scholarly journals JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab

2010 ◽  
Vol 68 (3) ◽  
pp. 384-391 ◽  
Author(s):  
Caroline F. Ryschkewitsch ◽  
Peter N. Jensen ◽  
Maria Chiara Monaco ◽  
Eugene O. Major
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Jc Virus ◽  
Virus Persistence ◽  
Multiple Sclerosis Patients

scholarly journals Lack of specific T- and B-cell clonal expansions in multiple sclerosis patients with progressive multifocal leukoencephalopathy

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Diego Bertoli ◽  
Alessandra Sottini ◽  
Ruggero Capra ◽  
Cristina Scarpazza ◽  
Roberto Bresciani ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Progressive Multifocal Leukoencephalopathy ◽  
B Cell ◽  
Jc Virus ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cell Repertoire ◽  
Disease Modifying Drugs ◽  
Multiple Sclerosis Patients

Abstract Progressive multifocal leukoencephalopathy (PML) is a rare, potentially devastating myelin-degrading disease caused by the JC virus. PML occurs preferentially in patients with compromised immune system, but has been also observed in multiple sclerosis (MS) patients treated with disease-modifying drugs. We characterized T and B cells in 5 MS patients that developed PML, 4 during natalizumab therapy and one after alemtuzumab treatment, and in treated patients who did not develop the disease. Results revealed that: i) thymic and bone marrow output was impaired in 4 out 5 patients at the time of PML development; ii) T-cell repertoire was restricted; iii) clonally expanded T cells were present in all patients. However, common usage or pairings of T-cell receptor beta variable or joining genes, specific clonotypes or obvious “public” T-cell response were not detected at the moment of PML onset. Similarly, common restrictions were not found in the immunoglobulin heavy chain repertoire. The data indicate that no JCV-related specific T- and B-cell expansions were mounted at the time of PML. The current results enhance our understanding of JC virus infection and PML, and should be taken into account when choosing targeted therapies.

scholarly journals Natalizumab-associated progressive multifocal leukoencephalopathy occurring at low positive anti-JC virus antibody level

2015 ◽  
Vol 42 (S1) ◽  
pp. S32-S32
Author(s):  
NE Parks ◽  
V Bhan
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Jc Virus ◽  
Cumulative Exposure ◽  
Antibody Index ◽  
Virus Antibody ◽  
Hyperintense Lesion ◽  
Mri Surveillance ◽  
Index Value ◽  
Multiple Sclerosis Patients

Background: Risk of progressive multifocal leukoencephalopathy (PML), a serious adverse event of natalizumab therapy, is higher with positive anti-JC virus antibody status, greater cumulative exposure to natalizumab and prior immunosuppressant use. Plavina et al. (2014) showed that plasma or serum anti-JC virus antibody index value may allow further PML risk stratification. Among anti-JC virus antibody positive multiple sclerosis patients with no prior immunosuppressant treatment receiving natalizumab, anti-JC virus antibody index >6 months prior to PML diagnosis was significantly higher among those who developed PML with 96% consistently having an anti-JC virus antibody index >0.9. Methods: We describe a case of natalizumab-associated PML with low positive anti-JC virus index value prior to diagnosis. Results: A 53 year old man with 20 year history of relapsing remitting multiple sclerosis was diagnosed with PML following 46 infusions of natalizumab. Glatiramer acetate was his only prior immunomodulatory therapy. Routine MRI surveillance resulted in diagnosis of PML following detection of a confluent right anterior frontal T2 hyperintense lesion extending across the corpus callosum. Six months prior, routine MRI surveillance demonstrated a small right frontal T2 hyperintensity with no diffusion restriction while serum anti-JC virus antibody index was 0.69. Conclusions: Natalizumab-associated PML may develop despite low positive anti-JC virus index value.

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

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1684
Author(s):  
Carla Prezioso ◽  
Alfonso Grimaldi ◽  
Doriana Landi ◽  
Carolina Gabri Nicoletti ◽  
Gabriele Brazzini ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Jc Virus ◽  
Point Mutations ◽  
Host Immunity ◽  
Binding Region ◽  
Disease Modifying Therapies ◽  
Multiple Sclerosis Patients ◽  
Coding Control ◽  
Receptor Binding Region

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.

scholarly journals JC Virus Seroprevalence and JCVAb Index in Polish Multiple Sclerosis Patients Treated with Immunomodulating or Immunosuppressive Therapies

2021 ◽  
Vol 10 (9) ◽  
pp. 1998
Author(s):  
Robert Bonek ◽  
Wojciech Guenter ◽  
Robert Jałowiński ◽  
Anna Karbicka ◽  
Anna Litwin ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Jc Virus ◽  
Dimethyl Fumarate ◽  
Risk Category ◽  
Seroprevalence Rate ◽  
Immunomodulatory Drugs ◽  
Cross Sectional ◽  
Treatment Type ◽  
Multiple Sclerosis Patients ◽  
The Impact

