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Progressive Multifocal Leukoencephalophay Associated With Efalizumab and Oral Fumaric Acid in the Treatment of Psoriasis

Rechelle Tull, MD

This article reviews reports of progressive multifocal leukoencephalopathy, a fatal demyelinating disease due to reactivation of John Cunningham virus, in the setting of long-term immunosuppressive therapy for psoriasis, including oral fumaric acid and efalizumab. 

Efalizumab and PML

Progressive multifocal leukoencephalopathy (PML) was first discovered in 1958 as a fatal demyelinating neurological condition due to John Cunningham (JC) virus infection of the central nervous system. Historically, PML was seen in patients with chronic immunosuppression in the setting of HIV infection or treatment for hematologic malignancy.1 Recently, PML has been associated with chronic use of certain immune-modulating monoclonal antibody medications, including efalizumab, an IgG monoclonal antibody against CD11a, which was previously approved for the treatment of moderate-to-severe psoriasis.1,2

Initial JC virus infection is usually asymptomatic and highly prevalent, with 70-90% seropositivity in adults in developed countries. JC virus is thought to lay dormant in B lymphocytes and pre-B lymphocytes, which shuttle the virus across the blood-brain barrier. PML occurs due to JC virus reactivation in immunosuppressed individuals. Infected oligodendrocytes are destroyed during viral replication, resulting in degeneration of the myelin sheath. Symptoms of PML include progressive worsening of speech, vision, mental function and/or motor ability with resultant dementia, blindness, paralysis, and death.3 While positive polymerase chain reaction (PCR) analysis for JC virus in cerebral spinal fluid confirms diagnosis in patients with corresponding symptoms and MRI findings, a negative PCR does not exclude diagnosis. Brain biopsy remains the gold standard diagnostic test for PML.1,2

There are reports of association between PML and efalizumab therapy. A black box warning for efalizumab was initially distributed after a psoriasis patient developed PML on chronic efalizumab therapy. Efalizumab was withdrawn from the market in April 2009 after FDA advisory was issued upon report of 3 additional cases of PML in psoriasis patients treated with efalizumab.2 All 4 patients developed PML after 3 or more years of efalizumab therapy and none received other immunosuppressive medications.1,2

There is no proven mechanism for this association. However, efalizumab blockade of CD11a, an intrinsic part of lymphocyte function-associated antigen-1, impedes targeted movement of leukocytes from peripheral blood to inflamed tissues. While this mechanism decreases overall inflammatory response, it can also disrupt the body’s ability to combat infection.2

In 2 reviews, Carson et al1 and Molloy et al2 suggested decreased immune surveillance and reduced ability for leukocytes to target infection in the CNS as possible contributing factors leading to JC virus reactivation and development of PML.

References

1. Carson KR, Focosi D, Major EO, et al. Monoclonal 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. Lancet Oncol. 2009;10(8):816-824. doi:10.1016/S1470-2045(09)70161-5

2. Molloy ES, Calabrese LH. Targeted but not trouble-free: Efalizumab and PML. Nat Rev Rheumatol. 2009;5(8):418-419. doi:10.1038/nrrheum.2009.142

Development of PML in Patients Receiving Oral Fumaric Acid Therapy for Psoriasis Vulgaris

Ermis et al reported a case of a 74-year-old male patient who developed progressive sensory aphasia after taking oral fumaric acid as monotherapy for psoriasis over 3 years.3 He had received maximum doses of dimethyl fumarate 120 mg twice daily and 95 mg monoethyl fumarate twice daily. The patient’s previous psoriasis treatments included topical corticosteroids, oral acitretin, and oral methotrexate.

The patient was diagnosed with progressive multifocal leukoencephalopathy (PML) after imaging and laboratory testing revealed white-matter lesions on brain magnetic resonance imaging (MRI), positive JC virus polymerase-chain reaction (PCR) analysis of brain tissue and cerebral spinal fluid (CSF), grade 3 lymphocytopenia and histopathological findings on evaluation of brain tissue. Workup was negative for other possible etiologies of PML, including myelodysplastic syndrome, paraneoplastic syndromes, neurotrophic viruses, and HIV.

The patient stopped oral fumaric acid and initiation of mefloquine and mirtazapine therapy. Subsequent development of immune reconstitution inflammatory syndrome (IRIS) was treated with methylprednisolone. Follow-up evaluation at 5 months showed continued sensory aphasia despite improved brain MRI with no enhancement and negative PCR assays of CSF and plasma for JC virus.3

In a second report by van Oosten et al,  a 42-year-old woman presented with right-sided hemiparesis that failed to improve after intravenous (IV) methylprednisolone therapy for possible multiple sclerosis.4 She had history of psoriasis treated for 5 years with Psorinovo, a formulation of oral slow-release dimethyl fumarate with copper gluconate (dosage 420 mg daily). Findings supportive of PML included multiple deep areas of enhancement on brain MRI and positive PCR assay of CSF for JC virus. Retrospective review showed the patient developed lymphocytopenia soon after initiating Psorinovo therapy. Serologic HIV testing was negative. Psoronivo was discontinued and the patient started mefloquine and mirtazapine for PML. The patient developed IRIS requiring IV methylprednisolone but stabilized after 2 months of PML treatment.4

Fumaric acid differs from other immunosuppressive medication associated with PML (ie. efalizumab [Raptiva], infliximab [Remicade], rituximab [Rituxan], and natalizumab[Tysabri]) as it is not a monoclonal antibody therapy.1 Authors of both reports believe chronic fumaric acid therapy may have led to development of PML in both patients.3, 4

References

1.  Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid. N Engl J Med. 2013;368(17):1657-1658. doi:10.1056/NEJMc1211805

2. van Oosten BW, Killestein J, Barkhof F, et al. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013;368(17):1658-1659. doi:10.1056/NEJMc1215357

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