Are Ethnicity and Duration of Natalizumab Exposure Risk Factors for JCV Infection?

Arecent study by Outteryck et al. confirmed the seroprevalence of John Cunningham virus (JCV) observed in other cohorts of patients with multiple sclerosis (MS) exposed to natalizumab (51%). The study also identified three independent risk factors for JCV seropositivity—higher age at the time of serology, longer natalizumab exposure duration, and North African origin. Although age is a well-established factor for JCV seropositivity, no previous studies had linked ethnicity and duration of natalizumab therapy to JCV seroprevalence.

Progressive multifocal leukoencephalopathy (PML) has recently emerged as a life-threatening complication among individuals on natalizumab therapy (Tyler et al.; Ryschkewitsch et al.). Stratifying patients on natalizumab therapy based on their risk of developing PML may help investigators develop strategies to prevent natalizumab-associated PML. Prior research, including a study by Bozic et al., has identified anti-JCV antibody status, duration of natalizumab therapy of 24 months or more, and prior exposure to immunosuppressive drugs as risk factors for developing PML.

It would indeed be important if we could confirm that ethnicity and duration of natalizumab therapy were independent risk factors for JCV infection. Without comparable pre- and post-natalizumab exposure serum showing a clear increase in the prevalence of JCV seropositivity during a given period (using the same test) after the initiation of natalizumab, it is not possible to reach any conclusion. Moreover, the authors themselves concluded that the prevalence of anti-JCV antibodies was not influenced by prior immunomodulatory or immunosuppressive use, and it is unlikely that natalizumab exposure duration causes high JCV seropositivity. Furthermore, the conclusion was based on two different tests with different sensitivities and may merely reflect the differences between these two tests. However, the study warrants a well-planned longitudinal study to determine conclusively whether natalizumab exposure duration has any effect on JCV infection or seroprevalence.

Another interesting and novel, but barely significant, finding of this study is the higher prevalence of JCV seropositivity among patients of North African origin, compared with patients of European descent. However, as the authors have rightly stated, most of these patients of North African origin were born in Africa and might have been exposed to JCV before migrating to France. The higher prevalence of JCV-seropositivity among them may represent environmental or regional factors, rather than ethnic or genetic factors.

References
Bozic C, Richman S, Plavina T, et al. Anti-John Cunnigham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1. Ann Neurol. 2011;70(5):742-750.
Outteryck O, Ongagna JC, Duhamel A, et al. Anti-JCV antibody prevalence in a French cohort of MS patients under natalizumab therapy. J Neurol. 2012;259(11):2293-2298.
Ryschkewitsch CF, Jensen PN, Monaco MC, Major EO. JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2010;68(3):384-391.
Tyler KL. Emerging viral infections of the central nervous system: part 2. Arch Neurol. 2008;66(9):1065-1074.