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BACKGROUND: Pregnancy is a common consideration for people with multiple sclerosis (pwMS); MS onset is typically between 20 and 45 years of age, during potential child-bearing years. Pregnancy and postpartum care are a significant factor influencing disease-modifying therapy (DMT) selection for many pwMS. To date, few DMTs are considered safe to continue during pregnancy and real-world treatment patterns before, during, and after pregnancy remain uncharacterized. Evolving guidance is needed regarding how to optimize management of the pregnancy and postpartum periods considering the changing DMT landscape. This analysis in two large claims databases describes DMT utilization for the treatment of MS before, during, and after pregnancy and relapse patterns during pregnancy and postpartum. METHODS: In this retrospective, observational study, the US MarketScan Commercial and Medicaid claims database was assessed for female patients aged 18-55 years with ≥1 insurance claim submitted under the diagnosis code of MS from 01 January 2016-30 April 2021 and continuous enrollment eligibility from ≥6 months prior to pregnancy date (preconception) through 6 months of follow-up following delivery (postpartum period). Comorbid conditions were examined preconception and postpartum, including anxiety and depression. Moderate/severe relapse was defined as MS-related hospitalization, or an outpatient visit and one claim within 7 days of the visit with steroids or total plasma exchange. RESULTS: A total of 944 patients (mean [standard deviation] age, 32.4 [5.0] years) were eligible; 688 (73%) were commercially insured and 256 (27%) received Medicaid. Compared with commercially-insured patients, use of DMTs was lower among Medicaid patients at 6 months preconception (25.4% vs 40.4%; p < 0.001), with similar patterns observed both during pregnancy and postpartum. Overall, prevalence of DMT use declined sharply during pregnancy, from 36.3% of patients in the 6 months preconception to 17.9%, 5.3%, and 5.8% in trimesters 1, 2 and 3, respectively. Postpartum DMT utilization increased to 20.9% at 0-3 months and 24.4% at 4-6 months. Of all patients in the preconception period, the most frequently used DMTs were glatiramer acetate (14.3%), dimethyl fumarate (6.0%), interferon (5.2%), and natalizumab (4.9%). Due to small sample size, information was limited for anti-CD20s and alemtuzumab. The proportion of patients with any moderate/severe relapse declined over pregnancy (preconception, n = 82 [8.7%]; pregnancy, n = 25 [2.6%]), but increased postpartum (n = 94 [10.0%]). Of the 889 patients who stopped DMT during pregnancy, the risk of postpartum relapses was lower in the patients who resumed DMT postpartum (10/192) than in patients who did not (76/697) (5.2% vs 10.9%; odds ratio, 0.455 [95% confidence interval 0.216-0.860], p = 0.018). Cases of postpartum depression and anxiety were significantly lower in commercially-insured patients vs Medicaid patients (postpartum depression, 13.7% vs 27.0%, p < 0.01; postpartum anxiety, 16.3% vs 30.5%, p < 0.01). CONCLUSION: DMT utilization declined sharply during pregnancy; it gradually increased postpartum but remained below pre-pregnancy use. The proportion of pwMS experiencing a moderate/severe relapse and number of relapses declined over pregnancy but increased postpartum. Reinitiation of DMT during the postpartum period was associated with lower risk of relapses, supporting a role for early reinitiation of DMT postpartum. STUDY SUPPORTED BY: Biogen.
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Fatores Imunológicos , Esclerose Múltipla , Período Pós-Parto , Complicações na Gravidez , Recidiva , Humanos , Feminino , Adulto , Gravidez , Estudos Retrospectivos , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/tratamento farmacológico , Pessoa de Meia-Idade , Adulto Jovem , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Adolescente , Estados Unidos/epidemiologia , Medicaid/estatística & dados numéricosRESUMO
Aim: To assess time to improvement in Quality of Life in Neurological Disorders (Neuro-QoL) domains for patients treated with natalizumab versus ocrelizumab. Methods: Patients enrolled in the MS PATHS network who initiated treatment with either natalizumab or ocrelizumab rated the Neuro-QoL domains of physical function, symptoms, emotional health, cognitive function and social ability. Results: Time to clinically meaningful improvement was significantly shorter with natalizumab versus ocrelizumab for cognitive function (event time ratio [95% CI]: 0.37 [0.24-0.57]; p < 0.001), sleep disturbance (0.45 [0.28-0.72]; p = 0.001), social role participation (0.37 [0.21-0.66]; p = 0.001) and social role satisfaction (0.5 [0.31-0.8]; p = 0.004). Conclusion: Natalizumab had shorter time to clinically meaningful improvement in cognitive, sleep, and social role Neuro-QoL domains versus ocrelizumab.
