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  • Casey, Romain  (7)
  • Ciron, Jonathan  (7)
  • Lebrun-Frenay, Christine  (7)
  • Vukusic, Sandra  (7)
  • 1
    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
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 2
    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
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2008225-3
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  • 3
    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
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    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 4
    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
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
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  • 5
    In: Neurotherapeutics, Elsevier BV, Vol. 19, No. 2 ( 2022-03), p. 476-490
    Type of Medium: Online Resource
    ISSN: 1878-7479
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2279496-7
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  • 6
    In: JAMA Neurology, American Medical Association (AMA), Vol. 81, No. 3 ( 2024-03-01), p. 273-
    Abstract: Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus. Objective To assess the real-world association of HET as an index treatment compared with MET with disease activity. Design, Setting, and Participants This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate. Exposure HET or MET at treatment initiation. Main Outcomes and Measures The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions. Results Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR] , 0.46; 95% CI, 0.31-0.67; P & amp;lt; .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09). Conclusions and Relevance Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.
    Type of Medium: Online Resource
    ISSN: 2168-6149
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2024
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  • 7
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 29, No. 2 ( 2023-02), p. 236-247
    Abstract: In relapsing-remitting multiple sclerosis (RRMS), early identification of suboptimal responders can prevent disability progression. Objective: We aimed to develop and validate a dynamic score to guide the early decision to switch from first- to second-line therapy. Methods: Using time-dependent propensity scores (PS) from a French cohort of 12,823 patients with RRMS, we constructed one training and two validation PS-matched cohorts to compare the switched patients to second-line treatment and the maintained patients. We used a frailty Cox model for predicting individual hazard ratios (iHRs). Results: From the validation PS-matched cohort of 348 independent patients with iHR ⩽ 0.69, we reported the 5-year relapse-free survival at 0.14 (95% confidence interval (CI) 0.09–0.22) for the waiting group and 0.40 (95% CI 0.32–0.51) for the switched group. From the validation PS-matched cohort of 518 independent patients with iHR 〉 0.69, these values were 0.37 (95% CI 0.30–0.46) and 0.44 (95% CI 0.37–0.52), respectively. Conclusions: By using the proposed dynamic score, we estimated that at least one-third of patients could benefit from an earlier switch to prevent relapse.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2023
    detail.hit.zdb_id: 2008225-3
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