CV Risk in PsA: Do Drugs Matter?

Psoriatic arthritis patients who initiated treatment with an inhibitor of interleukin (IL)-12/23 or IL-17 faced greater cardiovascular risk than those who began therapy with a tumor necrosis factor (TNF) inhibitor, French researchers reported.

After propensity score weighting, the hazard ratio for the composite endpoint of acute myocardial infarction or ischemic stroke was 2 (95% CI 1.3-3) for the IL-12/23 inhibitor ustekinumab (Stelara) compared with the reference group of TNF inhibitors, according to Pascal Claudepierre, MD, of Hôpital Henri Mondor in Créteil, France, and colleagues.

In addition, the hazard ratio for these events among patients initiating the IL-17 inhibitors secukinumab (Cosentyx) or ixekizumab (Taltz) was 1.9 (95% CI 1.2-3), the researchers reported online in Rheumatology.

Nonetheless, the overall risks for these major adverse cardiovascular events (MACE) were low, and the results should be “reassuring,” they observed.

Patients with psoriatic arthritis are at increased risk for cardiovascular events, which may result from both classical cardiovascular risk factors and the disease itself.

“Although the exact mechanism of the association is still unclear, systemic inflammation seems a central component resulting in insulin resistance, which in turn causes endothelial cell dysfunction and atherosclerosis. Pharmacological treatments could affect this phenomenon, and inhibition of tumor necrosis factor or interleukins could be a potent target for atherothrombotic protection in patients with inflammatory arthritis,” Claudepierre and colleagues wrote.

Other studies of biologic therapies and cardiovascular risk have had conflicting results, with some reports showing lower risks with TNF inhibition and others finding no differences. One U.S. study of 60,028 patients with psoriasis or psoriatic arthritis found no difference in incident atrial fibrillation or MACE among patients initiating ustekinumab compared with anti-TNF initiators. “Using two U.S. commercial insurance claims databases, we found a similar risk for MACE among ustekinumab initiators compared to TNF inhibitor initiators and the pooled adjusted HR was 1.10 (95% CI 0.80-1.52),” said lead author Seoyoung C. Kim, MD, ScD, of Harvard University and Brigham and Women’s Hospital in Boston.

The current nationwide French study utilized administrative data from the French National Health Insurance database, identifying psoriatic arthritis patients starting a biologic agent or the targeted synthetic drug apremilast (Otezla) from 2015 to 2019. (Another targeted oral agent, tofacitinib [Xeljanz], went on the market in late 2018 in France and was not included in the analysis.) Patients with a history of cardiovascular disease were excluded.

The analysis included 7,289 patients initiating a TNF inhibitor, 1,058 starting the IL-12/23 inhibitor, 1,163 using an IL-17 inhibitor, and 1,885 starting apremilast. Those starting a biologic agent were younger than those taking apremilast and had fewer cardiovascular risk factors such as diabetes and hypertension.

During follow-up through the end of 2019, there were 51 cases of acute myocardial infarction or cerebral infarction, for an overall incidence rate of 3.4 per 1,000 patient-years (2.2 per 1,000 for myocardial infarction and 1.2 per 1,000 for cerebral infarction).

Incidence rates by initial treatment were:

• 2.8 per 1,000 patient-years with a TNF inhibitor
• 3.1 per 1,000 with the IL-12/23 inhibitor
• 5.9 per 1,000 for IL-17 initiators
• 5.2 per 1,000 with apremilast

Mean ages at the time of these events ranged from 60 to 67, median time to the event was 12 months, and most patients were men.

Unlike the IL-12/23 and IL-17 inhibitors, the use of apremilast was not associated with a greater risk of MACE after propensity score weighting (HR 1.3, 95% CI 0.8-2.2), which probably reflected, at least in part, the fact that this drug is generally used by patients with milder disease and a lower inflammatory burden, according to the researchers.

They noted that it remains uncertain why the cardiovascular risk should be greater for patients on the IL-12/23 and IL-17 inhibitors. “Th17 cells, inhibited by these biologic disease-modifying antirheumatic drug classes, have a key role in cardiovascular phenomena, and the balance between pro-atherogenic and atheroprotective effects seems based on the cytokine environment. These cells could be essential for the stability of atherosclerotic plaques, and low serum level of IL-17 seems associated with increased risk of cardiovascular recurrence in patients with coronary artery disease,” Claudepierre and colleagues observed.

However, Kim pointed out that there were differences between her study of ustekinumab versus TNF inhibitors and the current report. “The new study included only psoriatic arthritis, and the cardiovascular outcome was stroke and myocardial infarction only,” she told MedPage Today. In her study, MACE included not only myocardial infarction and stroke but also coronary revascularization.

“Another difference to note is that our study included 74 total MACE events in over 9,000 ustekinumab initiators, while the new study included just five events from only 1,058 IL-12/23 users,” she said. The French researchers acknowledged that their analysis was limited by a small number of events.

It is likely that “more studies with a bigger sample size are needed to confirm one way or the other,” Kim said.