**1. Introduction**

Rheumatoid arthritis (RA) is the most common form of inflammatory polyarthropathies, affecting approximately 1% of the population worldwide. When the disease is not treated or treated insufficiently, it ultimately leads to permanent joint destruction, and subsequent disability [1]. In addition, as a member of systemic connective tissue diseases, RA is linked to an increased risk of internal organ involvements and systemic complications with premature atherosclerosis being the most important one. In the last two decades, significant therapeutic progress has been made and new therapeutic strategies implemented, resulting in better disease control and leading to a sustained remission or at least low disease activity. The new approach to RA treatment is based on the early introduction of synthetic disease-modifying antirheumatic drugs (DMARDs), mainly methotrexate (MTX), and is aimed to achieve remission or low disease activity. Unfortunately, only part of the patients responds well to such a treatment.

At the end of the last century, the therapeutic regimens for treating RA widened and new therapeutic strategies were implemented to the treatment repertoire. The new group of therapeutic molecules called biological DMARDs (bDMARDs) or simply biologics were introduced to the common clinical practice. The mode of action of biologics is based on blocking the inflammatory cytokines, depleting the population of antibody producing B-cells, and interfering in the co-stimulation of immunocompetent cells. This new approach revolutionized the treatment of RA. However, a substantial portion of patients still do not respond to such treatment. The limitation of these therapeutic strategies is the fact that biologics, which are high molecular weight compounds, are highly immunogenic and often produce adverse drug reactions such as tuberculosis, heart failure, neuropathies, and others [2–4]. Also of note is the fact that they are given parenterally, are expensive in manufacturing, and difficult to handle.

The progress made in immunology over the last 20 years contributed to the better understanding of the mechanisms of autoimmune diseases that translated directly to the development of new therapeutic approaches.

Among them, the Janus kinases/signal transducers and activators of transcription (JAK/STAT) pathway attracts high interest, and offers blockade of several cytokines with one small synthetic compound [5–8]. In line with the discovery of the JAK/STAT pathway, several synthetic compounds which are able to block this pathway have been developed [9]. This group of new synthetic DMARDs is called JAK inhibitors and indeed offer the blockade of many cytokines with one small compound (Table 1). Treatment with JAK inhibitors proven to be efficacious and relatively safe, and is recognized as equal and even superior to the conventional biologics [10]. This approach however may not be entirely free of risk of developing side effects. Blockade of several cytokines and interferons (IFNs) may bring many pathophysiological consequences as JAK/STAT pathway is deeply involved in several largely unknown regulatory networks and reduction of cytokine synthesis may contribute to the reduction of inflammatory process on one side in addition of dysregulating immune, cardiovascular, and nervous systems. As the example may serve tumor necrosis factor (TNF)-α inhibition that is responsible for worsening of the heart function in patients with congestive heart failure, lipid profile disturbances as the result of interleukin (IL)-6 inhibition, or increased risk of thromboembolism in the course of JAK inhibitor administration.

In this review, we tried to discuss the pathophysiological mechanism that may explain adverse drug reactions in the cardiovascular system during treatment with JAK inhibitors. Special emphasis was put on the role of cytokines blocked during the treatment with JAK inhibitors and their pathophysiological impacts on the functioning of the cardiovascular system.


**Table 1.** Currently available classes of disease-modifying antirheumatic drugs (DMARDs).


T-lymphocyte-associated protein.

**Table 1.** *Cont.*
