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.