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 HIV-associated progressive multifocal leukoencephalopathy: longitudinal study of JC virus non-coding control region rearrangements and host immunity

2013 ◽  
Vol 19 (3) ◽  
pp. 274-279 ◽  
Author(s):  
Marco Iannetta ◽  
Anna Bellizzi ◽  
Sara Lo Menzo ◽  
Elena Anzivino ◽  
Alessandra D’Abramo ◽  
...  
Keyword(s):  
Longitudinal Study ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Control Region ◽  
Jc Virus ◽  
Host Immunity ◽  
Coding Control

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.

Changes in John Cunningham virus index in Multiple Sclerosis patients treated with different disease-modifying therapies

2021 ◽  
Vol 19 ◽  
Author(s):  
Eleonora Sgarlata ◽  
Clara Grazia Chisari ◽  
Simona Toscano ◽  
Chiara Finocchiaro ◽  
Salvatore Lo Fermo ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Longitudinal Study ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Dimethyl Fumarate ◽  
John Cunningham Virus ◽  
Disease Modifying Therapies ◽  
Group A ◽  
The Mean ◽  
Disease Modifying ◽  
Multiple Sclerosis Patients

Background: Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection caused by John Cunningham virus (JCV) reactivation, potentially associated to natalizumab (NTZ) treatment for Multiple Sclerosis (MS). The anti-JCV antibodies titre (JCV index) increases during NTZ treatment; however, the effects of other disease modifying therapies (DMTs) on JCV index have not been fully explored. Objective: to evaluate changes in JCV index during treatment with several DMTs. Methods: This longitudinal study evaluated JCV index before starting DMT (T0) and on DMT (T1). Results: A total of 260 (65.4% females, mean age 43±11.3 ) were enrolled: 68 (26.2%) treated with fingolimod (FTY), 65 (25%), rituximab or ocrelizumab (RTX/OCR), 37 (14.2%), dimethyl-fumarate (DMF), 29 (11.2%), cladribine (CLD), 23 (8.8%), teriflunomide (TFM), 20 (7.7%), interferon or glatiramer acetate (IFN/GA), and 18 (6.9%) alemtuzumab (ALM). At T1, the percentage of patients with JCV index '0.90 was significantly increased in the ALM group (16.7% versus 66.7%, p=0.05), the percentage of patients with JCV index >1.51 was significantly reduced in RTX/OCR group (51.6% versus 37.5%, p=0.04). In the FTY group, a significant reduction in percentage of patients with JCV index '0.90 was also found (23.5% versus 1.4%, p=0.0006). The mean JCV index was reduced in RTX/OCR and ALM groups, while a significant increase was observed in the FTY group. Conclusion: DMTs with a T and/or B depleting mechanism of action induced a significant reduction of the JCV index. These results may suggest new possible sequencing strategies potentially maximizing disease control, while reducing PML risk.

scholarly journals Aging and lymphocyte changes by immunomodulatory therapies impact PML risk in multiple sclerosis patients

2018 ◽  
Vol 24 (8) ◽  
pp. 1014-1022 ◽  
Author(s):  
Elizabeth A Mills ◽  
Yang Mao-Draayer
Keyword(s):  
Multiple Sclerosis ◽  
Jc Virus ◽  
Immune Senescence ◽  
Moderate Risk ◽  
Susceptibility To Infection ◽  
Disease Modifying Therapies ◽  
Increased Risk ◽  
Multiple Sclerosis Patients ◽  
Immunomodulatory Therapies ◽  
Lymphocyte Number

New potent immunomodulatory therapies for multiple sclerosis (MS) are associated with increased risk for progressive multifocal leukoencephalopathy (PML). It is unclear why a subset of treated patients develops PML, but patient age has emerged as an important risk factor. PML is caused by the JC virus and aging is associated with immune senescence, which increases susceptibility to infection. With the goal of improving PML risk stratification, we here describe the lymphocyte changes that occur with disease-modifying therapies (DMTs) associated with high or moderate risk toward PML in MS patients, how these changes compare to immune aging, and which measures best correlate with risk. We reviewed studies examining how these therapies alter patient immune profiles, which revealed the induction of changes to lymphocyte number and/or function that resemble immunosenescence. Therefore, the immunosuppressive activity of these MS DMTs may be enhanced in the context of an immune system that is already exhibiting features of senescence.

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.

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