JAK Inhibitors and Cardiovascular Disease in Psoriatic Arthritis: Friends or Foe?

Psoriatic arthritis (PsA) is a heterogeneous autoimmune, inflammatory disease, with inflammatory skin, articular and extra-musculoskeletal involvement, [1, 2]. PsA occurs in about one-third of psoriasis patients [3]. Dysregulation of several molecules, including proinflammatory interleukins (ILs), interferons (IFNs), growth factors, and colony-stimulating factors (CSF) act as ligands for receptors connected to intracytoplasmic Janus kinases (JAKs). Consequently, JAKs activate signal transducer and activator of transcription (STAT) proteins, which translocate to the nucleus and induce the expression of inflammatory nuclear factor. The JAK/STAT pathways play a central role in the development and pathogenesis of PsA [4, 5]. Several studies have reported increased activation of JAK1/STAT3/STAT1, which may contribute to the articular inflammatory process characterized by the expansion of Th17 effector cells in the synovial fluid of patients with active PsA [6, 7]. By targeting these JAK/STAT pathways, JAK inhibitors effectively reduce inflammatory responses [7-9].

JAK inhibitors, including tofacitinib and upadacitinib, effectively target these pathways to reduce inflammation and improve symptoms in PsA patients. However, emerging evidence has raised concerns regarding the cardiovascular (CV) risks associated with JAK inhibitors. Both clinical trials and post-marketing surveillance have reported higher incidences of thromboembolism and other CV events in patients using these therapies, particularly at higher doses. Given the growing use of JAK inhibitors in PsA management, understanding the underlying mechanisms of CV risk is crucial for optimizing patient safety.

Since the publication of the Oral Surveillance Study [10], the use of JAK inhibitors has raised concerns regarding the potential increased risk of CV disease (CVD) in PsA patients. All known cytokines and chemokines create a unique network of self-interactions, activation and regulatory loops. Theoretically, inhibition of JAK should translate into reduction of both autoimmune diseases' activity and reduction of prothrombotic risk. However, JAK inhibitors are less specific than biologics due to the inherent redundancy of the JAK/STAT pathway and therefore may display an increase in off-target effects, which may be related to the association of increased Major Adverse Cardiovascular Events (MACE) and Venous Thromboembolism (VTE) observed [11].

The etiology of thrombotic tendency in PsA may also be linked to other mechanisms and causal factors, including antiphospholipid antibodies, hyperhomocysteinemia, and inflammation. 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 JAK inhibitor 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 [12]. This may explain why Baricitinib (JAK1/2) had higher thromboembolism risk compared to others.

On the other hand, atherosclerosis may be the major contributor to MACE in JAK inhibitor users. JAK/STAT signaling pathways have been indicated to play their part in atherosclerosis. The circulating levels of interleukin (IL)-6, IL-1beta and TNF-alpha were decreased by ruxolitinib (a specific JAK1/2 inhibitor, as compared to the animals left untreated [13]) as well, whereas IL-10 and IL-17 were increased. This was probably due to the inactivation of JAK2/STAT3 pathway, which has been previously indicated to contribute to the development and progression of atherosclerosis [14]. Whereas therapeutic interventions targeting JAK1/3 (tofacitinib) and JAK1/2 (baricitinib) may exert anti-atherogenic effects, at least in vitro and in animal models of atherosclerosis. At the moment, it is, therefore, unclear why patients treated with JAK inhibitor are at higher risk of developing MACE and VTE, further studies are needed to confirm the mechanisms in human.

The cardiovascular safety of other therapies like TNF or IL-17 inhibitors seems to be acceptable. One analysis of 4399 guselkumab-treated patients with psoriatic disease, guselkumab had a favorable adverse event (AE) profile, including MACE [15]. Also, IL-17 inhibitor use is not correlated with a change in MACE risk in patients with PsO/PsA who previously did not receive biologic disease-modifying anti-rheumatic drugs [16]. Moreover, no substantially different risk of incident AF or MACE after initiation of ustekinumab versus TNFi was observed in patients with psoriasis or PsA.

When comparing JAK inhibitor with other therapies, JAK inhibitor also showed to be acceptable regarding the CVD risk. For PsA patients, one meta-analysis confirmed that no significant difference was observed in MACE incidences in patients receiving anti-TNF, anti-IL12/23, anti-IL23 or anti-IL17 agents in comparison to the placebo [17]. For patients with chronic immune-mediated inflammatory diseases (IMIDs), one meta-analysis of phase 3 dermatology RCTs showed oral and topical JAK inhibitors (short-term) used to treat of the skin, did not elevate the risk of MACE or VTE compared with placebo or active comparator (other therapies like TNF or IL-17 inhibitors) [18]. Another network meta-analysis showed that TNF inhibitor, JAK inhibitors, and anti-IL12/23 antibodies were associated with increased risk of MACE compared with placebo, without any significant difference between these medication classes or when used in the various underlying IMIDs [19]. Moreover, real-world evidence also suggesting the safety of JAK inhibitor is favorable in PsA patients [20, 21]. It suggested that the increased risk of VTE in PsA patients appears to be related to the underlying comorbidities and not independently associated with PsA [22].

