Pain, fatigue, and physical activity are major determinants of life quality in rheumatoid arthritis (RA). Janus kinase (JAK) inhibitors have emerged as effective medications in RA and have been reported to exert direct analgesic effect in addition to reducing joint inflammation. This analysis aims to give an extensive summary of JAK inhibitors especially focusing on pain and patient reported outcomes (PRO). MEDLINE, CENTRAL, Embase, Scopus, and Web of Science databases were searched on the 26 October 2020, and 50 randomized controlled trials including 24,135 adult patients with active RA met the inclusion criteria. JAK inhibitors yielded significantly better results in all 36 outcomes compared to placebo. JAK monotherapy proved to be more effective than methotrexate in 9 out of 11 efficacy outcomes. In comparison to biological disease-modifying antirheumatic drugs, JAK inhibitors show statistical superiority in 13 of the 19 efficacy outcomes. Analgesic effect determined using the visual analogue scale and American College of Rheumatology (ACR) 20/50/70 response rates was significantly greater in the JAK group in all comparisons, and no significant difference regarding safety could be explored. This meta-analysis gives a comprehensive overview of JAK inhibitors and provides evidence for their superiority in improving PROs and disease activity indices in RA.

Difficult-to-treat (D2T) rheumatoid arthritis (RA) remains a major clinical challenge, affecting a significant proportion of patients who experience persistent symptoms despite multiple therapeutic regimens. This narrative review provides a comprehensive overview of potential molecular and cellular mechanisms that may underlie the D2T RA phenotype. We synthesize evidence across a broad biological landscape—the role of genetic and epigenetic factors, autoantibodies, and diverse immune cell subsets is detailed in the context of therapeutic resistance. Furthermore, we examine the potential role of synovial signatures and stromal cell-mediated pathways, which may drive chronicity independently of traditional immune targets. The review highlights the complex interplay of peripheral and central determinants that contribute to patient-reported outcomes such as pain. We also discuss comorbid conditions, environmental factors such as smoking and nutrition, and treatment-related factors relevant to the D2T population. By integrating these aspects, this work aims to facilitate better stratification and the identification of novel therapeutic targets for refractory disease.

Patients with RA often require alterations of their therapeutic regimen throughout the course of their illness, guided by specific outcomes in line with the treat-to-target principle. Importantly, a significant portion of the RA population fails to achieve sufficient disease control in the long term. Several years ago, the umbrella notion of difficult-to-treat (D2T) RA was introduced to facilitate more structured care and research efforts for patients who remain symptomatic despite having received multiple courses of targeted medications. D2T RA represents a heterogeneous condition sustained by a complex interplay of underlying factors. Biological therapies and Janus kinase inhibitors have demonstrated efficacy in alleviating disease activity in patients refractory to conventional treatments. The use of tailored non-pharmacological therapies (physiotherapy, psychological interventions, etc.) to complement pharmacotherapy chiefly addresses symptoms unrelated to ongoing inflammation. In this narrative review, we examine the current use and relevance of pharmacological and non-pharmacological approaches for D2T RA.