Table 6.

Major Metabolites implicated in Department of Defense Serum Biorepository study of 291 Pre-RA cases and 292 Matched controls, each with banked samples at two points in time prior to RA Diagnosis (or matched Index Date)

Pathway	Metabolites	Pre-RA Cases vs. Controls	Direction of Trajectory	Potential Role in RA Pathogenesis	Refs.
Steroid Biosynthesis	androsterone glucuronide, 17-hydroxypregnenolone sulfate isomer, pregnenolone sulfate	Lower	Decreasing	Androgen to estrogen conversion in inflammatory cells; systemic inflammation suppressing HPA axis and pregnenolone formation	18–24,26
Acyl Carnitines and related lipid metabolites	Hydroxymyristate, C2 carnitine, C9 carnitine, C40:7 PE plasmalogen	Lower	Decreasing	Enhanced cellular oxidation, oxidative stress	12,28–32
Amino Acid Metabolites	N-acetyl leucine, tyramine	Higher	Increasing	Amine acid and polyamine catabolism abnormal in RA	12,34,35
Food/Plant components and Xenobiotics	Levulinate, caffeine/xanthine metabolites (1,7-dimethyluric acid, caffeine, theophylline), naproxen	Levulinate, caffeine and xanthine metabolites: lower; naproxen: higher	Levulinate and caffeine/xanthine metabolites: decreasing; Naproxen: increasing	Levulinate and caffeine/xanthine: either decreased intake or increased catabolism Naproxen: taken for pre-RA symptoms	36–39