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

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.

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

Viruses ◽

10.3390/v13091684 ◽

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.

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Characteristics of multiple sclerosis patients treated with disease-modifying therapies in Puerto Rico

10.26226/morressier.5b719e445aff74008ae4cada ◽

2018 ◽

Author(s):

Lobat Hashemi

Keyword(s):

Multiple Sclerosis ◽

Puerto Rico ◽

Disease Modifying Therapies ◽

Disease Modifying ◽

Multiple Sclerosis Patients

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

Journal of Clinical Medicine ◽

10.3390/jcm10091998 ◽

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.

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Infection Mitigation Strategies for Multiple Sclerosis Patients on Oral and Monoclonal Disease-Modifying Therapies

Current Neurology and Neuroscience Reports ◽

10.1007/s11910-021-01117-y ◽

2021 ◽

Vol 21 (7) ◽

Author(s):

Tyler Ellis Smith ◽

Ilya Kister

Keyword(s):

Multiple Sclerosis ◽

Mitigation Strategies ◽

Disease Modifying Therapies ◽

Disease Modifying ◽

Multiple Sclerosis Patients

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NRAMP1 Polymorphism and Viral Factors in Sardinian Multiple Sclerosis Patients

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100009173 ◽

2008 ◽

Vol 35 (4) ◽

pp. 491-494 ◽

Cited By ~ 12

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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The Rationale for Monitoring Cognitive Function in Multiple Sclerosis: Practical Issues for Clinicians

The Open Neurology Journal ◽

10.2174/1874205x01812010031 ◽

2018 ◽

Vol 12 (1) ◽

pp. 31-40 ◽

Cited By ~ 8

Author(s):

Christos Bakirtzis ◽

Panagiotis Ioannidis ◽

Lambros Messinis ◽

Grigorios Nasios ◽

Elina Konstantinopoulou ◽

...

Keyword(s):

Multiple Sclerosis ◽

Clinical Practice ◽

Cognitive Function ◽

Cognitive Rehabilitation ◽

Assessment Tools ◽

Systematic Evaluation ◽

Presenting Symptoms ◽

Increased Risk ◽

Medication Side ◽

Multiple Sclerosis Patients

About half of patients with multiple sclerosis exhibit cognitive impairment which negatively affects their quality of life. The assessment of cognitive function in routine clinical practice is still undervalued, although various tools have been proposed for this reason. In this article, we describe the potential benefits of implementing cognitive assessment tools in routine follow -ups of MS patients. Early detection of changes in cognitive performance may provide evidence of disease activity, could unmask depression or medication side-effects and provide suitable candidates for cognitive rehabilitation. Since apathy and cognitive deficiencies are common presenting symptoms in Progressive Multifocal Leukoencephalopathy, we discuss the utility of frequent monitoring of mental status in multiple sclerosis patients at increased risk. In addition, we propose a relevant algorithm aiming to incorporate a systematic evaluation of cognitive function in every day clinical practice in multiple sclerosis.

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Real-World Adherence and Persistence to Oral Disease-Modifying Therapies in Multiple Sclerosis Patients Over 1 Year

Journal of Managed Care & Specialty Pharmacy ◽

10.18553/jmcp.2017.23.8.844 ◽

2017 ◽

Vol 23 (8) ◽

pp. 844-852 ◽

Cited By ~ 12

Author(s):

Kristen M. Johnson ◽

Huanxue Zhou ◽

Feng Lin ◽

John J. Ko ◽

Vivian Herrera

Keyword(s):

Multiple Sclerosis ◽

Real World ◽

Oral Disease ◽

Disease Modifying Therapies ◽

Disease Modifying ◽

Multiple Sclerosis Patients

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

Journal of Neurology ◽

10.1007/s00415-018-8996-3 ◽

2018 ◽

Vol 265 (10) ◽

pp. 2342-2345 ◽

Cited By ~ 6

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

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Onset of secondary progressive multiple sclerosis is not influenced by current relapsing multiple sclerosis therapies

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217318783347 ◽

2018 ◽

Vol 4 (2) ◽

pp. 205521731878334 ◽

Cited By ~ 6

Author(s):

Francisco Coret ◽

Francisco C Pérez-Miralles ◽

Francisco Gascón ◽

Carmen Alcalá ◽

Arantxa Navarré ◽

...

Keyword(s):

Multiple Sclerosis ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Secondary Progressive ◽

Disease Modifying Therapies ◽

Relapsing Remitting ◽

Disease Modifying ◽

Remitting Multiple Sclerosis ◽

Multiple Sclerosis Patients ◽

Relapsing Remitting Multiple Sclerosis

Background Disease-modifying therapies are thought to reduce the conversion rate to secondary progressive multiple sclerosis. Objective To explore the rate, chronology, and contributing factors of conversion to the progressive phase in treated relapsing–remitting multiple sclerosis patients. Methods Our study included 204 patients treated for relapsing–remitting multiple sclerosis between 1995 and 2002, prospectively followed to date. Kaplan–Meier analysis was applied to estimate the time until secondary progressive multiple sclerosis conversion, and multivariate survival analysis with a Cox regression model was used to analyse prognostic factors. Results Relapsing–remitting multiple sclerosis patients were continuously treated for 13 years (SD 4.5); 36.3% converted to secondary progressive multiple sclerosis at a mean age of 42.6 years (SD 10.6), a mean time of 8.2 years (SD 5.2) and an estimated mean time of 17.2 years (range 17.1–18.1). A multifocal relapse, age older than 34 years at disease onset and treatment failure independently predicted conversion to secondary progressive multiple sclerosis but did not influence the time to reach an Expanded Disability Status Scale of 6.0. Conclusions The favourable influence of disease-modifying therapies on long-term disability in relapsing–remitting multiple sclerosis is well established. However, the time to progression onset and the subsequent clinical course in treated patients seem similar to those previously reported in natural history studies. More studies are needed to clarify the effect of disease-modifying therapies once the progressive phase has been reached.

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