Original articleProgressive multifocal leukoencephalopathy associated with efalizumab use in psoriasis patients
Introduction
Progressive multifocal leukoencephalopathy (PML) is a rare, potentially fatal demyelinating disease characterized by multiple foci of demyelination affecting mainly the subcortical white matter in the brain and may manifest as a variety of neurological symptoms, including visual deficits, motor weakness, and behavior or cognitive changes.1, 2 Diagnostic testing for PML may include magnetic resonance imaging (MRI), detection of John Cunningham virus (JCV) in the cerebrospinal fluid (CSF), brain biopsy, and autopsy.1, 2 There is no known effective treatment for PML, though recent case reports suggest plasma exchange may improve outcomes.3, 4 Although JCV antibodies are present in about 80% of adults, PML occurs primarily in immunocompromised individuals and is thought to be caused by JCV reactivation.1, 5 As a result, PML has been reported primarily in patients with underlying immunosuppressive conditions (ie, HIV infection, AIDS, malignancies) and immunosuppressive medications, such as natalizumab.1, 3, 4, 6, 7, 8, 9, 10, 11 In addition, results from a study of a national hospital discharge database suggest that rheumatic diseases, including systemic lupus erythematosus and rheumatoid arthritis, are associated with a higher rate of PML compared to the background population.12
Efalizumab (Raptiva, Genentech Inc, South San Francisco, CA), an immunosuppressive recombinant humanized IgG1 kappa isotype monoclonal antibody that binds to human CD11a, was approved by the Food and Drug Administration (FDA) on Oct 27, 2003 for patients 18 years or older with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.13, 14 In September 2008, the FDA received an adverse event report of PML associated with efalizumab from a post-marketing safety registry.14 Based on this case, the efalizumab label was updated in October 2008 to include a boxed warning regarding PML.15 Additional information was added to the boxed warning in March 2009 following receipt of two additional confirmed cases of PML in October 2008 and January 2009.13 In July 2009, efalizumab was voluntarily withdrawn from the US market because of the risk of PML.16
Psoriasis affects approximately 2% of the population and is characterized by chronic inflammation of the skin, resulting in erythematous, pruritic skin plaques that are often painful and disfiguring.17 Treatment options may include steroids, vitamin D analogues, retinoids, coal tar, phototherapy, oral medications (ie, cyclosporine and methotrexate), and biologic agents.13, 17, 18, 19, 20, 21, 22, 23 Biologic agents that are FDA approved to treat psoriasis include adalimumab (Humira, Abbott Laboratories, North Chicago, IL), alefacept (Amevive, Astellas Pharma US, Inc, Deerfield, IL), efalizumab, etanercept (Enbrel, Amgen Inc., and Wyeth Pharmaceuticals, Thousand Oaks, CA), infliximab (Remicade, Centocor Ortho Biotech, Inc, Malvern, PA), and ustekinumab (Stelara, Centocor Ortho Biotech, Inc, Horsham, PA).13, 19, 20, 21, 22, 23
On the basis of adverse event reports submitted to the FDA, we describe 3 cases of PML in psoriasis patients treated with efalizumab who had no other known risk factors for PML.
Section snippets
Methods
The FDA's Adverse Event Reporting System (AERS) database is a collection of spontaneous domestic and foreign post-marketing adverse event reports; reporting to the FDA is voluntary for the public (ie, health care professionals, consumers) and mandatory for drug manufacturers.24, 25 In addition to structured data fields, these reports contain data in a free-text narrative that describes clinical details of the adverse events being reported. Adverse event terms are coded using the Medical
Characteristics of cases
The AERS search using the MedDRA terms Progressive Multifocal Leukoencephalopathy and JC Virus Infection retrieved 14 cases; the text word search of narratives retrieved two additional cases. Of the 16 cases, only 4 reported an indication of psoriasis; all 4 cases reported efalizumab use. Three of the efalizumab cases were classified as “confirmed” (Table I). The fourth efalizumab case was suggestive of PML, but did not report diagnostic tests confirming PML and is not discussed further. Eight
Discussion
The 3 confirmed PML cases identified in AERS support an association between efalizumab and PML. None of the cases were confounded by factors that may predispose a patient to the development of PML, such as HIV or AIDS or concomitant use of another immunosuppressive agent. Although PML is generally thought to be associated with immune suppression, a recent article suggests that this condition may also develop in patients with minimal or occult immunosuppression.31 Because psoriasis is not known
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Funding sources: None.
Conflicts of interest: None declared.
Disclosure: All authors are employed at the US Food and Drug Administration. The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from, the US Food and Drug Administration or the US government.