Background/Purpose: Despite novel treatment strategies in rheumatoid arthritis (RA), approximately 20-30% of patients remain symptomatic. The EULAR definition of difficult-to-treat (D2T) RA has recently been published with significant contributions from our research group (1).Many causes can lead to D2T RA, such as degenerative alterations, psychosocial factors like stress and depression, and central nervous system (CNS) dysfunction, including neuroinflammation and subsequent central pain sensitization. Recent literature suggests that peripheral blood mononuclear cells (PBMCs) can reflect the pathophysiological mechanisms of the CNS. Our main goal was to compare the transcriptomic profiles of PBMCs from D2T RA patients and healthy controls (HC) to identify differences in molecules and signaling pathways to reveal the connection between pain and inflammation.

Methods: This study has been conducted in two centers. 14 D2T RA patients, meeting the 2021 EULAR definition for D2T RA, and 11 HCs were included in Pécs, and 34 D2T RA patients and 20 HCs in Budapest, the data analysis for this group is currently under evaluation. Patients were divided into different subgroups based on their inflammatory and pain parameters. Transcriptomic analysis was performed using total RNA isolated from PBMCs through next-generation sequencing, and the results were evaluated using bioinformatics tools. A clinical examination, including psychology and fMRI experiments, was also conducted.

Results: D2T RA patients exhibited several differentially expressed genes compared to HCs, primarily involved in immune cell migration, activation, cytokine- and chemokine-mediated signaling, and neuronal regulation. Thus far, we have identified 35 upregulated genes, including interleukin 15 (IL-15) and chemokine receptor 2 (CCR2), playing an essential role in maintaining inflammation, and Sortilin1, contributing to neuropathic pain. 28 downregulated genes were found, e.g. tumor necrosis factor alpha-induced protein 3, which controls inflammatory responses. Compared to those with high inflammation and low pain, the subgroup of D2T RA patients with high inflammation and high pain exhibited significant differences in their transcriptomic profiles, particularly in the involvement of Type I Interferon and Interferon-β response. The results of the D2T RA subgroup with high pain and low inflammatory parameters revealed potential pain-related genes, such as the cholesterol-phospholipid efflux protein ABCA1 and EIF2AK2 encoding a serine/threonine kinase. Clinical and fMRI results and their correlation with the transcriptomic data are currently under evaluation.

Conclusion: Our analysis revealed many differences in the transcriptomic profiles of different subgroups of D2T RA patients and HCs. Therefore, PBMC transcriptomics proved to be a useful tool for identifying differentially expressed genes associated with pathophysiological mechanisms involved in inflammatory processes and pain sensitization. Confirming hypotheses generated with this unbiased omics approach can facilitate the development of novel therapies.

(1) Nagy G et al. EULAR definition of difficult-to-treat rheumatoid arthritis Ann Rheum Dis 2021;80:31-35.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcriptomic-analysis-of-peripheral-blood-mononuclear-cells-reveals-pain-and-inflammation-specific-alterations-in-difficult-to-treat-rheumatoid-arthritis/