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Two new studies delving into the relative safety of biologic drugs prescribed for rheumatoid arthritis (RA) have concluded that real-world applications of abatacept and tumor necrosis factor inhibitors (TNFi’s) are comparable to more conventional therapies in their associated risk of serious infections.
Triple Therapy
One study, in Arthritis Care & Research, found the risk of serious infection, including all bacterial and opportunistic infections requiring hospitalization or herpes zoster, wasn’t substantially different between TNFi plus methotrexate (MTX) therapy and triple therapy (MTX, hydroxychloroquine and sulfasalazine).1
The study was led by Seoyoung C. Kim, MD, ScD, MSCE, associate professor of medicine, Harvard Medical School, Boston. “While we still need to discuss other potential adverse events with our patients, at least our data provide real-world evidence on the risk of infection—one of the most common safety events—from the direct comparison,” she says. Dr. Kim is also a member of the Division of Pharmacoepidemiology and Pharmacoeconomics, and of the Division of Rheumatology, Immunology and Allergy at Brigham and Women’s Hospital, Boston.
Dr. Kim’s cohort study, based on claims data from Truven MarketScan, included 45,208 TNFi plus MTX initiators and 1,387 triple therapy initiators. The study calculated an incidence rate of 2.46 per 100 person-years for any serious infection in the TNFi plus MTX cohort and an incidence rate of 2.03 per 100 person-years in the triple therapy cohort. Using propensity score-based fine stratification and weighting, the researchers calculated a hazards ratio (with a 95% confidence interval) of 1.23 (0.87–1.74) for TNFi plus MTX versus triple therapy for any serious infection.
Abatacept
The second study, published in Arthritis Research & Therapy, found that abatacept was “well tolerated and did not result in an overall increased risk of malignancies, infections or autoimmune diseases” compared with other biologic disease-modifying anti-rheumatic drugs (bDMARDs) or conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).2
Senior author Kaleb Michaud, PhD, associate professor of immunology and rheumatology, University of Nebraska Medical Center, Omaha and co-director of FORWARD, the National Databank for Rheumatic Diseases, Wichita, Kan., says his team worked on the observational study for more than a decade.
The study reviewed FORWARD-registered RA patients, including 1,496 who initiated abatacept, 3,490 who initiated another bDMARD, and 1,520 who initiated a csDMARD. Based on the hazard ratios, patients on abatacept had a lower risk of hospitalized infections, although the analysis yielded wide confidence intervals in comparisons to other bDMARDs (0.37 [0.18–0.75]) and to csDMARDs (0.31 [0.09–1.05]). The comparisons found no statistically significant difference in the risk of malignancies or psoriasis, albeit again with wide confidence intervals.
Discussion
Dr. Michaud says rheumatologists have had years to optimize DMARD therapies based on patients’ preferences and medical histories, comorbidities, risk factors and other considerations, meaning they’ve been able to increasingly refine their prescription strategies. “What that tells me is that when you look at observational data and you see that everybody has a similar risk, it is a similar risk based on real-world ways of prescribing,” he says.
The observational studies, Dr. Kim emphasizes, cannot prove causality, but instead attempted to control for multiple confounders to point out associations. She noted the high confidence intervals in Dr. Michaud’s study, while conceding that her own study’s estimates and conclusions were limited by the “quite small” number of patients initiating triple therapy, even within a very large population-
based insurance claims database.
More broadly, Dr. Michaud agrees the small percentage of RA patients taking triple therapy is complicating the difficult task of conducting properly controlled safety analyses. Confounding by indication can intrude as well: New patients at high risk of infection are less likely to be prescribed a TNFi, while patients averse to taking multiple pills will be less likely to have a triple therapy prescription. Early on, patients with worse disease activity often received TNFi because they weren’t responding well to existing therapies and needed something new; their higher disease activity, though, already put them at higher risk for serious infection.
“It’s incredibly important that we conduct prospective, longitudinal studies looking at the safety of these drugs,” Dr. Michaud says. Patient cohorts can also change fundamentally in their makeup. Twenty years ago, those taking csDMARDs would have been the norm, but such patients are now more of an exception, whether due to preference, comorbidities, age, financial pressure or other factors.
After 10-plus years of data collection and efforts to adjust for confounding factors, seeing “no obvious signals of concern” regarding the risk of the assessed biologics compared with conventional therapies should be reassuring, Dr. Michaud says.
“It doesn’t mean that all of these drugs are safe, but we’ve got a general sense that the overall risks are somewhat comparable,” he says. “We will continue to monitor it, and the doctors will continue to learn what’s better and what’s not for their patients. It is definitely learning as we go.”
Some past observational studies have suggested a higher risk of serious infections among patients taking TNFi’s. Dr. Kim, though, points out that the studies used different reference groups and that relative measures can depend on which patient groups are used for comparison and on how their baseline characteristics are accounted for.
“Getting appropriate controls is by far the most difficult aspect of safety registries,” Dr. Michaud adds. For each patient, the ideal comparison for the therapy of choice might be the first runner-up. But, based on the myriad variables that go into choosing the best options and thanks to the ever-greater variety of options to choose from, the top two choices in any group of 10 patients may be vastly different.
“That’s what makes it so challenging,” Dr. Michaud says. He’s encouraged by the expansion of administrative datasets, but stresses their value also hinges on continued improvement in capturing granular data, such as comorbidities, disease activity and other factors that help drive prescription choices and patient outcomes.
Dr. Kim says her paper is only one part of a wider effort to conduct multiple, real-world, comparative safety studies of various bDMARDs and targeted synthetic DMARDs.
Bottom Line
Both Dr. Kim and Dr. Michaud are careful to emphasize the importance of educating rheumatologists and patients that triple therapy is still an effective weapon in the RA arsenal and may yield considerable cost savings over biologic therapies.
“While there is still a huge difference in the cost between the two treatment strategies (TNFi plus MTX versus triple therapy), it is reassuring to know the risk for serious infection is not substantially different between the two groups,” Dr. Kim says.
Bryn Nelson, PhD, is a medical journalist based in Seattle.
References
- Kang EH, Jin Y, Tong AY, et al. Risk of serious infection among initiators of TNF inhibitors plus methotrexate versus triple therapy for rheumatoid arthritis: A cohort study. Arthritis Care Res (Hoboken). 2019 Aug 3. doi: 10.1002/acr.24038. [Online ahead of print].
- Ozen G, Pedro S, Schumacher R, et al. Safety of abatacept compared with other biologic and conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: Data from an observational study. Arthritis Res Ther. 2019 Jun 7;21(1):141.
