Zoster protection for JAK inhibitor patients appears achievable Save

One of the primary questions about JAK inhibitor safety, ever since its first approval, has been the risk of herpes zoster. While our patients experience outsized morbidity from zoster, it has not been clear if herpes zoster vaccination is effective in them - but data at EULAR 2023 have helped to answer these questions.

Until now, few data have existed examining the efficacy and safety of Shingrix in rheumatic disease patients. This has been a substantial gap in the literature, for four related reasons. First, rheumatic disease patients are frequently at substantially increased risk of herpes zoster, from both their underlying disease and the therapies they require. Secondly, even in countries where live attenuated vaccinations are currently marketed, generally they are at least relatively contraindicated in patients on immunomodulatory therapies, because of documented fatal episodes of disseminated zoster reactivation. Thirdly, much as seen with other vaccines (including the influenza and COVID vaccinations), it remains plausible that therapies such as JAK inhibitors, methotrexate, and prednisolone might reduce vaccine immunogenicity, and it has not been clear that administering Shingrix would necessarily be a sufficiently fruitful exercise in such patients. Finally, the reactogenic adjuvant in Shingrix is known to cause rheumatic disease flares in some (https://pubmed.ncbi.nlm.nih.gov/33560302/), so it is not clear whether disease control might be compromised in this situation. In short, there were several reasons why this gap in the literature was particularly concerning for many rheumatic disease patients.

The investigators behind SELECT-COMPARE, a phase 3 trial comparing upadacitinib to adalimumab in RA patients with stable methotrexate therapy, opted to undertake a sub-study within the open-label extension period, and the results were presented by Dr. Kevin Winthrop at EULAR 2023 (OP0225). In this study, patients received two doses of Shingrix three months apart, and had humoral vaccine response documented four weeks after each dose, as well as cellular response in some patients. This represented an important opportunity to answer the questions regarding Shingrix in the context of upadacitinib and methotrexate for RA.

The results, while not as good as those that might be expected in immunocompetent individuals, were very reassuring for clinical practice. Four weeks after the second vaccine dose, 88% of patients had achieved a humoral response to Shingrix, conventionally defined as a four-fold increase in pre-vaccination concengration of anti-gE titers. Critically, similar rates were seen in both younger and older patients, and patients with and without concomitant corticosteroid use at baseline - suggesting that all rheumatic disease patients might benefit from Shingrix.

While the mean geometric mean fold rise of antibody titers was not quite as high as might be seen in immunocompetent individuals, it certainly represented a consistently robust response in this population. Furthermore, cellular response, which has traditionally remained a point of concern for many patients, was achieved in 66% of patients four weeks after the second vaccine dose. The vaccine was well tolerated, with only two patients experiencing flares in their rheumatic disease.

These data, while representing what might be standard practice for many clinicians, will give enormous encouragement about our capacity to prevent herpes zoster in rheumatic disease populations. Many estimates have suggested that zoster vaccination is underutilised by rheumatic disease patients, and these data will bolster the argument for our patients that this is remains an activity worth pursuing. Equally as encouraging for patients and clinicians will be the details of how this was administered - in this protocol, where no immunomodulators were withheld around the time of vaccination, rheumatic disease patients were able to achieve excellent immunogenic responses with very little risk of disease flare.

While broader data about factors affecting immunogenicity would be useful, these data should encourage broader action on vaccination for our patients, who deserve protection from infection wherever they can find it.