Risk Assessment of Progressive Multifocal Leukoencephalopathy in Multiple Sclerosis Patients during 1 Year of Ocrelizumab Treatment.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) caused by the JC virus is the main limitation to the use of disease modifying therapies for treatment of multiple sclerosis (MS). METHODS: To assess the PML risk in course of ocrelizumab, urine and blood samples were collected from 42 MS patients at baseline (T0), at 6 (T2) and 12 months (T4) from the beginning of therapy. After JCPyV-DNA extraction, a quantitative-PCR (Q-PCR) was performed. Moreover, assessment of JCV-serostatus was obtained and arrangements' analysis of non-coding control region (NCCR) and of viral capsid protein 1 (VP1) was carried out. RESULTS: Q-PCR revealed JCPyV-DNA in urine at all selected time points, while JCPyV-DNA was detected in plasma at T4. From T0 to T4, JC viral load in urine was detected, increased in two logarithms and, significantly higher, compared to viremia. NCCR from urine was archetypal. Plasmatic NCCR displayed deletion, duplication, and point mutations. VP1 showed the S269F substitution involving the receptor-binding region. Anti-JCV index and IgM titer were found to statistically decrease during ocrelizumab treatment. CONCLUSIONS: Ocrelizumab in JCPyV-DNA positive patients is safe and did not determine PML cases. Combined monitoring of ocrelizumab's effects on JCPyV pathogenicity and on host immunity might offer a complete insight towards predicting PML risk.

Natalizumab-associated progressive multifocal leucoencephalopathy: a practical approach to risk profiling and monitoring.

Natalizumab reduces relapse frequency, delays onset of disease progression and improves disease outcomes in relapsing-remitting multiple sclerosis (MS) and is a cost-effective treatment for rapidly evolving severe relapsing-remitting MS. However, it is associated with the development of progressive multifocal leucoencephalopathy (PML), a serious opportunistic brain infection caused by a neurotropic strain of the JC virus (JCV). Until May 2011, 83 300 patients had received natalizumab for MS. One hundred and twenty-four patients had developed PML, of whom 23 (19%) died. In order to maximise the benefit-risk ratio of natalizumab for MS patients it is important to develop a strategy for risk profiling and monitoring for PML. Central to this is an understanding of the biology of the JCV and the emerging clinical picture of natalizumab-associated PML. This paper reviews the evidence for managing the risk of PML in natalizumab-treated patients and the authors propose an algorithm for risk profiling and risk management. Key features of this algorithm include risk stratification based on emerging risk factors, heightened clinical vigilance for the clinical features of natalizumab-associated PML and considerations for temporary and permanent cessation of natalizumab dosing.

Assessment of the risk of polyomavirus JC reactivation in patients with immune-mediated diseases during long-term treatment with infliximab.

Polyomavirus JC (JCV) reactivation causing progressive multifocal leukoencephalopathy is a main concern during biological therapies. Here, JCV reactivation in patients suffering from immune-mediated diseases after a long-term treatment with anti-tumor necrosis factor alpha (TNF-α) inhibitor infliximab was investigated. Peripheral mononuclear blood cells (PBMC), plasma and urine samples were obtained from 61 immune-mediated diseases patients treated or not with infliximab in combination with steroid and other immunomodulators and from 20 healthy donors. JCV DNA was transiently detected in 12 PBMC of 40 patients at different doses of infliximab with a higher prevalence than that of the 21 patients untreated. Conversely, a stable JCV positivity in urine of treated and untreated patients was detected. Sequencing the noncoding control region (NCCR), all samples exhibited the archetype structure with few mutations in transcriptional factor binding regions. The consequence of anti-TNF-α treatment on viral persistence was examined monitoring Torquetenovirus viremia and investigating the TNF-α-induced microRNA regulators of transcriptional factors, with a binding site on NCCR. Although infliximab treatment in this study did not affect directly JCV reactivation, further investigation on host factor(s) regulated by it will be of warranty in the understanding the mechanism(s) that may affect viral persistence.

Progressive multifocal leukoencephalopathy and newer biological agents.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the brain due to a polyoma virus, JC virus. Despite the ubiquity of this virus, PML is rare and almost always seen in association with an underlying immunosuppressive condition. In the last 30 years, AIDS has been the most common predisposing factor. The observation of PML attending the use of certain monoclonal antibody therapies and other pharmacological agents has raised concerns about the safety profile of these agents, but has also provided a window into the pathogenesis of PML. Certain agents, such as the monoclonal antibodies natalizumab, an α4ß1 and α4ß7 integrin inhibitor, and efalizumab, an antibody directed against CD11a, appear to uniquely predispose to PML. Prior to their introduction for multiple sclerosis and Crohn's disease with respect to natalizumab, and psoriasis with respect to efalizumab, PML had never been observed with these disorders. PML occurring with other agents that currently carry US FDA-mandated 'black-box' warnings, such as rituximab, an antibody directed to CD20, or mycophenolate mofetil, a drug that inhibits T- and B-cell proliferation, typically occur in the background of underlying disorders that have already been identified as risks for PML. This review will focus on the available data regarding the risk for PML with monoclonal antibodies and other drugs. A biologically plausible explanation for the increased risk of PML will be proposed, as well as potential strategies for mitigating disease risk.

Assessment of JC polyoma virus in colon neoplasms.

PURPOSE: Research data have recently emphasized an intriguing association of JC polyoma virus with colon carcinogenesis. Tumorigenicity of JC virus is attributed to the T-antigen of its Mad-1 variant. Controversy arose when another research group did not confirm this association. The purpose of this study was to detect JC virus in a series of colon neoplasms from Greek patients. METHODS: A nested polymerase chain reaction assay was used to detect JC virus in 80 cancerous, 25 adenomatous specimens of large bowel, and 20 colonoscopic biopsy samples from normal patients without colorectal neoplasia. Quantitation of JC virus DNA was performed by real-time polymerase chain reaction. RESULTS: JC polyoma virus nucleotide sequence was detected in 61 percent of colon adenocarcinomas and in 60 percent of adenomas, at a viral load of 9 x 10(3) to 20 x 10(3) copies/microg DNA. Adjacent normal mucosa in 35 positive colon adenocarcinoma specimens, and normal mucosa from six patients of the control group, had low viral loads (50-450 copies/microg DNA). CONCLUSIONS: JC polyoma virus genome is present in colon neoplasms. JC virus detection in adenomas at comparable viral loads to malignant tumors suggests its implication at early steps of colonic carcinogenesis. Taking into consideration other published data, infection of colonic epithelium with JC virus might be a prime candidate for a role in chromosomal and genomic instability.