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Abatacept Versus TNF Inhibitors in RA: What Are the Risks of Infections? (CME/CE)

Action Points

  • Note that researchers using a propensity score-matched analysis of 11,248 pairs of patients with rheumatoid arthritis (RA) starting abatacept or tumor necrosis factor inhibitors (TNFis), found that the risk and incidence rate of hospitalized infections were lower among abatacept initiators (HR 0.78, 95% CI 0.64-0.95).
  • Be aware that in a subgroup analysis, risks for infection did not differ between etanercept and abatacept initiators, but the risk of infection for abatacept was reduced in comparison to infliximab.

CME Author: Zeena Nackerdien

Study Authors: Sarah K. Chen, MD, Katherine P. Liao, MD, MPH, et al.

Target Audience and Goal Statement: Rheumatologists and primary care physicians

The goal was to learn more about the comparative risk of hospitalized infections among patients with rheumatoid arthritis (RA) who started abatacept versus a tumor necrosis factor inhibitor (TNFi).

Background and Questions Addressed:

Game-changing biological agents used for the treatment of rheumatic and immunological conditions can also cause adverse events (AEs), including the elevated risk of severe infection and the risk for reactivation of tuberculosis. Some of the AEs may be caused by the functional inhibition of biologic-agent-targeted antigens, but the pleiotropic reasons for the pathogenesis of other AEs may complicate their prediction.

Because abatacept and TNFi have similar efficacies, the choice between the two biologic therapies mainly depends on minimizing the risk of infection. Therefore, the investigators chose to address the following questions:

  • What is the risk of hospitalized infections among patients with RA who started abatacept versus TNFi in a real-world setting?
  • Could they prove or disprove their initial hypothesis that the rates and risk of hospitalized infections would be reduced among patients with RA starting abatacept compared to TNFi?

Synopsis and Perspective:

A paradigm shift has occurred over the last decade in the treatment of RA, particularly for patients with arthritis who remained unresponsive to conventional disease-modifying antirheumatic drugs (DMARDs). Recently, it has become possible to control RA with several biological agents e.g., antitumor necrosis factor agents (infliximab, etanercept, adalimumab), an inhibitor of interleukin-(IL-)-6 receptor (tocilizumab), a small-molecule Janus-associated-kinase (Jak) inhibitor (tofacitinib), and an inhibitor of T-cell costimulation (abatacept). But the rise in use of these agents has been correlated with hospitalized infections such as general pneumonia and herpes zoster infections in compromised patients. Whether biological DMARDs or targeted synthetic DMARDs cause these infections remains a subject of ongoing investigation.

Seoyoung C. Kim, MD, ScD, and colleagues from Brigham and Women’s Hospital and Harvard Medical School in Boston used the Truven Marketscan database from 2006 to 2015 to identify adults with 2 or more RA diagnosis codes who had newly started on abatacept or TNFi. During the baseline period, abatacept initiators were allowed to use non-biologic DMARDs and TNFi and TNFi initiators were allowed to use non-biologic DMARDs and abatacept. Steroid use in the 30 days prior to study enrollment was common in both groups (44% for abatacept, 42% for TNFis). A total of 58% of the abatacept group had previously used TNFi, whereas only 4% of the TNFi group had prior exposure to abatacept.

The investigators identified 13,015 abatacept initiators who were propensity-score (PS) matched (1:1 ratio) to 52,719 TNFi initiators. This statistical technique controlled for more than 40 potential confounders at the same time, to generate a PS for the predicted probability of a patients starting abatacept versus TNFi given patient characteristics at baseline. The analysis was performed on 11,248 PS-matched pairs of abatacept and TNFi initiators (83% female with a mean age of 55 years; and 84% female with a mean age of 56 years, respectively).

Following hospitalization for the main diagnosis, the primary outcome was a composite endpoint of any infection acquired in that setting, including bacterial, viral, and other opportunistic infections. Secondary endpoints included bacterial infection, herpes zoster, and infections by affected organ system (bone/joint, cardiac, gastrointestinal, genitourinary, respiratory, skin/soft tissue, neurologic), based on the principal diagnosis for hospitalization.

