Effectiveness and Safety of Inebilizumab for IgG4-Related Disease in a Real-World Clinical Setting in Japan: Protocol for a Long-Term Prospective Observational Study (4SigHT Study).

Abstract

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that can cause irreversible organ dysfunction and life-threatening complications. Although glucocorticoids are the standard first-line therapy, frequent flares necessitate prolonged use, which is in turn associated with toxicity. Inebilizumab, a CD19-targeted antibody approved in Japan in November 2025, demonstrated efficacy in the phase 3 MITIGATE trial. However, the trial's eligibility criteria and controlled environment may not reflect the heterogeneity of the routine clinical setting or the long-term profile in the Japanese population. This study (4SigHT Study) aims to evaluate the long-term effectiveness and safety of inebilizumab in Japan. This multicenter, prospective, observational study plans to enroll 100 patients with definite or probable IgG4-RD who are initiating inebilizumab at up to 40 sites in Japan. The study runs from March 1, 2026 to March 31, 2032. It includes up to 14 scheduled visits over a maximum duration of 312 weeks and reflects real-world decisions without mandated interventions. Comprehensive baseline assessments capture disease characteristics, comorbidities, vaccination history, and clinical history, including the frequency and nature of flares over the preceding 52 weeks. Longitudinal data are collected via an electronic data capture system. To ensure data robustness, the study employs a rigorous adjudication process. Suspected flares treated by investigators are adjudicated by an independent data and safety monitoring board using standardized organ-specific flare criteria. The primary outcome is the proportion of participants with an adjudicated clinical flare through week 52. Secondary outcomes include treatment-free complete remission, glucocorticoid-free complete remission, time to clinical flare, annual clinical flare rate, proportion of patients who initiate additional treatment, time to treatment initiation for new or worsening symptoms, and cumulative glucocorticoid dose. Furthermore, the study evaluates the long-term safety of inebilizumab over 6 years. The study is registered with the Japan Registry of Clinical Trials (jRCT1031250749).