Knowledge of treatment-related benefits associated with medication choices, including improvement of quality of life (QoL), are strong influential factors for patients to start and continue their therapies. Little is known about patient-reported time to onset of functional improvement upon the initiation of medications for multiple sclerosis (MS). The Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network, a repository of collaborative international data on routine MS management, includes patient-reported information on the health-related QoL using the Quality of Life in Neurological Disorders (Neuro-QoL) measure. This study included data from 883 eligible patients enrolled in MS PATHS, with the aim of assessing and comparing the time to improvement in physical, mental and social health for patients treated with natalizumab versus ocrelizumab using Neuro-QoL. Natalizumab and ocrelizumab are both high-efficacy treatment options for relapsing forms of MS. The results demonstrated that, compared with ocrelizumab, natalizumab treatment led to faster effect on mental and social health, as well as quicker improvements in physical functioning in the arms and hands. Overall, it took shorter time for natalizumab-treated patients to achieve better QoL compared with ocrelizumab. These findings highlight the importance of QoL in disease management and provide a patient perspective for healthcare providers when making decisions about high-efficacy treatments for their patients with MS.
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Anticorpos Monoclonais Humanizados , Fatores Imunológicos , Natalizumab , Qualidade de Vida , Humanos , Masculino , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Natalizumab/uso terapêutico , Adulto , Pessoa de Meia-Idade , Fatores Imunológicos/uso terapêutico , Resultado do Tratamento , Fatores de Tempo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/psicologia , Doenças do Sistema Nervoso/tratamento farmacológicoRESUMO
BACKGROUND AND OBJECTIVES: Serum neurofilament light chain (sNfL) levels correlate with multiple sclerosis (MS) disease activity, but the dynamics of this correlation are unknown. We evaluated the relationship between sNfL levels and radiologic MS disease activity through monthly assessments during the 24-week natalizumab treatment interruption period in RESTORE (NCT01071083). METHODS: In the RESTORE trial, participants with relapsing forms of MS who had received natalizumab for ≥12 months were randomized to either continue or stop natalizumab and followed with MRI and blood draws every 4 weeks to week 28 and again at week 52 The sNfL was measured, and its dynamics were correlated with the development of gadolinium-enhancing (Gd+) lesions. Log-linear trend in sNfL levels were modeled longitudinally using generalized estimating equations with robust variance estimator from baseline to week 28. RESULTS: Of 175 patients enrolled in RESTORE, 166 had serum samples for analysis. Participants with Gd+ lesions were younger (37.7 vs 43.1, p = 0.001) and had lower Expanded Disability Status Scale scores at baseline (2.7 vs 3.4, p = 0.017) than participants without Gd+ lesions. sNfL levels increased in participants with Gd+ lesions (n = 65) compared with those without (n = 101, mean change from baseline to maximum sNfL value, 12.1 vs 3.2 pg/mL, respectively; p = 0.003). As the number of Gd+ lesions increased, peak median sNfL change also increased by 1.4, 3.0, 4.3, and 19.6 pg/mL in the Gd+ lesion groups of 1 (n = 12), 2-3 (n = 18), 4-9 (n = 21), and ≥10 (n = 14) lesions, respectively. However, 46 of 65 (71%) participants with Gd+ lesions did not increase above the 95th percentile threshold of the group without Gd+ lesions. The initial increase of sNfL typically trailed the first observation of Gd+ lesions, and the peak increase in sNfL was a median [interquartile range] of 8 [0, 12] weeks after the first appearance of the Gd+ lesion. DISCUSSION: Although sNfL correlated with the presence of Gd+ lesions, most participants with Gd+ lesions did not have elevations in sNfL levels. These observations have implications for the use and interpretation of sNfL as a biomarker for monitoring MS disease activity in controlled trials and clinical practice.
