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.
Pain is one of the more disabling symptoms of RA - other inflammatory musculoskeletal diseases - and it is the main domain of RA activity needing to be improved to reflect the disease remission.
Pain has a great impact on wellbeing, daily life activities, and workability: pain compromises the quality of life.
Commonly, RA-related pain has been merely considered the direct result of synovial inflammation; however, even when the disease seems well controlled by the treatment, many patients still report clinically meaningful residual pain. Indeed, pain is actually mediated by inflammatory and non-inflammatory mechanisms.
JAK/STAT pathway contirbutes both to inflammation and, to some extent, nociception. The expression of multiple cytokine receptors on sensory neurons, most of which are coupled with JAKs, suggest that targeting multiple cytokines could contribute on pain modulation. Supporting this hypotesis, clincal trials have demonstrated a fast effect of JAKi on patient reported outcomes, including pain evaluation. However, there are no direct evidence confirming the neuromodulatory effect of JAKi.
The central role of CGRP in the cross-talk between the immune system and inflammation is the starting point of the project.
Plasma and synovial fluid levels of the neuropeptide CRPG seem to be correlated with pain levels in different painful conditions, regardless of the etiology of pain; CGRP levels were also correlated with pruritus - another condition linked to altered nociception for which JAK inhibitors have been shown to be effective. Thus, CGRP could be considered a biomarker of neuroinflammatory pain. To date, there are no data on change of CGRP plasma levels after any pharmacological intervention for pain other than migraine except for a clinical trial on abdominal pain in ulcerative colitis, currently ongoing.
With our results, we expect to give a mechanistic explanation of neuro-inflammatory pain in RA, highlighting how targeting many nociceptive cytokines at a time with JAK inhibitors could represent a valuable therapeutic option. The clinical trial will outline the pain phenotype of RA patients better responding to JAK inhibitors, supporting an explanation for the fast reduction of pain observed with JAK inhibitors (as already reported in randomized clinical trials and observed in real life patients) compared with anti-cytokine therapies. At tissue levels, CGRP-positive sensory neurons are widely expressed, suggesting that the benefit of modulating the neuro-immune interplay through JAK inhibitors is not restricted to RA but also other conditions characterized by inflammatory and nociceptive pain could take advantage of this therapy.
The effect of JAKi on CGRP release evoked by different cytokines using JAK heterodimers for their signal transduction within the neuro-immune cross-talk explores the advantage of inhibiting a network signaling system instead of a single cytokine-dependent cascade. By the experimental in vitro design proposed in this project, we will evaluate the contribution of single cytokine (and related signal path) exerting specific different effects. Indeed, the anti-inflammatory cytokine IL-4 (for its ability to sensitizes neurons in chronic itch, supported by the effect of a JAK inhibitor - tofacitinib - on idiopathic itch) and the pro-inflammatory IL-6 and IFN-gamma will be tested.
The benefit of modulating the neuro-immune interplay through JAK inhibitors is not restricted to RA since other diseases characterized by inflammatory and nociceptive pain - associated to other inflammatory conditions but also neoplastic pain - could take advantage by the results of this study.