Patients with rheumatoid arthritis (RA) who were treated with a combination of two biologic agents had an increased risk for adverse events, a meta-analysis showed.
In a pooled analysis that included 623 patients, 94.6% of those receiving two biologics experienced adverse events 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), according to Jean-Hugues Salmon, MD, and colleagues from Reims University Hospitals in France.
Moreover, serious adverse events 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), the researchers reported in Seminars in Arthritis & Rheumatism.
Many therapeutic options now exist for the treatment of rheumatoid arthritis, including multiple types of biologic agents. However, some 20% to 40% of patients don’t achieve remission.
Some animal studies have suggested additional benefits with combinations of biologics, and recent data have shown promise for agents that target two molecules simultaneously.
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.
To examine the available evidence on this, Salmon and colleagues conducted a systematic review of the literature, identifying six studies. Combinations used in these studies were etanercept (Enbrel) plus anakinra, abatacept (Orencia) plus etanercept, rituximab (Rituxan) plus etanercept, etanercept or adalimumab (Humira) plus rituximab, rituximab plus tocilizumab (Actemra), and abatacept plus a tumor necrosis inhibitor or anakinra (Kineret).
Overall, there were 410 patients treated with a combination of biologics, while 213 controls were given a single biologic as monotherapy or with placebo.
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, though it did not reach significance (5.4% vs 0.47%, OR 3.46, 95% CI 1-11.97).
Two studies evaluated malignancy risks. In one, neoplasms were observed in 6.8% of the combination group and 1.6% of the control group, and in the other, there were no malignancies reported.
The researchers then performed a subgroup analysis that included only patients who were given full doses of the biologics.
In that analysis, the rate of overall adverse events was not significantly different (94.4% vs 89%, OR 2.15, 95% CI 1-4.62), but significantly higher risks were seen for serious adverse events (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 seen 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 adverse events: 94.6% vs 89.9%, OR 1.89 (95% CI 0.76-4.69)
- Serious adverse events: 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 pointed out.
They 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 appeared 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 wrote.
Until further studies can confirm the findings of this analysis, clinicians should consider the risk/benefit ratio when considering combination therapy in RA, they concluded.
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.
The authors reported no financial conflicts.