IgG4-related disease (IgG4-RD) poses significant challenges due to high relapse rates. While previous studies identified relapse predictors during active treatment, factors after complete drug withdrawal remain unexplored. To identify predictors of relapse after drug cessation in patients achieving sustained remission and establish a clinically relevant timepoint for predicting durable treatment-free remission after withdrawal.

We conducted a retrospective study of 80 IgG4-RD patients who achieved complete drug withdrawal after clinical remission. Patients were classified into no-relapse (n=35) and relapse (n=45) groups. Univariable and multivariable Cox regression analyses identified independent predictors of relapse. Cumulative risk factor analysis assessed the dose-response relationship between baseline disease burden and relapse risk. Kaplan-Meier analysis evaluated relapse-free survival patterns.

Relapse patients had greater baseline disease burden vs. no-relapse patients: more affected organs (median 4 vs. 3, p=0.003), higher IgG4-RD RI scores (8 vs. 6, p=0.025), higher eosinophil percentages (3.30% vs. 1.90%, p=0.002), and elevated serum IgG4 levels (7510 vs. 3679 mg/L, p=0.003). Salivary gland involvement was more prevalent in the relapse group (82.22% vs. 37.14%, p<0.001). Multivariable Cox regression identified salivary gland involvement as an independent risk factor (HR 2.94, 95% CI: 1.20–7.18, p=0.018) and initial immunosuppressant combination therapy as a protective factor (HR 0.45, 95% CI: 0.23–0.86, p=0.015), with Kaplan-Meier analysis confirming significantly superior relapse-free survival in the combination therapy group (log-rank p=0.0016). Cumulative risk stratification revealed a dose-response relationship: relapse rates of 25.0% (0–1 risk factors), 61.5% (2–3 factors), and 84.6% (4–5 factors) (p<0.001). Landmark analysis at 36 months post-discontinuation demonstrated that relapse-free survival stabilized at this timepoint, with only 5.41% of patients who remained relapse-free at 36 months subsequently relapsing, compared to 53.75% within the first 36 months (annualized rate ratio: 0.11, p<0.0001).

Early immunosuppressant combination therapy significantly reduces post-cessation relapse risk. Cumulative risk stratification provides a robust predictive framework. The 36-month timepoint represents a clinically meaningful milestone for predicting durable treatment-free remission.