The importance of interferons as a component of human antiviral host defense was first suggested by Isaacs and Lindenmann in 1957.1 It was not until the 1970s that a pathogenic role of interferons in systemic lupus erythematosus (SLE) was suspected.2 While it was recognized long ago that patients with systemic lupus were at increased risk of Herpes zoster reactivation (shingles), it was the phase 2 studies of sifalimumab and anifrolumab that highlighted the importance of this complication.3 4 Given the mechanism of action of sifalimumab and anifrolumab, namely their ability to dampen type I interferon pathway activation, it was no surprise that the incidence of Herpes zoster was as much as 8-fold higher in the treatment arms than in the placebo groups of the phase 2 and 3 SLE trials.4–6 In a post-hoc analysis of the phase II and the two phase III trials of anifrolumab, Tummala et al reported exposure-adjusted incidence rates (EAIR) per 100 patient-years of 6.9 and 1.5 in the 300 mg anifrolumab and placebo groups, respectively.7 Even higher frequencies of Herpes zoster were observed in the phase II anifrolumab trial in lupus nephritis with frequencies over the course of the study of 13.7% and 20.0% in the two treatment groups compared to 8.2% in the placebo group.8
Other drugs in development in SLE, such as litifilimab, daxdilimab, and deucravacitinib, also impact type I interferons. However, Herpes zoster was infrequent in these studies suggesting that the degree of inhibition of type I interferon pathway activation correlates with the risk of Herpes zoster. Despite a low basal incidence rate of Herpes zoster, vaccination with Zoster Vaccine Recombinant, Adjuvanted, is now recommended for adults aged ≥18 years who are or will be at increased risk for shingles because of immunodeficiency or immunosuppression caused by their underlying disease or therapy.
Isaacs A, Lindenmann J. Proceedings of the Royal Society of London. Series B, Biological Sciences 1957.
Hooks JJ, et al. Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med. 1979 Jul 5;301(1):5–8. doi: 10.1056/NEJM197907053010102.
Khamashta M, et al. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016 Nov;75(11):1909–1916. doi: 10.1136/annrheumdis-2015-208562.
Furie R, et al. Anifrolumab, an anti-Interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376–386. doi: 10.1002/art.39962.
Furie RA, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019, 1(4), e208–e219.
Morand EF, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020 Jan 16;382(3):211–221. doi: 10.1056/NEJMoa1912196.
Tummala R, et al. Safety profile of anifrolumab in patients with active SLE: an integrated analysis of phase II and III trials. Lupus Sci Med. 2021 Feb;8(1):e000464. doi: 10.1136/lupus-2020-000464.
Jayne D, et al. Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis. Ann Rheum Dis. 2022 Apr;81(4):496–506. doi: 10.1136/annrheumdis-2021-221478.
Discuss the role of interferons in the pathogenesis of SLE
Analyze SLE clinical trial data with respect to Herpes zoster incidence
Describe strategies for prevention of Herpes zoster
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