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Imageamento por Ressonância Magnética , Natalizumab , Proteínas de Neurofilamentos , Humanos , Proteínas de Neurofilamentos/sangue , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Natalizumab/uso terapêutico , Biomarcadores/sangue , Gadolínio , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Progressão da Doença , Fatores Imunológicos/uso terapêutico , Fatores Imunológicos/sangue , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Avaliação da Deficiência , Fatores de TempoRESUMO
BACKGROUND: Loss of brain gray matter fractional volume predicts multiple sclerosis (MS) progression and is associated with worsening physical and cognitive symptoms. Within deep gray matter, thalamic damage is evident in early stages of MS and correlates with physical and cognitive impairment. Natalizumab is a highly effective treatment that reduces disease progression and the number of inflammatory lesions in patients with relapsing-remitting MS (RRMS). OBJECTIVE: To evaluate the effect of natalizumab on gray matter and thalamic atrophy. METHODS: A combination of deep learning-based image segmentation and data augmentation was applied to MRI data from the AFFIRM trial. RESULTS: This post hoc analysis identified a reduction of 64.3% (p = 0.0044) and 64.3% (p = 0.0030) in mean percentage gray matter volume loss from baseline at treatment years 1 and 2, respectively, in patients treated with natalizumab versus placebo. The reduction in thalamic fraction volume loss from baseline with natalizumab versus placebo was 57.0% at year 2 (p < 0.0001) and 41.2% at year 1 (p = 0.0147). Similar findings resulted from analyses of absolute gray matter and thalamic fraction volume loss. CONCLUSION: These analyses represent the first placebo-controlled evidence supporting a role for natalizumab treatment in mitigating gray matter and thalamic fraction atrophy among patients with RRMS. CLINICALTRIALS.GOV IDENTIFIER: NCT00027300URL: https://clinicaltrials.gov/ct2/show/NCT00027300.
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Atrofia , Substância Cinzenta , Fatores Imunológicos , Imageamento por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente , Natalizumab , Tálamo , Humanos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/patologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Natalizumab/farmacologia , Natalizumab/uso terapêutico , Substância Cinzenta/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/efeitos dos fármacos , Adulto , Tálamo/patologia , Tálamo/diagnóstico por imagem , Tálamo/efeitos dos fármacos , Masculino , Feminino , Fatores Imunológicos/farmacologia , Atrofia/patologia , Pessoa de Meia-Idade , Aprendizado ProfundoRESUMO
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic offered an epidemiological opportunity to evaluate if isolation and masking affected John Cunningham (JC) virus transmission. OBJECTIVE: This study aimed to assess the proportion of natalizumab-treated patients who converted to a positive anti-JCV antibody serostatus before and during the pandemic. METHODS: Data from TYSABRI Outreach: Unified Commitment to Health (TOUCH) for 22,375 US patients treated with natalizumab with anti-JCV antibody records were assessed in epochs annually from 2017 to 2022. RESULTS: Pre-pandemic anti-JCV antibody serostatus change was observed for 7.4%-7.7%. During the first and second years of the pandemic, 7.3% and 7.2% of patients' serostatus changed, respectively. CONCLUSION: The proportion of patients with anti-JCV antibody serostatus change did not significantly differ during the first 2 years of the pandemic compared with prior years. In contrast to seasonal influenza, masking and social distancing had no discernable effect on JCV serostatus change.
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Anticorpos Antivirais , COVID-19 , Vírus JC , Esclerose Múltipla , Distanciamento Físico , Humanos , COVID-19/prevenção & controle , COVID-19/epidemiologia , COVID-19/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/tratamento farmacológico , Masculino , Feminino , Adulto , Anticorpos Antivirais/sangue , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Vírus JC/imunologia , Natalizumab/uso terapêutico , SARS-CoV-2/imunologia , Fatores Imunológicos/uso terapêuticoRESUMO
The immunomodulatory effects of disease-modifying therapies for multiple sclerosis might affect the immune response to vaccines for severe acute respiratory syndrome coronavirus 2. We analyzed the severe acute respiratory syndrome coronavirus 2-specific antibody response and lymphocyte profile before and after Ad26.COV2.S (Johnson & Johnson) vaccination in natalizumab-treated patients with multiple sclerosis. There was a 72-fold increase in mean anti-severe acute respiratory syndrome coronavirus 2 spike immunoglobulin G levels 4 weeks after vaccination and a 137-fold increase after 6 months. Other immune signals were within normal ranges. Natalizumab-treated patients with multiple sclerosis had a robust immune response to Ad26.COV2.S vaccine, and other immune signals were not significantly affected.
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Natalizumab (TYSABRI®) was the first high-efficacy monoclonal antibody disease-modifying therapy (DMT) approved as a monotherapy for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS. Because natalizumab is administered by intravenous infusion, infusion nurses play a key role in the care of natalizumab-treated patients. In the 16 years since approval, substantial data have been gathered on the long-term, real-world effectiveness and safety of natalizumab. This article provides a synopsis of this data, as well as practical information for optimizing patient care. This includes information on strategies to mitigate the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients, natalizumab use during pregnancy, and use with vaccines. It also includes guidance on the preparation and administration of natalizumab and monitoring of natalizumab-treated patients.
