PML and rheumatology: The contribution of disease and drugs

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ABSTRACTProgressive multifocal leukoencephalopathy (PML), a rare, typically fatal, opportunistic infection caused by the JC virus, is becoming relevant to physicians in multiple specialties, including those who prescribe biologic agents for the treatment of autoimmune disorders. Reports of PML have led to US Food and Drug Administration alerts and warning letters regarding four immunosuppressive agents in recent years (natalizumab, rituximab, efalizumab, and mycophenolate mofetil). Consequently, informed clinical decision-making requires understanding the risk of PML associated with these therapies. An estimate of the relative frequency of PML associated with specific rheumatic conditions has been generated. Systemic lupus erythematosus appears to be associated with susceptibility to PML that cannot be fully explained by the intensity of immunosuppressive therapy. Further, the use of rituximab in patients with rheumatic disease has raised concerns. However, definitive attribution of cause is precluded by the limitations of the currently available data. All patients with rheumatic disease, regardless of the intensity of their current immunosuppressive therapy, should be considered potentially at risk of PML. With an evolving understanding of a greater clinical heterogeneity of PML, advances in diagnostic methods, and significant implications for therapy, PML should be considered in the differential diagnosis of neurologic manifestations of rheumatic diseases.



Progressive multifocal leukoencephalopathy (PML) is a rare, typically fatal, opportunistic infection caused by the JC virus (JCV). Formerly an example of neurologic arcana, PML became an important clinical concern when it developed in patients with human immunodeficiency virus (HIV) infection. More recently, PML has attracted the attention of rheumatologists following reports of its being associated with the use of targeted therapies such as natalizumab and rituximab.1

A recent survey of rheumatologists’ knowledge of and attitudes towards PML revealed that concerns over PML affect decisions on the use of biologic agents. Further, rheumatologists have important real and perceived learning gaps regarding PML; for example, 41% of those surveyed could not identify the diagnostic test of choice for PML.2


The US Food and Drug Administration (FDA) issued an alert in December 2006 following documentation of two fatal cases of PML in patients with systemic lupus erythematosus (SLE), both of whom had been treated with rituximab.3 We subsequently performed a literature search to identify cases of PML associated with rheumatic diseases.1,4 Patients were included only if the information provided was sufficient to substantiate the diagnosis of PML and the rheumatic disease in question; patients were excluded if they had HIV or cancer or had undergone organ transplantation. The search revealed 50 patients with rheumatic diseases who had PML (Table 1); SLE was overrepresented (n = 32) despite a much lower population prevalence of SLE compared with rheumatoid arthritis.

Examination of the immunosuppressive therapies prescribed to these patients within 6 months of the onset of neurologic symptoms attributed to PML revealed that low-dose (≤ 15 mg/d) prednisone, with or without an antimalarial agent, was the only immunosuppressive therapy in 31% of patients with SLE and in 11% of patients with rheumatic diseases other than SLE. Three patients had no documented immunosuppressive therapy in the 6 months prior to the onset of PML. Two patients with SLE were prescribed rituximab; no cases were reported in association with biologic therapies other than rituximab.4

In order to circumvent reporting bias, a nationwide hospital discharge database representing nearly 300 million patient discharges was used to determine the relative frequency of PML in patients with rheumatic diseases.5 Because of the reliance on diagnostic coding, rheumatic diseases were likely underreported in this sample; information on therapies was unavailable. After excluding patients who had HIV or cancer or were organ transplant recipients, four cases of PML were identified per 100,000 SLE discharges. This rate was 10-fold higher than the rate associated with rheumatoid arthritis and 20-fold higher than that of the background population.

These data show that PML is a rare occurrence in patients with rheumatic diseases, and SLE appears to be associated with a predisposition to PML. This predisposition in patients with SLE does not appear to be proportional to the degree of iatrogenic immunosuppression, emphasizing the role of host factors.


In addition to certain disease states, disease-modifying biologic drugs have recently been associated with rare instances of PML.


The first case of rituximab-associated PML in the setting of rheumatoid arthritis was recorded in September 2008.6 The patient had longstanding rheumatoid arthritis and Sjögren syndrome. She received four courses of rituximab and was diagnosed with PML 18 months after the last dose; she died 1 month later. Her therapy for rheumatoid arthritis included a tumor necrosis factor (TNF) antagonist prior to rituximab initiation and treatment with methotrexate and steroids before, during, and after rituximab therapy. Oropharyngeal cancer developed in this patient 9 months prior to the onset of PML and was treated with chemotherapy and radiation therapy.

Another case of PML in a patient with rheumatic disease who had been treated with rituximab was notable because it was the first in which the patient had not previously been treated with an anti-TNF agent.7

Ascertaining cause of PML in patients treated with rituximab is difficult because the potential pathogenic mechanism remains unknown. Humoral immunity is not protective against PML, leading to speculation that the loss of other B-cell functions, such as those of antigen-presenting cells or cytokine production, may lead to a defect in cell-mediated immunity. Another theory posits that reconstitution of naïve B cells with latent JCV infection following B-cell depletion from rituximab therapy may somehow facilitate the development of PML.

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