Registry Data 'Reassure' on Biologics' Heart Attack Risk in Rheumatoid Arthritis

Sara Freeman

April 24, 2023

MANCHESTER, England — Rheumatoid arthritis (RA) patients are no more likely to have a heart attack if they are treated with an interleukin-6 inhibitor (IL-6i) than if they are treated with a tumor necrosis factor inhibitor (TNFi), according to data presented here at the British Society for Rheumatology Annual Conference.

Tian Zixing

Results of a large analysis from the long-running British Society for Rheumatology Biologics Register-Rheumatoid Arthritis (BSRBR-RA) found no statistical difference in the rate of myocardial infarction (MI), considering treatment in almost 21,000 patients. The overall propensity-score adjusted hazard ratio for MI risk comparing TNFi and IL-6i was 0.77, but the 95% confidence interval crossed the line for statistical significance.

"This result reassures patients and clinical teams about the long-term treatment effects on myocardial infarction in a real-world setting," said Tian Zixing, a PhD student at the University of Manchester in Manchester, England.

"Patients with rheumatoid arthritis have an increased risk of myocardial infarction, compared to the general population," Tian explained. However, this risk has been "considerably improved" with biologic treatment of rheumatoid arthritis, notably with the TNFi drugs vs nonbiologic disease-modifying antirheumatic drugs.

The reasoning behind the current analysis was to see if there was any risk associated with IL-6i, as these drugs have been noted to increase low-density cholesterol levels, which in turn can raise the risk for MI.


The study population consisted of all patients registered in the BSRBR-RA over the past 20 years who had started treatment with one of the many TNFi drugs available in the UK — adalimumab (Humira and biosimilars), etanercept (Enbrel), infliximab (Remicade and biosimilars), certolizumab pegol (Cimzia), and golimumab (Simponi) — or the two available drugs that target the effects of IL-6 — tocilizumab (RoActemra, but Actemra in the US), which targets IL-6 itself, and sarilumab (Kevzara), which targets the IL-6 receptor.

Clinical follow-up forms, death certificates, and patient reports confirmed by the clinical team were used to identify patients who experienced a MI, but only MIs that occurred while on treatment were counted.

More than 30,000 lines of therapy in 20,898 patients were recorded. Tian noted that most (> 90%) patients had been treated with a TNFi across all lines of therapy.

"It is very important to consider the treatment sequence," Tian said. "Most patients start first-line treatment with a TNF inhibitor, with only a few patients starting an IL-6 inhibitor," she said. "IL-6 inhibitors are more commonly used in the later stages of disease, when more cardiovascular risk factors have accumulated."

Thus, to ensure that the MI risk was fairly evaluated, the statistical analyses compared TNFi and IL-6i according to the line of treatment. "That means only patients on their first-line treatment will be compared to each other, and only those on their second-line treatment will be compared to each other, and so on," Tian explained.

Baseline characteristics were broadly similar for patients treated with TNFi and IL-6i drugs, except for hyperlipidemia, which was higher in patients treated with an IL-6i. Nevertheless, there was no suggestion of any difference in the MI rates after adjustment for cardiovascular risk factors.

There are a lot of strengths to these data, but of course the possibilities of residual confounding and confounding by indication exist, Tian said. There were also missing data that had to be imputed.

"There has been quite a bit around interleukin-1 blockers being cardiovascular protective," observed Kenneth Baker, MBChB, PhD, who chaired the RA oral abstracts session during which Tian presented the findings.

"IL-6 is quite good at suppressing CRP [C-reactive protein]," added Baker, who is a senior clinical research fellow at Newcastle University and honorary consultant rheumatologist at Freeman Hospital, both in Newcastle upon Tyne, England.

"You've hypothesized or extrapolated that the differences in the lipid levels may not be relevant," he said to Tian, "but do you think there might be an extra element going on here?" Maybe IL-6i drugs such as tocilizumab are better at suppressing inflammation, and that counterbalances the effects on lipids, he suggested.

Tian and Baker disclosed no relevant financial relationships. The BSRBR-RA is managed by the University of Manchester on behalf of the British Society for Rheumatology. The registry is supported by funding from multiple pharmaceutical companies, including AbbVie, Amgen, Celltrion Healthcare, Eli Lilly, Galapagos, Pfizer, Samsung Bioepis, and Sanofi, and in the past Hospira, Merck Sharp & Dohme, Roche, Sandoz, SOBI, and UCB.

British Society for Rheumatology Annual Conference: Abstract OA01. Presented April 24, 2023.

Sara Freeman is a medical journalist based in London, England.

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