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Vaccinate and consider tofacitinib monotherapy to prevent herpes zoster in RA

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Live zoster vaccine: Who, when, how

At a symposium during the 2015 annual meeting of the American College of Rheumatology, William Schaffner, MD, highlighted the connection between the seriousness of an infection, and the respect one has for the solution.

Dr. Schaffner said that “if you don’t fear the infection, you won’t value the solution.” Herpes zoster (HZ) should be feared, and the solution – the live zoster vaccine – valued.

Dr. John J. Cush

Dr. John J. Cush

HZ will affect one-third of adults in the United States during their lifetime, and it comes with a 20% risk of postherpetic neuralgia; the risks are even greater in certain populations – particularly those with autoimmune disease – and the risk is compounded by therapeutics used in such patients.

Live zoster vaccine (LZV) was approved in 2006 on the basis of a trial involving more than 38,500 adults over age 60 years, which showed a 51% HZ prevention rate (64% protection in the 60-69 year age group) and a two-thirds reduction in postherpetic neuralgia. Complications and disseminated infection were rare.

HZ vaccination should be offered regardless of a history of varicella infection or prior shingles, as HZ may recur.

There is an imperative need to know who is at risk, when and how they should be vaccinated, and what other risk reduction measures should be considered.

John J. Cush, MD, is director of clinical rheumatology at Baylor Scott & White Research Institute and professor of medicine and rheumatology at Baylor University Medical Center, both in Dallas. His comments are taken from his editorial accompanying the two studies by Winthrop et al. (Arthritis Rheumatol. 2017 Aug 28. doi: 10.1002/art.40188).



The results of two studies of tofacitinib treatment for rheumatoid arthritis offer evidence to support the use of the drug without concomitant conventional synthetic disease-modifying antirheumatic drugs in order to reduce the risk of risk of herpes zoster infection and the safety of starting the drug 2-3 weeks after administering live zoster vaccine.

The risk of herpes zoster infection was elevated among rheumatoid arthritis (RA) patients receiving tofacitinib (Xeljanz) with glucocorticoids, compared with those receiving tofacitinib monotherapy, according to an analysis of data from 19 phase 2, phase 3, and long-term extension studies of tofacitinib.

Dr. Kevin Winthrop

The finding suggests that tofacitinib monotherapy, which has shown similar efficacy as tofacitinib in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or glucocorticoids, “could represent a risk-reduction strategy for physicians and patients with regards to [herpes zoster] and provide an effective treatment strategy for the reduction of the signs and symptoms of RA, provided the patients’ RA remains controlled, Kevin L. Winthrop, MD, of Oregon Health and Science University, Portland, and his colleagues reported online in Arthritis & Rheumatology (2017 Aug 28. doi: 10.1002/art.40189).

“Further, physicians should continue to consider shingles vaccination prior to starting tofacitinib or biologic therapy,” they wrote.

Dr. Winthrop is the first author of a separate phase 2 study that also appears in Arthritis & Rheumatology, which suggests that live zoster vaccine (LZV) is safe in RA patients who start tofacitinib 2-3 weeks after vaccination. The study also showed that varicella-zoster virus (VZV)-specific humoral and cell-mediated immune responses to LZV are similar in tofacitinib- and placebo-treated patients.

“Our study provides the first data with this vaccine in the RA setting and suggests that these patients, even while using nonbiologic DMARDs at the time of vaccination, are capable of mounting adequate immune responses to this vaccine. Further, our data suggest that the use of tofacitinib following VZV vaccination in the RA setting did not impact negatively the vaccine immunogenicity or the time course of the immune response to the vaccine,” he and his colleagues wrote (Arthritis Rheumatol. 2017 Aug 28. doi: 10.1002/art.40187).

Increased herpes zoster risk in combination therapy

In the first study, herpes zoster (HZ) was reported in 636 of 6,192 patients over a median follow-up of 3 years of tofacitinib exposure, for an incident rate (IR) of 4.0 per 100 patient-years. However, IRs varied by region, ranging from 2.4 in Eastern Europe to 8.0 and 8.4 in Japan and Korea, respectively.

