Progressive Multifocal Leukoencephalopathy in MS
Progressive Multifocal Leukoencephalopathy in MS
Purpose of review Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system. It has been recently associated with selective immunosuppression in patients with multiple sclerosis. This review describes the pathogenesis, clinical presentation, diagnosis, and treatment of natalizumab-associated PML.
Recent findings Treatment of multiple sclerosis with natalizumab first involves risk stratifying patients. Clinicians can employ new tools for risk stratification including JC-virus antibody status, prior immunosuppression, and length of natalizumab treatment. These tools can help minimize the risk of developing PML. Identifying patients with natalizumab-associated PML poses a diagnostic challenge for clinicians. Unique clinical features, sensitive laboratory analyses, and advanced MRI techniques have been identified that aid in the diagnosis of natalizumab-associated PML.
Summary There continues to be significant gaps in our understanding of PML pathogenesis and its relationship with therapeutic immunosuppression. There have been advances made in our ability to treat multiple sclerosis, although these have come with the unintended risk of PML. Fortunately, natalizumab-associated PML remains a rare entity compared to multiple sclerosis-associated disability, and the risk may be mitigated with appropriate patient selection, accurate and rapid diagnosis, and aggressive treatment strategies.
Multiple sclerosis is a progressive autoimmune disease of the central nervous system. The natural course of the disease is variable; however, half of all patients suffer from progressive disability. As multiple sclerosis affects a young population, disability impacts education, employment, and the care of families. Until the early 1990s neurologists were limited in their ability to treat multiple sclerosis. With the approval of interferon-[beta] as a disease modifying therapy, the road for treatment of multiple sclerosis began. Interferon therapies were soon followed by glatiramer acetate, all of which have only shown moderate efficacy in reducing relapses. These first-line agents are considered well tolerated. Nevertheless, these therapies have only demonstrated relative risk reductions of approximately 30%, and absolute risk reductions of 0.3 relapses per year in patients with relapsing remitting multiple sclerosis.
Drug research and development has continued for the treatment of multiple sclerosis. Natalizumab is a selective monoclonal antibody (mAb) that inhibits a key step in the pathophysiology of multiple sclerosis. Studies have demonstrated a 68% relative risk reduction (absolute risk reduction 0.55 relapses per year) in annual relapse rate with natalizumab compared to placebo. Early enthusiasm for this new therapy was halted in 2005 when three cases of progressive multifocal leukoencephalopathy (PML) were identified in patients treated with natalizumab. After a thorough safety evaluation of more than 3000 patients, researchers concluded that the overall risk of natalizumab-associated PML was approximately 1 : 1000 patients. Owing to the efficacy of natalizumab and an overall low risk for PML, it was reintroduced in the market in 2006. During the period of treatment disruption, 21% of multiple sclerosis patients who received natalizumab experienced disease recurrence in approximately 4–7 months after discontinuation, which suggested that continued therapy with natalizumab is important in maintaining therapeutic benefit. Clinicians must now carefully risk stratify patients based on several key factors, and weigh the potential benefits of natalizumab with the serious or even fatal complication of PML.
Abstract and Introduction
Abstract
Purpose of review Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system. It has been recently associated with selective immunosuppression in patients with multiple sclerosis. This review describes the pathogenesis, clinical presentation, diagnosis, and treatment of natalizumab-associated PML.
Recent findings Treatment of multiple sclerosis with natalizumab first involves risk stratifying patients. Clinicians can employ new tools for risk stratification including JC-virus antibody status, prior immunosuppression, and length of natalizumab treatment. These tools can help minimize the risk of developing PML. Identifying patients with natalizumab-associated PML poses a diagnostic challenge for clinicians. Unique clinical features, sensitive laboratory analyses, and advanced MRI techniques have been identified that aid in the diagnosis of natalizumab-associated PML.
Summary There continues to be significant gaps in our understanding of PML pathogenesis and its relationship with therapeutic immunosuppression. There have been advances made in our ability to treat multiple sclerosis, although these have come with the unintended risk of PML. Fortunately, natalizumab-associated PML remains a rare entity compared to multiple sclerosis-associated disability, and the risk may be mitigated with appropriate patient selection, accurate and rapid diagnosis, and aggressive treatment strategies.
Introduction
Multiple sclerosis is a progressive autoimmune disease of the central nervous system. The natural course of the disease is variable; however, half of all patients suffer from progressive disability. As multiple sclerosis affects a young population, disability impacts education, employment, and the care of families. Until the early 1990s neurologists were limited in their ability to treat multiple sclerosis. With the approval of interferon-[beta] as a disease modifying therapy, the road for treatment of multiple sclerosis began. Interferon therapies were soon followed by glatiramer acetate, all of which have only shown moderate efficacy in reducing relapses. These first-line agents are considered well tolerated. Nevertheless, these therapies have only demonstrated relative risk reductions of approximately 30%, and absolute risk reductions of 0.3 relapses per year in patients with relapsing remitting multiple sclerosis.
Drug research and development has continued for the treatment of multiple sclerosis. Natalizumab is a selective monoclonal antibody (mAb) that inhibits a key step in the pathophysiology of multiple sclerosis. Studies have demonstrated a 68% relative risk reduction (absolute risk reduction 0.55 relapses per year) in annual relapse rate with natalizumab compared to placebo. Early enthusiasm for this new therapy was halted in 2005 when three cases of progressive multifocal leukoencephalopathy (PML) were identified in patients treated with natalizumab. After a thorough safety evaluation of more than 3000 patients, researchers concluded that the overall risk of natalizumab-associated PML was approximately 1 : 1000 patients. Owing to the efficacy of natalizumab and an overall low risk for PML, it was reintroduced in the market in 2006. During the period of treatment disruption, 21% of multiple sclerosis patients who received natalizumab experienced disease recurrence in approximately 4–7 months after discontinuation, which suggested that continued therapy with natalizumab is important in maintaining therapeutic benefit. Clinicians must now carefully risk stratify patients based on several key factors, and weigh the potential benefits of natalizumab with the serious or even fatal complication of PML.
Source...