A new non-live vaccine to help protect patients with RA against herpes zoster


Recent analyses provide further evidence of a higher risk of herpes zoster (HZ) in patients with rheumatoid arthritis (RA), where both the disease state and some RA therapies increase the risk.1,2 The EULAR guidelines state that HZ vaccination may be considered in high-risk adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) and that vaccination should ideally be completed before placing patients on biological disease modifying antirheumatic drugs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs),3 and the guidance has recently been updated to incorporate recommendations for the non-live vaccine, Shingrix (Recombinant Varicella Zoster Virus glycoprotein E antigen (AS01B adjuvanted vaccine)), which became available in Australia in June 2021.4 Prof. Peter Nash spoke to the limbic about which patients he prioritises for HZ vaccination and where Shingrix fits into his approach.

 HZ risk is elevated in RA and further elevated by RA treatments1,5-7

“The risk of herpes zoster in immunosuppressed patients is driven by age, use of steroids, Asian background, and the use of DMARDs,” explained Prof. Nash.

There is around a twofold increased HZ risk in patients with RA compared with the general population,1 and RA disease severity is associated with its development.2 Corticosteroids further elevate HZ risk,5 and although the results are inconsistent for anti-tumour necrosis factor (TNF) therapies,5 a number of studies have shown an increased risk with the Janus kinase (JAK) inhibitors.1,6,7

A recently published analysis8 from the German Rheumatoid Arthritis: Observation of biologic therapy register (RABBIT) in 13,991 patients (62,958 patient years) found evidence of a 3.6-fold increased HZ risk with targeted therapies. There was also an increased risk with biologic (b)DMARDS compared with conventional synthetic (cs)DMARDs.8

The analysis showed that exposure-adjusted event rates of HZ were highest for tsDMARDs (21.5, 95% CI 16.4–27.9), followed by B-cell targeted therapy (10.3, 95% CI 8.0–13.0), anti-TNF therapies (9.3, 95% CI 7.7–11.2), interleukin 6 inhibitors (8.8, 95% CI 6.9–11.0), and csDMARDs (7.1, 95% CI 6.0–8.3). Adjusted for age, sex and glucocorticoids, and weighted with inverse probability weights (to adjust for confounding by indication), there was an increased HZ risk for tsDMARDs (HR 3.66, 95% CI 2.38–5.63), monoclonal anti-TNF antibodies (HR 1.63, 95% CI 1.17–2.28), and B-cell targeted therapy (HR 1.57, 95% CI 1.03–2.40) compared with csDMARDs.8

Prof. Nash and colleagues recently published a study evaluating the incidence and risk factors for HZ in patients with RA treated with upadacitinib during the phase III clinical trial programme.1 They found an increased incidence and event rate for HZ with the JAK inhibitor compared to adalimumab plus methotrexate or methotrexate monotherapy.1

The analysis included data from 5,306 patients; the incidence rate of HZ/100 patient-years (95% CI) was 0.8 (0.3 – 1.9) with methotrexate monotherapy, 1.1 (0.5 to 1.9) with adalimumab plus methotrexate, 3.0 (2.6 – 3.5) with upadacitinib 15 mg dose group, and 5.3 (4.5 – 6.2) with upadacitinib 30 mg dose group.1

Clinical guidelines on HZ vaccination in patients with RA

The 2019 update of EULAR recommendations for vaccination in adults with AIIRD3 includes guidance to consider HZ vaccination in high-risk patients. The recommendations note that the live-attenuated vaccine, Zostavax, is preferably administered four weeks before the initiation of bDMARDs or tsDMARDs, but not during treatment with these agents. An alternative to Zostavax is Shingrix, a non-live recombinant subunit adjuvant zoster vaccine. While noting that Shingrix safety and efficacy have not yet been investigated in AIIRD patients, the guidelines say, “Based on the fact that Shingrix is a non-live vaccine, it may replace the live attenuated vaccine in patients with AIIRD.”3

While not providing specific recommendations for patients with RA, the Australian Technical Advisory Group on Immunisation (ATAGI) guidance for HZ vaccination explains that Zostavax is generally contraindicated in immunocompromised adults and advises that Shingrix should be used in these patients. However, it notes that Zostavax may be used in people with mild immunocompromise where Shingrix is not accessible. They note that Zostavax must only be given “after careful assessment of the degree of immunocompromise” due to the risk of rare disseminated varicella zoster virus infection, particularly in immunocompromised people.9

Shingrix – a non-live HZ vaccine – is now available in Australia*

Shingrix became available in Australia in June 2021 as a private prescription.4* It’s a recombinant Varicella Zoster Virus glycoprotein E antigen (AS01B adjuvanted vaccine) and indicated for the prevention of herpes zoster and post-herpetic neuralgia in adults 50 years of age or older.10 The primary vaccination schedule consists of two doses, administered intramuscularly, with the second dose administered 2–6 months after the initial dose. It is not indicated for the prevention of primary varicella infection (chickenpox) or for treatment of HZ or post-herpetic neuralgia.10

In the Shingrix registration studies in adults 50 years and older, the rate of reported solicited adverse events (both doses combined) were: pain (78.0%), redness (38.1%), and swelling (25.9%); and myalgia (44.7%), fatigue (44.5%), headache (37.7%), shivering (26.8%), fever (20.5%) and gastrointestinal symptoms (17.3%).