Further, in phase 3 studies, the IRs varied by tofacitinib dose, background use of conventional csDMARDs, and baseline glucocorticoid use; the rates were lowest among patients on tofacitinib monotherapy at a dose of 5 mg twice daily (IR, 0.6), and highest in those on tofacitinib at 10 mg twice daily with csDMARDs and glucocorticoids (IR, 5.4), the investigators found.

Independent risk factors for HZ included age, glucocorticoid use, tofacitinib dose, and enrollment within Asia, they said.

“Shingles, or reactivation of varicella virus, is a common and potentially debilitating illness. Around one-third of the general population will develop HZ in their lifetime, and approximately 10% of these patients develop postherpetic neuralgia which can last months to years and cause significant pain and morbidity,” the investigators wrote, adding that RA patients are at 1.5- to 2-fold greater risk vs. similarly aged individuals in the general population.

RA itself and treatment with glucocorticoids are known to increase HZ risk, but recent data have suggested that Janus kinase inhibitors, such as tofacitinib, and tumor necrosis factor antagonists are also associated with a higher rate of HZ. Additionally, a theoretical risk exists with various csDMARDs, they said.

“Given the increased risk of HZ observed among patients with RA versus the general population and the risk associated with RA therapies, it is possible that risk of HZ may be further increased when such therapies are combined,” they wrote.

Indeed, the findings of the study demonstrate an increased risk of HZ with tofacitinib in combination with glucocorticoids vs. tofacitinib monotherapy.

Further research is necessary to understand why Japanese and Korean patients are at elevated risk, and to understand the mechanism for the effects of combination therapy on VZV reactivation, they concluded.

LZV immunogenicity holds up during tofacitinib treatment

In the second study, 112 patients aged 50 years and older with active RA on background methotrexate received LZV and were then randomized to receive 5 mg tofacitinib twice daily or placebo 2-3 weeks after vaccination.

At 6 weeks after vaccination, VZV-specific IgG geometric mean fold rise (GMFR) was 2.11 and 1.74 in the tofacitinib and placebo patients, respectively; at all postvaccination time points at which VZV-specific IgG levels were evaluated, there was a trend toward numerically higher GMFR in tofacitinib patients, but the differences were not statistically significant. Also, the proportion of patients developing a 1.5-fold or greater postvaccination rise in IgG levels at 6 weeks trended higher for tofacitinib (57.4% vs. 43.4% with placebo).

VZV-specific T-cell GMFR at 6 weeks increased similarly in the groups (1.50 with tofacitinib and 1.29 with placebo).

Serious adverse events occurred in three patients in the tofacitinib group (5.5%) and in none of the placebo patients.

“The three SAEs included one case each of cholangitis and bronchitis, and once case of disseminated primary varicella,” the investigators said, noting that the onset of the latter was 16 days postvaccination, 2 days after starting tofacitinib. The rash resolved with discontinuation of tofacitinib and treatment with valacyclovir for 7 days.

The findings suggest that patients with active RA develop robust immune responses to HZ vaccine, and that starting tofacitinib 2-3 weeks after vaccination has no negative impact on the established immune response.

“Importantly, while our results suggest the vaccine is safe for patients with RA with prior VZV exposure, they also indicate the potential need to either screen for prior exposure before giving this vaccine or waiting longer than 2-3 weeks before starting immunosuppression with tofacitinib,” they said, noting that the current data suggest 4 weeks might be preferable.

Alternatively, testing patients who don’t recollect a history of chickenpox to ensure prior VZV exposure prior to vaccination could also mitigate the risk, they said.

“Further research is necessary to understand the risk of this complication, as well as the long-term effectiveness of this vaccine to prevent HZ in this high-risk population,” they concluded.

Both studies were sponsored by Pfizer. Dr. Winthrop has received research grants from and served as a scientific consultant to Pfizer. Other authors also reported financial relationships with Pfizer.

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