Increased Cardiovascular Disease in Rheumatoid Arthritis Patients Treated with Tocilizumab

Rheumatoid arthritis (RA) patients treated with tocilizumab saw an association between total cholesterol (high density lipoprotein [HDL]) and an increased risk of major adverse cardiovascular events (MACE), according to findings published in Arthritis & Rheumatology.

Researchers from Canada, the United Kingdom, and the United States conducted a retrospective analysis of RA patients in order to evaluate the associations between lipid levels, inflammation, and RA disease activity. The authors commented that RA patients have nearly double the risk of myocardial infarction (MI) and stroke compared to the general population, and some studies noted that traditional cardiovascular risk factors like diabetes, hypertension, smoking, and dyslipidemia may not be the only contributing factors.

The researchers reviewed almost 4,000 adult patients with moderate to severe RA who received ≥1 dose of tocilizumab (either 4 mg/ kg or 8 mg/ kg) intravenously every 4 weeks in various types of studies. The patients were observed and analyzed between baseline and at 24 weeks post treatment for MACE risk follow up. In the studies, the researchers said, treatment with tocilizumab resulted in elevations in average lipid levels, which encompassed total cholesterol, HDL, low density lipoprotein (LDL) cholesterol, and triglyceride. The changes are observed early on in the tocilizumab treatment period but remain stable during long term therapy.

The researchers found 50 independently adjudicated cases of MACE among 14,683 patient years of follow up — there were 0.34 MACE cases per 100 patient years. Between baseline and week 6, increased lipid parameters were observed soon after the initiation of tocilizumab. For example, the authors wrote, mean total cholesterol, LDL, HDL, and triglyceride levels rose by 16 percent, 19 percent, 7 percent, and 26 percent, respectively. Additionally, during the course of treatment, DAS 28 and higher swollen and tender joint counts by week 24 were linked to a future with MACE.

The researchers conducted a separate analysis, where greater reductions in the DAS 28 score and joint counts from baseline to week 24 were inversely associated with future MACE risk. In this setting, the changes in lipid parameters were not statistically significant or associated with the risk of MACE, the authors said.

“One possible explanation for the lack of an observed association between increased risk of cardiovascular events and elevated lipid levels in RA patients treated with tocilizumab is that inflammation, including that mediated by IL-6, can often lead to reduced lipid levels by mechanisms that are not yet fully understood,” the authors explained. “The lipid level increases observed in association with tocilizumab treatment may in part represent a predictable response to the suppression of inflammation.”

The researchers concluded by mentioning the actual number of MACE events identified was modest, and their findings were based on the extrapolation of the data. They do believe, though, that future studies would successfully be able to confirm their findings.

“However, and of more importance to clinical practice, the current analysis suggests that changes in measures of RA disease activity, but not necessarily changes in lipid levels, are associated with incident MACE in tocilizumab treated patients,” they wrote.