Additive effect of leflunomide and glucocorticoids compared with glucocorticoids monotherapy in preventing relapse of IgG4-related disease: A randomized clinical trial.

Objectives: To evaluate the efficacy and safety of leflunomide (LEF) and glucocorticoids (GCs) combination therapy compared with GCs monotherapy in preventing relapse of IgG4-related disease (IgG4-RD).

Methods: A 12-month, randomized, open-label, controlled trial was conducted at a large academic medical center (ClinicalTrials.gov: NCT02703194). Enrolled patients with active IgG4-RD were randomly allocated to the GCs + LEF (20 mg/day) combination therapy or GCs monotherapy group. All patients received GCs with a predefined taper regimen starting from a dosage of 0.5-0.8 mg/kg/d. The primary outcome was the time to relapse. The secondary outcomes included complete response, remission, GCs dosage, and serum IgG4 level.

Results: Sixty-six patients with active IgG4-RD were enrolled (33 patients in each group). The demographic and disease characteristics showed no statistically significant differences between groups. Additionally, the initial GCs dosages were similar (50.00 vs. 50.00 mg/day, P = 0.295). Disease relapses occurred in 6 (18.2%) and 14 (42.4%) patients in the combination therapy group and GCs monotherapy group, respectively (P = 0.032). The combination therapy was significantly superior to GCs monotherapy regarding the primary outcome, the time to relapse (HR, 0.35; 95% confidence interval [CI], 0.13-0.90; P = 0.023), as well as the secondary outcome, the time to complete response (HR, 1.75; 95% CI, 1.01-3.02; P = 0.034). A longer duration of remission was observed in the combination therapy group (7.00 vs. 3.00 months, P = 0.002) and less cumulative dosage of GCs was used (5103.13 vs. 5637.50 mg, P = 0.031). Additionally, a higher proportion of patients in the combination therapy group (54.5%) were able to reach a daily GCs dose of ≤5 mg/day compared with the GCs monotherapy group (18.2%) (P = 0.006). The incidences of adverse events were similar in the 2 groups (P = 0.325).

Conclusion: LEF in combination with GCs therapy is well-tolerated and significantly superior to GCs monotherapy in preventing the relapse of IgG4-RD. LEF can be used as a steroid-sparing agent in the management of IgG4-RD.