Diagnostic and Prognostic Metabolites Identified for Joint Symptoms in the KORA Population

Abstract

This study aims at identifying metabolites that significantly associate with self-reported joint symptoms (diagnostic) and metabolites that can predict the change from a symptom-free status to the development of self-reported joint symptoms after a 7 years period (prognostic). More than 300 metabolites were analyzed for 2246 subjects from the longitudinal study of the KORA (Cooperative Health Research in the Region of Augsburg, Germany), specifically the fourth survey S4 and its 7-year follow-up study F4. Two types of self-reported symptoms, chronic joint inflammation and worn out joints, were used for the analyses. Diagnostic analysis identified dysregulated metabolites in cases with symptoms compared with controls. Prognostic analysis identified metabolites that differentiate subjects in S4 who remained symptom-free after 7 years (F4) from those who developed any combination of symptoms. 48 metabolites were identified as nominally significantly (p < 0.05) associated with the self-reported symptoms in the diagnostic analysis, among which steroids show Bonferroni significance. 45 metabolites were identified as nominally significantly associated with developing symptoms after 7 years, among which hippurate showed Bonferroni significance. We show that metabolic profiles of self-reported joint symptoms are in line with metabolites known to associate with various forms of arthritis and suggest that future studies may benefit from that by investigating the possible use of self-reporting/questionnaire along with metabolic markers for the early referral of patients for further diagnostic workup and treatment of arthritis.

Large Scale Metabolic Profiling identifies Novel Steroids linked to Rheumatoid Arthritis

“…Moreover, anti-TNF agents used to treat RA have shown a reversal of these suppressive effects including an increase in DHEAS, improved physical functioning 32 and improved HPA response. As previously mentioned in 30 , 33 , the unknown metabolites X-12844 (tentatively identified as tetrahydrocortisone glucuronide), X-11440 (tentatively identified as hydroxypregnen-diol disulfate (or pregnenolone-diol disulfate)) and X-11444 (tentatively identified as urocortisol glucuronide or cortolone glucuronide) have also been previously reported to be associated with genetic variants related to steroid metabolism. For example, X-11440 has been found to be associated with a SNP near SULT2A1 which catalyzes the sulfation of steroids, particularly preferring the sulfation of DHEA.…”

“…In vitro studies have supported this view by demonstrating an inhibitory effect of inflammatory cytokines on adrenal steroidogenesis enzymes P450c17, P450scc, P450c21 P450c11 and the sulfation mechanism of DHEA 15 , 16 . In addition, DHEAS was observed to be decreased in RA patients 18 , 27 , in pre-RA patients 28 and in premenopausal women with RA 29 as well as in self-reported joint inflammation 30 , compared to controls. Perturbations in DHEAS levels were also linked to severity 31 and duration of RA 18 .…”

Immunometabolism in early and late stages of rheumatoid arthritis

“…Progress in technologies such as mass spectrometry and chromatography that enable increased mass precision and metabolite identification have driven interest in the measurement of hundreds of metabolites in cells, tissues and fluids. In patients with RA, plasma or serum, synovial fluid and synovial tissue have all been utilized for metabolomics studies 119–122 . No unifying metabolic marker(s) have been discovered, but some common signatures have emerged.…”