Rheumatoid arthritis disease activity during treatment with tocilizumab plays a significant role in patients’ risk for major adverse cardiovascular events, rather than increases in lipid levels observed during treatment with the interleukin-6 receptor inhibitor, according to a new analysis of phase III trials and extensions studies of the drug.
The study of 3,986 rheumatoid arthritis (RA) patients treated with tocilizumab for a mean of 3.68 years indicated that reductions in disease activity based on lower 28-joint disease activity score (DAS28) were significantly associated with fewer major adverse cardiovascular events (MACE), defined as definite or probable nonfatal myocardial infarction, nonfatal stroke, or death from a cardiovascular cause.
Conversely, risk for MACE rose with poorer response to treatment, as measured by increases in DAS28 and total swollen and tender joints (Arthritis Rheumatol. 2014 [doi:10.1002/art.38920]).
In addition to DAS28, some traditional risk factors at baseline – older age, history of cardiac disorders, and high ratio of total cholesterol to HDL cholesterol (known as the atherogenic index) – were independent predictors of MACE during treatment, reported Dr. Vijay U. Rao and his colleagues. Dr. Rao was a research fellow with Genentech during the study but is now a cardiologist in private practice in Indianapolis.
The presence of a cardiac disorder increased the risk of MACE, with a hazard ratio of 2.32, and for each 1-unit increase in DAS28, age, and atherogenic index, MACE risk rose by 36%, 7%, and 33%, respectively.
Predictors of future risk of MACE following the trials’ initial 24-week treatment period remained largely the same as baseline predictors for MACE during initial treatment, including measures of higher disease activity.
In contrast, baseline and 24-week levels of systemic markers of inflammation such as erythrocyte sedimentation rate (ESR) and C-reactive protein, as well as changes in ESR and interleukin-6 (IL-6) receptor levels and changes in lipid levels during 24 weeks of tocilizumab treatment, did not predict future risk of MACE.
The IL-6 receptor pathway is thought to play a role in cardiovascular disease, and tocilizumab’s action as a monoclonal antibody against that receptor suggested that its effects might reduce CV risk. However, baseline levels of IL-6 and IL-6 receptor, or levels of IL-6 receptor at 24 weeks, were not associated with MACE.
The investigators found 50 confirmed cases of MACE in pooled data from five randomized, controlled trials and their extension studies that enrolled 3,986 patients with moderate to severe RA who received tocilizumab 4 mg/kg or 8 mg/kg intravenously every 4 weeks in combination with methotrexate or other disease-modifying antirheumatic drugs. The MACE rate was 3.4/1,000 patient-years of exposure, and there were no obvious time trends observed.
Because the trials used in the post hoc analyses were not specifically powered for analyzing MACE risk, the findings should be viewed as “hypothesis generating,” the investigators said.
They also noted that because 31% of patients in the trials discontinued treatment and MACE cases that occurred beyond 6 months after discontinuation were not recorded, there is a chance that those who withdrew were at a different risk for MACE than were those who remained on treatment. They also did not evaluate hypertension and use of statins, antiplatelet medications, or glucocorticoids.
The findings support a previous registry study in which MI risk was halved in responders to antitumor necrosis factor-alpha therapy, compared with nonresponders, according to the authors, as well as in several observational studies in which control of disease activity with nonbiologic DMARDs was associated with lower risk for MI.
The study was funded by F. Hoffmann-La Roche, of which the manufacturer of tocilizumab, Genentech, is a subsidiary. Five of the nine authors were employed by or received funding from Roche or Genentech at the time of the study, two were consultants or received speaking fees from Roche or Genentech, and the remaining two had no disclosures.