OBJECTIVES:Patients with immune-mediated inflammatory diseases (IMIDs) treated with immunosuppressive therapies are at higher risk for infections, including those preventable by vaccines. Among these therapies, Janus kinase inhibitors (JAK-is) are increasingly used, though their association with varicella zoster virus (VZV) reactivation raises concerns. The recombinant zoster vaccine (Shingrix™) is recommended for immunocompromised individuals and has shown strong safety and efficacy; however, data on its immunogenicity in IMID patients-especially those receiving JAK-is, anti-TNF agents or MTX-remain limited. In the present study, we aimed to evaluate both humoral and cellular immune responses to the recombinant herpes zoster vaccine in IMID patients treated with different JAK inhibitors in comparison with IMID patients treated with 'conventional' therapies, i.e. anti-TNF and/or MTX. We also sought to assess whether immune responses differ between patients receiving pan-JAK-is vs selective JAK1 inhibitors, and to identify clinical factors associated with reduced vaccine-induced immunity. METHODS:This study investigated both humoral (seroconversion rate, titer of VZV-specific IgG antibodies) and cellular CD4 T cell (IL-2 plus IFN-γ) and CD8 T cell (Granzyme A and/or Granzyme B) immune responses following a two-dose regimen of the recombinant inactivated vaccine in two cohorts of IMID patients treated with JAK-i or anti-TNF and/or MTX. Immune responses were compared with responses in a cohort of healthy individuals matched by age and sex. We also sought to assess whether immune responses differ between patients receiving pan-JAK-is vs selective JAK1 inhibitors, and to identify clinical factors associated with reduced vaccine-induced immunity. RESULTS:A total of 176 participants (mean age 58.6 ± 9.9 years; 33% female) were included. Among them, 39 received non-selective JAK-is (14 baricitinib, 25 tofacitinib), 54 received selective JAK1 inhibitor (upadacitinib) and 46 were on anti-TNF and/or MTX; 37 healthy individuals served as controls. Seroconversion was lower in JAK-i-treated patients (74%) compared with anti-TNF/MTX (91%) and the controls (100%, P < 0.001). Median post-vaccination IgG titers were significantly lower in JAK-i-treated patients (1753 ± 1112 mIU/ml) than in the anti-TNF/MTX patients (2874 ± 1020 mIU/ml) and the controls (3185 ± 576 mIU/ml; P < 0.001). CD4 Th1 responses (IL-2 + IFN-γ) were observed in 28% of JAK-i patients, 67% of anti-TNF/MTX patients and 95% of controls (P < 0.001). CD8 T cell responses were similarly impaired: 29% (JAK-i) vs 41% (anti-TNF/MTX) vs 85% (controls) (P < 0.001). Non-selective JAK-is were associated with the poorest responses (baricitinib: 64% seroconversion; 0% CD4; 7% CD8), while upadacitinib-treated patients showed higher rates (83% seroconversion; 39% CD4; 39% CD8). Granzyme A/B, IL-2 and IL-6 levels post-vaccination were significantly higher in anti-TNF/MTX patients than in the JAK-i groups. Immunogenicity negatively correlated with cumulative glucocorticoid and MTX doses, longer JAK-i exposure and history of ≥2 DMARDs. CONCLUSIONS:Our study highlights impaired immune responses to the recombinant herpes zoster vaccine in IMID patients treated with JAK-is. These patients showed significantly reduced humoral and cellular responses, suggesting lower protection against VZV reactivation. While anti-TNF/MTX-treated patients had mildly reduced responses compared with controls, their immunogenicity was relatively preserved. In contrast, JAK-i-treated patients had markedly lower antibody titers and T cell responses. Notably, this impairment was more pronounced with non-selective JAK-is than with selective JAK1 inhibitors, underscoring differences within the JAK-i class.
Abstract Background/Aims Herpes zoster (HZ) is a common infection, particularly in older adults and women, and can lead to complications like neuropathic pain. The risk is higher in immunosuppressed individuals. Shingrix, a recombinant subunit vaccine, has proven effective in reducing HZ risk by stimulating robust CD4 and CD8 T-cell responses. However, data on its immunogenicity in patients with immune-mediated inflammatory diseases (IMIDs) remains limited. This study aimed to evaluate B-cell and T-cell immune responses to the recombinant HZ vaccine in IMID patients treated with JAK inhibitors (JAK-i), anti-TNF therapies, or methotrexate (MTX), and to identify factors associated with reduced vaccine-induced immunity. Methods This study investigated both humoral and cellular immune responses following a two-dose regimen of the recombinant inactivated vaccine in 131 patients with IMIDs treated with JAK-i, anti-TNF therapy, or MTX. The results were compared to those of 27 healthy controls matched for age and sex. Cellular immune responses were assessed through CD4 + (Th1) and CD8 + (cytotoxic) T-cell activation, while VZV-specific IgG antibody levels were used to evaluate humoral responses. Results Among 157 participants (mean age 58.2 years), JAK-i users had significantly lower immune responses. Seroconversion was 86% in JAK-i patients, compared to 97% in anti-TNF/MTX and 100% in controls (P = 0.03). VZV IgG titres were significantly lower in the JAK-i group (mean 1842 U/mL) versus anti-TNF/MTX and controls (both ∼3,000 U/mL, P < 0.0001). Only 28% of JAK-i patients had a full CD4+ Th1 response (vs. 74% anti-TNF/MTX, 93% controls), and CD8+ responses were similarly reduced (29% vs. 42% and 85%, respectively). Immunogenicity was negatively associated with cumulative MTX and glucocorticoid use, prior DMARDs, baricitinib and tofacitinib treatment, and longer JAK-i exposure. A positive correlation was seen between CD4+ and CD8+ responses (β = 0.36, P = 0.0002). Conclusion IMID patients treated with JAK inhibitors exhibit significantly reduced humoral and cellular immune responses to the HZ recombinant vaccine, suggesting lower protection against VZV reactivation. While some reduction was seen in the anti-TNF/MTX group, their immune responses remained relatively preserved. The findings underscore the impact of JAK inhibitors and cumulative immunosuppression on vaccine efficacy in this population.). Disclosure C. Sieiro Santos: None. J. Garcia Herrero: None. J. Ordas Martínez: None. R. Colindres: None. J. Ruiz de Morales: None.
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