Asymptomatic Reactivation of JC Virus in Patients Treated with Natalizumab

Abstract

Background Progressive multifocal leukoencephalopathy (PML) occurs in a fraction of patients with multiple sclerosis who were treated with natalizumab. Most adults who are infected with the JC virus, the etiologic agent in PML, do not have symptoms. We sought to determine whether exposure to natalizumab causes subclinical reactivation and neurotropic transformation of JC virus. Methods We followed 19 consecutive patients with multiple sclerosis who were treated with natalizumab over an 18-month period, performing quantitative polymerase-chain-reaction assays in blood and urine for JC virus reactivation; BK virus, a JC virus–related polyomavirus, was used as a control. We determined JC virus–specific T-cell responses by means of an enzyme-linked immunospot assay and antibody responses by means of an enzyme-linked immunosorbent assay and analyzed JC virus regulatory-region sequences. Results After 12 months of natalizumab therapy, the prevalence of JC virus in the urine of the 19 patients increased from a baseline value of 19% to 63% (P = 0.02). After 18 months of treatment, JC virus was detectable in 3 of 15 available plasma samples (20%) and in 9 of 15 available samples of peripheral-blood mononuclear cells (60%) (P = 0.02). JC virus regulatory-region sequences in blood samples and in most of the urine samples were similar to those usually found in PML. Conversely, BK virus remained stable in urine and was undetectable in blood. The JC virus–specific cellular immune response dropped significantly between 6 and 12 months of treatment, and variations in the cellular immune response over time tended to be greater in patients in whom JC viremia developed. None of the patients had clinical or radiologic signs of PML. Conclusions Subclinical reactivation of JC virus occurs frequently in natalizumab-treated patients with multiple sclerosis. Viral shedding is associated with a transient drop in the JC virus–specific cellular immune response.

Anti-JC virus antibody titres increase over time with natalizumab treatment

“…16 A second putative mechanism is that natalizumab could promote mobilisation of peripheral-blood mononuclear cells from the bone marrow, some of which may harbour latest JCV infection. [17][18][19] This study observed many "large increases" in prospective anti-JCV Ab index, disproportionate to the effect that would be expected from increasing age . 6 The mean increase in anti-JCV Ab index occurs regardless of baseline index, other than those with extreme high index (>3)..…”

Rituximab in Children with Resistant Idiopathic Nephrotic Syndrome

“…18 We cannot exclude the possibility that higher rituximab doses may be necessary to reduce proteinuria in resistant forms of INS. Moreover, it is important to emphasize that rituximab toxicity, including lung fibrosis 38 and progressive multifocal leukoencephalopathy, 39 could be a function of the number of infusions and cumulative dose. A program of virus monitoring in urine and blood cells of our patient cohort (e.g., JC virus, the etiologic agent of progressive multifocal leukoencephalopathy) for the next few years is in place.…”

Short-Term Effects of Rituximab in Children with Steroid- and Calcineurin-Dependent Nephrotic Syndrome

“…Potential complications have been described, such as lung fibrosis (33) and progressive multifocal leukoencephalopathy (34). Virus monitoring (e.g., JC virus-the etiologic agent of progressive multifocal leukoencephalopathy) in urine and blood cells and data on B cell deprivation are essential requirements for a long-term follow-up program.…”