Herpes zoster (also known as shingles) is a common disease, with over 1 million cases in the United States reported annually. In the general population, age-related immunosenescence is the major risk factor. In addition, patients with immunologic diseases such as RA, who are often on immune-based therapies, may be more vulnerable, even at younger ages. JAK inhibitors (ie, tofacitinib, baricitinib, upadacitinib) have been associated with an increased risk of herpes zoster in multiple studies. Compared with placebo, treatment with JAK inhibitors was associated with an incidence of approximately 25 cases per 1000 patient-years, with confidence intervals extending upward to roughly 30 to 60 cases per 1000 patient-years. This compares with a rate of approximately 3 cases per 1000 patient-years in the general population and 7 cases per 1000 patient-years in the over-50 age group. So, the risk of shingles in patients on JAK inhibitors might be increased by as much as 5- to 10-fold. The reason for the increased risk is unclear, but a leading theory relates to treatment-associated inhibition of interferon signaling pathways that are involved in antiviral defense.

It is important to protect against herpes zoster, as it is a very morbid disease. Postherpetic neuralgia is quite painful and can cause a loss of productivity. Herpes zoster is also associated with an increased risk of stroke. Since people with RA and other immune-mediated diseases already have an increased risk of stroke and an increased risk of shingles, the prevention of herpes zoster becomes even more urgent.

There are currently 2 US Food and Drug Administration–approved herpes zoster vaccines: a live zoster vaccine (ZVL; Zostavax) and the recombinant zoster vaccine (RZV; Shingrix). RZV is the preferred vaccine because the protection is much higher than that of ZVL (>90% vs 50%) in immunocompetent patients over age 50 years. Since RZV is not a live vaccine, concerns regarding the risk of disseminated varicella zoster infection in immunocompromised patients are not applicable. The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices has not made a recommendation regarding the use of RZV in adults with immunocompromising conditions such as RA. At the Cleveland Clinic, we use RZV in all patients aged 50 years or older regardless of previous ZVL exposure. Patients who are on JAK inhibitors or are starting these agents have a higher risk of herpes zoster infection. At our clinic, we engage our patients in shared and informed decision making and offer RZV, in its 2-dose series, for patients on these agents, even if they are not yet 50 years of age.

Patients need to understand the risks of vaccination. Although RZV is generally well tolerated, the rate of developing temporary side effects during the 12 to 36 hours after injection (eg, fever, injection site pain, chills, tiredness, muscle aches) is palpably high. Also, its adjuvanted formulation nonselectively activates innate immunity, so there is a theoretical concern that RZV might provoke rheumatologic disease flares. We await prospective data, but preliminary data by Stevens et al have been reassuring. Patients not covered by insurance must pay out of pocket for RZV; however, many individuals are willing to do this if they understand the risks of herpes zoster. We think that the benefits of vaccination outweigh the risks in these situations because this is a highly effective vaccine.