Over half of patients with rheumatoid arthritis (RA) report clinically meaningful pain, despite treatment with disease-modifying antirheumatic drugs (DMARDs). The prevalence of fibromyalgia, the prototypical centralized pain condition is 6-33% among RA patients, compared to 2-3% in the general population. In addition, we and others have shown that patients with RA, compared to healthy controls, have lower pressure pain thresholds in a widespread distribution, as well as abnormalities in other quantitative sensory testing (QST) measures of centralized pain. However, our ability to determine which patients will experience pain refractory to treatment is limited by our understanding of the mechanisms underlying RA-related pain centralization. There is a critical unmet need to elucidate these pathways and develop objective biomarkers to identify patients with pain centralization for enrollment into clinical trials. The objective of this high-risk, high-reward proposal is to generate cutting-edge insights into the relationship between peripheral blood mononuclear cells (PBMCs) and pain centralization in patients with RA. To test investigate potential immune biomarkers, we will use a two-step approach that leverages the capacity of: a) multi-parameter flow cytometry to discover associations between the immunophenotypic profiles of PBMCs and pain centralization and b) single-cell RNA-sequencing (scRNA-seq) to detect heterogeneity in gene expression among individual cells, with a particular interest in circulating monocytes. Our central hypothesis is that the composition and transcriptional heterogeneity of circulating immune cells will vary with centralized pain phenotype in RA patients. In Aim 1, we will determine the association between the immunophenotypic profile of PBMCs and pain centralization. We will enroll 50 RA patients with well-controlled joint inflammation but varying levels of systemic inflammation and pain to undergo QST to assess pain centralization and provide blood samples for flow cytometry. We will test whether pain centralization, assessed by pressure pain thresholds at the trapezius muscle, are associated with: a) the proportion of each cell type in circulation, and b) continuous measures of activation status for each cell type. In Aim 2, we will identify differences in the transcriptional heterogeneity of circulating PBMCs between patients with a centralized pain phenotype vs. those without a centralized pain phenotype. We will perform scRNA-seq on a subset of patients from Aim 1 with the highest (N = 10) and lowest (N = 10) levels of pain centralization. We will test whether for differences in transcriptional subpopulations and cell-type-specific gene expression between the two groups. Our proposal has high impact potential because, if successful, it will deliver novel insights into the role of circulating PBMCs in altered CNS pain regulation in patients with RA, the prototypical systemic inflammatory condition. Data from this proposal will be used to inform an R01 application to identify a reproducible peripheral blood biomarker for centralized pain in patients with RA.
|Effective start/end date||2/15/22 → 1/31/24|
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (5R21AR080351-02)
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