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Combo RA Tx May Boost Risk for Serious Adverse Events (CME/CE)

Action Points

  • This systematic meta-analysis evaluated safety when combining two biologic disease-modifying antirheumatic drugs (bDMARDs) for patients with RA, and showed that versus monotherapy, combination treatment appeared to increase the risk of serious adverse events (SAEs) during the first year of treatment.
  • Combination therapy with two bDMARDs did not improve efficacy in five clinical trials versus monotherapy, but did show improved efficacy in one observational study.

CME Author: Vicki Brower

Study Authors: Gonςalo Boleto, Lukshe Kanagaratnam, et al.

Target Audience and Goal Statement:

Rheumatologists, internists, family medicine specialists

The goal is to determine whether combining biologic disease-modifying antirheumatic drugs (bDMARDs) for rheumatoid arthritis (RA) is safe relative to monotherapy, and whether combinations increase serious adverse events (SAEs).

Questions Addressed:

  • How does safety of combination bDMARD therapy in RA patients compare with monotherapy? What is the rate of AEs and SAEs in combination treatments?
  • What were the secondary outcomes — the risk of overall AEs, overall infections, and serious infections independent of dose regimen, and when tapering doses?

Study Synopsis and Perspective:

Since the first bDMARD etanercept (Enbrel) received FDA approval in 1998 for RA, these drugs have shown efficacy in many patients. However, 20%-40% of patients treated with a bDMARD do not achieve remission for a variety of reasons. Because of this serious unmet medical need, researchers have tested combinations of bDMARDs in animals, and are also prescribing combinations for patients.

This study was designed to track SAEs in patients taking combinations of two bDMARDs compared with those taking monotherapies. The study found that patients taking combinations of two biologic agents had an increased risk for AEs in the first 12 months of treatment.

Jean-Hugues Salmon, MD, of Reims University Hospitals in France and colleagues, performed a meta-analysis of six studies (five clinical trials; one cohort study) with a median follow-up of 9.5 months. Overall, 410 patients were treated with a combination of biologics, while 213 controls were given a single biologic as monotherapy or a placebo.

They found that 94.6% of patients receiving two biologics experienced AEs during the first year of treatment compared with 89.1% of those receiving only one biologic (OR 2.07, 95% CI 1.11-3.86).

In this pooled analysis that included 623 patients, SAEs were seen in 14.9% of those who received two biologics compared with 6% who received one (OR 2.51, 95% CI 1.29-4.89), they reported in Seminars in Arthritis & Rheumatism.

Drug combinations used in these studies were etanercept plus anakinra (Kineret), abatacept (Orencia) plus etanercept, rituximab (Rituxan) plus etanercept, etanercept or adalimumab (Humira) plus rituximab, rituximab plus tocilizumab (Actemra), and abatacept plus a tumor necrosis factor inhibitor or anakinra.

Infection is one of the major concerns with biologic treatment, particularly because patients with RA are already at increased risk for serious infections. One study reported that 8% of patients with RA are hospitalized each year for infections. This raises particular concerns for treatment strategies with combinations of biologics.

For any infection, the pooled analysis found no increase in risk for the combination compared with single agent treatments (52.9% vs 46.6%, OR 1.18, 95% CI 0.81-1.74). There was an increase in serious infections, however, but it did not reach significance (5.4% vs 0.47%, OR 3.46, 95% CI 1-11.97).

Two studies analyzed also evaluated malignancy risks. In one, neoplasms were seen in 6.8% of the combination group, and 1.6% of the control group, and in the other, there were no malignancies reported.

In the second part of the current study, Salmon and colleagues performed a subgroup analysis that included only patients who were given full doses of the biologics. In that analysis, the rate of overall AEs was not significantly different (94.4% vs 89%, OR 2.15, 95% CI 1-4.62), but significantly higher risks were seen for SAEs (17.1% vs 6.2%, OR 2.72, 95% CI 1.30-5.69).

