Cardiovascular Risk in Patients With Axial Spondyloarthritis Treated With Nonsteroidal Anti-Inflammatory Drug

Abstract

Axial spondyloarthritis (axSpA) is a common rheumatic disease, which mainly affects people in young age, especially young man. However, the disease has nature of chronic inflammatory manifestations, which may affect old age people. Previous studies have shown that these inflammatory manifestations not only contribute to the development of arthropathy, tendinopathy, and enthesopathy but also significantly increase the risk of major cardiovascular events (MACEs) [1]. Previous studies demonstrated that the metabolic risk factors has the connection with axSpA, and the positive association with the disease activity. One systematic review and meta-analysis demonstrated a higher risk of type 2 diabetes mellitus, hypertension, and hyperlipidemia, in the patients diagnosed with axSpA [2]. Another population-based cohort study demonstrated similar results, including a higher risk of valvular heart disease, ischemic heart disease, congestive heart failure, and cerebrovascular disease [3]. A study focused on the function of homocysteine and axSpA demonstrated a potential link to cardiovascular disease (CVD) [4].

NSAIDs provide pain relief and reduce inflammation by inhibiting cyclooxygenase (COX) enzymes. Theoretically, patients with axSpA often have impaired vascular endothelial function [5]. When combined with comorbidities, such as hypertension, diabetes, or dyslipidemia, this dysfunction may accelerate atherosclerosis, increasing the risk of acute coronary syndromes [3, 6].

Selective COX-2 inhibitors, a subclass of NSAIDs, are associated with an elevated risk of thrombosis, [7] which may lead to ischemic heart disease [7, 8]. Additionally, NSAIDs contribute to sodium and water retention, exacerbating hypertension and increasing cardiovascular strain [5, 8]. These factors collectively raise the likelihood of adverse events such as myocardial infarction, stroke, and heart failure [7].

NSAIDs are well known to have a clear link to the risk of MACE. When considering gender, NSAID use in females is associated with an increased risk of CVD and stroke. Regarding age, chronic NSAID use in elderly individuals is linked to an increased risk of cardiovascular death [7]. NSAID use is also associated with a higher risk of myocardial infarction, stroke, and hospitalization due to heart failure [7].

In the early 21st century, COX-2 selective NSAIDs were found to have a higher risk of MACE [9]. The Adenoma Prevention with Celecoxib (APC) trial demonstrated that patients receiving celecoxib at doses of 200 mg twice daily and 400 mg twice daily had risk ratios of 1.6 and 1.9, respectively, compared to placebo for cardiovascular and thromboembolic disorders [10]. The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) demonstrated that celecoxib exhibited a nonsignificant statistical increase in stroke risk, while naproxen showed a higher risk of myocardial infarction, stroke, and congestive heart failure [11]. Similar results were found in the CLASS study, which demonstrated no significant difference in MACE between the groups [12]. Therefore, the following section discusses the need to investigate whether the risk of major cardiovascular events from COX-2 selective or nonselective NSAIDs in our specific patient group.

NSAIDs are the first-line therapy in axial axSpA, followed by biological agents. We have noted the increasing risk of cardiovascular events in axSpA and the use of NSAIDs. However, achieving low disease activity through anti-inflammatory treatment may lead to a lower risk of endothelial dysfunction and MACE in clinical practice. The balance between the risk of MACE and disease control with NSAIDs remains a complex issue.

Until 2024, several studies using different methods have focused on the risk of MACE associated with NSAID use among patients with spondyloarthritis, particularly the axial type. A study utilizing Taiwan's National Health Insurance Research Database (NHIRD) demonstrated no elevated risk of MACE among long-term NSAID users in patients with ankylosing spondylitis (AS). In fact, a lower risk of MACE was observed in frequent long-term NSAID users [13]. However, this study acknowledged limitations, including a lack of data on inflammatory status, the inability to evaluate drug compliance, and the uncertainty of whether patients purchased over-the-counter medications.

Similarly, a study utilizing the Swedish healthcare system indicated no increased risk of MACE among patients receiving NSAIDs, whether COX-2 selective or nonselective [14]. The authors reported more comorbidities among non-NSAID users, suggesting that clinical decision-making might have resulted in selection bias in the study. Another study conducted with the Swedish National Patient Register (NPR) defined the outcome as the first occurrence of MACE and reported that approximately 50% of the cohorts exposed to NSAIDs demonstrated an increased risk of acute coronary syndrome and stroke in patients diagnosed with AS [15].

A meta-analysis suggested that COX-2 NSAIDs exhibited a lower risk of composite cardiovascular events in patients diagnosed with AS, which differs from the general population [16]. Additionally, a nested case–control study showed similar findings, with no increased risk of MACE in NSAID users, even when considering the combination of conventional disease-modifying antirheumatic drugs (DMARDs) or tumor necrosis factor inhibitors (TNFis) [6]. A long-term nationwide study demonstrated a positive outcome, indicating that NSAIDs and TNFis are associated with a lower risk of MACE over an 8-year cumulative incidence period [17].

A recent population-based study utilizing the Korean National Health Insurance Database also demonstrated no increased risk of MACE, even with long-term NSAID use among patients with AS [5]. However, further analysis indicated that a higher dose of NSAIDs exhibited a higher risk of MACE in patients with AS [8]. Considering the dose dependence, the authors reported no associated data on inflammatory markers, which are related to disease activity in clinical assessment.

Table 1 shows the list of related studies.

In the past 10 years, Janus kinase inhibitors (JAKis) have emerged as a promising treatment option for immune-mediated inflammatory diseases, including axSpA. Therefore, data related to JAKi were discussed below.

A retrospective analysis indicated no increased risk of adverse events with JAKis compared to placebo [18]. Additionally, a real-world study utilizing the BIOBADASER registry demonstrated a comparable risk of cardiac adverse events between JAKis and TNFis among patients with spondyloarthritis [19]. The study of generic tofacitinib found no serious adverse events, although weight gain and elevated serum cholesterol were observed [20]. These findings underscore the importance of regular monitoring of traditional cardiovascular risk factors by physicians.

Further studies are needed to determine which subgroups of patients with axSpA would benefit from or be harmed by JAKis.

NSAIDs are the first-line treatment for AS. In cases of severe disease activity, high-dose NSAIDs may be required to control the condition. Current evidence in patients with axSpA shows that high-dose NSAIDs might be harmful, but low-dose NSAIDs mostly lead to neutral or protective effects in MACE.

Due to potential higher risk of CVD, AS patients should closely monitor and aggressively manage traditional cardiovascular risk factors, such as lifestyle, blood pressure, blood sugar, lipid levels, and obesity. Physicians should regularly assess the risk of MACE to enable early intervention and prevention. Further studies are anticipated to provide more detailed information, allowing for individualized and precise treatment.

S.T.-S., Y.H.-L., P.C.-S., and T.J.-L. had full access to the study data and verified the underlying study data. P.C.-S. led the conception. S.T.-S., Y.H.-L., and P.C.-S. wrote the original draft of this paper. S.T.-S., Y.H.-L., P.C.-S., and T.A.-L. contributed to the conception and writing with review and editing of this paper.

The authors declare no conflicts of interest.