Rising JCV-Ab index during natalizumab therapy for MS

Infection with JC virus (JCV) is not noticeable and is usually inconsequential. Natalizumab therapy, however, blocks the very late antigen-4 adhesion molecule on immune cells, preventing them from attaching to vascular cell adhesion molecule-1 on brain endothelial cells and then penetrating into the CNS. The dearth of T cells, and perhaps other factors, allows JCV to infect oligodendroglia and cause progressive multifocal leukoencephalopathy (PML), at a risk of 1/1,000 per year. In this issue of Neurology® Neuroimmunology & Neuroinflammation, Schwab et al. find that natalizumab markedly increases levels of the JCV antibodies that may foretell the risk of PML. Prevalence of JCV infection in non–multiple sclerosis (MS) and MS populations is roughly 1% for every year of age, with an increase of 1% per year in the United States. International rates differ, with similarly low rates in England, Ireland, and Australia, but higher rates in Austria, Portugal, and Turkey. Race and type of MS have no effect on JCV positivity. Interferon (IFN)–b and glatiramer therapy for MS do not increase JCV prevalence, and IFN-b reduces JCV viremia (circulating JCV DNA). Immunosuppressive and glucocorticoid therapy debatably increase the rate of JCV-positive sera. Recent cases of PML with 2 new oral agents mandate study of their effects on JCV. Natalizumab therapy, in large but relatively short-term MS studies, did not modify the frequency of JCV1 sera. Schwab et al. call this into question, and suggest that natalizumab markedly increases the rate of seroconversion. A second-generation ELISA, recently in wide use, allows accurate detection of serum antibodies to JCVlike particles and then quantitation of Ab titers. This JCV index reflects the degree of humoral immunity to circulating virus proteins. Higher titers suggest the immune system has been re-exposed to viral particles or to the virus itself, and implicate new enhanced replication of virus or inadequacy of cell-mediated immunity, the main force controlling virus spread. Schwab et al. studied 525 natalizumab-treated patients from Germany (55% JCV1) and 711 from France (59%) in a paired, longitudinal design, using this ELISA. The 2 groups of patients seroconverted from negative to positive at rates of 10.3% and 8.5% per year, far more than the expected rate of 1% in healthy controls and in patients with MS not treated with natalizumab. JCV indexes also rose, at 0.091 units (13%) per year. Their data extend earlier paired, longitudinal studies of natalizumab-treated patients with similar high rates of conversion and a rise in titers. In 470 German patients followed for nearly 8 months, using the first-generation assay, the annualized conversion to JCV1 was 8% per year. In 340 French patients, the conversion rate using first-generation then second-generation ELISA assays was 27% over 1 year. In 340 patients from London, conversion to JCV1 with this second-generation assay, per year, was 6% at 0–2 years, 10% at 2–4 years, and 7% at 4–7 years; the JCV index increase was 0.09, 0.22, and 0.11 during the same periods. In 111 patients from Chicago, the conversion rate was 9% per year. The rise in anti-JCV titers in this current article did not correlate with age, but did appear to rise most when the index is high (figure 3C). Arndt et al. used Bland-Altman statistics to show that JCV-Ab index values are most variable above a threshold of 1.5 units on repeat testing, and that the values rise over time. The JCV index appears to be a valid serummarker of risk for PML, with ,0.9 units 5 minimal risk and .1.5 5 increased risk. Other makers could add to its predictive value in the future. L-selectin on T cells initiates the initial slowing and rolling step of adhesion; low L-selectin expression reduces transmigration through the blood–brain barrier (BBB) and increases the risk of PML 55-fold. Other potential blood markers include human leukocyte antigen subtypes, viral DNA content in circulating B cells, and numbers of cytolytic T cells, interleukin-101 T cells, or anti-JCV effector memory T cells.