HZ vaccination should be considered in highest-risk patients with RA

Prof. Nash recommends HZ vaccination in all patients who are being initiated onto a JAK inhibitor. “When I come to the commencement of a JAK inhibitor, I have to have a discussion with the patient about vaccination,” he said. This situation represents a substantial proportion of RA patients, he explained. “Roughly 25-30% of RA patients are on a JAK inhibitor. About one in three methotrexate inadequate-responders and one in three TNF inadequate-responders will go onto a JAK inhibitor,” he said. “When Actemra [tocilizumab] is unobtainable due to COVID, a lot of patients have been switched to a JAK inhibitor waiting for supplies to return,” he added.

Using the live HZ vaccine can lead to logistical issues, since there’s a need to halt immunosuppressive therapy at the time of vaccination. “When you’re initiating a patient on a biologic or targeted therapy, it’s usually at a time when the patient has a flare in their RA, and it’s not ideal to stop treatment for two to three weeks in order to give a live HZ vaccine before then recommencing or starting a therapy,” Prof. Nash explained. He welcomed the availability of the non-live Shingrix vaccine, which potentially avoids this dilemma.

Prof. Nash pointed out that there have been reports of RA flare with Shingrix.11 A single-centre retrospective chart review of 300 patients with RA or other systemic rheumatic diseases11 reported a  3% of RA flare in patients following the first dose and 2.86% following the second dose. All flares were mild and self-limited, responded to treatment with low-dose glucocorticoids, and did not warrant change in immunosuppressive therapy.11

Zoster is very nasty and can cause issues if it’s multi-dermatomal or ophthalmic zoster. Postherpetic neuralgia is also difficult to manage. It’s preventable so why wouldn’t you consider HZ vaccination?” said Prof. Nash.

Disclosure

This article was sponsored by GSK. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Shingrix product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

*Shingrix is not on the NIP or PBS. Zostavax is funded on the NIP for adults 70-79 years.

Shingrix is subject to additional monitoring in Australia. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse events at www.tga.gov.au/reporting-problems

References

  1. Winthrop KL, 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 Epub ahead of print: 29 October 2021. Doi:10.1136/annrheumdis-2021-220822
  2. Veetil B et al. Incidence and time trends of Herpes zoster in rheumatoid arthritis: a population-based cohort study. Arthritis Care Res 2013; 65(6): 854-861
  3. Furer V et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 2020;79:39–52.
  4. National Centre for Immunisation Research and Surveillance. Zoster vaccine for Australian adults fact sheet October 2021. https://www.ncirs.org.au/sites/default/files/2021-06/Zoster%20vaccine%20f
  5. Winthrop KL & Furst DE. Rheumatoid arthritis and herpes zoster: risk and prevention in those treated with anti-tumour necrosis factor. Ann Rheum Dis 2010; 69:1735–1737.
  6. Winthrop KL, Curtis JR, Lindsey S, et al. Herpes zoster and tofacitinib: clinical outcomes and the risk of concomitant therapy. Arthritis Rheumatol 2017;69:69.
  7. Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat 26 Rev Rheumatol 2017;13:234–43.
  8. Redeker I et al. Risk of herpes zoster (shingles) in patients with rheumatoid arthritis under biologic, targeted synthetic and conventional synthetic DMARD treatment: data from the German RABBIT register. Ann Rheum Dis. Doi:10.1136/annrheumdis-2021-220651
  9. Australian Technical Advisory Group for Immunisation. Statement on the clinical use of Zoster Vaccines in older adults in Australia. October 2021, Statement of the Clinical use of Zoster vaccines in older adults in Australia https://www.health.gov.au/resources/publications/statement-on-the-clinical-use-of-zoster-vaccine-in-older-adults-in-australia-statement-on-the-clinical-use-of-zoster-vaccine-in-older-adults-in-australia (accessed October 2021)
  10. Shingrix Australian product information available at https://www.tga.gov.au/sites/default/files/auspar-recombinant-varicella-zoster-virus-glycoprotein-e-antigen-181212-pi.pdf
  11. Stevens E, Weinblatt ME, Massarotti E, et al. Safety of the Zoster recombinant adjuvanted vaccine in rheumatoid arthritis patients: a single center’s experience with 300 patients. Annals of the Rheumatic Diseases 2019;78::695.

 

 

 

 

 

 

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