Herpes zoster more common with upadacitinib than adalimumab plus methotrexate in RA
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Among patients with rheumatoid arthritis, herpes zoster is more common in those treated with upadacitinib than with adalimumab plus methotrexate or with methotrexate alone, according to a speaker at ACR Convergence 2020.
The researchers also found that herpes zoster events were more common in those treated with 30 mg of upadacitinib compared with 15 mg.
“In general, we know that herpes zoster, or shingles, is a class effect so far with the JAK inhibitors,” Kevin Winthrop, MD, MPH, of Oregon Health & Science University, in Portland, told attendees at the virtual meeting. “It’s been noted to occur with increased frequency with tofacitinib, baricitinib and upadacitinib — all three approved JAK inhibitors currently in use for rheumatoid arthritis.”
“We know that rheumatoid arthritis increases the risk for herpes zoster itself, as do steroids, age and a number of other risk factors,” he added. “Patients with RA are at probably 1.5- or 2-fold higher risk than a similarly aged or sexed individual in the general population, and we know that JAK inhibitors roughly double that risk.”
To assess the incidence of, and risk for, herpes zoster among patients with RA who receive upadacitinib (Rinvoq, AbbVie), Winthrop and colleagues analyzed data from five randomized, phase 3 trials. These studies included the SELECT-EARLY, SELECT-MONOTHERAPY, SELECT-NEXT, SELECT-COMPARE and SELECT-BEYOND trials, of which four analyzed both 15 and 30 mg daily doses of upadacitinib.
The other trial — SELECT-COMPARE — evaluated only the 15 mg upadacitinib daily dose. The SELECT-COMPARE trials also examined herpes zoster incidence in patients who received combination therapy with adalimumab (Humira, AbbVie) and methotrexate, while the SELECT-EARLY study analyzed incidence in those treated with methotrexate alone. In all, Winthrop and colleagues studied data on 2,629 patients who received 15 mg of upadicitinib, 1,204 who received 30 mg of upadicitinib, 579 patients treated with adalimumab and methotrexate, and 314 individuals treated with methotrexate alone.
The researchers used univariate and multivariate Cox regression models to assess risk factors for herpes zoster. Few than 5% of included patients across the treatment groups reported receiving prior herpes zoster vaccination.
According to the researchers, herpes zoster occurred in 142 patients (3.1 per 100 patient-years; 95% CI, 2.6-3.7) who received 15 mg of upadacitinib, 126 pts (5.5; 95% CI, 4.5-6.5) who received 30 mg of upadacitinib, eight patients (1; 95% CI, 0.4-2.1) in the adalimumab-methotrexate group, and in five patients (1.1; 95% CI, 0.4-2.6) treated with methotrexate alone. Approximately 71% of herpes zoster cases with upadacitinib, as well as all cases in the adalimumab and methotrexate groups, involved a single dermatome.
Ophthalmic involvement was seen in 4.2% and 2.4% cases in the 15 and 30 mg upadacitinib groups, respectively. Meanwhile, unilateral involvement with multiple dermatomes was reported in 18.3% and 18.3% of cases, respectively. There was a single case of herpes zoster meningitis in a Japanese patient treated with 30 mg of upadacitinib. In the multivariate analyses, a prior history of herpes zoster and Asian region were associated with an increased risk for herpes zoster in both upadacitinib groups (P .01).
Patients aged 65 years or older demonstrated an increased risk for herpes zoster in the 15 mg upadacitinib group.
“Shingles events in patients with RA receiving upadacitinib in the phase 3 clinical trial program were more common in the 30 mg group, and they were also more common overall with upadacitinib as compared to the other exposure groups — adalimumab and methotrexate,” Winthrop said. “As we have seen with other JAK inhibitor programs, the majority of these cases are cutaneous in single or adjacent dermatomal cases. Risk factors for development of herpes zoster while receiving upadacitinib were prior history, Asian region and older age.”
“What was interesting about this risk factor analysis is the risk associated with prior zoster being counterintuitive,” he added. “There is something special about those people and they deserve further study. And the reason why the risk if higher in Asia, we still don’t know. This is something that we keep seeing and we don’t have a good explanation for it yet, so I look forward to that explanation.”
Perspective
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Treatment options are always needed as rheumatoid arthritis is a lifelong disease, but safety issues are always a concern. The select JAK1 inhibitor at 15 mg once a day already showed superiority to adalimumab in combination with methotrexate for ACR 50, HAQ-DI and pain reduction in the SELECT-COMPARE trial.
JAK inhibitors in general have caused concerns in relation to herpes zoster, infections, thromboembolic events and laboratory changes. The SELECT data looked at over 3500 and 4000 patient years of exposure. The findings were similar to the side effects of adalimumab as far as infections, malignancies, major adverse cardiovascular events and venous thromboembolic events. There were also higher rates of herpes zoster and elevations in creatinine phosphokinase.
As a health care provider, these are encouraging findings. We can protect our patients from herpes zoster with prophylactic vaccination with Shingrix, and can monitor labs every 2-3 months to look for any medication toxicity with patients on methotrexate.
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Winthrop K. Abstract 2002. Presented at: ACR Convergence 2020; November 5-9, 2020 (virtual meeting).
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