Identification of pathological RA endotypes using blood-based biomarkers reflecting tissue metabolism. A...

There is an increasing demand for accurate endotyping of patients according to their pathogenesis to allow more targeted treatment. We explore a combination of blood-based joint tissue metabolites (neoepitopes) to enable patient clustering through distinct disease profiles. We analysed data from two RA studies (LITHE (N = 574, follow-up 24 and 52 weeks), OSKIRA-1 (N = 131, follow-up 24 weeks)). Two osteoarthritis (OA) studies (SMC01 (N = 447), SMC02 (N = 81)) were included as non-RA comparators. Specific tissue-derived neoepitopes measured at baseline, included: C2M (cartilage degradation); CTX-I and PINP (bone turnover); C1M and C3M (interstitial matrix degradation); CRPM (CRP metabolite) and VICM (macrophage activity). Clustering was performed to identify putative endotypes. We identified five clusters (A-E). Clusters A and B were characterized by generally higher levels of biomarkers than other clusters, except VICM which was significantly higher in cluster B than in cluster A (p<0.001). Biomarker levels in Cluster C were all close to the median, whilst Cluster D was characterised by low levels of all biomarkers. Cluster E also had low levels of most biomarkers, but with significantly higher levels of CTX-I compared to cluster D. There was a significant difference in ΔSHP score observed at 52 weeks (p<0.05). We describe putative RA endotypes based on biomarkers reflecting joint tissue metabolism. These endotypes differ in their underlining pathogenesis, and may in the future have utility for patient treatment selection.