Delay from treatment start to full effect of immunotherapies for multiple sclerosis DOI Open Access
Izanne Roos, Emmanuelle Leray, Federico Frascoli

et al.

Brain, Journal Year: 2020, Volume and Issue: 143(9), P. 2742 - 2756

Published: June 24, 2020

Abstract In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce activity, the time required to attain maximal effect unclear. this study we aimed develop a method that allows identification manifest fully and clinically sclerosis treatments (‘therapeutic lag’) on clinical activity represented relapses progression-of-disability events. Data from two registries, MSBase (multinational) OFSEP (French), were used. Patients diagnosed with minimum 1-year exposure treatment, 3-year pretreatment follow-up yearly review included in analysis. For analysis disability progression, all events subsequent 5-year period included. Density curves, representing incidence 6-month confirmed progression events, separately constructed for each sufficiently therapy. Monte Carlo simulations performed identify first local derivative after start; point stabilization effect, maximum was observed. The developed discovery cohort (MSBase), externally validated separate, non-overlapping (OFSEP). A merged MSBase-OFSEP used analyses. Annualized relapse rates compared before following commencement We identified 11 180 eligible epochs 4088 progression. External validation four therapies, no significant difference bootstrapped mean differences therapeutic lag duration between registries. calculated 10 ranged 12 30 weeks. seven 70 Significant pre- versus post-treatment annualized rate present apart intramuscular interferon beta-1a. conclusion have developed, validated, objectively quantify different patients more than 3 years onset. Objectively defined periods expected insights into evaluation response randomized trials may guide decision-making who experience early on-treatment This will subsequently be applied studies evaluate patient characteristics lag.

Language: Английский

Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study DOI
Anna He,

B. Merkel,

J William L Brown

et al.

The Lancet Neurology, Journal Year: 2020, Volume and Issue: 19(4), P. 307 - 316

Published: March 18, 2020

Language: Английский

Citations

323
Treatment decisions in multiple sclerosis — insights from real-world observational studies DOI
Maria Trojano, Mar Tintoré, Xavier Montalbán

et al.

Nature Reviews Neurology, Journal Year: 2017, Volume and Issue: 13(2), P. 105 - 118

Published: Jan. 13, 2017

Language: Английский

Citations

172
Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study DOI
Tomáš Kalinčík, J William L Brown, Neil P. Robertson

et al.

The Lancet Neurology, Journal Year: 2017, Volume and Issue: 16(4), P. 271 - 281

Published: Feb. 11, 2017

Language: Английский

Citations

149
Towards personalized therapy for multiple sclerosis: prediction of individual treatment response DOI Open Access
Tomáš Kalinčík, Ali Manouchehrinia, Lukáš Sobíšek

et al.

Brain, Journal Year: 2017, Volume and Issue: 140(9), P. 2426 - 2443

Published: June 29, 2017

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models individual are lacking. Our aims were: (i) to develop algorithms using demographic, clinical and paraclinical predictors patients with (ii) evaluate accuracy, internal external validity these algorithms. This study evaluated 27 seven disease-modifying therapies MSBase, a large global cohort study. Treatment was analysed separately progression, regression, relapse frequency, conversion secondary progressive disease, change the cumulative disease burden, probability discontinuation. Multivariable survival generalized linear were used, together principal component analysis reduce model dimensionality prevent overparameterization. Accuracy prediction tested its separate, non-overlapping cohort. External geographically distinct cohort, Swedish Multiple Sclerosis Registry. In training (n = 8513), most prominent modifiers comprised age, duration, course, previous activity, disability, predominant phenotype therapy. Importantly, magnitude direction associations varied outcomes. Higher progression during injectable predominantly associated greater at start For fingolimod, natalizumab or mitoxantrone, it mainly lower pretreatment activity. The regression pre-baseline Relapse incidence age relapsing strength varying therapies. 1196) resulting high (>80%) first year outcomes, moderate Years 2–4 low validation showed similar results, demonstrating burden We conclude that information helps predict time their commencement.

