Transcriptional Profiles of Circulating Monocytes and their Association with Pain Centralization and DMARD response in Rheumatoid Arthritis

Chronic pain is widely prevalent in patients with systemic inflammatory conditions. Treatments are usually focused on decreasing peripheral inflammation, but pain often persists despite inflammatory disease control. For example, rheumatoid arthritis (RA) patients with abnormalities in central nervous system regulation of pain, termed “pain centralization”, experience chronic pain, despite good control of joint inflammation. Effective options for treating chronic pain in patients with RA have not been identified. The development of these agents is hindered by a gap in knowledge regarding the biological pathways underlying chronic pain in RA. The objective of this application is to generate new insights into the relationship between circulating monocytes and pain centralization, an important cause of chronic pain, in patients with RA. The central hypothesis is that functional genomic profiling of monocytes will lead to the identification of novel transcriptional signatures associated with specific mechanisms of pain centralization and predict whether patients with RA continue to have ongoing pain, despite treatment with disease-modifying antirheumatic drugs (DMARDs). The central hypothesis will be tested by two specific aims: 1) to identify transcriptional signatures in monocytes associated with pain centralization in RA, and 2) to establish whether the transcriptional profile of monocytes predicts pain response after DMARD treatment. Fifty RA patients will be enrolled. Participants will be assessed at baseline and 12 weeks after initiation of DMARD therapy. Participants will complete validated, patient-reported outcome measures to phenotype the clinical pain experience and undergo quantitative sensory testing to characterize pain mechanisms at baseline and 12-weeks after DMARD initiation. Specifically, pressure pain thresholds at the trapezius will be used to assess overall pain centralization. Temporal summation will be used to assess pain facilitation, and conditioned pain modulation will be used to assess endogenous descending modulation of pain. Blood will be drawn to isolate circulating monocytes for RNA-seq at baseline. Transcriptional signatures associated with overall pain centralization and two specific sub-types of pain centralization will be identified. Machine learning techniques will be used to model whether gene expression in monocytes is predictive of pain response after 12 weeks of DMARD therapy. The proposed research is innovative because it represents a substantive departure from the status quo by: 1) using cutting-edge functional genomic approaches to identify biological pathways associated with chronic pain in RA, 2) examining a cell population, circulating monocytes, which have been shown to play a role in pain centralization, and 3) using QST to assess pain centralization in addition to self-reported measures of pain. The proposed research is significant because it would enable the development of non-opioid therapeutics for chronic pain in patients with systemic inflammatory conditions. This proposal is directly in line with the Foundation’s goal to support research that investigates biological parameters associated with clinical manifestations and responses to therapy.