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  • 1
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    CD34+ progenitor cells mobilized by natalizumab are not a relevant reservoir for JC virus
    SAGE Publications ; 2011
    In:  Multiple Sclerosis Journal Vol. 17, No. 2 ( 2011-02), p. 151-156
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 17, No. 2 ( 2011-02), p. 151-156
    Abstract: Background: Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment in patients with multiple sclerosis (MS). It has been hypothesized that natalizumab mobilizes JC virus (JCV)-infected haematopoietic progenitor cells mediating viraemia and subsequently this disease. Objective: The objective of this study was to investigate peripheral haematopoietic progenitor cells for evidence of JCV DNA in MS patients treated with natalizumab. Methods: We assessed JCV and cytomegalovirus (CMV) DNA in magnetically separated CD34+ haematopoietic progenitor cells, peripheral blood mononuclear cells and plasma of 67 natalizumab-treated patients with MS and six PML patients. Results: Viral DNA was not detectable in CD34+ haematopoietic progenitor or peripheral blood mononuclear cells from any sample. Two plasma samples from patients with MS while undergoing natalizumab treatment were JCV-positive. In one case clinically manifest PML developed 8 months thereafter. Conclusions: Our findings do not support the hypothesis that natalizumab mobilizes JC virus-infected CD34+ cells from the bone marrow mediating JC viraemia. Notably, JC viraemia was detected in one patient with MS prior to developing clinical PML. This warrants further study.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458510385834
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2011
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  • 2
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    Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study
    SAGE Publications ; 2022
    In:  Multiple Sclerosis Journal Vol. 28, No. 6 ( 2022-05), p. 910-924
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 28, No. 6 ( 2022-05), p. 910-924
    Abstract: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUC τ ) and maximum plasma concentration ( C max ) for Weeks 8–12. B-cell depletion and safety/tolerability were assessed. Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUC τ , 487.7 vs 474.1 h × µg/mL (ratio 1.03); C max , 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/13524585211044479
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
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  • 3
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    Distinct pattern of lesion distribution in multiple sclerosis is associated with different circulating T-helper and helper-like innate lymphoid cell subsets
    SAGE Publications ; 2017
    In:  Multiple Sclerosis Journal Vol. 23, No. 7 ( 2017-06), p. 1025-1030
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 23, No. 7 ( 2017-06), p. 1025-1030
    Abstract: Distinct lesion topography in relapsing-remitting multiple sclerosis (RRMS) might be due to different antigen presentation and/or trafficking routes of immune cells into the central nervous system (CNS). Objective: To investigate whether distinct lesion patterns in multiple sclerosis (MS) might be associated with a predominance of distinct circulating T-helper cell subset as well as their innate counterparts. Methods: Flow cytometric analysis of lymphocytes derived from the peripheral blood of patients with exclusively cerebral (n = 20) or predominantly spinal (n = 12) disease manifestation. Results: Patients with exclusively cerebral or preferential spinal lesion manifestation were associated with increased proportions of circulating granulocyte-macrophage colony-stimulating factor (GM-CSF) producing T H 1 cells or interleukin (IL)-17-producing T H 17 cells, respectively. In contrast, proportions of peripheral IL-17/IL-22-producing lymphoid tissue inducer (LTi), the innate counterpart of T H 17 cells, were enhanced in RRMS patients with exclusively cerebral lesion topography. Conclusions: Distinct T-helper and T-helper-like innate lymphoid cell (ILC) subsets are associated with different lesion topography in RRMS.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458516662726
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2017
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  • 4
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    Real-world disability improvement in patients with relapsing–remitting multiple sclerosis treated with natalizumab in the Tysabri Observational Program
    SAGE Publications ; 2021
    In:  Multiple Sclerosis Journal Vol. 27, No. 5 ( 2021-04), p. 719-728
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 27, No. 5 ( 2021-04), p. 719-728
    Abstract: Natalizumab has been associated with disability improvement as indicated by a confirmed Expanded Disability Status Scale (EDSS) score decrease. Objective: The aim of this study was to characterize disability improvement in patients in the Tysabri Observational Program (TOP), an ongoing observational study of relapsing–remitting multiple sclerosis patients initiating natalizumab in clinical practice. Methods: TOP data as of November 2018 were included. Confirmed disability improvement (CDI) was defined as a decrease ⩾1.0 confirmed 24 weeks later from a baseline EDSS score ⩾2.0. Confirmed functional system (FS) improvement was defined as a decrease ⩾1.0 confirmed 24 weeks later from a baseline score ⩾1.0 in that FS. Results: Of 5384 patients, 1287 (23.9%) had CDI; 51.8% experienced CDI in the first treatment year. Among patients with CDI, 56.6% had CDI ⩾1.5 points; 34.4% had CDI ⩾2.0 points. The cumulative probability of maintaining improvement 8 years after the CDI event was 52.6%. At treatment initiation, 5363 patients (85.2%) had impairment in ⩾1 FS. At 8 years, the cumulative probability of confirmed improvement in any FS was 88.8% and ranged from 38.3% to 58.6% in individual FS. Conclusion: These results highlight disability improvement as a potential benefit of natalizumab treatment. Improvements across all FS demonstrate the range of functional improvement.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458520926869
