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  • 1
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    Online Resource
    Delay from treatment start to full effect of immunotherapies for multiple sclerosis
    Oxford University Press (OUP) ; 2020
    In:  Brain Vol. 143, No. 9 ( 2020-09-01), p. 2742-2756
    Details
    In: Brain, Oxford University Press (OUP), Vol. 143, No. 9 ( 2020-09-01), p. 2742-2756
    Abstract: In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments (‘therapeutic lag’) on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa231
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 2
    Online Resource
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    Determinants of therapeutic lag in multiple sclerosis
    SAGE Publications ; 2021
    In:  Multiple Sclerosis Journal Vol. 27, No. 12 ( 2021-10), p. 1838-1851
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 27, No. 12 ( 2021-10), p. 1838-1851
    Abstract: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups. Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation. Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants. Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) 〈 6 and ARR 〈 1 had mean lag of 26.6 weeks (95% CI = 18.2–34.9), males with EDSS 〈 6 and ARR 〈 1 31.0 weeks (95% CI = 25.3–36.8), females with EDSS 〈 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5–65.1), and females with EDSS ⩾ 6 and ARR 〈 1 54.3 weeks (95% CI = 47.2–61.5). Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458520981300
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2008225-3
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  • 3
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    COVID-19 outcomes in patients with multiple sclerosis: Understanding changes from 2020 to 2022
    SAGE Publications ; 2024
    In:  Multiple Sclerosis Journal
    Details
    In: Multiple Sclerosis Journal, SAGE Publications
    Abstract: Epidemiologic studies on coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (pwMS) have focused on the first waves of the pandemic until early 2021. Objectives: We aimed to extend these data from the onset of the pandemic to the global coverage by vaccination in summer 2022. Methods: This retrospective, multicenter observational study analyzed COVISEP registry data on reported COVID-19 cases in pwMS between January 2020 and July 2022. Severe COVID-19 was defined as hospitalization or higher severity. Results: Among 2584 pwMS with confirmed/highly suspected COVID-19, severe infection rates declined from 14.6% preomicron wave to 5.7% during omicron wave ( p 〈 0.001). Multivariate analysis identified age (odds ratio (OR) = 1.43, 95% confidence interval (CI) = [1.25–1.64] per 10 years), male sex (OR = 2.01, 95% CI = [1.51–2.67] ), obesity (OR = 2.36, 95% CI = [1.52–3.68]), cardiac comorbidities (OR = 2.36, 95% CI = [1.46–3.83] ), higher Expanded Disability Status Scale (EDSS) scores (OR = 2.09, 95% CI = [1.43–3.06] for EDSS 3–5.5 and OR = 4.53, 95% CI = [3.04–6.75] for EDSS ⩾6), and anti-CD20 therapies (OR = 2.67, 95% CI = [1.85–3.87]) as risk factors for COVID-19 severity. Vaccinated individuals experienced less severe COVID-19, whether on (risk ratio (RR) = 0.64, 95% CI = [0.60–0.69] ) or off (RR = 0.32, 95% CI = [0.30–0.33]) anti-CD20. Discussion: In pwMS, consistent risk factors were anti-CD20 therapies and neurological disability, emerging as vital drivers of COVID-19 severity regardless of wave, period, or vaccination status.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/13524585231218149
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2024
    detail.hit.zdb_id: 2008225-3
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  • 4
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    Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Neurology Vol. 99, No. 17 ( 2022-10-25), p. e1926-e1944
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 99, No. 17 ( 2022-10-25), p. e1926-e1944
    Abstract: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. Methods This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. Results A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43–0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08–0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1–2 ARR: 0.80, 0.70–0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, −0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1–10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72–0.81) and disability accumulation (0.73, 0.65–0.80). Discussion The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod). Classification of Evidence This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000201029
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 5
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    Kappa Free Light Chain Biomarkers Are Efficient for the Diagnosis of Multiple Sclerosis : A Large Multicenter Cohort Study
