Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

Abstract

In recent years, the landscape of pro- and anti-inflammatory cytokines has rapidly expanded with the identification of new members proven to be involved at different extent in the pathogenesis of chronic immune mediated inflammatory diseases including rheumatoid arthritis (RA). The advance of our understanding of mediators involved in the pathogenesis of RA and in consequence, the development of novel targeted therapies is necessary to provide patients not responding to currently available strategies with novel compounds. The aim of this review article is to provide an overview on recently identified cytokines, emphasizing their pathogenic role and therapeutic potential in RA. A systematic literature review was performed to retrieve articles related to every cytokine discussed in the review. In some cases, evidence from animal models and RA patients is already consistent to move forward into drug development. In others, conflicting observation and the paucity of data require further investigations.Forty years after the discovery of IL-1, the landscape of cytokines is continuously expanding with increasing possibilities to develop novel therapeutic strategies in RA. Electronic supplementary material The online version of this article (10.1186/s41927-017-0001-8) contains supplementary material, which is available to authorized users.

Exposure–Response Analyses for Upadacitinib Efficacy and Safety in the Crohn's Disease CELEST Study and Bridging to the Extended‐Release Formulation

“…17 This difference between the optimal dose needed for the different immune diseases can possibly be driven by the inflammatory burden and different primary sites of inflammation among diseases as well as the cytokines involved; IL-17, IL-23, and IL-32 are upregulated in CD, whereas in RA, TNF-α, IL-1, IL-6, IL-12, and IL-17 seem to be key cytokines involved in the inflammatory process. 41,42 There were no meaningful differences in the predicted clinical outcomes between weeks 12 and 16, indicating that a treatment duration of 12 weeks with upadacitinib would be sufficient to assess induction of remission in CD. Of note, another JAK inhibitor (tofacitinib, targeting JAK3 > JAK1 > JAK2) did not demonstrate efficacy in two phase II studies in patients with CD, although it is efficacious in the treatment of RA; however, relatively high placebo responses in these studies may have contributed to the lack of difference between treatment arms and placebo.…”

“…was also demonstrated in subjects with moderate‐to‐severe ulcerative colitis . This difference between the optimal dose needed for the different immune diseases can possibly be driven by the inflammatory burden and different primary sites of inflammation among diseases as well as the cytokines involved; IL‐17, IL‐23, and IL‐32 are upregulated in CD, whereas in RA, TNF‐α, IL‐1, IL‐6, IL‐12, and IL‐17 seem to be key cytokines involved in the inflammatory process . There were no meaningful differences in the predicted clinical outcomes between weeks 12 and 16, indicating that a treatment duration of 12 weeks with upadacitinib would be sufficient to assess induction of remission in CD.…”

“…Filgotinib, another JAK inhibitor more selective than tofacitinib for JAK1 has shown efficacy in CD . Therefore, it is possible that given the differential involvement of various cytokines in the pathophysiology of different autoimmune disease, some JAK inhibitors with different selectivity profiles may be efficacious in one disease but not in the other . Moreover, efficacious exposures of the same drug can vary among autoimmune diseases, as observed with upadacitinib in the CELEST study as well as with biologic therapies …”

“…45 Therefore, it is possible that given the differential involvement of various cytokines in the pathophysiology of different autoimmune disease, some JAK inhibitors with different selectivity profiles may be efficacious in one disease but not in the other. 41,42,46 Moreover, efficacious exposures of the same drug can vary among autoimmune diseases, as observed with upadacitinib in the CELEST study as well as with biologic therapies. 47 In conclusion, the percentage of subjects achieving different clinical and endoscopic end points in patients with CD evaluated during the CELEST phase II trial induction period increased with increasing upadacitinib plasma exposures.…”

Interleukin 6 Metabolism and Functional Kidney Status in Early Rheumatoid Arthritis

“…В інших випадках відзначені суперечливі результати і брак даних. Виходячи з цього, вкрай необхідним є подальше вивчення нових медіаторів, що беруть участь в патогенезі РА, з метою виявлення нових цільових методів лікування пацієнтів з цим захворюванням [13].…”