Clinical Aspects of Janus Kinase (JAK) Inhibitors in the Cardiovascular System in Patients with Rheumatoid Arthritis

Abstract

Janus kinase (JAK) inhibitors, a novel class of targeted synthetic disease-modifying antirheumatic drugs (DMARDs), have shown their safety and efficacy in rheumatoid arthritis (RA) and are being intensively tested in other autoimmune and inflammatory disorders. Targeting several cytokines with a single small compound leads to blocking the physiological response of hundreds of genes, thereby providing the background to stabilize the immune response. Unfortunately, blocking many cytokines with a single drug may also bring some negative consequences. In this review, we focused on the activity of JAK inhibitors in the cardiovascular system of patients with RA. Special emphasis was put on the modification of heart performance, progression of atherosclerosis, lipid profile disturbance, and risk of thromboembolic complications. We also discussed potential pathophysiological mechanisms that may be responsible for such JAK inhibitor-associated side effects.

Keywords: JAK/STAT; Janus kinase inhibitors; cardiovascular system; cytokines; heart failure; lipid profile disturbances; rheumatoid arthritis; thromboembolic.

Figure 1

Several cytokine families utilize type I receptors. Receptors with gp130 component transmits signals from IL-6, IL-11, and IL-27 with subsequent activation of JAK1-JAK2 and TYK2 molecules. Cytokines activate (mainly IL-6) heart survival pathway resulting in stabilization of the heart function in ischemia/reperfusion conditions. The same pathway contributes however in deterioration of heart function and increases the risk of major adverse cardiovascular events (MACE), leading to heart fibrosis with subsequent development of heart failure. Cytokines IL-12 and IL-23 that interact with p40 receptor component transmit signals via activation of JAK2 and TYK2 molecules resulting in cardiomyocytes apoptosis. Moreover IL-12 facilitates IL-17 overexpression leading to myocardial/reperfusion injury. Blocking JAK/STAT pathway with JAK inhibitors may therefore result in blocking the heart failure survival pathway but also may reduce MACE incidence and fibrosis of the heart. Blocking of JAK/STAT pathway (mainly IL-6 mediated arm) is also responsible for unfavorable lipids profile changes mediated by reduced LDL catabolism, but this effect may be ameliorated by reduced expression of scavenger receptor class B and ATP-binding cassette G-1. Leading to improvement of lipid composition. Several pathological conditions upregulate JAK/STAT pathway activity (hyperglycemia, reactive oxygen species formation, and angiotensin II) facilitating transmission signals from proinflammatory cytokines.

Figure 2

JAK inhibitors targeting JAKs of type I and II receptors. Based on cytokine profile inhibition of JAK/STAT pathway, diverse biological consequences are observed. Inhibition of JAK attached to γ-chain receptor resulting either in beneficial (blocking IL-15, high concentration mediated IL-2 transmission) or detrimental (inhibition of beneficial activity of low IL-2-impaired tissue healing and repair). Inhibition of JAK fused with gp130 receptor reduces IL-6 level. Based on the pathophysiological circumstances, reduced level of IL-6 may contribute to the reduction of heart survival pathway activity or favorably modify heart failure pathway. As far as IL-12 operating via p40 receptor subunit is concerned, inhibition of JAK results in reduction of IL-12-mediated signaling and exerts favorable effects on the cardiovascular system halting progression of atherosclerosis, reducing risk of developing ischemic cardiomyopathy, and myocardial fibrosis. Inhibition of JAK/STAT system transmitting signal from interferon receptor results in reduction of activity of IFN-dependent genes that translates directly to the reduction of foam cell formation and halting progression of atherosclerosis. Finally, some negative consequences may arise as the result of erythropoietin blockade with subsequent anemia development (indirectly contributing to worsening of heart function).

Figure 3

Interferons after ligating to type II receptors activate JAK/STAT pathway resulting in foam cells formation leading directly to atherosclerosis development. That same pathway that transmits signals from interferons contributes to reduced expression of the liver X receptor and decrease synthesis of ATP-binding cassette transporter leading to pro-atherosclerotic lipid composition.