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  • 1
    Online Resource
    Online Resource
    Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Neurology
    Details
    In: Journal of Neurology, Springer Science and Business Media LLC
    Abstract: It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case–control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications.
    Type of Medium: Online Resource
    ISSN: 0340-5354 , 1432-1459
    URL: Article
    DOI: 10.1007/s00415-023-11980-z
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1421299-7
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  • 2
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    Comparative Effectiveness and Cost-Effectiveness of Natalizumab and Fingolimod in Patients with Inadequate Response to Disease-Modifying Therapies in Relapsing-Remitting Multiple Sclerosis in the United Kingdom
    Springer Science and Business Media LLC ; 2022
    In:  PharmacoEconomics Vol. 40, No. 3 ( 2022-03), p. 323-339
    Details
    In: PharmacoEconomics, Springer Science and Business Media LLC, Vol. 40, No. 3 ( 2022-03), p. 323-339
    Type of Medium: Online Resource
    ISSN: 1170-7690 , 1179-2027
    URL: Article
    DOI: 10.1007/s40273-021-01106-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2043876-X
    SSG: 15,3
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  • 3
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    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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  • 4
    Online Resource
    Online Resource
    Risk of relapse phenotype recurrence in multiple sclerosis
    SAGE Publications ; 2014
    In:  Multiple Sclerosis Journal Vol. 20, No. 11 ( 2014-10), p. 1511-1522
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 20, No. 11 ( 2014-10), p. 1511-1522
    Abstract: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. Methods: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. Results: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8–5, p = 10 -14 ). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. Conclusion: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458514528762
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2014
    detail.hit.zdb_id: 2008225-3
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  • 5
    Online Resource
    Online Resource
    Quantifying risk of early relapse in patients with first demyelinating events: Prediction in clinical practice
    SAGE Publications ; 2017
    In:  Multiple Sclerosis Journal Vol. 23, No. 10 ( 2017-09), p. 1346-1357
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 23, No. 10 ( 2017-09), p. 1346-1357
    Abstract: Characteristics at clinically isolated syndrome (CIS) examination assist in identification of patient at highest risk of early second attack and could benefit the most from early disease-modifying drugs (DMDs). Objective: To examine determinants of second attack and validate a prognostic nomogram for individualised risk assessment of clinical conversion. Methods: Patients with CIS were prospectively followed up in the MSBase Incident Study. Predictors of clinical conversion were analysed using Cox proportional hazards regression. Prognostic nomograms were derived to calculate conversion probability and validated using concordance indices. Results: A total of 3296 patients from 50 clinics in 22 countries were followed up for a median (inter-quartile range (IQR)) of 1.92 years (0.90, 3.71). In all, 1953 (59.3%) patients recorded a second attack. Higher Expanded Disability Status Scale (EDSS) at baseline, first symptom location, oligoclonal bands and various brain and spinal magnetic resonance imaging (MRI) metrics were all predictors of conversion. Conversely, older age and DMD exposure post-CIS were associated with reduced rates. Prognostic nomograms demonstrated high concordance between estimated and observed conversion probabilities. Conclusion: This multinational study shows that age at CIS onset, DMD exposure, EDSS, multiple brain and spinal MRI criteria and oligoclonal bands are associated with shorter time to relapse. Nomogram assessment may be useful in clinical practice for estimating future clinical conversion.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458516679893
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2017
    detail.hit.zdb_id: 2008225-3
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  • 6
    Online Resource
    Online Resource
    Predictors and dynamics of postpartum relapses in women with multiple sclerosis
    SAGE Publications ; 2014
    In:  Multiple Sclerosis Journal Vol. 20, No. 6 ( 2014-05), p. 739-746
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 20, No. 6 ( 2014-05), p. 739-746
