Higher Risk of Serious Adverse Events With Certolizumab and Tocilizumab

New analysis compares the risk of serious adverse events among all 10 FDA-approved biological and targeted synthetic disease-modifying antirheumatic drugs.

Certolizumab pegol and tocilizumab may be associated with a higher risk of serious adverse events (SAEs) than other biologic and targeted synthetic disease-modifying antirheumatic drugs (b/ts-DMARDs) among patients with rheumatoid arthritis (RA), according to a study published in Rheumatology.

“Approval of b/ts-DMARDs has been based on their ability to achieve clinical response relative to placebo (with or without background csDMARDs) without causing severe toxicity. However, the studies are not adequately powered to fully determine the potential harmful effects of these drugs,” the researchers, led by Simon Tarp, PhD, MSc, of Copenhagen Hospital University at Bispebjerg and Frederiksberg in Denmark, wrote.

When deciding between treatments that appear to be equally effective, potentially harmful effects are an important factor that should be taken into account. However, data from meta-analyses comparing adverse events of bDMARDs in randomized trials are conflicting. Adaptive trial designs may contribute to the inconsistent results due to high dropout rates in the control arms, potentially skewing rates of adverse events.

High Yield Data Summary

  • Certolizumab therapy should be carefully scrutinized, despite current treatment guidelines that rank most biologics equally for the treatment of RA.

In a meta-analysis and systemic review, Dr Tarp and colleagues compared the risk of SAEs among all 10 b/ts-DMARDs approved by the US Food and Drug Administration (FDA) or European Medicines Agency using methodology that accounts for the issues associated with adaptive trial design.

Data from 47,615 patients with RA from 117 studies were included for analysis. SAEs were defined by the study definition for SAEs in each individual trial.

Certolizumab pegol was associated with higher rates of SAEs compared with golimumab (rate ratio [RR], 1.45), abatacept (RR, 1.58), etanercept (RR, 1.60), adalimumab (RR, 1.36), rituximab (RR, 1.63), tofacitinib (RR, 1.44), and control (RR, 1.45).

SAEs also occurred more frequently with tocilizumab than with etanercept (RR, 1.31), abatacept (RR, 1.30), and rituximab (RR, 1.34).

“We assessed the confidence in the SAE rate ratios as moderate to very low for all 55 comparisons (moderate 24%, low 34%, very low 42%), suggesting the true effects are likely to be different from the estimated effects,” the authors wrote.

Summary and Clinical Applicability

The decision to use b/ts-DMARDs in RA is often based on several factors, including potentially harmful effects. This meta-analysis compared SAEs of all 10 approved b/ts-DMARDs and took into account the effects of adaptive trial design that likely contributed to conflicting results in prior meta-analyses.

“In contrast to current treatment guidelines for RA, which ranks most biologics equally in the treatment algorithm after failure of conventional DMARDs, our findings suggest that certolizumab therapy should be considered more carefully than the use of other biologics because it may be associated with a higher rate of SAEs compared with equally effective alternatives,” Dr Tarp said in an interview with Rheumatology Advisor.

Limitations and Disclosures

“Our study findings must be interpreted in the context of several limitations, which include publication bias, a wide publication period spanning 16 years among included trials, and the lack of head-to-head trials. Our low confidence in the study results reflects these limitations,” Dr Tarp said.

This study was funded by The Oak Foundation and The Danish Health and Medicines Authority.

Dr Tarp and several authors report financial relationships with various pharmaceutical companies. A full list of disclosures can be found in the journal article.

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Tarp S, Furst DE, Boers M, et al. Risk of serious adverse effects of biological and targeted drugs in patients with rheumatoid arthritis: a systematic review meta-analysis [published online December 24, 2016]. Rheumatology. doi:10.1093/rheumatology/kew442

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