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Leucoencefalopatia Multifocal Progressiva , Esclerose Múltipla , Adulto , Humanos , Natalizumab/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológicoRESUMO
INTRODUCTION: In STRIVE, natalizumab treatment demonstrated effectiveness in clinical, magnetic resonance imaging (MRI), and patient-reported outcomes (PROs) in patients with early relapsing-remitting multiple sclerosis (RRMS). This post hoc analysis examined the effectiveness and safety of natalizumab in patients who self-identified as either Black/African American (AA) or Hispanic/Latino. METHODS: Clinical, MRI, and PROs were assessed for the Black/AA subgroup (n = 40) and compared with the non-Hispanic White subgroup (n = 158). As a result of the very small sample size, outcomes for the Hispanic/Latino subgroup (n = 18) were assessed separately, including a sensitivity analysis with Hispanic/Latino patients who completed the 4-year study on natalizumab. RESULTS: Clinical, MRI, and PROs were comparable between the Black/AA and non-Hispanic White subgroups except for MRI outcomes at year 1. A higher proportion of non-Hispanic White than Black/AA patients achieved MRI no evidence of disease activity (NEDA; 75.4% vs. 50.0%, p = 0.0121) and no new or newly enlarging T2 lesions (77.6% vs. 50.0%, p = 0.0031) at year 1; these differences were not observed in years 2-4 of the study. For the Hispanic/Latino subgroup in the intent-to-treat population, 46.2% and 55.6% achieved NEDA at years 1 and 2; 66.7% and 90.0% achieved clinical NEDA at years 3 and 4. Annualized relapse rate was reduced by 93.0% at year 1 versus the year before natalizumab initiation; this reduction was maintained throughout the study. Over 4 years, 37.5-50.0% of patients had a clinically meaningful improvement in their Symbol Digit Modalities Test score, and 81.8-100.0% and 90.9-100.0% had stable/improved Multiple Sclerosis Impact Scale-29 physical and psychological scores, respectively. Similar results were observed in the sensitivity analysis with Hispanic/Latino subgroup of the 4-year natalizumab completers. CONCLUSION: These results highlight the effectiveness and safety of natalizumab in patients with early RRMS who self-identified as Black/AA or Hispanic/Latino. CLINICALTRIALS: GOV: NCT01485003.
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BACKGROUND: STRIVE was a prospective, 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative patients with early relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: Study objectives examined the effects of natalizumab on cognitive processing speed, confirmed disability improvement (CDI), and patient-reported outcomes (PROs). METHODS: Clinical and PRO secondary endpoints were assessed annually over 4 years in STRIVE. The Symbol Digit Modalities Test (SDMT) was used as a measure of cognitive processing speed. PROs were assessed using the Multiple Sclerosis Impact Score (MSIS-29) and the Work Productivity and Activity Impairment Questionnaire (WPAI). RESULTS: At all four annual assessments, the proportion of patients in the intent-to-treat (ITT) population (N = 222) who exhibited clinically meaningful improvement in their SDMT score from baseline (i.e., change ≥ 4 points) ranged from 41.9 to 54.0%. The cumulative probability of CDI at 4 years in patients in the ITT population with a baseline Expanded Disability Status Scale score ≥ 2 (N = 133) was 43.9%. Statistically significant reductions in the mean change from screening in the MSIS-29 physical and psychological scores, indicating improved quality of life, were observed over all 4 years (P ≤ 0.0012 for all). A statistically significant decrease from screening in the impact of MS on regular activities, signifying an improvement in this WPAI measure, was also observed over all 4 years of the study. CONCLUSION: These results further extend our knowledge of the effectiveness, specifically regarding improvements in cognitive processing speed, disability and PROs, of long-term natalizumab treatment in early RRMS patients. CLINICALTRIALS: GOV: NCT01485003 (5 December 2011).