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Neurology - Neuroimmunology Neuroinflammation Vol. 10, No. 1 ( 2023-01), p. e200049-
    Details
    In: Neurology - Neuroimmunology Neuroinflammation, Ovid Technologies (Wolters Kluwer Health), Vol. 10, No. 1 ( 2023-01), p. e200049-
    Abstract: Kappa free light chains (KFLC) seem to efficiently diagnose MS. However, extensive cohort studies are lacking to establish consensus cut-offs, notably to rule out non-MS autoimmune CNS disorders. Our objectives were to (1) determine diagnostic performances of CSF KFLC, KFLC index, and KFLC intrathecal fraction (IF) threshold values that allow us to separate MS from different CNS disorder control populations and compare them with oligoclonal bands' (OCB) performances and (2) to identify independent factors associated with KFLC quantification in MS. Methods We conducted a retrospective multicenter study involving 13 French MS centers. Patients were included if they had a noninfectious and nontumoral CNS disorder, eligible data concerning CSF and serum KFLC, albumin, and OCB. Patients were classified into 4 groups according to their diagnosis: MS, clinically isolated syndrome (CIS), other inflammatory CNS disorders (OIND), and noninflammatory CNS disorder controls (NINDC). Results One thousand six hundred twenty-one patients were analyzed (675 MS, 90 CIS, 297 OIND, and 559 NINDC). KFLC index and KFLC IF had similar performances in diagnosing MS from nonselected controls and OIND ( p = 0.123 and p = 0.991 for area under the curve [AUC] comparisons) and performed better than CSF KFLC ( p 〈 0.001 for all AUC comparisons). A KFLC index of 8.92 best separated MS/CIS from the entire nonselected control population, with better performances than OCB ( p 〈 0.001 for AUC comparison). A KFLC index of 11.56 best separated MS from OIND, with similar performances than OCB ( p = 0.065). In the multivariate analysis model, female gender ( p = 0.003), young age ( p = 0.013), and evidence of disease activity ( p 〈 0.001) were independent factors associated with high KFLC index values in patients with MS, whereas MS phenotype, immune-modifying treatment use at sampling, and the FLC analyzer type did not influence KFLC index. Discussion KFLC biomarkers are efficient tools to separate patients with MS from controls, even when compared with other patients with CNS autoimmune disorder. Given these results, we suggest using KFLC index or KFLC IF as a criterion to diagnose MS. Classification of Evidence This study provides Class III evidence that KFLC index or IF can be used to differentiate patients with MS from nonselected controls and from patients with other autoimmune CNS disorders.
    Type of Medium: Online Resource
    ISSN: 2332-7812
    URL: Article
    DOI: 10.1212/NXI.0000000000200049
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2767740-0
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  • 6
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    Comparative effectiveness of teriflunomide vs dimethyl fumarate in multiple sclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Neurology Vol. 93, No. 7 ( 2019-08-13), p. e635-e646
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 93, No. 7 ( 2019-08-13), p. e635-e646
    Abstract: In this study, we compared the effectiveness of teriflunomide (TRF) and dimethyl fumarate (DMF) on both clinical and MRI outcomes in patients followed prospectively in the Observatoire Français de la Sclérose en Plaques. Methods A total of 1,770 patients with relapsing-remitting multiple sclerosis (RRMS) (713 on TRF and 1,057 on DMF) with an available baseline brain MRI were included in intention to treat. The 1- and 2-year postinitiation outcomes were relapses, increase of T2 lesions, increase in Expanded Disability Status Scale score, and reason for treatment discontinuation. Propensity scores (inverse probability weighting) and logistic regressions were estimated. Results The confounder-adjusted proportions of patients were similar in TRF- compared to DMF-treated patients for relapses and disability progression after 1 and 2 years. However, the adjusted proportion of patients with at least one new T2 lesion after 2 years was lower in DMF compared to TRF (60.8% vs 72.2%, odds ratio [OR] 0.60, p 〈 0.001). Analyses of reasons for treatment withdrawal showed that lack of effectiveness was reported for 8.5% of DMF-treated patients vs 14.5% of TRF-treated patients (OR 0.54, p 〈 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39, p 〈 0.001). Conclusions After 2 years of treatment, we found similar effectiveness of DMF and TRF in terms of clinical outcomes, but with better MRI-based outcomes for DMF-treated patients, resulting in a lower rate of treatment discontinuation due to lack of effectiveness. Classification of evidence This study provides Class III evidence that for patients with RRMS, TRF and DMF have similar clinical effectiveness after 2 years of treatment.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000007938
