Introduction

There have been several case series reporting progressive multifocal leukoencephalopathy (PML) in patients with a variety of autoimmune diseases treated with biologic agents, including natalizumab, rituximab, and efalizumab as well as in patients taking mycophenolate mofetil.[1-4] On the basis of these reports, PML is of particular concern to rheumatologists treating patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or other rheumatic diseases with rituximab and/or mycophenolate mofetil. PML is a demyelinating disease caused by reactivation of the JC virus. Latent JC virus infection is common, and it is thought that the virus may reactivate in settings of immunosuppression induced by disease, such as HIV, or medications. PML typically presents with altered mental status, visual changes, and ataxia. Brain imaging may show patchy areas of demyelination, usually without edema. Diagnosis may be made by demonstration of JC virus in cerebrospinal fluid (CSF) or on brain biopsy (gold standard). When PML occurs in rheumatic diseases, immunosuppression is typically stopped, and prescribers may try agents, such as cytarabine, mirtazapine, and cidofovir, although there are no controlled trials demonstrating benefit and prognosis is poor, with life expectancy after diagnosis in non-HIV cases of only a few months.

Study Summary

To generate estimates of the rate of PML in US patients with rheumatic diseases, the study authors investigated the frequency of PML using the US Nationwide Inpatient Sample database, which contains data from approximately 300 million hospital discharges between 1998 and 2005; 9675 cases of PML were identified, with the following rates of PML (per 100,000 discharges): 4 for SLE; 0.4 for RA; and 2 for other connective tissue diseases, which included Sjögren's syndrome, dermato- and polymyositis, and scleroderma. These rates differ from a background rate of PML (after excluding HIV, cancer, or organ transplant) in 0.2 per 100,000 discharges. PML was not associated with seronegative spondyloarthropathies or systemic vasculitic syndromes. Of note, for PML associated with SLE, there were no other associated disease risk factors for PML (HIV, cancer, or transplantation); however, in RA-associated PML, 60% of cases had at least 1 additional disease risk for PML. The study authors concluded that PML may occur more commonly in SLE than other rheumatic diseases, perhaps due to disease-specific issues; however, due to limitations of the database they could not identify particular treatment regimens that were more likely to be associated with PML.

Viewpoint

On the basis of these data, PML, although rare, does appear to have increased frequency in rheumatic diseases, particularly SLE. Unfortunately, this study does not tell us what particular aspects of rheumatic disease -- disease pathogenesis and/or treatments -- may lead to increased risk for PML. Of importance, the authors stated that diagnosis of PML may be difficult in patients with rheumatic diseases because neurologic symptoms may be attributed to other causes, especially CNS SLE. As such, given the increased risk for PML, we should be aware of the possibility of this disease and be sure to exclude it if suspected in patients with CNS dysfunction. Of note, the JC virus may not be detectable by polymerase chain reaction (PCR) in CSF, and brain tissue may need to be obtained for diagnosis. Going forward, we'll need studies to determine exact mechanisms for PML in rheumatic diseases, and to construct clear recommendations for risk for PML on the basis of therapies in patients with rheumatic diseases, and hopefully treatments for this devastating disease.

CONCLUSION: This study was confined to hospitalized patients with rheumatic diseases, and it was also limited by the lack of information regarding immunosuppressive therapy. Nevertheless, the findings suggest that, although rare overall, PML occurs more commonly in SLE than in other rheumatic diseases.