The use of a highly-effective treatment for multiple sclerosis (MS) is associated with a severe risk of developing complications, such as progressive multifocal leukoencephalopathy (PML) caused by the John Cunningham virus (JCV). The aim of this study was to evaluate the correlation between anti-JCV Ab seroprevalence, anti-JCV AI, demographic and clinical factors as well as the type of therapy used in the Polish MS population. This is a multicentre, prospective and cross-sectional study involving 1405 MS patients. The seroprevalence of anti-JCV Ab and anti-JCV AI levels as well as AI categories were analysed with the use of a second-generation two-step ELISA test (STRATIFY JCV DxSelect). The overall prevalence of anti-JCV Ab was 65.8%. It was shown that seroprevalence increases with the patient’s age. The seroprevalence was significantly associated with the treatment type, and the highest values (76%) were obtained from immunosuppressant-treated patients. Overall, 63.3% of seropositive patients had an antibody index (AI) level of >1.5. In the seropositive patient group, the mean AI level amounted to 2.09. Similarly to the seroprevalence, AI levels correlated with the patient’s age; AI level for patients above 40 years old and from subsequent age quintiles plateaued, amounting to at least 1.55. Patients treated with immunosuppressants and immunomodulatory drugs obtained the highest (1.67) and lowest (1.35) AI levels, respectively. Of the immunosuppressants used, the highest mean AI levels were observed in mitoxantrone and cladribine groups, amounting to 1.75 and 1.69, respectively. In patients treated with immunomodulatory drugs, the lowest AI levels were observed in the dimethyl fumarate (DMF) group (1.11). The seroprevalence rate in the Polish MS population is one of the highest in Europe. The majority of seropositive patients had an anti-JCV Ab level qualifying them for a high-risk category. The highest mean AI levels are observed in patients receiving immunosuppressants, especially mitoxantrone and cladribine. Patients receiving immunomodulatory drugs have lower AI levels compared to treatment-naïve subjects, especially when treated with DMF. Further studies, especially longitudinal studies, are required to determine the impact of MS drugs on the seroprevalence of anti-JCV Ab and AI levels.

scholarly journals NRAMP1 Polymorphism and Viral Factors in Sardinian Multiple Sclerosis Patients

2008 ◽  
Vol 35 (4) ◽  
pp. 491-494 ◽  
Author(s):  
Maria Gazouli ◽  
Leonardo Sechi ◽  
Daniela Paccagnini ◽  
Stefano Sotgiu ◽  
Giannina Arru ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Autoimmune Disease ◽  
Promoter Region ◽  
Viral Infections ◽  
Jc Virus ◽  
Allelic Variation ◽  
Sardinian Population ◽  
Multiple Sclerosis Patients ◽  
Viral Sequences

Background:Multiple sclerosis (MS) is believed to be an autoimmune disease occurring in genetically predisposed individuals after an appropriate environmental exposure such as viral infections. Recent studies suggest a significant association between MS and the functional 5’-(GT)n polymorphism in the promoter region of the NRAMP1 gene. In the present study we aimed to evaluate the contribution of the allelic variation in the NRAMP1 promoter to MS susceptibility and to study the role of viral infection in relation to specific NRAMP1 genotypes, in a Sardinian cohort.Methods:Sixty MS patients and 66 healthy individuals were genotyped, and screened for the presence of Epstein-bar virus (EBV) and JC virus (JCV) sequences.Results:Consistent with previous autoimmune disease studies, allele 3 at the functional 5’(GT)n promoter region repeat polymorphism, was significantly overrepresented among MS patients when compared to controls (p=0.02). The EBV and JCV sequences were detected in 8/60 (13.33%) and in 4/60 (6.66%) of MS patients respectively and in 5/66 (7.57%) and in 0/66 of controls.Conclusion:The allelic variation in the NRAMP1 promoter may contribute to MS susceptibility in the Sardinian population. The viral sequences were not confined to a specific NRAMP1 genotype.

Anti-JC virus antibody index changes in rituximab-treated multiple sclerosis patients

2018 ◽  
Vol 265 (10) ◽  
pp. 2342-2345 ◽  
Author(s):  
Ursela Baber ◽  
Andrew Bouley ◽  
Emily Egnor ◽  
Jacob A. Sloane
Keyword(s):  
Multiple Sclerosis ◽  
Jc Virus ◽  
Antibody Index ◽  
Virus Antibody ◽  
Index Changes ◽  
Multiple Sclerosis Patients

JC virus urinary excretion and seroprevalence in natalizumab-treated multiple sclerosis patients

2014 ◽  
Vol 21 (6) ◽  
pp. 645-652 ◽  
Author(s):  
Serena Delbue ◽  
Francesca Elia ◽  
Camilla Carloni ◽  
Valentina Pecchenini ◽  
Diego Franciotta ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Urinary Excretion ◽  
Jc Virus ◽  
Multiple Sclerosis Patients

Blood miRNA expression pattern is a possible risk marker for natalizumab-associated progressive multifocal leukoencephalopathy in multiple sclerosis patients