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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  • 7
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    Investigating the Long-term Effect of Pregnancy on the Course of Multiple Sclerosis Using Causal Inference
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Neurology Vol. 100, No. 12 ( 2023-03-21), p. e1296-e1308
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 100, No. 12 ( 2023-03-21), p. e1296-e1308
    Abstract: The question of the long-term safety of pregnancy is a major concern in patients with multiple sclerosis (MS), but its study is biased by reverse causation (women with higher disability are less likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in patients with MS and secondarily the short-term effects (during the perpartum and postpartum years) and delayed effects (occurring beyond 1 year after delivery). Methods We conducted an observational cohort study with data from patients with MS followed in the Observatoire Français de la Sclérose en Plaques registry between 1990 and 2020. We included female patients with MS aged 18–45 years at MS onset, clinically followed up for more than 2 years, and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS score at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least 1 pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first 3 years of follow-up). Results We included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least 1 pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS score at 9 years (causal mean difference [95% CI] = 0.00 [−0.16 to 0.15] ) or on the annual probability of relapse (causal risk ratio [95% CI] = 0.95 [0.93–1.38] ). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the perpartum year and significantly increased it during the postpartum year, but no significant delayed effect was found on the EDSS and relapse rate. Discussion Using a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000206774
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
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  • 8
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    Existe-t-il un biomarqueur universel sanguin de réponse aux traitements dans la sclérose en plaques ? Étude UBITMUS (Universal BIomarker of Treatment in MS)
    Elsevier BV ; 2019
    In:  Revue Neurologique Vol. 175 ( 2019-04), p. S94-
    Details
    In: Revue Neurologique, Elsevier BV, Vol. 175 ( 2019-04), p. S94-
    Type of Medium: Online Resource
    ISSN: 0035-3787
    URL: Article
    DOI: 10.1016/j.neurol.2019.01.265
    RVK:
    XA 10000
    Language: French
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2036356-4
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  • 9
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    Comparative Effectiveness of Natalizumab Versus Anti-CD20 in Highly Active Relapsing–Remitting Multiple Sclerosis After Fingolimod Withdrawal
    Elsevier BV ; 2022
    In:  Neurotherapeutics Vol. 19, No. 2 ( 2022-03), p. 476-490
    Details
    In: Neurotherapeutics, Elsevier BV, Vol. 19, No. 2 ( 2022-03), p. 476-490
    Type of Medium: Online Resource
    ISSN: 1878-7479
    URL: Article
    DOI: 10.1007/s13311-022-01202-1
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2279496-7
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  • 10
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    Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults : The MOGADOR study
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Neurology Vol. 90, No. 21 ( 2018-05-22), p. e1858-e1869
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 90, No. 21 ( 2018-05-22), p. e1858-e1869
    Abstract: To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis. Methods Clinical data were obtained from 197 MOG-Ab-positive patients ≥18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included. Results Median age at onset was 36.46 (range 18.0–76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab-positive patients were thalamic and pontine lesions. Cortical and leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab-positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26–0.79) compared to AQP4-Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22–0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07–0.72). Finally, MOG-Ab titers were higher at relapse than in remission ( p = 0.009). Conclusion In adults, MOG-Ab-associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000005560
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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