Language: Английский

Citations

120
Observatoire Français de la Sclérose en Plaques (OFSEP): A unique multimodal nationwide MS registry in France DOI
Sandra Vukusic, Romain Casey, Fabien Rollot

et al.

Multiple Sclerosis Journal, Journal Year: 2018, Volume and Issue: 26(1), P. 118 - 122

Published: Dec. 13, 2018

The care of multiple sclerosis (MS) in France is based on two complementary interlinked networks: MS expert centers university hospitals and regional networks neurologists. routine use European database for (EDMUS) all those has paved the way constitution a national registry, designated as Observatoire Français de la Sclérose En Plaques (OFSEP). It promotes prospective, standardized, high-quality, multimodal collection data. On June 2018, there were 68.097 files, with 71.1% females, representing 761,185 person-years. This huge open to scientific community might contribute exploring unresolved issues unmet needs MS.

Language: Английский

Citations

104
Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis DOI
Tomáš Kalinčík, Eva Havrdová, Dana Horáková

et al.

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2019, Volume and Issue: 90(4), P. 458 - 468

Published: Jan. 13, 2019

Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.We identified all patients with sclerosis treated teriflunomide, dimethyl fumarate or fingolimod, minimum 3-month persistence follow-up the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised rates hazards accumulation, improvement discontinuation (analysed negative binomial models weighted conditional survival models, censoring).The eligible cohorts consisted 614 (teriflunomide), 782 (dimethyl fumarate) 2332 (fingolimod) patients, followed over median 2.5 years. Annualised lower fingolimod teriflunomide (0.18 vs 0.24; p=0.05) (0.20 0.26; p=0.01) similar (0.19 0.22; p=0.55). No differences accumulation (p≥0.59) (p≥0.14) found between therapies. In ≥3-month persistence, subsequent discontinuations less likely than (p<0.001). Discontinuation (p=0.68).The frequency was superior to fumarate. The three oral therapies outcomes during initial years treatment. Persistence two comparator drugs.

Language: Английский

Citations

77
Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis DOI
Izanne Roos,

Stella Hughes,

Gavin McDonnell

et al.

JAMA Neurology, Journal Year: 2023, Volume and Issue: 80(8), P. 789 - 789

Published: June 12, 2023

Importance Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, chimeric anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab. Objective To evaluate whether effectiveness rituximab noninferior ocrelizumab MS. Design, Setting, Participants This was observational cohort study conducted between January 2015 March 2021. Patients were included treatment group for duration therapy recruited from MSBase registry Danish MS Registry (DMSR). Included patients had history treated or rituximab, minimum 6 months follow-up, sufficient data calculate propensity score. comparable baseline characteristics 1:6 matched score on age, sex, duration, (Expanded Disability Status Scale), prior relapse rate, therapy, disease activity (relapses, accumulation, both), magnetic resonance imaging lesion burden (missing values imputed), country. Exposure Treatment after 2015. Main outcomes Measures Noninferiority comparison annualized rate (ARRs), prespecified noninferiority margin 1.63 ratio. Secondary end points 6-month confirmed accumulation pairwise-censored groups. Results Of 6027 who total 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled inclusion criteria analysis (898 MSBase, 715 DMSR). A 710 (414 296 DMSR) 186 (110 76 Over pairwise censored mean (SD) follow-up 1.4 (0.7) years, ARR ratio higher than those (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P &amp;lt; .001). The cumulative hazard among (hazard 2.1; 1.5-3.0). No difference risk observed sensitivity analyses. Conclusion In this comparative study, results did not show As administered everyday practice, associated efficacy at uniform doses intervals being further evaluated randomized clinical trials.

Language: Английский

Citations

26
Regenerating Immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant DOI Creative Commons
Jennifer Massey,

Ian Sutton,

D. F. David

et al.

