Distinct single cell gene expression in peripheral blood monocytes correlates with tumor necrosis factor inhibitor treatment response groups defined by type I interferon in rheumatoid arthritis

Previously, we demonstrated that type I IFN (IFNβ/α) activity can predict non-response to tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA). In this study, we examine the biology of TNFi non-response in monocytes from RA patients. We compared single cell gene expression in purified classical (CL, n=342) and non-classical (NC, n=359) monocytes. RA patients were grouped according to their pre-TNFi IFNβ/α activity: those likely to have EULAR no response (non-response group, IFNβ/α 0 or >1.3, n=9) and those likely to have EULAR moderate or good response (response group, IFNβ/α > 0 and ≤1.3, n=6). Major differences in gene expression were apparent in principal component and unsupervised cluster analyses. CL monocytes from the non-response group were unlikely to express JAK1 and IFI27 (p <0.0001 and p 0.0005, respectively). In NC monocytes from the same group, expression of IFNAR1, IRF1, TNFA, TLR4 (p ≤0.0001 for each) and others was enriched. Interestingly, JAK1 expression was absent in CL and NC monocytes from 9 patients. This pattern strongly associated with the non-response IFNβ/α group, suggesting a major biological difference between JAK1 expressors and non-expressors. The type I IFN activity that was previously found to predict TNFi response associated with changes in gene expression in monocytes that suggest differential IFN pathway activation in RA patients who are either likely to respond or to have no response to TNFi. This work could suggest mechanisms for TNFi non-response, and potential therapeutic strategies for those patients unlikely to respond to TNFi.