Analysis: Upadacitinib Raises Herpes Zoster Risk in Patients With RA

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Results of a pooled analysis showed patients with rheumatoid arthritis who take upadacitinib may be at increased risk of herpes zoster.

A new pooled analysis suggested patients with rheumatoid arthritis (RA) are at a higher risk of herpes zoster when they take upadacitinib (Rinvoa), compared with methotrexate and/or adalimumab (Humira).

The report adds to existing data suggesting Janus kinase (JAK) inhibitors can increase herpes zoster risk. The report was published in the Annals of the Rheumatic Diseases.

The general population has a lifetime risk of herpes zoster of about 30%, wrote corresponding author Kevin L. Winthrop, MD, MPH, of the Oregon Health and Science University. However, patients with RA have approximately double the risk.

“This risk can be further increased by immunomodulatory therapies prescribed for the treatment of RA, such as glucocorticoids, and some biologic disease-modifying antirheumatic drugs (bDMARDs),” Winthrop and colleagues wrote. “More recently, Janus kinase (JAK) inhibitors, a class of targeted synthetic DMARDs that modulate signaling downstream of cytokine receptors, have been linked with an increased risk of herpes zoster in patients with RA.”

Upadacitinib is a more selective JAK inhibitor, tailored to inhibit JAK1, as opposed to other Janus kinases. Winthrop and colleagues therefore questioned whether the drug would still carry the same degree of herpes zoster risk.


To find out, they assessed 6 randomized phase III trials conducted before June 30, 2020, and looked at herpes zoster incidence rates among patients receiving upadacitinib, methotrexate monotherapy, and methotrexate in combination with adalimumab.

The 6 studies included a total of 5,306 patients. Herpes zoster rates were calculated on a per 100 patient-years basis, with 95% confidence intervals (CIs).

Among patients prescribed methotrexate monotherapy, the incidence rate of herpes zoster was 0.8 cases per 100 patient-years (95%CI, 0.3-1.9). Among patients taking adalimumab plus methotrexate, the rate was 1.1 cases per 100 patient-years (95% CI, 0.5-1.9).

In patients prescribed upadacitinib, however, rates were higher and increased with dosing level. Patients prescribed 15 mg daily doses had a rate of 3 cases per 100 patient-years (95% CI, 2.6-3.5). Those given 30 mg per day had a rate of 5.3 cases per 100 patient-years (95% CI, 4.5-6.2). However, the authors also found that the majority of cases of herpes zoster in patients taking upadacitinib were non-serious and involved a single dermatome.

Winthrop and colleagues said patients with a history of herpes zoster, and those from Asia were at a particularly high risk.

“The reasons for this are currently unknown, although it has been suggested that genetic predisposition, regional differences in reporting and other cultural or medical factors could be involved,” they wrote. “Further research is warranted to determine why Asian patients with RA who are treated with JAK inhibitors, particularly those from East Asia, are at higher risk of herpes zoster.”

Unlike previous studies, the current analysis did not show a correlation between concomitant glucocorticoid use and herpes zoster risk. The data showed that herpes zoster risk was constant over time, “suggesting that there is not a ‘high-risk period’ shortly after starting therapy, as has been observed for serious bacterial infections in RA,” the authors noted.

Winthrop and colleagues said the design of their study does not allow for a direct comparison between upadacitinib and other JAK inhibitors, although they said their findings are roughly in line with the results of studies on similar JAK inhibitors.

“In conclusion, this analysis provides further support for the need for continued vigilance and monitoring for signs of herpes zoster in patients receiving [upadacitinib], particularly in Asian populations and those with a history of herpes zoster,” the investigators concluded.


Winthrop KL, Nash P, Yamaoka K, et al. Incidence and risk factors for herpes zoster in patients with rheumatoid arthritis receiving upadacitinib: a pooled analysis of six phase III clinical trials. Ann Rheum Dis. Published online October 6, 20201. doi:10.1136/annrheumdis-2021-220822