Cardiovascular safety of Janus kinase inhibitors in patients with rheumatoid arthritis: systematic review and network meta-analysis

Abstract

Background: Janus kinase (JAK) inhibitors have emerged as a progressively utilized therapeutic approach for the management of rheumatoid arthritis (RA). However, the complete determination of their cardiovascular safety remains inconclusive. Hence, the primary objective of this network meta-analysis is to meticulously assess and juxtapose the cardiovascular risks linked to distinct JAK inhibitors employed in RA patients. Methods: A systematic review and network meta-analysis were meticulously conducted, encompassing a collection of randomized controlled trials (RCTs) that focused on investigating the incidence of major adverse cardiovascular events (MACE) and all-cause mortality associated with Janus kinase (JAK) inhibitors administered to patients with rheumatoid arthritis (RA). Extensive exploration was performed across multiple electronic databases, incorporating studies published until March 2023. To be included in this analysis, the RCTs were required to involve adult participants diagnosed with RA who received treatment with JAK inhibitors. To ensure accuracy, two authors independently undertook the selection of eligible RCTs and meticulously extracted aggregate data. In order to examine the outcomes of MACE and all-cause mortality, a frequentist graph theoretical approach within network meta-analyses was employed, utilizing random-effects models. Third study has been registered on PROSPERO under the reference CRD42022384611. Findings: A specific selection encompassing a total of 14 meticulously chosen randomized controlled trials was undertaken, wherein 13,524 patients were assigned randomly to distinct treatment interventions. The analysis revealed no notable disparity in the occurrence of major adverse cardiovascular events (MACE) between the interventions and the placebo group. However, in comparison to adalimumab, the employment of JAK inhibitors exhibited an association with higher rates of all-cause mortality [odds ratio (OR): 1.7, 95% confidence interval (CI): 1.02-2.81]. This observed increase in risk primarily stemmed from the usage of tofacitinib (OR: 1.9, 95% CI: 1.12-3.23). None of the other JAK inhibitors exhibited a statistically significant variance in all-cause mortality when compared to adalimumab. Interpretation: Our study suggests that JAK inhibitors may not increase the risk of MACE in RA patients but may be associated with a higher risk of all-cause mortality compared to adalimumab, primarily due to tofacitinib use. Rheumatologists should carefully consider the cardiovascular risks when prescribing JAK inhibitors, particularly tofacitinib, for RA patients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=384611, CRD42022384611.

Keywords: Janus kinase inhbitors; all-cause mortality; cardiovascular safety; major cardiovascular adverse events; network meta-analysis; rheumathoid arthritis.

FIGURE 1

PRISMA flow diagram of the study selection process.

FIGURE 2

Network diagrams for each outcome measure. Annotation: Each node in the network plot represents an intervention, with the size of the node reflecting the sample size. The links between nodes represent the existence of direct comparison relationships among these interventions. The thickness of the link represents the number of direct comparisons between two interventions, which is reflected by the number of solid lines connecting the two nodes. (A): MACE for category; (B): all-cause mortality for category; (C): MACE for individual drug; (D): all-cause mortality for individual drug.

FIGURE 3

Results of network meta-analysis (relative effects league table and GRADE rating). Annotation: League tables were used to summarize the research data, where each cell in the table represents the relative effect size between the intervention of the row and that of the column. The color of each cell represents the GRADE rating, indicating the strength of evidence for that comparison. Different colors are used to represent different GRADE ratings, blue for moderate quality evidence, yellow for low quality evidence, and red for very low quality evidence. (A): for category; (B): for individual drug.

FIGURE 4

Scatter Plot of p-values. Annotation: In this scatter plot, the x-axis represents the P-score of MACE, and the y-axis represents the P-score of mortality. Each data point represents a study drug, and different colors indicate different study drugs. The position of each data point indicates the corresponding study’s P-score. The higher the P score, the lower the incidence of MACE and all-cause mortality for the intervention. Drugs with higher P-scores for MACE will be located on the right side of the scatter plot, while drugs with higher P-scores for mortality will be located above the scatter plot. (A): for category; (B): for individual drug.