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Progressive multifocal leukoencephalopathy (PML) is a rare, serious, and usually fatal demyelinating disease that occurs predominantly in severely immunosuppressed patient populations. The etiologic agent is the JC virus (JCV), a polyomavirus that is widely distributed as a latent infection in the general population but becomes activated, leading to destruction of myelin-producing oligodendrocytes. Patients who survive this complication are left with devastating neurologic sequelae. PML has been described mainly in patients infected with the human immunodeficiency virus (HIV). However, other immunosuppressed patient populations, including those with malignancies, organ transplants, and systemic lupus erythematosus (SLE) (1–20) and other rheumatic diseases (22–32), are at risk of developing this complication. The appearance of PML in 0.1% of patients treated in clinical trials with the biologic therapeutic agent natalizumab (33,34), an antagonist of 4 integrin, greatly hindered the development of this promising new agent for the treatment of multiple sclerosis (MS), as well as plans for expanded indications for this agent in Crohn’s disease and rheumatoid arthritis (RA), for which it was already in clinical trials. In addition, on December 18, 2006, the US Food and Drug Administration (FDA) in conjunction with Genentech and Biogen Idec, the makers of rituximab, a recently approved biologic agent for the treatment of RA, issued a warning to health care providers, informing them that 2 patients receiving rituximab for the treatment of SLE (an unapproved indication) had developed PML (35). Recent years have witnessed advances in better understanding of the pathologic response to JCV and the pathogenesis of PML (36). An evolving clinical picture is emerging: PML is a protean disease that is difficult to distinguish clinically from immune-mediated diseases of the central nervous system (CNS), such as MS, neuropsychiatric SLE, and vasculitis of the CNS (37,38). Thus, it is timely to review PML. We describe herein the microbiology, epidemiology, immunology, and pathology of PML, its changing clinical and pathologic spectrum, recent advances in our understanding of the pathogenesis of PML, and its relevance to physicians treating patients with rheumatic disorders. We report the results of a systematic literature review of all 36 patients with rheumatic diseases who have developed PML, including a previously unreported case in a patient treated at Cleveland Clinic. Nearly two-thirds of the cases of PML occurred in patients with SLE, and many cases of PML in SLE occurred in patients who had had minimal immunosuppression, which raises the possibility that SLE itself may predispose to PML.

Objective The precipitating event(s) that triggers Wegener's granulomatosis (WG) is unknown. Cytokines, costimulatory molecules, and counterregulatory molecules control the quality and intensity of immune responses. Thus, they are relevant candidates for genetic studies of immune dysregulation in WG, the pathogenesis of which may be facilitated by multiple acquired and/or inherited factors. This study was undertaken to investigate possible genetic associations of various proinflammatory cytokines and CTLA-4, a receptor for T cell inhibition, with WG. Methods Using polymerase chain reaction–based DNA genotyping, we investigated the polymorphisms located in the genes encoding a variety of proinflammatory cytokines and CTLA-4 in 117 American patients with WG and 123 ethnically matched healthy controls. Results Compared with controls, patients with WG had a significantly lower frequency of homozygosity for the shortest allele (designated allele 86) of the Ctla4 microsatellite polymorphism (AT)n located in the 3′-untranslated region (3′-UTR) of exon 3 (47.0% versus 69.9%; P = 0.0005). Significant differences between patients and controls in the allelic and genotypic frequencies of polymorphisms in the other cytokine and cytokine receptor genes studied (tumor necrosis factor α [TNFα], TNF receptor I [TNFRI], TNFRII, interleukin-1β [IL-1β], IL-6) were not found. Conclusion The Ctla4 (AT)n 86 allele has been previously demonstrated to be crucial for maintenance of normal levels of CTLA-4 expression and balance between T cell activation and inhibition. Our results in American patients confirm findings from a Scandinavian cohort in which a positive association between WG and longer alleles of (AT)n in the Ctla4 3′-UTR was demonstrated. Diminished frequencies of the most effective allele for CTLA-4 expression may represent a WG-related susceptibility mutation that accounts, in part, for increased T cell activation and clonal expansion in WG. Blockade of T cell costimulation using CTLA-4Ig might be a useful therapeutic intervention, providing an alternative or complementary approach to conventional treatment with immunosuppressive agents.