Thromboembolic Adverse Drug Reactions in Janus Kinase (JAK) Inhibitors: Does the Inhibitor Specificity Play a Role?

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.

Keywords: JAK kinase inhibitor; JAK/STAT pathway; deep vein thrombosis; prothrombotic effect; venous thromboembolism.

Figure 1

Possible mechanism for the prothrombotic effects associated with the administration of Jakinibs. JAKs in various combinations bind to cytokine receptors that transmit prothrombotic and proinflammatory signals from a wide range of cytokines. With the exception of IL-10, IFNβ and IFNλ that exert anti-thrombotic potential, signaling downstream of these cytokines creates a permissive background for thrombus formation. Non-specific Jakinibs that target both of the IL-10R-associated JAKs (JAK1 and TYK2) or IFNβ and IFNλ associated JAKs (JAK1 and TYK2) may result in an imbalance in the pro- and anti-thrombotic signaling resulting in thrombus priming.

Figure 2

Diverse role of cytokines in thrombus formation. Cytokines belonging to the IL-10 family exert different functions; the three anti-inflammatory cytokines (IL-10, IL-19, IL-22) exert anti-thrombotic potential whilst other cytokines in family (namely IL-20, IL-24, IL-26) show strong proinflammatory activity. These pro and anti-inflammatory activities are transmitted via different JAK pairings; JAK1/TYK2 and JAK1/JAK2 for pro and anti-thrombotic activity respectively. Targeted inhibition of a given JAK can thus either block or augment the prothrombotic activity. Proinflammatory cytokines from the IL6 and IL-12 families also signal through JAK1, JAK2 and TYK2, thus administration of Jakinibs may block pro-inflammatory (pro-thrombotic) signals downstream of these cytokines. The more diverse type of signaling is observed in IFN family. IFN-α and IFN-γ exert strong proinflammatory potential, while IFN-β and IFN-λ show anti-inflammatory activity. Among all four types of INFs only IFN-γ is signaling via JAK1/JAK2 pair The remaining ones utilize JAK1/TYK2 pair. This shows that type of signaling (pro or anti-inflammatory) is unrelated to JAK composition, but the clinical effect depends on the extent to which the pro- and anti-inflammatory pathways are blocked by any particular Jakinib.

Figure 3

Pro and anti-thrombotic activities of cytokines. Cytokines which signal through the common gamma chain receptor family, and hematopoietins (TPO, EPO and G-CSF) transmit proinflammatory and prothrombotic signals resulting in higher expression of adhesion molecules, vascular wall inflammation and platelet synthesis, which promote thrombus formation. IL-4 and IL-13 are involved in the humoral response, antibody synthesis and lymphocyte polarization toward the Th2 response, thus playing anti-inflammatory roles. Multiple cytokines signal via the same JAK, thus blocking any single JAK may simultaneously inhibit transmission of multiple pro- and anti-thrombotic signals. TPO, thrombopoietin; EPO, erythropoietin; G-CSF, granulocyte-colony stimulating factor.