Among abatacept and TNFi initiators, the infection rate (IR) per 1,000 person years for any hospitalized infection was 37 and 47, respectively. No significant difference was found when comparing the hazard ratio (HR) for the risk of any hospitalized infection linked to abatacept versus adalimumab and etanercept; the HR for the risk of any hospitalized infection associated with abatacept versus TNFi was (HR 0.78, 95% CI 0.64-0.95) and remained lower versus infliximab (HR 0.63, 95% CI 0.47-0.85). Risks of secondary outcomes were similar between the PS-matched groups, with the exception of a lower risk for abatacept initiators with respect to respiratory infections.

“In this large cohort of RA patients who used abatacept or TNFi as a first or second-line biologic agent, we found a lower risk of hospitalized infection after initiating abatacept versus TNFi, which was mostly driven by infliximab,” the authors concluded.

Study limitations were potential confounders such as partially measured covariates and a lack of information on other covariates that may impact the risk of infection. Steroid use – a covariate used in the analysis and an independent risk factor for infection – could be indirectly related to disease activity. The investigators were also unable to collect and adjust the results for socioeconomic status, race, and ethnicity.

Source Reference: Arthritis Care & Research, Dec. 20, 2018; DOI: 10.1002/acr.23824

Study Highlights: Explanation of Findings

Using a PS-matched study of 11,248 pairs of patients with RA starting abatacept or TNFi, the incidence rate and risk of hospitalized infections were lower among abatacept initiators (HR 0.78, 95% CI 0.64-0.95). A key strength of this study was the use of PS-matching to “minimize confounding by indication and control for imbalance among the abatacept and TNFi treatment groups to including patient characteristics, regional variation and adjusted for a large number of baseline confounders between the two cohorts such as prior antibiotic and antiviral use, and history of vaccinations,” the authors wrote.

IRs in this study were comparable to literature values of 31 per 1,000 person-years for abatacept and 60 per 1,000 person-years for TNFi obtained in separate studies. The results were in line with a separate analysis of Medicare data from 2006 to 2011. This study showed that, for biologic-agent-treated patients with RA, the subsequent exposure to etanercept, infliximab, or rituximab was associated with a greater 1-year risk of hospitalized infection compared with the risk associated with exposure to abatacept.

The American College of Rheumatology made a conditional recommendation in 2015 to use herpes zoster immunization at age 50 and older prior to starting biologics, considering the higher infection risk due to RA and its treatments, which is in keeping with FDA approval for that vaccine, but contrasts with the CDC recommendations to use the vaccine in the general population starting at age 60.

The authors performed a separate analysis comparing the risk of hospitalized infections in abatacept initiators versus the 3 most commonly prescribed TNFis and found that the reduced risk for hospitalized infections in abatacept initiators was driven mostly by infliximab initiators (HR 0.63, 95% CI 0.47-0.85). Infection risk was not significantly higher when the authors compared abatacept to etanercept (HR 1.19, 95% CI 0.92-1.53) and remained numerically lower for abatacept versus adalimumab initiators (HR 0.78, 95% CI 0.57-1.06).

Different routes of administration, pharmacokinetic/pharmacodynamic profiles, and structures may account for the results. Adalimumab and etanercept are administered as subcutaneous injections, while infliximab is given as an intravenous infusion. The peak serum concentration of infliximab is higher than the other two agents. Etanercept clearance is higher compared to infliximab and adalimumab, resulting in lower steady-state drug levels. Compared to infliximab (up to 3:1), the binding avidity to TNF subunits is less for etanercept (1:1 ratio). Infliximab is a monoclonal antibody against TNF that can exert a cytotoxic effect by binding to cells that express TNF on their membranes, whereas etanercept is a TNF receptor fusion protein that binds only to circulating TNF.

As to the lower risk of infection with abatacept, the reason is “unknown but may potentially be due to the fact that abatacept indirectly blocks T-cell costimulation rather than the mechanism of directly inhibiting cytokines for TNFis,” Kim and colleagues wrote.

Nancy Walsh wrote the original story for MedPage Today.


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