Rheumatoid Arthritis (RA) is the most common inflammatory joint disease, affecting up to 1% of the population. Biological Disease Modifying Anti-Rheumatic Drugs (DMARDs) used for treating RA patients might attenuate pain reducing synovial inflammation neutralizing proinflammatory cytokines. However, many patients treated with bDMARDs still report residual pain. Some of the cytokines orchestrating the immune dysregulation characterizing RA - interleukin (IL)6, IL1ß, IL17, Tumor Necrosis Factor (TNF) - are also involved in the nociception. Acting on Janus Kinases (JAK), JAK inhibitors (JAKi) modulate the intracellular signaling pathways of many pro and anti-inflammatory cytokines. The results of randomized clinical trials demonstrated a rapid effect on pain of all the JAKi currently approved for RA. Acting on more cytokine at a time, JAKi could affect the neuro-immune cross-talk, also modulating the nociception mechanisms.
Aim of the project is to determine how JAKi could impact neuro-immune cross-talk responsible for inflammatory pain in RA. Primary objective will be to define in vitro the role of the pro-inflammatory and vasoactive neuropeptide Calcitonine Gene Related Peptide (CGRP) as a possible mediator of the neuro-immune cross-talk in RA. We expect to give a mechanistic explanation of neuro-inflammatory pain in RA. To address this objective, we will assess the release of CGRP by nociceptor neurons and synovial fibroblast after stimulation with different cytokines involved in neuro-inflammation and the effect of JAKi in the cell systems. Further objective of the study will be to define the neuro-inflammatory component of pain in RA patients to outline the pain phenotype better responding to JAKi, supporting an explanation of the fast reduction of pain observed with JAKi compared with anti-cytokine therapies. To this aim, we will perform a 12-months, open-label trial on RA patients, to assess the effect of JAKi on pain and CGRP levels.
