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
PML IN RHEUMATIC DISEASES
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.
DISEASE-MODIFYING DRUGS AND PML RISK
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.