Editorial

Predicting Risk of Progressive Multifocal Leukoencephalopathy from Natalizumab

Allan H. Ropper, M.D.

N Engl J Med 2012; 366:1938-1939May 17, 2012DOI: 10.1056/NEJMe1201395

Article

After a century of futility in the treatment of multiple sclerosis, there is now a deluge of drugs that alter the course of the disease. The half-dozen new oral drugs have excited the most interest, but the monoclonal antibodies, and specifically natalizumab, have a more focused biologic activity and are more potent. It is ironic that natalizumab can cause not just a second neurologic disease, progressive multifocal leukoencephalopathy (PML), but one that, like multiple sclerosis itself, affects the oligodendrocytes and central nervous system myelin.

Once it was apparent that PML was related to natalizumab treatment, and the drug was withheld from the market, Biogen Idec supported several postmarketing surveillance programs to determine the frequency of PML and the factors that predict its emergence. At the time of the initial reports of three cases of PML, Yousry and colleagues found only one additional instance of PML among 3417 patients with multiple sclerosis, Crohn's disease, and rheumatoid arthritis who were involved in clinical trials and who had received a mean of 18 doses (1 per month) of natalizumab — an estimated risk of PML of 1 case per 1000 patients.1

In this issue of the Journal, Bloomgren and colleagues, all from Biogen Idec, take an algorithmic approach to stratifying the risk of PML according to the duration of drug use, additional immunosuppression, and, particularly, serologic status for JC virus.2 The study made use of a large amount of data from three trials and from a registry of patients with multiple sclerosis, covering a period of up to 4 years — longer than the follow-up time in earlier reports. Blood samples had been saved before treatment in only one quarter of the patients and were tested with the use of a two-step antibody assay that was developed for the purpose of the current investigation and is commercially available. Among the 5896 patients tested, 55% were seropositive for JC virus, reflecting the expected rate in the general population of patients with multiple sclerosis. This analysis allows updated point estimates for the risk of PML in patients with positive serologic screening (Table 1Table 1Risk of Progressive Multifocal Leukoencephalopathy among Patients Who Are Positive for Anti-JC Virus Antibodies, According to Use of Immunosuppressants.).

All the patients in whom PML developed had tested positive for anti–JC virus antibodies before the onset of PML. Because the test used by Bloomgren et al. has a false negative rate of about 3%, and seropositivity is calibrated with an arbitrary cutoff point,3 the authors performed a sensitivity analysis and estimated that for seronegative patients, the upper limit of the 95% confidence interval for the rate of PML was 0.48 cases per 1000 patients. In contrast, for seropositive patients with prior immunosuppressant use and 25 to 48 months of natalizumab treatment, the estimated rate is a disquieting 11 cases per 1000 patients, or 1 in 90. There are no reliable data about the rate of PML with natalizumab treatment for longer than 4 years.

Can patients now be reassured about natalizumab? If the antibody test is negative, the answer is still ostensibly yes. There are, however, basic limitations to serologic tests for JC virus, since there is no standard by which to judge the absence of the virus. For example, one quarter of patients with human immunodeficiency virus in whom PML has developed have been seronegative,4 including some with viremia. The seroprevalence of JC virus also increases with age, and patients can undergo seroconversion at any time; retesting is therefore advisable during treatment with natalizumab. It is even possible that patients fare worse if their first exposure to JC virus occurs during the time they are receiving immunosuppression. Because multiple sclerosis and PML have similar characteristics on magnetic resonance imaging (MRI), serologic screening should not be confused with tests to establish the diagnosis of PML, such as measurement of JC virus titer in cerebrospinal fluid.

Fascinating clinical and biologic dimensions have emerged from the natalizumab–PML story. Natalizumab may reactivate the JC virus without causing symptoms or lesions on MRI.5 When the JC virus transits from the urinary tract to the brain, it also undergoes mutations in its capsid protein.6 These alterations change the virus's receptor binding to neurons in a manner that favors the emergence of PML; whether natalizumab affects the emergence of the mutation is not known. Finally, plasma exchange may be used to remove the drug and restore lymphocyte trafficking adequately to induce an immune reconstitution inflammatory response (IRIS),7 much the same as happens in patients with AIDS during antiretroviral treatment. Under these circumstances, patients with PML can survive with varying degrees of disability, although preventing the disease by attending to the risk factors is certainly preferable. In a 2006 editorial that accompanied reports in the Journal on natalizumab therapy in patients with multiple sclerosis, I suggested that newer monoclonal antibodies would not carry the risk of PML.8 This has so far been incorrect.

We should not overlook the fact that much of the grave disability associated with multiple sclerosis occurs during an irreversible chronic progressive phase that ensues after a relapsing–remitting course or is the result of a relentless, primary progressive type of multiple sclerosis. Immune-modulating treatments reduce the rate of relapses but do not prevent either form of chronic progression. There is a major need for drugs to address this problem.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

This article (10.1056/NEJMe1201395) was updated on June 7, 2012, at NEJM.org.

Source Information

From the Department of Neurology, Brigham and Women's Hospital, Boston.

References

References

1. 1

   Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924-933
   Free Full Text | Web of Science | Medline

2. 2

   Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870-1880
   Free Full Text | Web of Science | Medline

3. 3

   Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010;68:295-303
   CrossRef | Web of Science | Medline

4. 4

   Viscidi RP, Khanna N, Tan CS, et al. JC virus antibody and viremia as predictors of progressive multifocal leukoencephalopathy in human immunodeficiency virus-1-infected individuals. Clin Infect Dis 2011;53:711-715
   CrossRef | Web of Science

5. 5

   Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 2009;361:1067-1074[Erratum, N Engl J Med 2011;364:1882.]
   Free Full Text | Web of Science | Medline

6. 6

   Gorelik L, Reid C, Testa M, et al. Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity. J Infect Dis 2011;204:103-114
   CrossRef | Web of Science

7. 7

   Vermersch P, Kappos L, Gold R, et al. Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology 2011;76:1697-1704
   CrossRef | Web of Science

8. 8

   Ropper AH. Selective treatment of multiple sclerosis. N Engl J Med 2006;354:965-967
   Full Text | Web of Science | Medline

Citing Articles (5)

Citing Articles

1. 1

   Kurt Samson. (2013) PML Reported in Patients Taking Psoriasis Compounds Sharing Ingredient with Oral MS Drug. Neurology Today 13:11, 6-7
   

2. 2

   Gary Bloomgren, Sandra Richman, Christophe Hotermans, Meena Subramanyan, Susan Goelz, Amy Natarajam, Sophia Lee, Tatiana Plavina, James V. Scanlon, Alfred Sandrock, Carmen Bozic. (2012) Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy. Survey of Anesthesiology 56:6, 329-330
   

3. 3

   Till Sprenger, Ludwig Kappos. (2012) Alemtuzumab for multiple sclerosis: who and when to treat?. The Lancet 380:9856, 1795-1797
   

4. 4

   Ropper , Allan H. , . (2012) The “Poison Chair” Treatment for Multiple Sclerosis. New England Journal of Medicine 367:12, 1149-1150
   Full Text

5. 5

   Susan Fitzgerald. (2012) Levels of Risk Identified for MS Patients Taking Natalizumab. Neurology Today 12:13, 18-19