Abstract
Recent advances in immunology enabled the characterization of several signal transmitting pathways responsible for proper cytokine and chemokine signaling. Among them, Janus kinases (JAKs) are essential components of receptor activation systems. The discovery of JAK kinases enabled the synthesis of JAK kinase inhibitors (JAKi or Jakinibs), which have proven to be efficacious in the treatment of hematologic malignancies and several rheumatological disorders and continue to be investigated in many clinical indications. Blocking multiple cytokines belonging to several cytokine families with a single small molecule may, however, create a potential risk for the patients. Recently, a higher risk of thromboembolic complications, namely, deep vein thrombosis and pulmonary embolism, has been recognized as the main concern during treatment with Jakinibs. At present, it is not entirely clear whether this increased risk is related to direct cytokine blockade, the presence of concomitant diseases in treated patients or other unknown circumstances that work together to increase the risk of this side effect. In this review, we discuss data on the risk of thromboembolic side effects, with special emphasis on the mechanism that may be responsible for this increased risk. Many indirect data indicate that higher thromboembolic risk may be related to the specificity of JAK inhibitor action, such that preferentially blocking one signaling pathway upsets the balance between pro and anti-thrombotic activities.
Highlights
Autoimmune diseases have various pathophysiological backgrounds characterized by the aberrant or defective immune response
Inhibition of Janus kinases (JAKs) should translate into reduction of both autoimmune diseases’ activity and reduction of prothrombotic risk. It is, unclear why patients treated with Jakinibs are at higher risk of developing thromboembolic side effects
The clinical situations where Jakinibs should be administered with caution included patients who have experienced previous thromboembolic episodes and those who are taking sex hormone therapy or who are at an advanced age
Summary
Autoimmune diseases have various pathophysiological backgrounds characterized by the aberrant or defective immune response. Following the introduction of tofacitinib (the first FDAapproved JAK inhibitor), several synthetic compounds with potential to block this pathway have been developed and intensively tested in various indications [9] This group of fully synthetic immune modulators is called JAK inhibitors (JAKi) or Jakinibs and offers the blockade of many cytokines with a single small molecule. The therapeutic approach based on the blockade of multiple cytokines and interferons may have many pathophysiological consequences as the role of the JAK/STAT pathway in the development of immune diseases has not been completely explained. This pathway is a key element of many mostly undercharacterized regulatory networks; real-world clinical data accumulation is essential. IFNλ associated JAKs (JAK1 and TYK2) may result in an imbalance in the pro- and anti-thrombotic signaling resulting in thrombus priming
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