Data for this Review were identified by searches of Medline by use of the following search terms: “progressive multifocal leucoencephalopathy”, “monoclonal antibody”, “rituximab”, “natalizumab”, “efalizumab”, “epidemiology”, and “pathophysiology”. No language restrictions were imposed and selected papers published between Jan 1, 1930, and April 30, 2009, were included. Searches of websites and safety databases maintained by the FDA, the EMEA, and other regulatory agencies were also
ReviewMonoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project
Introduction
Progressive multifocal leucoencephalopathy (PML), a usually fatal demyelinating disorder, was first described half a century ago by Astrom and colleagues1 as a complication of chronic lymphocytic leukaemia and Hodgkin's lymphoma. Although this was the first report describing this disease entity as PML, reports describing a similar demyelinating pathology in patients with dementia date back as early as 1930.2 The viral nature of PML was first postulated in 1959 and then confirmed in 1967 by Zu Rhein and co-workers,3 who noted polyoma-like virions on electron microscopy of a tissue sample from a patient with PML.4 This polyoma virus was named JC virus by Padgett and colleagues,5 based on the initials of the patient from whom the virus was first isolated in 1971. A note should be made that JC virus is in no way related to Creutzfeldt–Jakob disease, a neurodegenerative disorder caused by infectious prions. 50 years after the first description of PML, and 40 years after the first direct finding of JC virus, the precise mechanism by which a common, usually asymptomatic virus can become the cause of a highly destructive neurological disease remains an area of intense investigation.
Since the identification of PML in two patients with multiple sclerosis treated with natalizumab in 2005, there has been great interest in this disease in patients treated with natalizumab. PML reported in patients who have received the monoclonal antibodies rituximab or efalizumab has also raised concern about these drugs. The mechanism of PML development after monoclonal antibody treatment remains controversial, although for natalizumab and efalizumab, inhibition of T-lymphocyte trafficking into the CNS is thought to be responsible, at least in part (figure 1). In this paper, we review the general features of PML, the clinical and epidemiological issues and proposed pathogenesis, and the risk-management issues for PML after treatment with rituximab, natalizumab, and efalizumab (table).
For the first 20 years after the report by Astrom and colleagues,1 PML was a rare disease, seen mainly in patients with haematological malignancies or connective-tissue disorders. In their 1984 review of PML, Brooks and Walker11 identified only 230 cases of PML reported between 1958 and 1984, and five of these patients had AIDS. As the HIV epidemic grew in the 1980s, PML emerged as a major complication of HIV infection (both HIV-1 and HIV-2). The incidence of PML increased 50-fold between 1979 and 1994.12 Since then, highly active antiretroviral therapy (HAART) has helped reduce the progression and the severity of PML in individuals with HIV, although HIV infection continues to account for about 80% of all new PML diagnoses.13 However, even with the use of HAART, the incidence of PML remains between 3% and 5% in patients with AIDS, which is an incidence similar to that reported in the pre-HAART era.14 HIV-infected patients with PML who are treated with HAART can also have immune reconstitution inflammatory syndrome that requires steroid treatment.15 More recently, certain cytotoxic chemotherapeutic agents, and other immunosuppressive medications have been associated with PML, including fludarabine, cyclophosphamide, methotrexate, mycophenolate, and corticosteroids.16, 17, 18 Solid organ and haemopoietic transplantation have also been associated with PML, probably due to the considerable immunosuppression associated with both procedures.19
Initial infection with JC virus occurs early in life, with most people becoming seropositive by the age of 17 years. In developed countries, 70% to 90% of adults have detectable antibodies to JC virus.20, 21 Primary infection is typically asymptomatic,22 and the exact mechanisms of viral transmission remain controversial.23 Debate remains as to whether the development of PML is due to primary infection, reactivation of a latent infection, or the virulent mutation of an active but asymptomatic infection. The latter theories are supported by the difference in median age of patients diagnosed with primary JC virus infection and PML, and the finding that most patients are immunosuppressed at the time of diagnosis. PML usually occurs in people with immunosuppression from HIV or haematological malignancies, but has also been reported in patients with autoimmune disorders or tuberculosis, and after haemopoietic or solid-organ transplantation.19, 24
