To the best of our knowledge, this is the first study investigating the effect of treatment with JAK inhibitors on coronary microvascular function in patients with RA. Although preliminary, results of the present study do not support a significant impact of JAK inhibition on myocardial perfusion in treated patients with RA. Importantly, the study population presented with a cluster of cardiovascular risk factors (age ≥ 65 years, history of current or past smoking, other cardiovascular risk factors such as diabetes, obesity, hypertension), which would have rendered them more vulnerable to adverse cardiovascular effects according to the EULAR recommendations and EMA safety warnings. The present study findings further imply that potential cardiovascular aspects of JAK inhibition may be elicited through other mechanisms directly or indirectly affecting the cardiovascular system, rather than directly affecting coronary blood flow [12].

Despite credible safety concerns raised from the ORAL surveillance study [2], the impact of JAK inhibition on cardiovascular health in treated patients with RA remains under investigation. A meta-analysis of pooled data from a total of 215,278 patients revealed no statistically significant difference for major adverse cardiovascular events [15]. Likewise, recent real-world data appear rather reassuring with cardiovascular outcomes largely dependent on the accumulation of cardiovascular risk factors [16, 17, 18]. Concordantly, in a nationwide cohort study of 4,230 RA patients without baseline cardiovascular disease, JAK inhibitors were not associated with the occurrence of major adverse cardiovascular events compared to biological DMARDs [19]. Increasing evidence from real-world prospective studies and narrative literature reviews consistently points to a null impact of JAK inhibitors on the cardiovascular system at least among individuals without exaggerated cardiovascular risk at baseline, as some cardiovascular metabolic factors are increased while others are decreased following treatment with JAK inhibitors [20, 21].

Results from cohort studies highlight the significant role of coronary microvascular dysfunction as a potential contributor to increased cardiovascular risk and mortality in RA, similar to what has been observed in diabetes mellitus. They also provide evidence of a mechanistic connection between inflammation and cardiovascular disease [22]. Increasing evidence indicates that RA patients without clinically evident coronary microvascular dysfunction exhibit more pronounced endothelial dysfunction compared to matched non-RA controls, even in the early stages of the disease [23]. In another RA cohort with a low prevalence of cardiovascular risk factors, nearly half of the participants exhibited coronary microvascular dysfunction at baseline. While reduction of inflammation was not associated with improved myocardial flow reserve, a modest decrease in interleukin-1b, without involvement of other inflammatory pathways, was linked to a reduction in asymptomatic myocardial injury [24]. Sophisticated immunosuppressive treatments, including JAK inhibitors, may help sustain vascular function by reducing inflammation. Findings from basic research suggest that JAK inhibition may help preserve cardiovascular function to some extent by suppressing vascular inflammation [25]. Remarkably, the JAK/STAT pathway has been implicated in the pathogenesis of atherosclerosis, with a causal role of its downstream signaling factors in this process [26].

By contrast, studies assessing in vivo vascular effects of JAK inhibitors in patients with RA remain to date extremely limited. As previously published in the same group of patients as of this study, three months’ treatment with JAK inhibitors may induce significant alterations in microvascular capillaroscopic parameters, whereas markers of macrovascular function and morphology, i.e. arterial stiffness and carotid atherosclerosis, remained largely unaffected [12]. Consistent with these results, one-year tofacitinib treatment did not affect arterial stiffness in a larger cohort of 30 RA individuals. Although JAK inhibition effectively suppressed systemic inflammation and improved functional status, robust markers of endothelial function (flow-mediated dilation and asymmetric dimethylarginine) remained unchanged and further increases in carotid intima-media thickness were observed at follow-up [27]. Our study adds to the existing literature by suggesting that myocardial perfusion remains unaltered during treatment with JAK inhibitors in patients with RA. Unless further clinical investigation provides a better understanding of underlying mechanisms, cardiovascular manifestations of JAK inhibitors will remain controversial.

Strengths of the present study include its prospective design and a solid methodological approach using a widely applied, noninvasive index of myocardial perfusion. The study is limited by the absence of a control group and the small sample size, which does not allow for appropriate adjustment for potential confounders, such as disease activity and inflammation, that may interfere with SEVR values as previously shown [10]. In addition, a larger population might have been able to reveal statistically significant differences in SEVR. As follow-up was limited to three months, long-term cardiac effects of JAK inhibitors were not assessed. It is possible that treatment with JAK inhibitors, or any other drug, requires a prolonged period of treatment to induce significant changes in SEVR. In a previous study of 31 patients with RA emerging from a primary cohort who were about to start anti-inflammatory treatment, SEVR did not change over a follow-up period of 12 months [10]. Hence, results of the present study may be considered as preliminary unless verified from larger studies.

In conclusion, three-month treatment with JAK inhibitors did not affect coronary microvascular blood flow in the present cohort of RA patients, as captured non-invasively in vivo with SEVR. Future studies are warranted to clarify whether treatment with JAK inhibitors exerts any direct or indirect cardiac effects in patients with RA, specify the duration of treatment potentially associated with such effects, and clearly define the profile of patients who are mostly at risk.