Frontiers in Immunology, Journal Year: 2018, Volume and Issue: 9

Published: March 12, 2018

Multiple Sclerosis (MS) is an inflammatory disorder of the central nervous system where evidence implicates aberrant adaptive immune response in accrual neurological disability. The phase disease responds to immunomodulation varying degrees efficacy, however no therapy has been proven arrest progression Recently, more intensive therapies, including immunoablation with autologous haematopoietic stem cell transplantation (AHSCT) have offered as a treatment option retard disease, prior patients becoming irreversibly disabled. Empirical clinical observations support notion that reconstitution occurs following AHSCT associated sustained therapeutic benefit, neither pathogenesis MS nor mechanism by which results benefit clearly delineated. Although antigenic target not defined, accumulated data suggest immunotolerant state through deletion pathogenic clones combination direct ablation and induction lymphopenic driving replicative senescence clonal attrition. Restoration immunoregulation evidenced changes regulatory T populations normalisation genetic signatures homeostasis. Furthermore, some exists may induce rebooting thymic function regeneration diversified naïve repertoire equipped appropriately modulate future challenge. In this review, we discuss immunological mechanisms focusing on AHSCT, means recalibrating dysfunctional observed MS.

Language: Английский

Citations

72
Risk of secondary progressive multiple sclerosis: A longitudinal study DOI Open Access

Adam Fambiatos,

Vilija Jokubaitis, Dana Horáková

et al.

Multiple Sclerosis Journal, Journal Year: 2019, Volume and Issue: 26(1), P. 79 - 90

Published: Aug. 9, 2019

Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. Objective: aim of this study was determine the demographic, clinical and paraclinical features that influence sclerosis. Methods: Patients with adult-onset relapsing–remitting at least four recorded disability scores were selected MSBase, a global observational cohort. objectively defined evaluated time points per patient using multivariable marginal Cox regression models. Sensitivity analyses performed. Results: A total 15,717 patients included in primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR 1.01, 0.038), higher Expanded Disability Status Scale score 1.30, more rapid trajectory 2.82, 0.001) greater number relapses previous year 1.07, 0.010) independently associated an increased Improving 0.62, 0.039) disease-modifying therapy exposure 0.71, 0.007) lower risk. Recent cerebral magnetic resonance imaging activity, evidence spinal cord lesions oligoclonal bands cerebrospinal fluid not conversion. Conclusion: Risk increases age, illness worsening decreases improving disability. Therapy may delay onset progression.

Language: Английский

Citations

69
Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years DOI
Tomáš Kalinčík, Ibrahima Diouf, Sifat Sharmin

et al.

Neurology, Journal Year: 2020, Volume and Issue: 96(5)

Published: Dec. 28, 2020

Objective

To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled outcomes 14,717 patients.

Methods

We studied patients from MSBase followed for ≥1 year, with ≥3 visits, visit per and exposed to MS therapy, a subset of ≥15-year follow-up. Marginal structural models were used compare cumulative hazards 12-month confirmed increase decrease disability, Expanded Disability Status Scale (EDSS) step 6, incidence relapses between treated untreated periods. continuously readjusted patient age, sex, pregnancy, date, disease course, time first symptom, prior relapse history, MRI activity.

Results

A total studied. During periods, less likely experience (hazard ratio 0.60, 95% confidence interval [CI] 0.43–0.82, p = 0.0016), worsening (0.56, 0.38–0.82, 0.0026), progress EDSS 6 (0.33, 0.19–0.59, 0.00019). Among 1,085 follow-up, (0.59, 0.50–0.70, 10−9) (0.81, 0.67–0.99, 0.043).

Conclusion

Continued treatment immunotherapies reduces accrual by 19%–44% (95% CI 1%–62%), risk need walking aid 67% 41%–81%), frequency 40–41% 18%–57%) over 15 years. This study provides evidence disease-modifying therapies are effective improving long term.

Classification Evidence

Class IV that, MS, exposure neurologic disability.

Language: Английский

Citations

69