, “Further studies are needed to perform absolute quantifications and to assess whether these metabolites could be biomarkers of RA risk.”

Disclosure: One study authors declared affiliations with a biotechnology company. Please see the original reference for a full list of the author’s disclosure.


Costenbader KH, DiIorio M, Chu SH, et al. Circulating blood metabolite trajectories and risk of rheumatoid arthritis among military personnel in the Department of Defense Biorepository. Ann Rheum Dis. Published online March 22, 2021. doi:10.1136/annrheumdis-2020-219682