Novel Therapeutic Approaches in Rheumatoid Arthritis: Role of Janus Kinases Inhibitors

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and several systemic features. Cardiovascular, pulmonary, psychological, and muscle involvement are the main comorbidities of RA and are responsible for the severity of the disease and long-term prognosis. Pharmacological treatment of rheumatic diseases has evolved remarkably over the past years. In addition, the widespread adoption of treat to target and tight control strategies has led to a substantial improvement of outcomes, so that drug-free remission is nowadays a realistic goal in the treatment of RA. However, despite the availability of multiple therapeutic options, up to 40% of patients do not respond to current treatments, including biologics. Small-molecule therapies offer an alternative to biological therapies for the treatment of inflammatory diseases. In the past 5 years, a number of small-molecule compounds targeting Janus Kinases (JAKs) have been developed. Since JAKs are essential for cell signaling in immune cells, in particular controlling the response to many cytokines, their inhibitors quickly became a promising class of oral therapeutics that proved effective in the treatment of RA. Tofacitinib is the first Janus Kinase (JAK) inhibitor approved for the treatment of RA, followed more recently by baricitinib. Several other JAK inhibitors, are currently being tested in phase II and III trials for the treatment of a different autoimmune diseases. Most of these compounds exhibit an overall acceptable safety profile similar to that of biologic agents, with infections being the most frequent adverse event. Apart from tofacitinib, safety data on other JAK inhibitors are still limited. Long-term follow-up and further research are needed to evaluate the general safety profile and the global risk of malignancy of these small molecules, although no clear association with malignancy has been reported to date. Here, we will review the main characteristics of JAK inhibitors, including details on their molecular targets and on the clinical evidences obtained so far in the treatment of RA.