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  • 1
    Online Resource
    Online Resource
    Anti-JCV serology during natalizumab treatment: Review and meta-analysis of 17 independent patient cohorts analyzing anti-John Cunningham polyoma virus sero-conversion rates under natalizumab treatment and differences between technical and biological sero-converters
    SAGE Publications ; 2018
    In:  Multiple Sclerosis Journal Vol. 24, No. 5 ( 2018-04), p. 563-573
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 24, No. 5 ( 2018-04), p. 563-573
    Abstract: Anti-John Cunningham virus (JCV) serology has been studied with varying results concerning longitudinal changes. Objectives and methods: Results from 17 published natalizumab-treated multiple sclerosis (MS) patient cohorts were analyzed with common parameters and subsequently verified in two large independent cohorts with 722 and 499 patients from Germany and the United States. Results: Published studies and the verification showed (1) a mean of 10.80% sero-negative patients presented with sero-status change to positivity per year; (2) patients, who sero-convert to index values 〈 0.9, convert from near the threshold and have a high probability of reverting with time; (3) patients, who convert to index values 〉 0.9, start with low index values; (4) while JCV sero-positive patients with low index values sometimes revert to sero-negativity, patients with high index values almost never revert; and (5) the conversion rate of natalizumab-treated patients is three to four times higher than the biological conversion by age. Conclusion: JCV sero-conversion was comparable using standardized parameters and indicates influence of natalizumab on JCV immune control. Converters to low index values are probably consistently infected with JCV with varying low levels of activity, in line with their low risk to develop progressive multifocal leukoencephalopathy (PML). Patients with high index values rarely revert back to sero-negativity.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458517728814
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2018
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  • 2
    Online Resource
    Online Resource
    Immunological and clinical consequences of treating a patient with natalizumab
    SAGE Publications ; 2012
    In:  Multiple Sclerosis Journal Vol. 18, No. 3 ( 2012-03), p. 335-344
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 18, No. 3 ( 2012-03), p. 335-344
    Abstract: Background: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). Objectives: We present a patient study through therapy, the diagnosis of PML (after 29 infusions), plasma exchange (PE) and development of immune reconstitution inflammatory syndrome (IRIS). Methods: Routine diagnostics, magnetic resonance imaging (MRI), immunological status (flow cytometry, T-cell migration assays and T-cell repertoire analysis), and brain biopsy with immunohistological analysis. Results: CD49d decreased after 12 months of treatment. At PML diagnosis, CD49d expression and migratory capacity of T cells was low and peripheral T-cell receptor (TCR) complexity showed severe perturbations. The distribution of peripheral monocytes changed from CCR5+ to CCR7+. After PE some changes reverted: CD49d increased and overshot earliest levels, migratory capacities of T cells recovered and peripheral TCR complexity increased. With no clinical, routine laboratory or cerebrospinal fluid (CSF) changes, MRI 2 months after PE demonstrated progressive lesion development. Brain histopathology confirmed the presence of infiltrates indicative of IRIS without clinical signs, immunologically accompanied by CCR7/CCR5 recovery of peripheral monocytes. Conclusion: Natalizumab-associated immunological changes accompanying PML were reversible after PE; IRIS can occur very late, remain asymptomatic and be elusive to CSF analysis. Our study may provide insights into the changes under treatment with natalizumab associated with JC virus control.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458511421919
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2012
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  • 3
    Online Resource
    Online Resource
    High anti-JCPyV serum titers coincide with high CSF cell counts in RRMS patients
    SAGE Publications ; 2021
    In:  Multiple Sclerosis Journal Vol. 27, No. 10 ( 2021-09), p. 1491-1496
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 27, No. 10 ( 2021-09), p. 1491-1496
