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04-06-2022 | EULAR 2022 | Conference coverage | News

Mixed results for MACE risk with JAK inhibitors in RA

Author: Lucy Piper


medwireNews: Two real-world studies looking at the risk for major cardiovascular events (MACE) with Janus kinase (JAK) inhibitors versus tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA) show contradicting outcomes.

The studies, presented at the EULAR 2022 Congress in Copenhagen, Denmark, were prompted by the noninferiority ORAL Surveillance trial, which showed an increased risk for MACE with tofacitinib versus TNF inhibitors.

Click through for an overview of JAK inhibitor safety in rheumatic diseases including the ORAL Surveillance study findings.

However, presenter Adeline Ruyssen-Witrand (CHU de Toulouse, France) pointed out that this risk appeared to be limited to patients with known cardiovascular risk. Together with colleagues, she assessed the rate of MACE and venous thromboembolism (VTE) with JAK inhibitors versus TNF inhibitors using the World Health Organization Global Individual Case Safety Report database (VigiBase®).

A total of 290,608 adverse events were reported from patients with RA, aged 18–75 years, between January 2011 and April 2022, of which 50,694 were for a JAK inhibitor (tofacitinib, baricitinib, upadacitinib, filgotinib) and 239,914 were for a TNF inhibitor (etanercept, adalimumab, infliximab, certolizumab pegol, golimumab).

In all, there were 4196 incidences of MACE (myocardial infarction, stroke, or cardiovascular death) reported: 817 (1.6%) in patients treated with JAK inhibitors and 3379 (1.4%) in those treated with TNF inhibitors. And a respective 23% and 33% were reported by physicians.

Disproportionality analyses indicated an increased risk for MACE with JAK inhibitor versus TNF inhibitor use but only in physician-reported cases, said Ruyssen-Witrand. The risk for physician-reported MACE was increased by 45% with JAK inhibitor use, primarily due to increased physician-reported myocardial infarction.

VTE events were also significantly disproportionally reported. Of a total 1414 VTE events (deep vein thrombosis, pulmonary embolism), 596 (1.2%) were among patients taking JAK inhibitors and 818 (0.3%) among those taking TNF inhibitors. Of these, 46% and 38% were physician reported.

This gave a significantly increased reporting odds ratio (ROR) for VTE of 3.48 in patients taking JAK inhibitors, said Ruyssen-Witrand, which was amplified to 8.51 for physician-reported events and was seen for both deep vein thrombosis and pulmonary embolism when considered separately.

The majority of events occurred in patients over the age of 60 years and tofacitinib was the JAK inhibitor most commonly used.

By contrast, an observational real-world study described by Yvette Meissner (German Rheumatism Research Centre, Berlin) failed to find an increased risk for MACE with JAK inhibitor use among patients with RA enrolled in the biologics register RABBIT who initiated treatment from 2017 onwards.

Among these patients, 2030 were treated with JAK inhibitors (46% tofacitinib; 54% baricitinib), 2338 with TNF inhibitors, and 871 with conventional synthetic (cs)DMARDs. The mean age was 58–60 years.

Patients in the JAK inhibitor group, compared with the other participants, had a longer mean duration of RA (13 vs 6–9 years), were more likely to be rheumatoid factor or anti-citrullinated-protein antibody positive (79 vs 66–74%), and had more previous biologic DMARD treatments (mean 2.0 vs 0–0.7). They also had a higher degree of functional impairment on average (63% of full physical function vs 69–72%) and a higher mean number of comorbidities (2.9 vs 2.2–2.6).

There were 28 reported MACEs, including 11 in the JAK inhibitor group, and crude incidence rates per 100 patient–years were similar across the JAK inhibitor, TNF inhibitor, and csDMARD treatment groups, said Meissner, at 0.41, 0.45, and 0.26, respectively. This was confirmed in adjusted Poisson regression analysis.

There was also no increased incidence for a selected group of 2977 high-risk patients, who were aged at least 50 years and had one or more cardiovascular risk factors (hypertension, coronary heart disease, diabetes, hyperlipoproteinemia, or current smoking). The incidence rates per 100 patient–years were 0.63 with JAK inhibitors, 0.85 with TNF inhibitors, and 0.44 with csDMARDs.

Meissner noted that the 0.63 incidence rate for JAK inhibitors among this high-risk group was lower than the 0.91 and 1.83 incidence rates reported in the ORAL Surveillance and STAR-RA studies, respectively, whereas the incidence rates for TNF inhibitors was higher than in ORAL Surveillance (0.85 vs 0.73).

She reported that “the only factors associated with an increased risk for MACE were the number of comorbidities and in the complete cohort glucocorticoid [use].”

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