Efficacy and Safety of B-Cell-Targeted and Conventional Immunomodulatory Therapies for IgG4-Related Disease: A Systematic Review and Meta-Analysis of Randomized Trials

Introduction: Immunoglobulin G4-related disease (IgG4-RD) frequently relapses during or after glucocorticoid tapering. The comparative efficacy and safety of conventional immunomodulatory and B-cell-targeted treatments remain uncertain. Methods: Randomized controlled trials (RCTs) identified in PubMed, Embase, Web of Science, and the Cochrane Library were synthesized using random-effects pairwise meta-analysis. Outcomes included remission, relapse or disease flare, adverse events, annualized flare rates, and additional glucocorticoid exposure. Results: Five RCTs included 521 analyzable participants. Active treatment increased remission (risk ratio [RR], 1.81; 95% confidence interval [CI], 1.44–2.28; I² = 20.1%), with no significant difference between treatment categories (P = 0.1463). Active treatment also reduced relapse (RR, 0.35; 95% CI, 0.22–0.55; I² = 53.6%), without a significant between-category difference (P = 0.7181). Any adverse events (AEs) did not differ significantly overall (RR, 1.28; 95% CI, 0.90–1.83), and the between-category difference was not significant (P = 0.113). Serious adverse events (SAEs) also showed no significant overall difference (RR, 1.00; 95% CI, 0.36–2.74). Inebilizumab demonstrated a greater placebo-relative reduction in annualized flare rates than obexelimab (rate ratios, 0.14 vs. 0.48; P = 0.009). Cumulative additional glucocorticoid exposure was numerically reduced to a greater extent with inebilizumab, although the between-treatment difference was not statistically significant (mean differences, −1.27 vs. −0.60 g; P = 0.061). Conclusion: Conventional immunomodulatory and B-cell-targeted therapies improved remission and reduced relapse compared with their respective controls. An exploratory indirect comparison suggested a larger placebo-relative reduction in annualized flare rates with inebilizumab, without establishing direct comparative superiority.