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
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  • 5
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    Simultaneous early-onset immune thrombocytopenia and autoimmune thyroid disease following alemtuzumab treatment in relapsing-remitting multiple sclerosis
    SAGE Publications ; 2016
    In:  Multiple Sclerosis Journal Vol. 22, No. 9 ( 2016-08), p. 1235-1241
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 22, No. 9 ( 2016-08), p. 1235-1241
    Abstract: We report two cases of patients with relapsing-remitting multiple sclerosis with early-onset thrombocytopenia and autoimmune thyroid disease after the first treatment course with 60-mg alemtuzumab. Methods: Case series and review of the literature. Results: Both patients showed severe thrombocytopenia with platelet counts of 2 × 10 9 and 11 × 10 9 /L, respectively, as well as increased thyroid antibodies within only a few months after initiating alemtuzumab treatment (11 and 9 months). Both patients responded considerably well to medical therapy including corticosteroids and intravenous immunoglobulins with slow platelet recovery over several weeks. Interestingly, both patients were previously treated with fingolimod and showed a marked lymphocytopenia that led to discontinuation. Conclusion: These cases emphasize the necessity of careful clinical surveillance and proper education of patients treated with alemtuzumab as proposed by the safety-monitoring program. Previous severe lymphocytopenia under therapy with other disease-modifying therapies may be a risk factor for the development of immune thrombocytopenia.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458516638558
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2016
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  • 6
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    Evidence for early, non-lesional cerebellar damage in patients with multiple sclerosis: DTI measures correlate with disability, atrophy, and disease duration
    SAGE Publications ; 2016
    In:  Multiple Sclerosis Journal Vol. 22, No. 1 ( 2016-01), p. 73-84
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 22, No. 1 ( 2016-01), p. 73-84
    Abstract: Common symptoms of multiple sclerosis (MS) such as gait ataxia, poor coordination of the hands, and intention tremor are usually the result of dysfunctionality in the cerebellum. Magnetic resonance imaging (MRI) has frequently failed to detect cerebellar damage in the form of inflammatory lesions in patients presenting with symptoms of cerebellar dysfunction. Objective: To detect microstructural cerebellar tissue alterations in early MS patients with a “normal appearing” cerebellum using diffusion tensor imaging (DTI). Methods: A total of 68 patients with relapsing–remitting MS (RRMS) and without cerebellar lesions and 26 age-matched healthy controls were admitted to high-resolution MRI and DTI to assess microstructure and volume of the cerebellar white matter (CBWM). Results: We found cerebellar fractional anisotropy (FA) and CBWM volume reductions in the group of 68 patients. Interestingly, a subgroup of these patients that was derived by including only patients with early and mild MS ( N=23, median age 30 years, median Expanded Disability Status Scale =1.5, median duration 28 months) showed already cerebellar FA but no CBWM volume reductions. FA reductions were correlated with disability, atrophy, and disease duration. Conclusion: “Normal appearing” cerebellar white matter can be damaged in a very early stage of RRMS. DTI seems to be a sensitive tool for detecting this hidden cerebellar damage.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458515579439
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2016
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  • 7
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    Safety experience with continued exposure to ofatumumab in patients with relapsing forms of multiple sclerosis for up to 3.5 years
    SAGE Publications ; 2022
    In:  Multiple Sclerosis Journal Vol. 28, No. 10 ( 2022-09), p. 1576-1590
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 28, No. 10 ( 2022-09), p. 1576-1590
    Abstract: Ofatumumab is approved for the treatment of relapsing multiple sclerosis (RMS). Ongoing safety reporting is crucial to understand its long-term benefit–risk profile. Objective: Report the safety and tolerability of ofatumumab in RMS after extended treatment up to 3.5 years. Methods: Patients completing ASCLEPIOS I/II (phase 3), APLIOS, or APOLITOS (phase 2) trials could enter ALITHIOS, a phase 3b, open-label, long-term safety study. We analyzed cumulative data of continuous ofatumumab treatment and of patients newly switched from teriflunomide. Results: The safety population had 1969 patients: 1292 continuously treated with ofatumumab (median time-at-risk 35.5 months, 3253 patient-years) and 677 newly switched (median time-at-risk 18.3 months, 986 patient-years). A total of 1650 patients (83.8%) had ⩾1 adverse events and 191 (9.7%) had ⩾1 serious adverse events. No opportunistic infections or progressive multifocal leukoencephalopathy events were identified; the risk of malignancies was low. Mean serum immunoglobulin (Ig) G levels remained stable. Mean IgM levels decreased but remained above the lower limit of normal in most. Serious infection incidence was low; decreased Ig levels were not associated with serious infections. Conclusion: In patients with up to 3.5 years’ exposure, ofatumumab was well tolerated, with no new safety risks identified. These findings, with its established effectiveness, support a favorable benefit–risk profile of ofatumumab in RMS.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/13524585221079731