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BACKGROUND: Some multiple sclerosis (MS) disease-modifying therapies (DMTs) impair responses to vaccines, emphasizing the importance of understanding COVID-19 vaccine immune responses in people with MS (PwMS) receiving different DMTs. METHODS: This prospective, open-label observational study enrolled 45 participants treated with natalizumab (n = 12), ocrelizumab (n = 16), fumarates (dimethyl fumarate or diroximel fumarate, n = 11), or interferon beta (n = 6); ages 18-65 years inclusive; stable on DMT for at least 6 months. Responder rates, anti-SARS-CoV-2 spike receptor-binding domain IgG (anti-RBD) geometric mean titers (GMTs), antigen-specific T cells, and vaccination-related adverse events were evaluated at baseline and 8, 24, 36, and 48 weeks after first mRNA-1273 (Moderna) dose. RESULTS: At 8 weeks post vaccination, all natalizumab-, fumarate-, and interferon beta-treated participants generated detectable anti-RBD IgG titers, compared to only 25% of the ocrelizumab cohort. At 24 and 36 weeks post vaccination, natalizumab-, fumarate-, and interferon beta-treated participants continued to demonstrate detectable anti-RBD IgG titers, whereas participants receiving ocrelizumab did not. Anti-RBD GMTs decreased 81.5% between 8 and 24 weeks post vaccination for the non-ocrelizumab-treated participants, with no significant difference between groups. At 36 weeks post vaccination, ocrelizumab-treated participants had higher proportions of spike-specific T cells compared to other treatment groups. Vaccine-associated side effects were highest in the ocrelizumab arm for most symptoms. CONCLUSIONS: These results suggest that humoral response to mRNA-1273 COVID-19 vaccine is preserved and similar in PwMS treated with natalizumab, fumarate, and interferon beta, but muted with ocrelizumab. All DMTs had preserved T cell response, including the ocrelizumab cohort, which also had a greater risk of vaccine-related side effects.
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BACKGROUND: STRIVE was a prospective, 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative patients with early relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: Study objectives examined the effects of natalizumab on cognitive processing speed, confirmed disability improvement (CDI), and patient-reported outcomes (PROs). METHODS: Clinical and PRO secondary endpoints were assessed annually over 4 years in STRIVE. The Symbol Digit Modalities Test (SDMT) was used as a measure of cognitive processing speed. PROs were assessed using the Multiple Sclerosis Impact Score (MSIS-29) and the Work Productivity and Activity Impairment Questionnaire (WPAI). RESULTS: At all four annual assessments, the proportion of patients in the intent-to-treat (ITT) population (N = 222) who exhibited clinically meaningful improvement in their SDMT score from baseline (i.e., change ≥ 4 points) ranged from 41.9 to 54.0%. The cumulative probability of CDI at 4 years in patients in the ITT population with a baseline Expanded Disability Status Scale score ≥ 2 (N = 133) was 43.9%. Statistically significant reductions in the mean change from screening in the MSIS-29 physical and psychological scores, indicating improved quality of life, were observed over all 4 years (P ≤ 0.0012 for all). A statistically significant decrease from screening in the impact of MS on regular activities, signifying an improvement in this WPAI measure, was also observed over all 4 years of the study. CONCLUSION: These results further extend our knowledge of the effectiveness, specifically regarding improvements in cognitive processing speed, disability and PROs, of long-term natalizumab treatment in early RRMS patients. CLINICALTRIALS: GOV: NCT01485003 (5 December 2011).
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Cognição , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Qualidade de VidaRESUMO
BACKGROUND: Multiple disease-modifying therapies (DMTs) have been approved by the U.S. Food & Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS). In separately conducted clinical trials, peginterferon beta-1a, subcutaneous interferon beta-1a (SC IFN beta-1a), glatiramer acetate (GA), and teriflunomide have demonstrated efficacy for reducing relapses. No head-to-head phase III clinical trials have directly compared the treatment efficacy of peginterferon beta-1a with these other DMTs. OBJECTIVES: A propensity score-based comparison was conducted of the treatment effectiveness of peginterferon beta-1a vs. SC IFN beta-1a, GA, and teriflunomide among patients with RRMS identified from a large U.S. administrative healthcare claims database. METHODS: Adult patients (18-65 years of age) who had ≥1 claim for an MS diagnosis between November 2013 and June 2017 and ≥1 claim for peginterferon beta-1a, SC IFN beta-1a, GA, or teriflunomide between November 1, 2014, and March 31, 2017 were identified from the IBM® MarketScan® Commercial database. The index date was the first claim of a patient's DMT initiated. Only patients who had ≥12 months of insurance enrollment pre-index (baseline period) and ≥90 days post-index (variable length follow-up period) were included. Patients were grouped into cohorts according to the index DMT. Patient demographics and clinical characteristics were evaluated. Propensity score matching (PSM) was separately conducted for pairwise comparisons of treatment effectiveness between peginterferon beta-1a and the other DMT cohorts. During the post-index follow-up period, annualized relapse rate (ARR; relapse defined as hospitalization or outpatient visit with subsequent treatment), annualized number and length of inpatient stays, and the number of claims for durable medical equipment were evaluated. RESULTS: With PSM, there were 325 patients (mean age: 46.0 years) in the peginterferon beta-1a cohort compared to 967 (mean age: 46.9 years) in the SC IFN beta-1a cohort; likewise there were 564 patients (mean age: 47.4 years) in the peginterferon beta-1a and 1688 (mean age: 47.6 years) in the GA cohort; and finally there were 584 patients (mean age: 49.1 years) in the peginterferon beta-1a cohort and 1742 (mean age: 49.0 years) in the teriflunomide cohort. During the post-index follow-up period, the ARR did not significantly differ between the peginterferon beta-1a and SC IFN beta-1a cohorts; the ARR was lower among patients treated with peginterferon beta-1a than among those treated with GA (Least squares mean [LSM] estimate: 0.25 vs. 0.31; LSM ratio: 0.809; P=0.027) or teriflunomide (LSM estimate: 0.26 vs. 0.37; LSM ratio: 0.704; P<0.001). The annualized mean number and length of inpatient stays and the mean number of claims for durable medical equipment during the post-index follow-up did not differ between the matched peginterferon beta-1a and GA cohorts nor the peginterferon beta-1a and teriflunomide cohorts. CONCLUSION: In this real-world comparative analysis of patients with similar patient characteristics, treatment with peginterferon beta-1a was associated with lower ARRs than treatment with either GA or teriflunomide; ARRs did not differ among patients treated with SC IFN beta-1a. Also, all other measured secondary outcomes did not differ between study cohorts. These real-world data may help support decision-making in the treatment of patients with RRMS.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Adulto , Crotonatos , Acetato de Glatiramer/uso terapêutico , Humanos , Hidroxibutiratos , Interferon beta-1a/uso terapêutico , Interferon beta , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Nitrilas , Polietilenoglicóis , Pontuação de Propensão , Toluidinas , Resultado do TratamentoRESUMO
Reactive oxygen species (ROS) are implicated in a range of degenerative conditions, including aging, neurodegenerative diseases, and neurological disorders. Myelin is a lipid-rich multilamellar sheath that facilitates rapid nerve conduction in vertebrates. Given the high energetic demands and low antioxidant capacity of the cells that elaborate the sheaths, myelin is considered intrinsically vulnerable to oxidative damage, raising the question whether additional mechanisms prevent structural damage. We characterized the structural and biochemical basis of ROS-mediated myelin damage in murine tissues from both central nervous system (CNS) and peripheral nervous system (PNS). To determine whether ROS can cause structural damage to the internodal myelin, whole sciatic and optic nerves were incubated ex vivo with a hydroxyl radical-generating system consisting of copper (Cu), hydrogen peroxide (HP), and ortho-phenanthroline (OP). Quantitative assessment of unfixed tissue by X-ray diffraction revealed irreversible compaction of myelin membrane stacking in both sciatic and optic nerves. Incubation in the presence of the hydroxyl radical scavenger sodium formate prevented this damage, implicating hydroxyl radical species. Myelin membranes are particularly enriched in plasmalogens, a class of ether-linked phospholipids proposed to have antioxidant properties. Myelin in sciatic nerve from plasmalogen-deficient (Pex7 knockout) mice was significantly more vulnerable to Cu/OP/HP-mediated ROS-induced compaction than myelin from WT mice. Our results directly support the role of plasmalogens as endogenous antioxidants providing a defense that protects ROS-vulnerable myelin.
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Sequestradores de Radicais Livres/farmacologia , Bainha de Mielina/metabolismo , Plasmalogênios/farmacologia , Animais , Quelantes/farmacologia , Avaliação Pré-Clínica de Medicamentos , Ácido Edético/farmacologia , Formiatos/farmacologia , Camundongos Knockout , Bainha de Mielina/efeitos dos fármacos , Nervo Óptico/metabolismo , Nervo Óptico/patologia , Oxirredução , Estresse Oxidativo , Receptor 2 de Sinal de Orientação para Peroxissomos , Carbonilação Proteica , Espécies Reativas de Oxigênio/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Nervo Isquiático/metabolismo , Nervo Isquiático/patologiaRESUMO
Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3ß (GSK3ß) in nerves of mutant mice. Treatment with GSK3ß inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling.
