Long-term efficacy of maintenance therapy with Rituximab for IgG4-related disease

Highlights

• Univocal strategies to maintain IgG4-RD remission are lacking.

• Rituximab every 6 months prevents IgG4-RD flare with no major adverse events.

• Rituximab 1 g every 6 months should be considered as remission maintenance strategy.

Abstract

Background

IgG4-Related Disease (IgG4-RD) promptly responds to glucocorticoids but relapses in most patients. Rituximab (RTX) represents a promising strategy to avoid IgG4-RD flares but its administration for maintaining disease remission has never been assessed in terms of optimal timing of infusion, dosage, and duration of treatment. In the present study we aimed to evaluate the efficacy and safety of RTX for maintenance of IgG4-RD remission.

Methods

Fourteen patients with IgG4-RD were treated with RTX as induction of remission therapy at the San Raffaele Scientific Institute in Milan, Italy. The cohort was then divided into two study groups: patients re-treated only in case of disease relapse (Group 1, n = 7), and patients regularly re-treated with RTX every 6 months for maintenance therapy (Group 2, n = 7). Data on free-relapse rate and adverse events were collected and retrospectively analysed.

Results

Median follow-up time and baseline clinical-serological features were similar between Group 1 and 2 (p > 0.05). The free relapse rate 18 months after induction of remission treatment was significantly lower in Group 1 (29%) than in Group 2 (100%) (p = 0.006). Infectious complications developed in 6/14 patients (3 in Group 1 and 3 in Group 2).

Conclusion

Administration of RTX every 6 months as maintenance of remission therapy prevents IgG4-RD flares.

Introduction

IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder involving virtually any organ system [1,2]. Clinical-pathological hallmarks of IgG4-RD include mass-forming lesions, elevated serum IgG4 levels in the majority of patients, and a highly conserved histopathology of the affected organs [1,3]. IgG4-RD promptly responds to glucocorticoids (GC) therapy but relapses are observed in up to 50% of patients within three years, not only after corticosteroids withdrawal but also during tapering [4,5]. This characteristic relapsing-remitting course represents a major clinical challenge because it increases the risk of irreversible organ damage due to repeated flares of tissue inflammation. Predictors of relapse at disease onset include multiorgan involvement, hyper-eosinophilia, high serum IgG4 or IgE levels, and memory B cell increase after GC induced remission [6], [7], [8]. When these negative prognostic factors are present, low-to-medium dose GCs and disease modifying anti-rheumatic drugs (DMARDs) are usually administered to maintain disease remission [5,[9], [10], [11]]. Alternative therapeutic approaches though are warranted both to avoid high cumulative doses of GC and because the data on DMARDs efficacy in IgG4-RD are controversial [5,12].

Rituximab (RTX), an anti-CD20 monoclonal antibody, represents a promising strategy to avoid IgG4-RD flares because it leads to prompt clinical remission by depleting B-lymphocytes that have been linked to disease activity and tissue fibrosis, such as plasmablasts and memory B cells [13], [14], [15]. In particular, plasmablasts - the precursors of plasma cells - are expanded in the peripheral blood of patients with active IgG4-RD, decrease after RTX induced remission, and re-emerge at disease relapse [16,17]. Periodical administration of RTX in patients at risk of flare may, thus, prevent re-expansion of circulating plasmablasts and disease recurrence. The use of RTX for maintaining remission in patients with IgG4-RD, however, has never been systematically assessed in terms of optimal timing of administration, dosage, and duration of treatment. In the present work we retrospectively evaluated the efficacy and safety of RTX administered every 6 months to maintain disease remission in patients with IgG4-RD.