Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event

Joseph R Berger,Paul Brunetta,Stuart Lacey,Vineeta Malik,Patricia B Lehane

doi:10.1007/s13365-018-0615-7

Abstract

This report assesses the observed risk of PML in patients treated with the anti-CD20 monoclonal antibody rituximab in the regulatory authority-approved autoimmune indications rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). This was a cumulative analysis of confirmed PML cases in patients receiving rituximab for RA or GPA/MPA from both spontaneous reports and clinical trial sources, as captured in the manufacturer global company safety and clinical databases. Overall reporting rates were calculated and patient case details were summarized. As of 17 November 2015, there were nine confirmed PML cases among patients who had received rituximab for RA and two for GPA. Corresponding estimated reporting rates were 2.56 per 100,000 patients with RA (estimated exposure ≈ 351,396 patients) and < 1 per 10,000 patients with GPA/MPA (estimated exposure 40,000–50,000 patients). In all cases, patients had ≥ 1 potential risk factor for PML independent of rituximab treatment. In the RA population, the estimated reporting rate of PML generally remained stable and low since 2009 despite increasing rituximab exposure. There was no pattern of latency from time of rituximab initiation to PML development and no association of PML with the number of rituximab courses. Global post-marketing safety and clinical trial data demonstrated that the occurrence of PML is very rare among rituximab-treated patients with RA or GPA/MPA and has remained stable over time.

Highlights

Treatment with immunosuppressive biological agents has been reported as a potential risk factor for progressive multifocal leukoencephalopathy (PML), a rare, often fatal demyelinating disease of the central nervous system caused by the John Cunningham virus.Rituximab is a chimeric anti-CD20 monoclonal antibody that targets and depletes CD20+ B cells
From the first rituximab exposure in rheumatoid arthritis (RA) clinical trials in 2002 up to a cutoff date of 17 November 2015, the company global safety database contained 11 confirmed PML cases in autoimmune disorders approved for rituximab treatment (9 in RA and 2 in granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA); Fig. 1)
Our findings indicate: (1) the reported occurrence of PML is very rare in both populations (2.56 cases per 100,000 patients in RA and < 1 case per 10,000 in GPA/ MPA); (2) in the RA population, the estimated reporting rate of PML appears to have generally decreased since 2010 and stabilized despite increasing rituximab exposure in patients with RA receiving multiple treatment courses over time; and (3) all confirmed PML cases were associated with other risk factors, independent of rituximab treatment

Summary

Introduction

Treatment with immunosuppressive biological agents has been reported as a potential risk factor for progressive multifocal leukoencephalopathy (PML), a rare, often fatal demyelinating disease of the central nervous system caused by the John Cunningham virus. Rituximab is a chimeric anti-CD20 monoclonal antibody that targets and depletes CD20+ B cells. Approved worldwide to treat non-Hodgkin lymphoma and chronic lymphocytic leukemia, rituximab was subsequently approved in combination with methotrexate (MTX) for the treatment of adult patients with moderate to severely active rheumatoid arthritis (RA) who have had an inadequate response to ≥ 1 tumor necrosis factor inhibitor therapies. Rituximab later achieved global regulatory approval in combination with glucocorticoids for induction of remission in the anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides: granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) (Fig. 1) (Rituxan PI 2014, MabThera PI 2016).

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