JAK/STAT pathway and nociceptive cytokine signalling in rheumatoid arthritis and psoriatic arthritis

The key role of pro-inflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) is strongly supported by the observation that their blockage is effective in the treatment of these diseases. Indeed, blockade of cytokine signal transduction mechanisms, including the JAK-STAT pathway, may be critical in the treatment of RA and PsA. The Janus kinase (JAK) inhibitors tofacitinib and baricitinib target JAKs with high potency and have a well-established rationale for clinical therapeutic use in RA and PsA by affecting multiple cytokines involved in both development and propagation of the disease. Nociceptive responses are also important to consider in the treatment RA and PsA. In this regard, cytokines have also been implicated in modulation of pain and nociception and the JAK/STAT pathway is receiving increasing attention in modulation of nociceptive responses given to its clear role in cytokine signalling. Therefore, inhibition of JAK/STAT pathway with specific JAK inhibitors has the potential to modulate pain in patients with RA and PsA. Data from randomised controlled trials and real-world settings on large numbers of patients with RA (tofacitinib and baricitinib) and randomised controlled trials in patients with PsA (tofacitinib) have shown that a rapid effect on the pain component in these diseases is observed. Thus, it can be hypothesised that JAK inhibitors may have a dual therapeutic role by modulating inflammation and nociception, which leads to clinical benefits including reduction of pain beyond that related to inflammation. The present review will overview the impact of pain in patients with rheumatic disease and the physiological basis of modulating nociceptive pain. Current knowledge about the role of cytokines in mediation of pain and the involvement of the JAK/STAT pathway in modulating nociceptive responses will then be summarised, followed by an analysis of clinical data on pain modulation by JAK inhibitors in the treatment of RA and PsA.