Tofacitinib Linked to Twofold Greater Risk for Herpes Zoster in RA
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Among patients with rheumatoid arthritis, tofacitinib is associated with a 2-fold greater risk for herpes zoster infection compared with etanercept, abatacept, adalimumab, golimumab, certolizumab, infliximab and tocilizumab, according to data published in The Lancet Rheumatology.
“While an increased risk of infection is a well-known side effect for all biologic or targeted synthetic DMARDs, such as tofacitinib, to our knowledge this is the first study assessing serious infection risk in tofacitinib vs. seven biologic DMARDs — including all five TNF inhibitors, abatacept and tocilizumab — in head-to-head comparison in routine care,” Seoyoung C. Kim, MD, of Brigham and Women's Hospital and Harvard Medical School, told Healio Rheumatology.
“Our study also includes the most comprehensive comparative assessment of the risk of specific types of serious infections,” she added. “Furthermore, our study provides generalizable real-world data as it includes RA patients from both U.S. public and private health plans.”
To analyze the risk for serious infection among patients with RA receiving tofacitinib (Xeljanz, Pfizer) compared with seven biologic DMARDs, Pawar and colleagues conducted a cohort study of public and private health insurance programs. The researchers studied data from 130,718 adults with RA included in Medicare, from 2012 to 2015, as well as Optum Clinformatics from 2012 to 2018, and IBM MarketScan from 2012 to 2017. Eligible patients had one inpatient, or two or more outpatients visits at least 7 days apart, for RA.
The primary outcome was hospital admission for serious infection, included bacterial, viral and opportunistic infections, as recorded by inpatient principle-diagnosis codes. Secondary outcomes included individual infection types, including herpes zoster. The researchers adjusted their data for more than 60 confounders using propensity score-based inverse probability treatment weighting in each database.
According to the researchers, 3,140 serious infections occurred during 100,790 person-years of follow-up, representing a crude incidence rate of 3.12 per 100 person-years (95% CI, 3.01-3.23). The adjusted HRs for serious infection associated with tofacitinib were 1.41 (95% CI, 1.15-1.73) compared with etanercept (Enbrel, Amgen); 1.2 (95% CI, 0.97-1.49) compared with abatacept (Orencia, Bristol-Myers Squibb); 1.23 (95% CI, 0.94-1.62) compared with golimumab (Simponi, Janssen); and 1.17 (95% CI, 0.89-1.53) compared with tocilizumab (Actemra, Genentech).
The risk for serious infection associated with tofacitinib was similar to both adalimumab (Humira, AbbVie) and certolizumab (Cimzia, UCB), with adjusted HRs of 1.06 (95% CI, 0.87-1.3) and 1.02 (95% CI, 0.8-1.29), respectively. However, the risk for serious infection with tofacitinib was lower than that of infliximab (Remicade, Janssen), with an adjusted hazard ratio of 0.81 (95% CI, 0.65-1). Regarding herpes zoster specifically, tofacitinib was associated with a 2-fold higher risk compared with all biologic DMARDs.
“We found potential differences between tofacitinib and several biologic DMARDs in the risk for hospitalization with serious infection,” Kim said. “The risk for serious infection was 40% increased among tofacitinib initiators vs. etanercept initiators.”
“Our results provide comprehensive head-to-head assessment of infection risk related to biologic DMARDs or tofacitinib,” she added. “Such information would be useful in making more evidence-based treatment decision in a clinical setting. Furthermore, our study underlines the importance of providing vaccination for herpes zoster in patients before initiating DMARDs, in particular among those starting tofacitinib.” – by Jason Laday
Disclosure: Kim reports research grants to the Brigham and Women's Hospital from AbbVie, Bristol-Myers Squibb, Pfizer and Roche. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Carolyn Zic, RN, BSN, CPN
The outcomes from this multidatabase cohort study by Pawar and colleagues reinforces to clinicians the importance in educating patients on the risks of infection when they are receiving targeted synthetic DMARD therapy and biologic DMARD therapy. Although it may be commonly understood that patients on any type of DMARD therapy are at risk for serious infections, this study compared the risk of tofacitinib (target synthetic DMARD) to the different biologic DMARDs.
The differences that this study found in the risk of serious infection in patients with RA who are on DMARD therapy may prove useful to clinicians when weighing treatment options for patients. Clinicians can use this as an opportunity to reiterate to patients not only the risk of infection but also the signs and symptoms of infection, as well as when and where to seek treatment.
Patients should be educated on the different types of infections that they are at risk of contracting; this is especially true when there is data that indicates different DMARDS are more likely to put patients at a higher risk for certain infections. For example, the researchers concluded from data obtained in this study that patients on tofacitinib were at a higher risk for herpes zoster infections. This highlights how imperative it is for clinicians to monitor a patient’s immunization status and ensure that they are up to date with important recommended vaccinations.
Additionally, this research lays a foundation for further studies for infection risk in other patient populations who are receiving DMARD therapies. Further studies such as this will allow clinicians to treat a patient’s disease while weighing the risks and side effects of medication in order to obtain the best possible treatment outcomes.
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David A. McLain, MD, FACP, FACR
Serious infection is a major concern for rheumatologists treating rheumatoid arthritis with biologic DMARDs and JAK inhibitors. In this retrospective study using Medicare and commercial databases, the researchers searched for bacterial, viral and opportunistic infections, including herpes zoster, among almost 131,000 patients with RA taking tofacitinib vs. one of seven biologic DMARDs.
The risk for infection was elevated with tofacitinib vs. the other biologic DMARDs — but this was not significant — with several exceptions. There was a 1.4 times greater risk of infection with tofacitinib than etanercept and a lower risk of serious infection with tofacitinib than with infliximab — again not statistically significant. The composite serious infection rates per 100 patient years were for tofacitinib (3.52), etanercept (2.32) and infliximab (5.75).
There was a doubling in the risk of herpes zoster with tofacitinib vs. the biologic DMARDs. Looking at the actual data of the reported incidence per 100 patient years has tofacitinib (4.28) vs. abatacept (2.74), adalimumab (2.21), certolizumab (2.53), etanercept (2.22), golimumab (2.54), infliximab (3.28) and tocilizumab (2.44).
I think there are three important observations from the data. First, the risk of herpes zoster is not zero with any of these agents. Second, we rarely mention herpes in the context of biologic DMARDs vs. JAK inhibitors when counseling patients. Third, the absolute risk difference of herpes zoster between tofacitinib vs. biologic DMRDs in this study is 1 to 2 episodes per 100 patient years, which is a very small risk difference. We focus on “doubling the risk” of zoster rather than looking at this absolute risk difference.
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