Patients with rheumatoid arthritis treated with baricitinib (Olumiant) were at increased risk for infection in a dose-dependent manner, a review of data from eight double-blind randomized trials and one long-term extension study found.
The incidence rates of treatment-emergent infections in all patients enrolled in the included trials were 75.9 per 100 patient-years for placebo, 84 per 100 for patients receiving 2-mg baricitinib per day (P not significant vs placebo), and 88.4 per 100 for those given 4 mg of baricitinib per day (P≤0.001), according to Kevin Winthrop, MD, of Oregon Health and Science University in Portland, and colleagues.
But the incidence rates of serious infections were similar in the placebo and baricitinib groups, showing no increased incidence over time, the researchers reported online in Annals of the Rheumatic Diseases.
Patients with rheumatoid arthritis have an increased likelihood of infection, because of the underlying disease, comorbidities, and use of immunosuppressive medications such as conventional disease-modifying antirheumatic drugs (DMARDs) and biologics.
Treatment with the emerging class of targeted synthetic DMARDs known as JAK inhibitors also has been implicated in several types of infection, but long-term data are needed to determine the extent and nature of the risk.
Therefore, Winthrop and colleagues pooled data from eight randomized trials and an ongoing extension study in which all patients received 2- or 4-mg baricitinib per day, to characterize the rates and types of infection. Their analysis included 3,492 patients and 7,860 patient-years of exposure.
For serious infections, the incidence rates in the placebo-controlled trials per 100 patient-years were 4.2, 4.2, and 3.8 for the placebo, 2-mg, and 4-mg groups, respectively, and in the extension study, the rates were 3.3 and 4.8 per 100 in the 2-mg and 4-mg groups, respectively. For all baricitinib-treated patients, the incidence rate was 3.0 (95% CI 2.6-3.4) per 100.
The most common types of serious infections were pneumonia (0.6 per 100 patient-years), herpes zoster (0.4 per 100), urinary tract infections (0.2 per 100), cellulitis (0.2 per 100), and sepsis (0.2 per 100). Factors that were associated with serious infections included age 65 and older, being underweight or overweight, residence in Asia, and the use of glucocorticoids.
Seven patients died of infections, for an incidence rate of 0.2 per 100 patient-years.
A total of 11 cases of tuberculosis were reported, all in endemic areas such as Argentina, India, and South Africa, and in patients on the higher dose. All stopped their baricitinib and received anti-tuberculosis treatment; six recovered and two resumed baricitinib, one died of disseminated disease, and the remainder were still receiving treatment for tuberculosis at the time of study completion.
Herpes zoster has been reported in patients receiving other JAK inhibitors such as tofacitinib (Xeljanz), particularly at higher doses and in Asian patients. Among patients in the placebo-controlled baricitinib trials, the incidence rate for herpes zoster was significantly higher in the 4-mg group compared with placebo (4.3 vs 1.0 per 100, P≤0.01), though not in the 2-mg group (3.1 per 100). Most cases were mild to moderate, with 12% being serious and 8.5% being multidermatomal. Risk factors included residence in Asia and older age, and treatment guidelines recommend vaccination before initiating a JAK inhibitor in patients 50 and older.
Opportunistic infections were uncommon, including cytomegalovirus in five patients, pneumocystis in four, and candidiasis in 10. Other unusual infections included Epstein-Barr virus in one patient, hepatitis B in two, and hepatitis E in two.
Several potential mechanisms could contribute to the elevated infection risk in patients treated with agents acting through the JAK-STAT/interleukin-6 (IL-6) signaling pathway, according to the researchers. “IL-6 plays an important role in fighting infection as a lymphocyte-stimulating factor. Inhibition of IL-6 could lead to impaired innate and adaptive immunity, important in defence against viral, parasitic and bacterial infections,” they explained.
Other factors that could contribute to infection with JAK inhibition include inhibition of natural killer cells and T cells, as well as interference with interferon signaling, they suggested.
This analysis should be followed by longer-term population-based studies to more fully characterize the real-world infection risks with baricitinib and other targeted therapies among patients with rheumatoid arthritis, Winthrop and colleagues concluded.
A limitation of the study was the use of concomitant DMARDs among patients receiving placebo, which also could influence infection risks.
The study was funded by Eli Lilly under license from Incyte.
The authors reported financial relationships with multiple companies, including Eli Lilly, Bristol-Myers Squibb, Pfizer, AbbVie, Amgen, Galapagos, Gilead, UCB, Eisai, Ono, Takeda, Novartis, Asahi Kasei, Astellas, AstraZeneca, Chugai, Daiichi Sankyo, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Taiho, Taisho Toyama, GlaxoSmithKline, Celgene, Centrexion, Genentech, Merck, Samsung, Sanofi-Aventis, Taiho, and Medimmune.