In the setting of haematological malignancies, one population-based study estimated a 0·07% incidence of PML.25 This incidence estimate was based on three cases of PML identified in patients with haematological malignancies over a period of 11 years in a single Canadian province.25 Another study showed a higher incidence of 0·52% in patients with chronic lymphocytic leukaemia, although all of these patients were also treated with fludarabine.26 Accurately calculating the risk of PML attributable to the underlying malignancy as opposed to immunosuppression from treatment is complicated by the rarity of the disease and few large clinical trials from which incidence can prospectively be determined. Fludarabine is the chemotherapeutic agent most closely associated with PML and its well known side-effects of T-lymphocyte depletion and complicating opportunistic infections similar to those seen in AIDS make such an association intuitive.17
Section snippets
Pathogenesis
Although JC virus resides in the kidney in an asymptomatic state,27 molecular studies suggest this is not the source of the virus responsible for CNS infection.28 The tropism of JC virus for B lymphocytes and detection of JC virus in tonsil tissue has led to the postulation that the virus might persist in circulating B lymphocytes and pre-B lymphocytes.29 CD34+ haemopoietic progenitor cells can also harbour latent JC virus.30 Once in the bloodstream and bone marrow, haemopoietic cells
Clinical manifestations, diagnosis, and treatment of PML
Clinically, PML often progresses slowly at first, with gradual impairment of mental function and disturbance of speech and vision. Motor function can also be affected and is frequently the clinical sign that prompts further assessment. As the disease progresses, the velocity of neurological decline often accelerates. The clinical course spans over weeks or months, resulting in severe disability, with symptoms such as dementia, blindness, paralysis, and finally coma and death.
The gold standard
Rituximab
Rituximab, a chimeric IgG1 anti-CD20 monoclonal antibody, is approved in the USA for treatment of non-Hodgkin lymphoma, with several different specific indications, and in combination with methotrexate for adult patients with moderate to severe rheumatoid arthritis who have had an inadequate response to one or more tumour necrosis factor-alpha inhibitors. In Europe, rituximab is also approved in combination with chemotherapy for use in patients with previously untreated chronic lymphocytic
Natalizumab
Natalizumab is a humanised IgG4 monoclonal antibody that binds to the α4 subunit of the very late antigen-4 integrin, and is approved as monotherapy for relapsing multiple sclerosis in the USA and Europe and Crohn's disease in the USA. Antibodies against α4 integrins inhibit the binding of cells expressing α4β1 integrin and α4β7 integrin (eg, lymphocytes) to vascular-cell adhesion molecule 1 on endothelial cells, a crucial step in the movement of T-lymphocytes across the endothelial-cell basal
Efalizumab
Efalizumab is a humanised IgG1 monoclonal antibody that targets CD11a, the α-subunit of leucocyte function associated antigen 1 (LFA-1). In the absence of efalizumab, LFA-1 binds to intracellular adhesion molecule-1, which is an important step in the migration of T lymphocytes through the endothelial lining of the vascular system during inflammation.75 This process is thought to be a crucial step in the pathogenesis of skin disorders such as psoriasis, but is also important in other types of
Conclusion
The monoclonal antibody rituximab has increased disease-free survival and overall survival for many lymphoid malignant diseases, and is also licensed for treatment of rheumatoid arthritis. Rituximab is also an emerging therapy for a wide range of immunological diseases. Natalizumab has proven benefits in the treatment of relapsing multiple sclerosis and Crohn's disease, and efalizumab decreases the size and severity of skin lesions associated with moderate to severe plaque psoriasis.
Search strategy and selection criteria
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