Progressive Multifocal Leukoencephalopathy in MS Patients Treated with Natalizumab - Are We Closer to Understanding the Risk?
Progressive Multifocal Leukoencephalopathy in MS Patients Treated with Natalizumab - Are We Closer to Understanding the Risk?
Abstract & Commentary
By Susan Gauthier, DO, MS, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Gauthier reports no financial relationships relevant to this field of study.
Synopsis: Two recent cases of progressive multifocal leukoencephalopathy in patients with multiple sclerosis that had received natalizumab monotherapy are presented. They survived after discontinuation of the drug and the initiation of plasma exchange.
Sources: Chen Y, et al Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 2009;361:1067-1074. Wenning W, et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N Engl J Med 2009;361:1075-1080. Linda H, et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 2009;361:1081-1087.
Natalizumab effectively reduces the inflammatory burden in patients with multiple sclerosis (MS) as measured by a reduction in relapse rate and MRI activity; however, treatment with natalizumab carries a risk of progressive multifocal leukoencephalopathy (PML). The mechanism by which natalizumab increases the risk of PML, and which patients are at risk to develop the disease, remains unknown.
PML is caused by reactivation of the JC virus which remains latent in the kidney and lymphoid organs in healthy individuals, and under normal conditions can be detected in the urine, and less often, in the serum. Chen and colleagues studied 19 asymptomatic MS patients who were treated with natalizumab for up to 18 months and found that by 12 months, the presence of JC virus in the urine increased to 63% of the patients from a baseline level of 19%. Interestingly, in three patients the JC virus disappeared after 12 months of exposure to natalizumab. In the serum, the virus was initially undetectable but was present in 20% (3/15 patients) at 18 months. The level of virus in the peripheral-blood mononuclear cells (PBMCs) increased and was present in 60% (9/15 patients) over the same time period. Sequence analysis of the viral clones isolated from urine and PBMCs revealed similar regulatory sequences as those found in the central nervous system isolate MAD-1, although with differing point mutations. Finally, T-cell-mediated immune responses to JC virus decreased over time in patients with JC viremia as compared to those without a viremia.
The original reported risk of PML in natalizumab-treated patients was 1 in 1,000 patients who had 18 months of exposure, and combination therapy appeared to put patients at a higher risk.1 Two recently published cases of PML associated with natalizumab provide further insight into the risk and ultimate prognosis for patients on this treatment. Wenning and colleagues reported a patient with MS, treated with long-term low- dose azathioprine, who developed PML after 12 infusions of natalizumab monotherapy. The patient was treated initially with two courses of intravenous methylprednisolone for the presumed diagnosis of a MS relapse. After worsening neurological status and MRI findings atypical for a MS lesion, plasma exchange was initiated. The patient improved immediately after the exchange, then quickly worsened, and contrast-enhancement on the MRI was appreciated; the patient was then diagnosed with immune reconstitution inflammatory syndrome (IRIS). Stabilization was achieved with pulse-steroid therapy and the patient continued to slowly improve on mefloquine and mirtazapine. Linda and colleagues reported on a treatment-naïve patient who developed PML after receiving 14 doses of natalizumab monotherapy. Plasma exchange was initiated and within a few weeks IRIS developed. The diagnosis of PML in this patient was based upon an atypical MRI lesion and worsening of symptoms on steroid treatment. The JC virus was undetectable in the CSF at a local laboratory on two occasions, but was eventually detected by quantitative PCR at a reference laboratory. Stabilization was reported after the patient received pulse-steroids for IRIS.
Commentary
Natalizumab is an effective drug for the treatment of relapsing forms of MS, although cases of PML continue to be reported. Since its reintroduction, 13 cases of PML have been confirmed worldwide in patients treated with natalizumab monotherapy for multiple sclerosis. As described in the cases above, with early detection and treatment, patients can survive with varying degrees of disability. PML associated with natalizumab can occur in the following situations: 1) in treatment-naïve patients, 2) during monotherapy, and 3) with as few as 12 doses of natalizumab. The diagnosis of PML should be suspected in MS patients with atypical MRI lesions and symptoms atypical for a relapse. Plasma exchange has been demonstrated to quickly and effectively lower serum levels of natalizumab;2 however, as demonstrated in these cases, IRIS can occur within only a few weeks after the plasmas exchange, as compared to three months with drug discontinuation only.3
Is it possible to identify patients at risk? Detection of JC virus in the urine is not uncommon in healthy individuals, but in this MS cohort, an increase in urine detection occurred before the observed viremia, and urinary monitoring may be a good screen. The viremia in this study was primarily cell-associated as opposed to free-floating. Given that the mechanism of natalizumab action is to act as an inhibitor of the a4-integrin adhesion molecule, the PBMCs containing virus would also be blocked, but detection of virus in these blood cells would place a patient at increased risk for developing PML. At the present time, there is no clear method to screen for patients at risk for PML while being treated with natalizumab, and clinical surveillance remains our only method for early detection.
References
1. Yousry TA, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924-933.
2. Khatri BO, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009;72:402-409.
3. Langer-Gould A, et.al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375-381.
Two recent cases of progressive multifocal leukoencephalopathy in patients with multiple sclerosis that had received natalizumab monotherapy are presented. They survived after discontinuation of the drug and the initiation of plasma exchange.Subscribe Now for Access
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