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

Abstract

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.

Introduction

IgG4-related disease (IgG4-RD) is a recently described fibrotic autoimmune systemic disorder [1], [2], [3]. In the recent guidelines for IgG4-RD, glucocorticoids (GCs) therapy was recommended as the first-line therapy for the remission induction. However, many patients may fail to maintain remission during or after the tapering of GCs [4]. Moreover, recurrent flares lead to irreversible organ damage and higher cumulative GCs doses [5]. In order to address the unmet need of a treatment allowing patients with IgG4-RD to reduce their dependence on GCs, the efficacy of steroid-sparing immunosuppressive agents (IMs), including biological agents or conventional IMs, has been explored by several studies [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Rituximab has been indicated to have a good efficacy according to a prospective, open-label, single-arm trial [6]. however, it is less accessible to individuals of a lower socio-economic status as it is less likely to be covered by medical insurances in many countries. The use of conventional IMs including azathioprine [7], [8], [9], mycophenolate mofetil (MMF) [10,11]. cyclophosphamide [12], leflunomide (LEF) [13], tacrolimus [14], and methotrexate [15] has been reported for treating IgG4-RD. However, their clinical utilization is challenged by the lack of high-quality evidence [[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16],17]. So far, most of the reports were observational studies [17], except for one randomized controlled trial (RCT) evaluating the efficacy of MMF in IgG4-RD [10].

Increasing evidences have been emerging to support the pathogenic role of B cell-T cell interaction at the onset of IgG4-RD and the latest studies have highlighted a key role of specific T cell subsets like the CD4⁺ SLAMF7⁺ cytotoxic T cells and T follicular helper cells in IgG4-RD [18], [19], [20], [21]. LEF targets at the metabolism of pyrimidines to influence the proliferation of the lymphocytes, especially T cells [22]. LEF has been widely used in treating diseases associated with T-cell disorders such as Takayasu arteritis [23,24] and giant cell arteritis [25]. Considering the associated T-cell disorder in IgG4-RD, LEF may have potential benefits for individuals with this condition. Base on the efficacy of the GCs + LEF combination therapy in IgG4-RD observed in our clinical practice, we reported the preliminary outcomes of the patients received the GCs + LEF combination therapy [13]. The promising preliminary results prompted us to conduct this investigator-initiated, randomized, open-label, controlled clinical trial to quantitatively evaluate the additive effect of LEF compared with GCs monotherapy.