    Abstract: Progressive multifocal leukoencephalopathy (PML) can in rare cases occur in natalizumab-treated patients with high serum anti-JCPyV antibodies, hypothetically due to excessive blockade of immune cell migration. Objective: Immune cell recruitment to the central nervous system (CNS) was assessed in relapsing-remitting multiple sclerosis (RRMS) patients stratified by low versus high anti-JCPyV antibody titers as indicator for PML risk. Methods: Cerebrospinal fluid (CSF) cell counts of 145 RRMS patients were quantified by flow cytometry. Generalized linear models were employed to assess influence of age, sex, disease duration, Expanded Disability Status Scale (EDSS), clinical/radiological activity, current steroid or natalizumab treatment, as well as anti-JCPyV serology on CSF cell subset counts. Results: While clinical/radiological activity was associated with increased CD4, natural killer (NK), B and plasma cell counts, natalizumab therapy reduced all subpopulations except monocytes. With and without natalizumab therapy, patients with high anti-JCPyV serum titers presented with increased CSF T-cell counts compared to patients with low anti-JCPyV serum titers. In contrast, PML patients assessed before ( n = 2) or at diagnosis ( n = 5) presented with comparably low CD8 and B-cell counts, which increased after plasma exchange ( n = 4). Conclusion: High anti-JCPyV indices, which could be indicative of increased viral activity, are associated with elevated immune cell recruitment to the CNS. Its excessive impairment in conjunction with viral activity could predispose for PML development.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458520970103
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
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  • 4
    Online Resource
    Online Resource
    Dual action by fumaric acid esters synergistically reduces adhesion to human endothelium
    SAGE Publications ; 2018
    In:  Multiple Sclerosis Journal Vol. 24, No. 14 ( 2018-12), p. 1871-1882
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 24, No. 14 ( 2018-12), p. 1871-1882
    Abstract: Dimethyl fumarate (DMF) is prescribed against relapsing-remitting multiple sclerosis (MS). Here, we investigated the effects of DMF and monomethyl fumarate (MMF), its metabolite in vivo, at the (inflamed) blood–brain barrier (BBB). Methods: Effects of fumaric acid esters were analyzed using primary human brain–derived microvascular endothelial cells (HBMECs) in combination with peripheral blood mononuclear cells (PBMCs) derived from DMF-treated MS patients. Results: MMF-binding to brain endothelium cells leads to activation of nuclear factor (erythroid-derived 2)–related factor 2 (Nrf2)–induced downregulation of vascular cell adhesion molecule 1 (VCAM-1). This might be mediated via the G-protein-coupled receptor (GPCR) hydroxycarboxylic acid receptor 2 (HCA 2 ), a known molecular target of MMF, as we could demonstrate its expression and regulation on HBMECs. DMF treatment in vivo led to a strongly reduced expression of VCAM-1’s ligand very late antigen 4 (VLA-4) by selectively reducing integrin high-expressing memory T cells of MS patients, potentially due to inhibition of their maturation by reduced trans-localization of NFκB. Conclusion: DMF-mediated VCAM-1 downregulation on the endothelial side and reduction in T cells with a migratory phenotype on the lymphocyte side result in a synergistic reduction in T-cell adhesion to activated endothelium and, therefore, to reduced BBB transmigration in the setting of MS.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458517735189
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2018
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  • 5
    Online Resource
    Online Resource
    PML risk stratification using anti-JCV antibody index and L-selectin
    SAGE Publications ; 2016
    In:  Multiple Sclerosis Journal Vol. 22, No. 8 ( 2016-07), p. 1048-1060
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 22, No. 8 ( 2016-07), p. 1048-1060
    Abstract: Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L-selectin (CD62L) have been proposed as additional risk stratification parameters. Objective: This study aimed at verifying and integrating both parameters into one algorithm for risk stratification. Methods: Multicentric, international cohorts of natalizumab-treated MS patients were assessed for JCV index (1921 control patients and nine pre-PML patients) and CD62L (1410 control patients and 17 pre-PML patients). Results: CD62L values correlate with JCV serostatus, as well as JCV index values. Low CD62L in natalizumab-treated patients was confirmed and validated as a biomarker for PML risk with the risk factor “CD62L low” increasing a patient’s relative risk 55-fold ( p 〈 0.0001). Validation efforts established 86% sensitivity/91% specificity for CD62L and 100% sensitivity/59% specificity for JCV index as predictors of PML. Using both parameters identified 1.9% of natalizumab-treated patients in the reference center as the risk group. Conclusions: Both JCV index and CD62L have merit for risk stratification and share a potential biological relationship with implications for general PML etiology. A risk algorithm incorporating both biomarkers could strongly reduce PML incidence.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458515607651
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2016
    detail.hit.zdb_id: 2008225-3
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