Abstract
Previously, we demonstrated in test and validation cohorts that type I IFN (T1IFN) activity can predict non-response to tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA). In this study, we examine the biology of non-classical and classical monocytes from RA patients defined by their pre-biologic treatment T1IFN activity. We compared single cell gene expression in purified classical (CL, n = 342) and non-classical (NC, n = 359) monocytes. In our previous work, RA patients who had either high IFNβ/α activity (>1.3) or undetectable T1IFN were likely to have EULAR non-response to TNFi. In this study comparisons were made among patients grouped according to their pre-biologic treatment T1IFN activity as clinically relevant: “T1IFN undetectable (T1IFN ND) or IFNβ/α >1.3” (n = 9) and “T1IFN detectable but IFNβ/α ≤ 1.3” (n = 6). In addition, comparisons were made among patients grouped according to their T1IFN activity itself: “T1IFN ND,” “T1IFN detected and IFNβ/α ≤ 1.3,” and “IFNβ/α >1.3.” Major differences in gene expression were apparent in principal component and unsupervised cluster analyses. CL monocytes from the T1IFN ND or IFNβ/α >1.3 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 nine patients. This pattern most strongly associated with the IFNβ/α>1.3 group. Differences in gene expression in monocytes among the groups suggest differential IFN pathway activation in RA patients who are either likely to respond or to have no response to TNFi. Additional transcripts enriched in NC cells of those in the T1IFN ND and IFNβ/α >1.3 groups included MYD88, CD86, IRF1, and IL8. This work could suggest key pathways active in biologically defined groups of patients, and potential therapeutic strategies for those patients unlikely to respond to TNFi.
Highlights
Rheumatoid Arthritis (RA) is the most common inflammatory joint disease world-wide, characterized by a destructive arthritis and serious extra-articular manifestations, including accelerated vascular disease [1]
Using a novel single cell PCR approach, we used a panel of T1IFN and innate immune system related genes to define gene expression states in monocytes from RA patients grouped by their pre-treatment blood T1IFN activity
This is based on our previous study, which showed in test and validation cohorts that patients with IFNβ/α activity > 1.3 were not likely to respond to Tumor necrosis factor inhibitors (TNFi) therapy, and that those with undetectable T1IFN were not likely to respond
Summary
Rheumatoid Arthritis (RA) is the most common inflammatory joint disease world-wide, characterized by a destructive arthritis and serious extra-articular manifestations, including accelerated vascular disease [1]. Remission or very low disease activity within the first 3 months is the goal [2, 3]. New therapies have made remission possible for a greater number of patients. The current treatment strategy is one of trial-and-error, as we are not able to predict which medication will work for an individual patient. Tumor necrosis factor inhibitors (TNFi) are the most common biologic treatment employed [4]. We studied pretreatment circulating IFN-alpha (IFNα), IFN-beta (IFNβ), and total T1IFN activity in RA patients just prior to receiving a TNFi [11] in independent test and validation cohorts. The ratio of IFNβ to IFNα activity (IFNβ/α) > 1.3 was strongly predictive of nonresponse to TNFi therapy (specificity = 77% in the validation cohort). No patient with a ratio >1.3 achieved remission or low disease activity
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