However, long-term studies of Tofacitinib and Upadacitinib have reported cases of heart attacks, strokes, MACE, and thromboembolic events (TE) among users [23, 24]. There is also a dose dependent variation in CVD risk, for example, Tofacitinib 10 mg twice daily has increased risk than 5 mg twice daily [25]. Additionally, there is an increased frequency of comorbidities such as hypertension, diabetes, dyslipidemia, obesity, metabolic syndrome, and other cardiovascular manifestations in PsA patients [2, 26, 27]. These findings highlight the need for clinicians to carefully assess the risk–benefit ratios and guide clinical decisions when administering JAK inhibitors to PsA patients.

Tofacitinib and upadacitinib are currently approved JAK inhibitors in the treatment of PsA patients. Tofacitinib is a pan-JAK inhibitor that effectively blocks JAK1 and JAK3. Two double-blind, OPAL Broaden [28] trial and OPAL Beyond [29] trial as well as a long-term extension analysis up to 48 months (OPAL balance trial) [30] had reported an acceptable safety profile of tofacitinib in PsA patients. Real-word data also confirmed the safety of tofacitinib [20]. Upadacitinib is a selective oral inhibitor of JAK1 and, to a lesser extent, JAK2. Two main phase III trials (SELECT-PsA 1 and SELECT-PsA 2) have shown an acceptable safety profile of this agent comparable to adalimumab. Rates of MACE and TE were similar across groups [31, 32]. Likewise, long-term observation indicated similar rate of MACE between upadacitinib and adalimumab groups [33, 34]. Currently investigational JAK inhibitors evaluated in PsA include filgotinib and two tyrosine kinase 2 (TYK2) Inhibitors (deucravacitinib and brepocitinib). Filgotinib is a selective JAK1 inhibitor with minimal JAK2 selectivity. A phase II trial placebo-controlled RCT (EQUATOR trial) showed no statistical significance in MACE and TE [35], even in the long-term extension study with 100-week data [36]. Recent results from a phase III RCT with randomization of active PsA patients [37] also demonstrated deucravacitinib was generally well tolerated, no cases of thromboembolic events were verified. As for brepocitinib, another phase IIb RCT showed no major adverse cardiovascular events, venous thromboembolic events occurred at Week 52 [38].

Currently, the use of JAK inhibitors is recommended only in the absence of adequate therapeutic alternatives, in patients over 65 years of age and in those at increased risk of MACE or cancer, in patients with risk factors for venous thromboembolism (VTE) and in those who smoke or have smoked [39, 40]. However, abovementioned recent trials and real-world data showed acceptable safety profile of JAK inhibitors. The latest EULAR recommendation indicated the use of JAK inhibitors is proposed primarily after biological disease-modifying anti-rheumatic drugs (bDMARDs) failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. In this context, for the licensed JAK inhibitors, it is expected that for some PsA patients whose CV risk is low (estimated 10-year CVD risk of < 10% according to established guideline [41]), JAK inhibitors may be the first choice for these patients or those prefer oral therapy.

The association between PsA and CVD comorbidities is attributed to the shared inflammatory pathways [42]. Effective control of inflammation using an appropriate DMARD, including the use of a JAK inhibitors, is of paramount importance, not only to improve the articular outcome, but also to prevent CV comorbidities. Therefore, it is crucial to conduct a thorough risk assessment before initiating JAK inhibitors in each PsA patient.

Assessment before initialing JAK inhibitors includes evaluating traditional CV risk factors such as age, sex, smoking status, hypertension, diabetes, family history of CVD; and measurement of blood pressure, lipid profile, blood glucose levels, electrocardiogram (ECG) if indicated. By conducting a comprehensive assessment of these factors, healthcare providers can better understand a patient's CV risk profile and make informed decisions regarding the initiation of JAK inhibitors in PsA treatment. This approach allows for personalized care and appropriate management of potential CV risks associated with JAK inhibitor therapy. For PsA patients with well-controlled CV risk factors who are receiving treatment of JAK inhibitors, ongoing monitoring and adopting healthy lifestyle intervention are crucial.

As the effect of JAK inhibitor on CVD remains a controversial topic, there is a need to address future directions in research. Conducting long-term safety studies is crucial to fully understand the CV risk associated with JAK inhibitor. These studies should aim to provide more robust data on the incidence of CV events and identify specific patient populations that may be at higher risk. Additionally, investigating biomarkers that could predict CV risk in patients treated with JAK inhibitor is a critical area of research. The identification of such biomarkers could assist clinicians in tailoring treatments more effectively and closely monitoring patients. Furthermore, conducting comparative effectiveness research comparing JAK inhibitor with other treatments for PsA, such as tumor necrosis factor (TNF) inhibitors or IL-17 inhibitors, can offer valuable insights into the relative CV safety of these therapies. Such research can help inform treatment decisions and optimize patient outcomes. Lastly, enhancing clinical recommendations on CV risks of JAK inhibitors in different patient populations can provide specific clinical recommendations in high-risk patients, and address the safe use based on their clinical characteristics.

JAK inhibitors represent a major advancement in the treatment of PsA, providing notable benefits in symptom control and enhancing quality of life. These medications demonstrate rapid efficacy, even in patients who have not responded to prior therapies. Much of the decision-making regarding JAK inhibitor hinges on a risk–benefit assessment that can be adjusted and managed in clinical practice. As evidence continues to accumulate, we will move closer to achieving a balanced approach regarding pros and cons that enables the most informed and prudent clinical decision-making.

All authors critically revised the manuscript for important intellectual content. Specific roles included: study design (Jenny Lin-Hong Shi) and drafting and revising of the manuscript (Jenny Lin-Hong Shi, Wei-Yuan Chuang, Lai-Shan Tam).

The authors declare no conflicts of interest.