Arthritis Rheumatol. 2015 Feb;67(2):372-80.

An evaluation of risk factors for major adverse cardiovascular events during tocilizumab therapy.

Rao VU,1,2 Pavlov A,3 Klearman M,4 Musselman D,4 Giles JT,5 Bathon JM,5 Sattar N,6 Lee JS.7
1Genentech Research Fellow, South San Francisco, California 94080, USA; 2Staff Cardiologist, Franciscan Provider Network, Indiana Heart Physicians, Indianapolis, Indiana 46237, USA; 3Everest Clinical Research Services, Toronto, Ontario L3R 0B8, Canada; 4Genentech, South San Francisco, California 94080, USA; 5Division of Rheumatology, Columbia University, New York, New York 10027, USA; 6University of Glasgow, Glasgow G12 8QQ, United Kingdom; 7Roche, Nutley, New Jersey 07110, USA.




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.


In retrospective post hoc analyses, data were pooled for 3986 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 follow-up.


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.


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

PMID: 25332171



Patients with rheumatoid arthritis (RA) have approximately double the risk of myocardial infarction or stroke as the general population.1 This heightened incidence of cardiovascular disease is not fully explained by conventional risk factors such as hypertension, diabetes, and obesity. In particular, hypercholesterolemia may not be as strong a risk factor in RA; in RA patients with a high burden of inflammation (as shown by elevated erythrocyte sedimentation rates [ESR]), low total cholesterol and low-density lipoprotein (LDL) cholesterol levels paradoxically appear to increase the risk of cardiovascular outcomes.2

Interleukin-6 (IL-6), a key mediator in RA-related inflammation, has been implicated in cardiovascular disease in the general population and in RA patients. In clinical trials of the IL-6 receptor-α inhibitor tocilizumab, mean lipid levels (total cholesterol, high-density lipoprotein [HDL] cholesterol, LDL cholesterol, and triglycerides) increased during the first few weeks of treatment and then remained stable. Therefore, we sought to understand in RA patients treated with tocilizumab whether factors such as demographic characteristics, lipid levels, inflammation, and RA disease activity at the start of therapy are associated with major adverse cardiovascular events (MACE) and whether changes in lipid levels, circulating inflammatory markers, or RA-specific disease activity measures that occur with tocilizumab treatment are associated with a risk of MACE. In our study of 3,986 patients treated with tocilizumab, 50 patients experienced MACE, which translates to a rate of 3.4/1,000 patient-years and is comparable to rates in other biologic-treated RA populations such as those in the British Biologics Registry (5.3/1,000 patient-years).

We found that older age, history of cardiac disorders, greater disease activity at baseline as indicated by higher disease activity score based on 28 joints (DAS28), and higher total cholesterol to HDL cholesterol ratio at the start of therapy were independently associated with MACE during tocilizumab treatment (Figure 1).



Figure 1. Age, ratio of total cholesterol to HDL cholesterol at baseline, and history of cardiac disease were associated with occurrence of MACE during tocilizumab treatment and greater reductions in RA disease activity from baseline to week 24 were associated with lower risk of future MACE. P values for associations that were statistically significant are shown. CI, confidence interval; HR, hazard ratio based on multivariable Cox regression models.


We also found that at week 24, higher disease activity (DAS28, area under the curve for DAS28, and greater number of swollen and tender joints) predicted future MACE. Greater reductions in RA disease activity from the start of treatment with tocilizumab to week 24 were associated with a lower risk of future MACE, whereas less robust therapeutic responses were associated with a higher risk (hazard ratio >1). In contrast, reductions in ESR, changes in IL-6 receptor levels, and changes in lipid levels between baseline and 24 weeks were not statistically significantly associated with future MACE (Figure 1)

Importance of our study: In tocilizumab-treated patients, the ratio of total cholesterol to HDL cholesterol at the start of treatment appears to be associated with increased risk of MACE. Although no association was found between the changes in lipid levels that occur during tocilizumab treatment and the risk of MACE, changes in measures of disease activity were associated with MACE.



  1. Solomon DH, Goodson NJ, Katz JN , Weinblatt ME, Avorn J, Setoguchi S, Canning C, Schneeweiss S 2006 Patterns of cardiovascular risk in rheumatoid arthritis. Ann Rheum Dis 65:1608-1612
  2. Myasoedova E, Crowson CS, Kremers HM , Roger VL, Fitz-Gibbon PD, Therneau TM, Gabriel SE 2011 Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis 70:482-487



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