Treatment Combinations in RA May Not Be So Unique After All

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Methotrexate is the standard initial treatment for patients with rheumatoid arthritis, but if it fails to control the disease, adding a biologic is one of the options. But which one to choose?

German researchers have conducted a systematic review and network meta-analysis to try to answer this question. Their findings, published in The BMJ, show that in most cases the choice makes little difference: they found little difference between the benefits and harms of different methotrexate/biologic combinations.

They identified 45 randomised controlled trials with a minimum duration of 24 weeks that aimed to compare the benefits and harms of biological medicines combined with methotrexate in patients with rheumatoid arthritis after methotrexate failure. These trials were assessed for a systematic review, which formed part of a health technology assessment of biological medicines in rheumatoid arthritis by the German health technology assessment agency, the Institute for Quality and Efficiency in Health Care (IQWiG).

The researchers then conducted a network meta-analysis using data from 38 sufficiently similar studies, including aggregate results from reanalysed individual patient data provided by the sponsors of some of the studies, to compare the different combinations. Overall, the researchers were able to compare eight methotrexate/biologic combinations; these were methotrexate combined with abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab or tocilizumab. Recently approved Janus kinase inhibitors (JAK) could not be included.

“Our study did not show major differences between the biologic/methotrexate combinations we have investigated,” said Dr Beate Wieseler, head of the department of drug assessment at the Institute for Quality and Efficiency in Health Care (IQWiG) in Köln, Germany. “For patients with rheumatoid arthritis after methotrexate failure, our network meta-analysis using rigorous methods showed overall minor differences in benefits and harms between biological medicines in combination with methotrexate.”

She added: “An exception was anakinra which resulted in less remission and low disease activity than the other biologics.”

“Except for anakinra, the lack of proven added benefit of one biologic combined with methotrexate over the other means that these drugs are similar suitable treatment choices. Thus, treatment choice could consider comorbidities and possible relevance of adverse events and patient preference.”

In terms of harms, the certolizumab/methotrexate combination showed more serious adverse events and infections than the other biologic/methotrexate combinations, she added.

“Given minor differences between the biologics the costs of treatment can also be considered,” Dr Wieseler said. “This is even more relevant with the increasing number of biosimilars becoming available.”

Some outcomes for particular combinations had very wide 95% confidence intervals, potentially implying unidentified differences between the eight biological medicines, the researchers pointed out, but these wide 95% confidence intervals were less prominent for low disease activity, serious adverse events, and infections.

The researchers did not look at whether any specific subgroups of patients, such as those with particular comorbidities or taking certain concomitant treatments, might benefit from combining methotrexate with a specific biologic.

They said their analysis was hampered by a lack of long-term direct comparative studies and more studies were needed. The lack of head-to-head trials, meant that their findings were based mainly on indirect comparisons.

“We found that the study landscape in rheumatology is poor with only few studies directly comparing different biologics and few long-term studies,” Dr Wieseler said. “Given the fact that several biologics have been available for about 20 years and that rheumatoid arthritis affects many patients, the dominance of placebo-controlled short-term studies indicates a failure in study planning. Rheumatologist should aim to inform their practice with relevant studies directly comparing different treatment options in robust study designs.”

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REFERENCES

Janke K, Biester K, Krause D et al. "Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic review and network meta-analysis including aggregate results from reanalysed individual patient data." BMJ. 2020;370:m2288 http://dx.doi.org/10.1136 bmj.m2288

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