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
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  • 8
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    Risks and risk management in modern multiple sclerosis immunotherapeutic treatment
    SAGE Publications ; 2019
    In:  Therapeutic Advances in Neurological Disorders Vol. 12 ( 2019-01), p. 175628641983657-
    Details
    In: Therapeutic Advances in Neurological Disorders, SAGE Publications, Vol. 12 ( 2019-01), p. 175628641983657-
    Abstract: In recent years, there has been a paradigm shift in the treatment of multiple sclerosis (MS) owing to the approval of a number of new drugs with very distinct mechanisms of action. All approved disease-modifying drugs primarily work directly on the immune system. However, the identification of an ‘optimal choice’ for individual patients with regard to treatment efficacy, treatment adherence and side-effect profile has become increasingly complex including conceptual as well as practical considerations. Similarly, there are peculiarities and specific requirements with regard to treatment monitoring, especially in relation to immunosuppression, the development of secondary immune-related complications, as well as the existence of drug-specific on- and off-target effects. Both classical immunosuppression and selective immune interventions generate a spectrum of potential therapy-related complications. This article provides a comprehensive overview of available immunotherapeutics for MS and their risks, detailing individual mechanisms of action and side-effect profiles. Furthermore, practical recommendations for patients treated with modern MS immunotherapeutics are provided.
    Type of Medium: Online Resource
    ISSN: 1756-2864 , 1756-2864
    URL: Article
    DOI: 10.1177/1756286419836571
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2019
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  • 9
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    Factors associated with depressive mood at the onset of multiple sclerosis - an analysis of 781 patients of the German NationMS cohort
    SAGE Publications ; 2023
    In:  Therapeutic Advances in Neurological Disorders Vol. 16 ( 2023-01)
    Details
    In: Therapeutic Advances in Neurological Disorders, SAGE Publications, Vol. 16 ( 2023-01)
    Abstract: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce. Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort. Design: Cross-sectional analysis within a multicenter observational study. Methods: Baseline data of n = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms. Results: Mean age was 34.3 years (95% confidence interval: 33.6–35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II  〉  8) were present in n = 256 (32.8%), 25-OH-VD deficiency ( 〈 20 ng/ml) in n = 398 (51.0%), n = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient ( c) = 1.48, p = 0.016], more severe fatigue ( c = 0.26, p  〈  0.0001), lower 25-OH-VD ( c = −0.03, p = 0.034) and smoking ( c = 0.35, p = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not. Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies.
    Type of Medium: Online Resource
    ISSN: 1756-2864 , 1756-2864
    URL: Article
    DOI: 10.1177/17562864231197309
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2023
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  • 10
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    Specific aspects of modern life for people with multiple sclerosis: considerations for the practitioner
    SAGE Publications ; 2014
    In:  Therapeutic Advances in Neurological Disorders Vol. 7, No. 2 ( 2014-03), p. 137-149
    Details
    In: Therapeutic Advances in Neurological Disorders, SAGE Publications, Vol. 7, No. 2 ( 2014-03), p. 137-149
    Abstract: Multiple sclerosis (MS) is a chronic, debilitating, neurodegenerative disease that has a high impact on patients’ quality of life. Individuals are often diagnosed in early adulthood and are faced with the difficulty of managing their lifestyle within the context of this chronic illness. Here we review factors that influence the disease course and the challenges that might be encountered when managing patients with MS. The majority of diagnosed patients are women of childbearing age, making pregnancy-related issues a key concern. MS typically stabilizes during pregnancy and evidence suggests that the disease has no impact on the risk of complications or outcomes. However, the effect of disease-modifying therapies on outcomes is less clear, and discontinuation of treatment prior to pregnancy or when breastfeeding is recommended. Awareness of genetic risk factors is important for patients planning a family, as several genes increase the risk of MS. Further aspects that require consideration include infections, vaccinations, environmental factors, surgery and the emergence of osteoporosis. Vaccinations are generally not a risk factor for MS and may be beneficial in terms of protection against infection and reducing the number of relapses. Environmental factors such as vitamin D deficiency, low exposure to sunlight, smoking and Epstein−Barr virus infection can all negatively influence the disease course. Furthermore, osteoporosis is generally higher in patients with MS than the general population, and the risk is increased by the environmental and genetic factors associated with the disease; bone mineral density should be assessed and smoking cessation and correction of serum vitamin D levels are recommended. Finally, as patients with MS are typically young, they are at low risk of surgery-related complications, although they should be carefully monitored postoperatively. Awareness of, and planning around, these factors may minimize the impact of the disease on patients’ lifestyle.
    Type of Medium: Online Resource
    ISSN: 1756-2864 , 1756-2864
    URL: Article
    DOI: 10.1177/1756285613501575
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2014
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