Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis

Abstract

Objective: To describe the development of progressive multifocal leukoencephalopathy (PML) in patients with rheumatoid arthritis (RA) treated with rituximab.

Design: Case study.

Setting: Clinical care for patients with rheumatologic diseases. Most were referred to academic centers for care after diagnosis (Washington University, St Louis, Missouri; Karolinska Insitute, Stockholm, Sweden; and Royal Melbourne Hospital, Melbourne, Australia) while one was cared for in a neurology practice in Dallas, Texas, with consultation by an academic neurovirologist from the University of Colorado in Denver.

Patients: Four patients developing PML in the setting of rituximab therapy for RA.

Intervention: Rituximab therapy.

Main outcome measures: Clinical and pathological observations.

Results: Four patients from an estimated population of 129 000 exposed to rituximab therapy for RA are reported in whom PML developed after administration of this drug. All were women older than 50 years, commonly with Sjögren syndrome and a history of treatment for joint disease ranging from 3 to 14 years. One case had no prior biologic and minimal immunosuppressive therapy. Progressive multifocal leukoencephalopathy presented as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. Two patients died in less than 1 year from PML diagnosis, while 2 remain alive after treatment withdrawal. Magnetic resonance scans and tissue evaluation confirmed the frequent development of inflammatory PML during the course of the disease.

Conclusion: These cases suggest an increased risk, about 1 case per 25 000 individuals, of PML in patients with RA being treated with rituximab. Inflammatory PML may occur in this setting even while CD20 counts remain low.

Figure 1

Magnetic resonance imaging of progressive multifocal leukoencephalopathy lesions from cases 1 to 4. A, Case 1 T2 fluid-attenuated inversion recovery (FLAIR) brain image demonstrating predominant left parietal lesion (arrow) in the setting of many presumed vascular lesions that had been seen on a previous scan a year prior to onset of progressive multifocal leukoencephalopathy symptoms and signs. B, T2 FLAIR image from case 2, who developed a right cerebellar lesion (arrow) radiating into the brainstem that was not visible at the onset of disease but was seen here at 8 months after clinical concerns began. C, Case 3 presented with left frontal white matter disease seen on this T2 magnetic resonance image (arrows). D, T2 FLAIR image from case 4. The patient presented with a small left posterior parietal subcortical white matter lesion (arrow) that subsequently progressed markedly (see Figure 3).

Figure 2

Magnetic resonance characteristics of a progressive multifocal leukoencephalopathy lesion. A-D, Apparent diffusion coefficient (ADC) (A) and diffusion-weighted (B) imaging with the pathologic correlates at post mortem (C and D). Note the inverse relationship of the gliotic lesion where ADC is bright (arrowhead) (A) contrasted with the necrotic core bright on the diffusion-weighted image (arrowhead) (B) and seen at the arrowhead in part C. The active rim of the lesion where viral replication is inducing cytotoxic edema and swelling of oligodendrocytes is highlighted in the ADC image (A). Whole-mount image immunostained for CD68, a marker of macrophages, shows the necrotic core lesion (arrowhead) and the rim of gliosis (arrow) (C) (original magnification ×1). CD68 microscopic image shows many macrophages from the rim of active disease (D) (original magnification ×40).

Figure 3

Evolution of progressive multifocal leukoencephalopathy in the setting of rituximab therapy. The earliest lesion on fluid-attenuated inversion recovery images is seen in the May 2009 series, with slow evolution particularly in the right occipital lesion over the months from initial symptoms until diagnosis in September 2009 at the time of a brain biopsy. Plasma exchange was performed prior to the November 2009 series and the marked inflammatory response that followed then waned in this surviving patient. Typical of progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome, the magnetic resonance images show marked expansion with perilesional edema that then resolved over months following immune control of progressive multifocal leukoencephalopathy. These same lesions demonstrated gadolinium contrast enhancement (not shown).

Figure 4

Pathology of rituximab-associated progressive multifocal leukoencephalopathy. A, Case 1 demonstrating a large demyelinated and focally necrotic white matter lesion at autopsy, especially prominent at the arrow. B, Hematoxylineosin–stained section of the brain from case 1 showing marked perivascular inflammation consistent with immune reconstitution inflammatory syndrome in progressive multifocal leukoencephalopathy. The inset is a CD3 immunostain demonstrating the presence of T lymphocytes in both perivascular and parenchymal regions (original magnification ×100; inset, ×200). C, Histological analysis from the brain biopsy in case 4 demonstrating viral inclusions (arrows) and gliotic changes, with some perivascular inflammation (lower right inset), and the immunohistochemical detection of JC virus (upper right inset) (original magnification ×400; upper right inset, ×200; lower right inset, ×100). D, Electron micrograph from the brain biopsy specimen of case 4 demonstrating classic intranuclear papova viral particles, consistent with JC virus (original magnification × 100 000).

Figure 5

Immunohistochemical staining performed at autopsy of case 1. A, CD3 immunostain marks T cells, here demonstrating increased overall numbers as well as focal clumping around neurons (arrowhead), an atypical feature of progressive multifocal leukoencephalopathy that is more reminiscent of the neuronophagia encountered in cases of viral encephalitis (original magnification ×400). B, CD20 immunostain demonstrates B cells present in small numbers in the brain of the rituximab-treated patient (arrow) (original magnification ×200). C, CD68 immunostain shows numerous macrophages within an area of active demyelination (arrow) (original magnification ×200). D, JC virus immunohistochemical stain identifies numerous infected oligodendrocytes in the postmortem brain (arrow), even though rapidly declining JC viral loads were found in the blood prior to patient death (original magnification ×400).