For any infection, no difference was seen (55.6% vs 46%, OR 1.28, 95% CI 0.85-1.94), but significantly higher risks for serious infection were found in the combination group compared with controls (6.7% vs 0.6%, OR 5.58, 95% CI 1.25-24.90).

An additional subgroup analysis of patients who tapered the dose of at least one of the biologics found no differences in risk for these events:

  • Overall AEs: 94.6% vs 89.9%, OR 1.89 (95% CI 0.76-4.69)
  • SAEs: 12.3% vs 3.4%, OR 2.36 (95% CI 0.68-8.14)
  • Serious infections: 3.7% vs 0%, OR 2.54 (95% CI 0.42-15.26)

There were insufficient data to analyze overall infections in this subgroup analysis. And while the tapered doses seemed to be associated with fewer events, that observation should be interpreted with caution because of low numbers and wide confidence intervals, the researchers noted.

This study also considered efficacy, and in the five studies that were clinical trials, there was no clear advantage of combination therapy. However, in the single observational “real-life” study, there did appear to be clinical benefits with the combination of rituximab and etanercept.

“Since there are substantial differences in RA patients’ characteristics between randomized controlled trials and observational studies, the question of efficacy of a combination strategy should deserve further investigation in real-world settings,” Salmon’s group concluded.

Until further studies can confirm the findings of this analysis, clinicians should consider the risk/benefit ratio when considering combination therapy in RA, they wrote.

A strength of the study was the lack of heterogeneity in the included studies (I 2 = 0% for all), while a limitation was the lack of availability of information on background medications, such as corticosteroid and methotrexate.

Source References: Seminars in Arthritis & Rheumatism, Dec. 18, 2018, DOI:10.1016/j.semarthrit.2018.12.003

Study Highlights: Explanation of Findings

This systematic review included a meta-analysis of safety and efficacy of combination bDMARD treatment in RA patients. The researchers’ findings confirmed results from some earlier studies, which suggested that combination treatments increase SAEs risks, and the risk for serious infections in particular.

It is known that RA itself increases patients’ risks of infectious diseases, as well as respiratory and cardiovascular diseases. Researchers noted that a recent study indicated that 8% of RA patients needed to be hospitalized annually due to serious infections, and another meta-analysis found that in the short term, biologics were associated with statistically significant higher rates of total AEs and serious infections. But data was scarce, and the concern was that dual therapy would increase the risk of AEs, including serious infections.

Because 20%-40% of RA patients do not attain disease remission with one bDMARD, physicians do give some patients combination therapy, which is backed by some animal studies. These have suggested additional benefits with combinations of biologics, and recent data have shown promise for agents that target two molecules simultaneously. However, infection is still a major issue in RA patients, and also with biologic treatment of these patients. The new study’s aim was to develop a clearer picture of the risk/benefit ratio of treating RA patients for whom monotherapy did not work, with combinations of bDMARDs.

The researchers concluded that their meta-analysis “showed a modest but increased risk of total AEs, SAEs, but not in overall infections and serious infections in patients treated with two bDMARDs concomitantly. Interestingly, the risk of serious infections was significantly higher in patients receiving only full doses of bDMARDs, thus suggesting that using higher doses may be associated with higher AEs in particular serious infections,” they wrote.

When they performed an exploratory analysis on the subgroup of patients who received tapered doses of at least one of the bDMARDs, they did not observe any significant increase in overall AEs, SAEs, or serious infections. Again, these findings should be interpreted with caution due to the low number of events. Researchers recommended additional research to investigate dose tapering to increase safety in RA patients treated with combinations of bDMARDs.

They also noted that previous studies found a slightly lower incidence of SAEs than in their study.

The bottom line in the new study is that “overall, data from the five clinical trials included showed modest clinical effects with no clear evidence of an efficacy advantage in RA patients receiving combination therapy.” However, the one “real-life” (observational) study of rituximab and etanercept seemed to show clinical and biological benefits. The differences in patients in clinical trials and observational studies is “substantial” enough to warrant additional studies in “real-life” settings.

Original story for MedPage Today by Nancy Walsh

  • Reviewed by
    Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco
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