An Evaluation of Risk Factors for Major Adverse Cardiovascular Events During Tocilizumab Therapy

Abstract

Objective. To evaluate associations between lipid levels, inflammation, and rheumatoid arthritis (RA) disease activity, at baseline and during treatment, with the risk of major adverse cardiovascular events (MACE) in tocilizumab-treated patients with RA.Methods. In retrospective post hoc analyses, data were pooled for 3,986 adult patients with moderate to severe RA who received >1 dose of tocilizumab (4 mg/kg or 8 mg/kg) intravenously every 4 weeks in randomized controlled trials and extension studies. Cox proportional hazards modeling was used to evaluate associations between baseline characteristics and posttreatment changes in laboratory and disease characteristics (week 24) and change in disease activity and laboratory values from baseline to week 24 with the risk of future MACE during extended followup.Results. We identified 50 independently adjudicated cases of MACE during 14,683 patient-years of followup (0.34 MACE cases/100 patient-years). At baseline, age, a history of cardiac disorders, the Disease Activity Score in 28 joints (DAS28), and the total cholesterol:high-density lipoprotein cholesterol ratio were independently associated with MACE in multivariable models (P < 0.05 for all). During treatment, a higher DAS28 and higher swollen and tender joint counts at week 24 were associated with future MACE. In separate models, greater reductions in the DAS28 and joint counts from baseline to week 24 were inversely associated with future MACE; changes in lipid parameters were not statistically significantly associated with the risk of MACE.Conclusion. In this population of patients treated with tocilizumab, an association was observed between the baseline total cholesterol:high-density lipoprotein cholesterol ratio and an increased risk of MACE. The risk of MACE while receiving treatment, however, was associated with control of disease activity but not lipid changes. Larger studies are needed to confirm these findings.Patients with rheumatoid arthritis (RA) have approximately double the risk of myocardial infarction (MI) and stroke compared with that in the general population (1,2). Several studies suggest that the increased incidence of cardiovascular disease (CVD) in RA is not completely explained by traditional CV risk factors such as diabetes mellitus, hypertension, smoking, and dyslipidemia (3-5). Indeed, the HLA-DRB1 shared epitope, higher erythrocyte sedimentation rates (ESRs), and RA comorbidities such as vasculitis and pulmonary disease are associated with an increased risk of CVDrelated mortality (4,6). In a population-based incidence cohort of RA patients with high ESRs, those with much lower total cholesterol and low-density lipoprotein

Modulation of Autoimmunity and Atherosclerosis – Common Targets and Promising Translational Approaches Against Disease –

“…62 Paradoxically, regarding the potential use of anti-IL-6 in CVD, IL-6 blockade has been shown to upregulate ApoA1 and ApoB and, consequently, raise HDL and LDL plasma levels, respectively. 63, 64 These findings are consistent with previous work, in which IL-6 inhibited the production of apolipoproteins in hepatocytes in vitro. 65 In experimental atherosclerosis, the administration of recombinant IL-6 was found to accelerate atherogenesis in Apoe -/-mice.…”

“…67 Long-term IL-6 blockade is considered safe and does not increase CV event rates in RA patients. 64 However, larger studies that assess the risk of IL-6 blockade in autoimmune disease patients are needed to support its use for preventing and treating CVD in the general population.…”

Safety and Efficacy of Biological Disease-Modifying Antirheumatic Drugs in Older Rheumatoid Arthritis Patients: Staying the Distance

“…However, compared to other biologics, the elderly patients treated with tocilizumab do not seem to 18 have an increased risk of myocardial infarction and even have a reduced risk of coronary heart disease outcome (myocardial infarction, percutaneous coronary intervention or coronary artery bypass grafting) [72]. Age, statin use, higher cholesterol levels and history of cardiac disorders, often encountered in seniors, are independent predictors of cardiovascular events in patients treated with tocilizumab [88]. An association was observed between the baseline total cholesterol:high-density lipoprotein cholesterol ratio and an increased risk of major adverse cardiovascular events.…”

Editorial: Lipid Changes With Different Antiinflammatory Regimens in Rheumatoid Arthritis: Developing a Pragmatic Approach to Complex Data

“…As such, one should not focus solely on the complex, and as-yetuncertain, relevance of quantitative lipid changes. In this respect it is notable that in a recent analysis, the risk of major CV events among patients receiving tocilizumab (although the number of events was modest [n 5 50]) was associated with control of disease activity, but not necessarily with lipid changes (9). For now, it would seem sensible to prescribe antiinflammatory therapies based on contemporary RA treatment algorithms and not to be overly influenced by differential lipid changes with distinct therapies.…”