Assuntos
Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/fisiologia , Plasmalogênios/fisiologia , Células de Schwann/citologia , Células de Schwann/fisiologia , Animais , Diferenciação Celular/fisiologia , Condrodisplasia Punctata Rizomélica/etiologia , Condrodisplasia Punctata Rizomélica/patologia , Condrodisplasia Punctata Rizomélica/fisiopatologia , Feminino , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Mutantes Neurológicos , Modelos Neurológicos , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/fisiologia , Regeneração Nervosa , Receptor 2 de Sinal de Orientação para Peroxissomos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Citoplasmáticos e Nucleares/deficiência , Receptores Citoplasmáticos e Nucleares/genética , Transdução de SinaisRESUMO
PURPOSE: Alterations in mRNA for myelin proteins are reported in animal models of chemotherapy-induced peripheral neuropathies (CIPN); however, ultrastructural changes in aldehyde-fixed and plastic-embedded myelin are not evident by electron microscopy. Therefore, we used X-ray diffraction (XRD) to investigate more subtle changes in myelin sheath structure from unfixed nerves. EXPERIMENTAL DESIGN: We used in vivo chronic animal models of CIPN in female Wistar rats, administering cisplatin (CDDP 2mg/kg, i.p. twice/week), paclitaxel (PT 10mg/kg, i.v. once/week) or bortezomib (0.20mg/kg, i.v. three times/week) over a total period of 4weeks. Animal weights were monitored, and tail nerve conduction velocity (NCV) was determined at the end of the treatments to assess the occurrence of peripheral neuropathy. Sciatic nerves were collected and the myelin structure was analyzed using electron microscopy (EM) and XRD. RESULTS: All the rats treated with the chemotherapy agents developed peripheral neuropathy, as indicated by a decrease in NCV values; however, light and electron microscopy indicated no severe pathological alterations of the myelin morphology. XRD also did not demonstrate significant differences between sciatic nerves in treated vs. control rats with respect to myelin period, relative amount of myelin, membrane structure, and regularity of membrane packing. CONCLUSIONS: These results indicate that experimental peripheral neuropathy caused by CDDP, PT, and bortezomib-which are among the most widely used chemotherapy agents-does not significantly affect the structure of internodal myelin in peripheral nerve.
Assuntos
Antineoplásicos/toxicidade , Proteínas da Mielina/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Microscopia Eletrônica de Transmissão , Proteínas da Mielina/ultraestrutura , Bainha de Mielina/patologia , Bainha de Mielina/ultraestrutura , Condução Nervosa/efeitos dos fármacos , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/patologia , Nervo Óptico/ultraestrutura , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Ratos , Ratos Wistar , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Nervo Isquiático/ultraestrutura , Difração de Raios XRESUMO
P0 constitutes 50-60% of protein in peripheral nerve myelin and is essential for its structure and stability. Mutations within the P0 gene (MPZ) underlie a variety of hereditary neuropathies. MpzS63C transgenic mice encode a P0 with a serine to cysteine substitution at position 34 in the extracellular domain of mature P0 (P0S34C), associated with the hypomyelinating Déjérine-Sottas syndrome in human. S63C mice develop a dysmyelinating neuropathy, with packing defects in peripheral myelin. Here, we used x-ray diffraction to examine time-dependent packing defects in unfixed myelin. At â¼7 h post-dissection, WT and S63C(+/+) myelin showed native periods (175 Å) with the latter developing at most a few percent swollen myelin, whereas up to â¼50% of S63C(+/-) (mutant P0 on heterozygous P0 null background) or P0(+/-) myelin swelled to periods of â¼205 Å. In the same time frame, S63C(-/-) myelin was stable, remaining swollen at â¼210 Å. Surprisingly, treatment of whole S63C(-/-) nerves with a reducing agent completely reverted swollen arrays to native spacing and also normalized the swollen arrays that had formed in S63C(+/-) myelin, the genotype most closely related to the human disorder. Western blot revealed P0-positive bands at â¼27 and â¼50 kDa, and MALDI-TOF mass spectrometry showed these bands consisted of Ser(34)-containing peptides or P0 dimers having oxidized Cys(34) residues. We propose that P0S34C forms ectopic disulfide bonds in trans between apposed Cys(34) side chains that retard wrapping during myelin formation causing hypomyelination. Moreover, the new bonds create a packing defect by stabilizing swollen membrane arrays that leads to demyelination.
