Dataset Information

Association of Inflammation and Disability Accrual in Patients With Progressive-Onset Multiple Sclerosis.

ABSTRACT: Importance:The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested. Objective:To examine the association of superimposed relapses in progressive-onset MS on disease outcomes. Design, Setting, and Participants:Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From 44?449 patients at time of extraction, 1419 eligible patients (31.9%) were identified for analysis. Inclusion criteria consisted of primary progressive MS (PPMS) or progressive-relapsing MS (PRMS), adult-onset disease, and minimum data set (including ?3 visits with disability recorded, ?3 months between second and last visit). Data were analyzed using multivariable regression models (Andersen-Gill) with mixed effects. Two sensitivity analyses to exclude both relapse-related disability progression and bout-onset progressive MS were performed. Exposures:Grouped according to presence or absence of relapse, defined as an acute episode of clinical worsening. Quantifiable disability change or correlation on imaging was not required to confirm relapse. Main Outcomes and Measures:Cumulative hazard of disability progression. Results:Patients with PRMS were younger than those with PPMS (mean [SD] age, 46 [15] vs 51 [10] years, Cohen d?=?0.40) and demonstrated a mean lower Expanded Disability Status Scale score (mean [SD] score, 4.0 [3] vs 4.5 [2.5], Cohen d?=?0.28) at inclusion. The ratio of men to women was similar in the PRMS and PPMS groups (252:301 vs 394:472). The overall mean (SD) age was 48 (11) years for men and 50 (10) years for women. Likelihood of confirmed disability progression was lower in patients with superimposed relapses (hazard ratio [HR], 0.83; 95% CI, 0.74-0.94; P?=?.003). Proportion of follow-up time spent on disease-modifying therapy significantly reduced the hazard of confirmed disability progression in the cohort with relapse (HR, 0.96; 95% CI, 0.94-0.99; P?=?.01) but not in those without relapse (HR, 1.02; 95% CI, 0.99-1.05; P?=?.26). When accounting for relapse-related progression, the association of disease-modifying therapy in the cohort with superimposed relapse was no longer observed (HR, 1.10; 95% CI, 0.96-1.24; P?=?.16). Conclusions and Relevance:In progressive-onset MS, superimposed relapses are associated with a lower risk of confirmed disability progression. This is most likely attributed to the association of disease-modifying therapy with the prevention of relapse-related disability accrual in patients with superimposed relapse. These findings suggest that inflammatory relapses are an important and modifiable determinant of disability accrual in progressive-onset disease.

SUBMITTER: Hughes J

PROVIDER: S-EPMC6248114 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Association of Inflammation and Disability Accrual in Patients With Progressive-Onset Multiple Sclerosis.

Hughes Jordana J Jokubaitis Vilija V Lugaresi Alessandra A Hupperts Raymond R Izquierdo Guillermo G Prat Alexandre A Girard Marc M Duquette Pierre P Grand'Maison Francois F Grammond Pierre P Sola Patrizia P Ferraro Diana D Ramo-Tello Cristina C Trojano Maria M Slee Mark M Shaygannejad Vahid V Boz Cavit C Lechner-Scott Jeanette J Van Pesch Vincent V Pucci Eugenio E Solaro Claudio C Verheul Freek F Terzi Murat M Granella Franco F Spitaleri Daniele D Alroughani Raed R Jun Jae-Kwan JK Fambiatos Adam A Van der Walt Anneke A Butzkueven Helmut H Kalincik Tomas T

JAMA neurology 20181101 11

<h4>Importance</h4>The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested.<h4>Objective</h4>To examine the association of superimposed relapses in progressive-onset MS on disease outcomes.<h4>Design, setting, and participants</h4>Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From ...[more]

PMID: 30083762

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Project description:ImportanceTherapeutic options for patients with secondary progressive multiple sclerosis (SPMS) are limited.ObjectiveTo analyze disability progression in patients with SPMS treated with rituximab compared with matched control patients never treated with rituximab.Design, setting, and participantsThis retrospective cohort study analyzed data obtained from patients with SPMS at 3 multiple sclerosis centers located in Basel and Lugano, Switzerland, and Amsterdam, the Netherlands, from 2004 to 2017. Patients were included for analysis if they had received a diagnosis of SPMS, were treated (57 eligible; 54 included) or never treated (504 eligible; 59 included) with rituximab, and had at least 1 follow-up visit. The variables used for propensity score matching were sex, age, Expanded Disability Status Scale (EDSS) score, and disease duration. Follow-up duration was up to 10 years, with a mean (SD) of 3.5 (2.6) years for rituximab-treated patients and 5.4 (2.4) years for controls in the total cohort and a mean (SD) of 3.5 (2.7) years for rituximab-treated patients and 4.8 (2.2) years for controls in the matched cohort.ExposuresComparing EDSS score progression in patients with SPMS (treated with rituximab vs not treated with rituximab) using propensity score matching.Main outcomes and measuresThe primary end point was progression of EDSS score after baseline, and the secondary end point was time to confirmed disability progression.ResultsAfter 1:1 propensity score matching, 44 matched pairs (88 patients) were included in the analysis. At baseline, patients treated with rituximab had a mean (SD) age of 49.7 (10.0) years, mean (SD) disease duration of 18.2 (9.4) years, and mean (SD) EDSS score of 5.9 (1.4), and 26 (59%) were women, whereas controls had a mean (SD) age of 51.3 (7.4) years, mean (SD) disease duration of 19.4 (8.7) years, and mean (SD) EDSS score of 5.70 (1.29), and 27 (61%) were women. In the covariate-adjusted analysis of the matched set, patients with SPMS who were treated with rituximab had a significantly lower EDSS score during a mean (SD) follow-up of 3.5 (2.7) years (mean difference, -0.52; 95% CI, -0.79 to -0.26; P < .001). Time to confirmed disability progression was significantly delayed in the rituximab-treated group (hazard ratio, 0.49; 95% CI, 0.26-0.93; P = .03).Conclusions and relevanceIn this study, patients with SPMS treated with rituximab had a significantly lower EDSS score for up to 10 years of follow-up and a significantly delayed confirmed progression compared with matched controls, suggesting that B-cell depletion by rituximab may be therapeutically beneficial in these patients. A prospective randomized clinical trial with a better level of evidence is needed to confirm the efficacy of rituximab in such patients.

Project description:ImportanceIt is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS).ObjectiveTo examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation.Design, setting, and participantsIn this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53 680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020.ExposuresThe association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated.Main outcomes and measuresTwo outcomes were analyzed as measures of disability accumulation during SPMS: the rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models).ResultsOf 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P = .009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent.Conclusions and relevanceIn this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS.

Project description:The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS.

Dataset Information

Association of Inflammation and Disability Accrual in Patients With Progressive-Onset Multiple Sclerosis.

Publications

Association of Inflammation and Disability Accrual in Patients With Progressive-Onset Multiple Sclerosis.

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