Saturday 24 October
Virtual Lunch Symposium
Prospects for JAK inhibitors in the treatment of rheumatoid arthritis
Presentation 1: Mechanisms of action of JAK inhibitors in rheumatoid arthritis
It has been 8 years since the first JAK inhibitor (JAKi), tofacitinib, came to be used in clinics. Now we have 4 JAKi with another possibly approved in the near future. JAK inhibitors are low-molecular-weight compounds, which exert anti-rheumatic effects by suppressing the action of JAK, an intracellular tyrosine kinase. Of note, biologics bind to extracellular proteins and block their activity. The availability of JAK inhibitors that are as effective as bDMARDs, despite the completely different route of administration and mode of action, has enabled the treatment of rheumatoid arthritis to enter a new stage. I will discuss the modes of actions of JAK inhibitors in this seminar.
JAKs are tyrosine kinases within cells. When a type I or type II cytokine binds with its receptors, JAKs are activated to in turn activate STAT molecules, and activated STATs translocate to the nucleus to work as a transcription factor. JAKi is an oral drug with low molecular weight and inhibits the kinase activity of JAKs. At cellular levels, JAKi have anti-rheumatic effects on various type of cells, including synovial fibroblast, macrophages, and lymphocytes. Interestingly, even the outcomes of stimulation by TNFα, LPS, or anti-CD3 are also blocked by JAKi. This is because these stimulations induce endogenous type I or type II cytokines such as IFNα or LIF, which lead to various outcomes, and JAKi shut down of the autocrine loops of these cytokines.
Recently it is reported that various immune cells are involved in synovitis, and both inflammatory responses and IFN signature seem to play significant roles. The characteristics of JAKi is that they inhibit actions of multiple cytokines compared to the bDMARDs which specifically inhibits single cytokine.
Clinical efficacy of JAKi is equivalent to that of biologics in general. JAKi are effective in various patients including DNARD-IR, MTX-IR, TNFi-IR and DMARD-naïve cases. The clinical responses are relatively quick. Recently patient reported outcome (PRO) has become one of main topics in RA treatment since JAKi has proven to improve PRO, in particular, pain and fatigue. At the same time JAKi is also ascribed to their adverse actions such as herpes zoster, hyperlipidemia and so on. Higher incidence of herpes zoster is reported, in particular, in Japan and Korea.
From the long-term experiences, JAKi is now placed in the same position to bDMARDs in the EULAR guideline of treatment of RA. We need to understand the mode of action, efficacy and adverse events of JAKi, and use them appropriately.
Presentation 2: Musculoskeletal ultrasound in treatment for rheumatoid arthritis with molecular targeting drugs
Musculoskeletal ultrasound visualizes synovial/tenosynovial inflammation and bone erosion, characteristic pathological features of rheumatoid arthritis (RA), more accurately than clinical examination and radiograph. Interestingly, however, extraarticular lesions such as tenosynovitis and peritendinitis have recently been reported to be one of the earliest pathologies detected by imaging in patients with clinically suspected arthralgia who subsequently develop arthritis and RA.
Ultrasound also helps rheumatologists to determine indication for the use of molecular targeted drugs by confirming or excluding the presence of inflammation. Furthermore, ultrasound is expected to guide tapering and discontinuation of molecular targeted drugs, which will improve the cost/safety-benefit balance of treatment of RA.