Fig. 3. Timeline of PML disease eras.

From an epidemiological perspective, three distinct eras of progressive multifocal leukoencephalopathy (PML) have been identified. In the early years, following its first description, PML was rare and almost uniformly fatal, seen most commonly in patients with haematological malignancy. During the AIDS pandemic, the incidence of PML increased dramatically — up to 5% of patients with AIDS developed the disease. With the introduction of combined antiretroviral therapies (cART) in 1996, this proportion declined substantially, and immune reconstitution was established as a way to prevent PML and to increase the chance of survival. Although the majority of PML cases worldwide are still associated with AIDS, iatrogenic PML is linked to a growing number of therapies that target immune function. Most notable of these are natalizumab for the treatment of relapsing–remitting multiple sclerosis (MS), rituximab for the treatment of haematological cancers and rheumatological disorders, and efalizumab for the treatment of psoriasis (efalizumab was withdrawn from the market in 2009 after reports of association with PML). JCV, JC virus; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.