Evaluation of Serious Infection in Pediatric Patients with Low Immunoglobulin Levels Receiving Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis

Abstract

Introduction: The aim of this work was to assess the impact of prolonged low immunoglobulin (IgG or IgM) serum concentrations on the potential cumulative serious infection (SI) risk in pediatric patients following rituximab treatment for granulomatosis with polyangiitis or microscopic polyangiitis (GPA/MPA) in PePRS.

Methods: Patients aged ≥ 2 to < 18 years received four weekly intravenous rituximab infusions of 375 mg/m2 and concomitant glucocorticoid taper. After 6 months, patients could receive further rituximab and/or other immunosuppressants per investigator discretion. Immunoglobulin levels and SIs were assessed throughout the 4.5-year observation period. Prolonged low IgG or IgM was defined as below the lower limit of normal age-specific reference range for ≥ 4 months.

Results: A total of 25 patients were included, of whom 19 (76%) had GPA and six (24%) had MPA; 18 (72%) had newly diagnosed disease and seven (28%) had relapsing disease. All 25 patients completed the rituximab induction regimen; 24 completed ≥ 18 months of follow-up. At month 18, eighteen patients (72%) had prolonged low IgG; 19 (76%), prolonged low IgM; and 15 (60%), both. Seven patients (28%) had nine SIs; one occurred during or after prolonged low IgG only, two during or after prolonged low IgM only, and six during or after concurrent prolonged low IgG and IgM. No patients died or discontinued the study due to SI. All patients had complete and sustained peripheral B-cell depletion for ≥ 6 months.

Conclusions: The majority of pediatric patients who received rituximab for GPA/MPA with prolonged low immunoglobulin levels did not experience SIs. In patients with SIs, these events were manageable, and the number of SIs did not increase over time or with multiple rituximab treatments. These observations are consistent with the rituximab safety profile in adults with GPA/MPA.

Trial registration: ClinicalTrials.gov identifier, NCT01750697.

Keywords: Granulomatosis with polyangiitis; Immunoglobulins; Infections; Microscopic polyangiitis; Pediatrics; Rituximab.

© 2022. The Author(s).

Figures

Fig. 1

Rituximab administration over the course of the study. Vertical lines represent month 6, month 12, month 18, and every 6 months thereafter. X one rituximab infusion. Five patients received rituximab infusions (375 mg/m2) approximately every 6 months administered once weekly for 4 weeks, and five received one infusion of rituximab (375 mg/m2) every 6 months; a further seven patients received other varied doses of rituximab within individualized regimens

Fig. 2

Median immunoglobulins by study visit. a IgG. b IgMa. Error bars represent the interquartile range. The horizontal lines on the graphs show the ULN and the LLN for IgG (12.29 g/l and 7.68 g/l) and IgM (1.97 g/l and 0.6 g/l). IgG immunoglobulin G, IgM immunoglobulin M, LLN lower limit of normal, ULN upper limit of normal. aFigure originally published in (7)

Fig. 3

Patient flow chart: distribution of patients with prolonged low IgG and/or IgM levels and SI. IgG immunoglobulin G, IgM immunoglobulin M

Fig. 4

Representative individual patient plots of IgG and IgM values over time. a A patient with prolonged low IgG and IgM levels and with SI. b A patient with prolonged low IgG and IgM levels and without SI. c A patient without prolonged low IgG or IgM levels and without IS. d A patient without prolonged low IgG levels, with prolonged low IgM levels and with SI. Vertical lines represent rituximab infusion. Vertical gray block indicates timing of serious infection. H indicates immunoglobulin levels > ULN; L indicates immunoglobulin levels < LLN. IgG immunoglobulin G, IgM immunoglobulin M, LLN lower limit of normal, SI serious infection, ULN upper limit of normal