    Abstract: Several studies have shown that pregnancy reduces multiple sclerosis (MS) relapses, which increase in the early postpartum period. Postpartum relapse risk has been predicted by pre-pregnancy disease activity in some studies. Objective: To re-examine effect of pregnancy on relapses using the large international MSBase Registry, examining predictors of early postpartum relapse. Methods: An observational case–control study was performed including pregnancies post-MS onset. Annualised relapse rate (ARR) and median Expanded Disability Status Scale (EDSS) scores were compared for the 24 months pre-conception, pregnancy and 24 months postpartum periods. Clustered logistic regression was used to investigate predictors of early postpartum relapses. Results: The study included 893 pregnancies in 674 females with MS. ARR (standard error) pre-pregnancy was 0.32 (0.02), which fell to 0.13 (0.03) in the third trimester and rose to 0.61 (0.06) in the first three months postpartum. Median EDSS remained unchanged. Pre-conception ARR and disease-modifying treatment (DMT) predicted early postpartum relapse in a multivariable model. Conclusion: Results confirm a favourable effect on relapses as pregnancy proceeds, and an early postpartum peak. Pre-conception DMT exposure and low ARR were independently protective against postpartum relapse. This novel finding could provide clinicians with a strategy to minimise postpartum relapse risk in women with MS planning pregnancy.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458513507816
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2014
    detail.hit.zdb_id: 2008225-3
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  • 7
    Online Resource
    Online Resource
    Long-term disability trajectories in primary progressive MS patients: A latent class growth analysis
    SAGE Publications ; 2018
    In:  Multiple Sclerosis Journal Vol. 24, No. 5 ( 2018-04), p. 642-652
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 24, No. 5 ( 2018-04), p. 642-652
    Abstract: Several natural history studies on primary progressive multiple sclerosis (PPMS) patients detected a consistent heterogeneity in the rate of disability accumulation. Objectives: To identify subgroups of PPMS patients with similar longitudinal trajectories of Expanded Disability Status Scale (EDSS) over time. Methods: All PPMS patients collected within the MSBase registry, who had their first EDSS assessment within 5 years from onset, were included in the analysis. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM), using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups showing similar characteristics. Results: A total of 853 PPMS (51.7% females) from 24 countries with a mean age at onset of 42.4 years (standard deviation (SD): 10.8 years), a median baseline EDSS of 4 (interquartile range (IQR): 2.5–5.5), and 2.4 years of disease duration (SD: 1.5 years) were included. LCMM detected three different subgroups of patients with a mild ( n = 143; 16.8%), moderate ( n = 378; 44.3%), or severe ( n = 332; 38.9%) disability trajectory. The probability of reaching EDSS 6 at 10 years was 0%, 46.4%, and 81.9% respectively. Conclusion: Applying an LCMM modeling approach to long-term EDSS data, it is possible to identify groups of PPMS patients with different prognosis.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458517703800
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2018
    detail.hit.zdb_id: 2008225-3
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  • 8
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    Online Resource
    Disability accrual in primary and secondary progressive multiple sclerosis
    BMJ ; 2023
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 94, No. 9 ( 2023-09), p. 707-717
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 94, No. 9 ( 2023-09), p. 707-717
    Abstract: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. Methods We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. Results Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2–47.3) vs 43.9 (43.3–44.4); p 〈 0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78–0.94); p 〈 0.001) and similar age at wheelchair dependence. Conclusions We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2022-330726
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 1480429-3
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  • 9
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    Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial
    BMJ ; 2023
    In:  Journal of Neurology, Neurosurgery & Psychiatry
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ
    Abstract: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. Methods Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. Results 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. Conclusions The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2023-331499
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 1480429-3
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  • 10
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    Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis
    American Medical Association (AMA) ; 2023
    In:  JAMA Neurology Vol. 80, No. 7 ( 2023-07-01), p. 702-
    Details
    In: JAMA Neurology, American Medical Association (AMA), Vol. 80, No. 7 ( 2023-07-01), p. 702-
    Abstract: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%] ) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR] , 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%] ) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%] ) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD] , 0.09 [0.34] vs 0.06 [0.32] ), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.
    Type of Medium: Online Resource
    ISSN: 2168-6149
    URL: Article
    DOI: 10.1001/jamaneurol.2023.1184
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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