2014 ◽  
Vol 20 (14) ◽  
pp. 1851-1859 ◽  
Author(s):  
M Muñoz-Culla ◽  
H Irizar ◽  
T Castillo-Triviño ◽  
M Sáenz-Cuesta ◽  
L Sepúlveda ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Differential Expression ◽  
Expression Pattern ◽  
Mirna Expression ◽  
Disease Biomarkers ◽  
Mirna Expression Pattern ◽  
Increased Risk ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients

Background: Natalizumab has shown its efficacy in reducing multiple sclerosis (MS) relapses and progression of disability; however, it has been associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML). The differential expression of microRNA (miRNA), the small non-coding RNAs that regulate gene expression, in natalizumab-treated patients has been reported and miRNA have also been described as good candidates for disease biomarkers. Objective: To characterize the effect of natalizumab therapy on the miRNA expression pattern and to search for miRNAs that can predict PML on an individual basis. Methods: The expression of 754 microRNAs was measured in blood samples from 19 relapsing–remitting MS patients at three time points during natalizumab therapy, using TaqMan OpenArray panels. Two patients included in this study developed PML after more than 2 years of therapy. Results: We found that the expression level of three miRNAs (let-7c, miR-125a-5p and miR-642) was affected after 6 months of therapy (t6). Furthermore, we observed a differential expression of another three miRNAs (miR-320, miR-320b and miR-629) between the PML and non-PML groups after 12 months of treatment (t12); and a positive correlation was found between therapy time and the expression of miR-320. Conclusions: Natalizumab modified the expression levels of three miRNAs after a 6-month treatment. We suggest miR-320, miR-320b and miR-629 as possible biomarkers for individual PML risk assessment.

First Estimates of Incidence of Progressive Multifocal Leukoencephalopathy Developing Among 10,459 Non-HIV Lymphoma VA Patients Who Receive Rituximab: Results From the Veterans Administration Database (1999–2012).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2752-2752
Author(s):  
Gowtham Rao ◽  
Peter Georgantopoulos ◽  
Kathlyn Sue Haddock ◽  
Kenneth R. Carson ◽  
LeAnn Norris ◽  
...  
Keyword(s):  
Relative Risk ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Hodgkin’S Lymphoma ◽  
Jc Virus ◽  
The United States ◽  
Veterans Affairs ◽  
Small Sample ◽  
Hodgkin's Lymphoma ◽  
United States Government ◽  
Multiple Sclerosis Patients

Abstract Abstract 2752 Introduction: Progressive multifocal leukoencephalopathy (PML) is a rare but fatal disease that is the result of activation of a highly prevalent dormant JC virus during immunosuppressed states such as advanced HIV, malignancy or immune-modulating medications. Rituximab, an immunomodulator, has been approved for both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). We previously reported 57-non-HIV patients developed PML after rituximab (1). This report identified the need for epidemiological cohort studies to further evaluate incidence rates and risk factors for PML by comparing Rituximab treated patients with suitable non-treated patients. Of note, natilzumab-associated PML is now well-characterized, with a reported incidence of 21 PML cases per 10,000 natilizumab-treated persons (2). Methods: In this first such epidemiological study we identified from the national data of the Department of Veteran's Affairs (VA), 61,132 patients with a primary International Classification of Diseases version 9 (ICD-9) code for either HL or NHL between 1999 to 2011 and reported the use of Rituximab among patients with and without PML. This project was conducted inside the Veterans Affairs Informatics and Computing Infrastructure (VINCI) after obtaining approvals from the VA Institutional Review Board and other oversight groups. Results: We identified 62,642 with a primary diagnosis of HL or NHL and excluded 1,510 (2.4%) patients with VA lab confirmed HIV. Our final cohort had 61,132 patients, 10,459 (17.1%) received Rituximab. A total of 12 (0.020%) patients had developed PML, 5 (0.008%) belonged to the Rituximab group and 7 (0.011%) to non-rituximab group; which results in a statistically significant unadjusted relative risk of 3.46 (95% confidence interval 1.1, 10.9). Univariate analyses of outcomes other than rate-estimates are not statistically significant between PML patients who received rituximab and those that did not receive rituximab, primarily due to extremely small sample sizes (5 and 7 patients, respectively) (Table 1). Overall, compared to non-rituximab PML patients, rituximab PML patients were younger at PML diagnosis and age of death by more than 6-years; although they did appear to live slightly longer post PML diagnosis by about 4-months. Conclusions: These results show that among lymphoma patients, the use of Rituximab is associated with a statistically significant relative risk for documented PML of 3.46. We now report a baseline rate among Veterans of 4.78 PML cases per 10,000 rituximab treated Veterans with lymphoma (25% of the rate reported among natilizumab-treated multiple sclerosis patients). As with hepatitis B, measurement of JC virus might be considered prior to initiation of rituximab therapy. Acknowledgment: This project was supported through the resources of the Wiliam JB Dorn Veterans Affairs Medical Center. Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. Disclosures: No relevant conflicts of interest to declare.

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