Assuntos
Regulação da Expressão Gênica , Mutação , Proteína P0 da Mielina/metabolismo , Bainha de Mielina/genética , Animais , Doença de Charcot-Marie-Tooth/genética , Cisteína/química , Modelos Animais de Doenças , Dissulfetos/química , Genótipo , Neuropatia Hereditária Motora e Sensorial , Camundongos , Camundongos Transgênicos , Bainha de Mielina/química , Fosfinas/química , Estrutura Terciária de Proteína , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Although the Schwann cell basement membrane (BM) is required for normal Schwann cell terminal differentiation, the role of BM-associated collagens in peripheral nerve maturation is poorly understood. Collagen XV is a BM zone component strongly expressed in peripheral nerves, and we show that its absence in mice leads to loosely packed axons in C-fibers and polyaxonal myelination. The simultaneous lack of collagen XV and another peripheral nerve component affecting myelination, laminin α4, leads to severely impaired radial sorting and myelination, and the maturation of the nerve is permanently compromised, contrasting with the slow repair observed in Lama4-/- single knock-out mice. Moreover, the Col15a1-/-;Lama4-/- double knock-out (DKO) mice initially lack C-fibers and, even over 1 year of age have only a few, abnormal C-fibers. The Lama4-/- knock-out results in motor and tactile sensory impairment, which is exacerbated by a simultaneous Col15a1-/- knock-out, whereas sensitivity to heat-induced pain is increased in the DKO mice. Lack of collagen XV results in slower sensory nerve conduction, whereas the Lama4-/- and DKO mice exhibit increased sensory nerve action potentials and decreased compound muscle action potentials; x-ray diffraction revealed less mature myelin in the sciatic nerves of the latter than in controls. Ultrastructural analyses revealed changes in the Schwann cell BM in all three mutants, ranging from severe (DKO) to nearly normal (Col15a1-/-). Collagen XV thus contributes to peripheral nerve maturation and C-fiber formation, and its simultaneous deletion from neural BM zones with laminin α4 leads to a DKO phenotype distinct from those of both single knock-outs.
Assuntos
Membrana Basal/fisiologia , Colágeno/genética , Colágeno/fisiologia , Laminina/genética , Laminina/fisiologia , Nervos Periféricos/fisiologia , Distúrbios Somatossensoriais/genética , Potenciais de Ação/fisiologia , Animais , Axônios/fisiologia , Axônios/ultraestrutura , Membrana Basal/ultraestrutura , Comportamento Animal/fisiologia , Eletrofisiologia , Ensaio de Imunoadsorção Enzimática , Masculino , Camundongos , Camundongos Knockout , Microscopia Imunoeletrônica , Neurônios Motores/fisiologia , Bainha de Mielina/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Condução Nervosa/fisiologia , Nervos Periféricos/ultraestrutura , Estimulação Física , Reflexo/fisiologia , Células Receptoras Sensoriais/fisiologia , Limiar Sensorial/fisiologia , Distúrbios Somatossensoriais/fisiopatologia , Difração de Raios XRESUMO
Adult-onset demyelinating disorders of the central nervous system represent the most common neurological abnormalities in young adults. Nevertheless, our understanding of disease pathogenesis and recovery in demyelinating disorders remains incomplete. To facilitate investigation into these processes, we have developed a new mouse model system that allows for the induction of dipththeria toxin A subunit expression in adult oligodendrocytes, resulting in widespread oligodendrocyte loss and demyelination of the central nervous system. These mice develop severe ataxia and tremor that correlates with impaired axonal conduction in the spinal cord. Strikingly, these animals fully recover from their motor and physiological defects and display extensive oligodendrocyte replenishment and widespread remyelination. This model system demonstrates the robust reparative potential of myelin in the central nervous system and provides a promising model for the quantitative assessment of therapeutic interventions that promote remyelination.
Assuntos
Axônios/patologia , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Bainha de Mielina/patologia , Oligodendroglia/patologia , Animais , Doenças Desmielinizantes/genética , Eletrofisiologia , Citometria de Fluxo , Camundongos , Camundongos Transgênicos , Bainha de Mielina/genética , Regeneração Nervosa/genética , Condução Nervosa/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Teste de Desempenho do Rota-RodRESUMO
The controlling factors that prompt mature oligodendrocytes to myelinate axons are largely undetermined. In this study, we used a forward genetics approach to identify a mutant mouse strain characterized by the absence of CNS myelin despite the presence of abundant numbers of late-stage, process-extending oligodendrocytes. Through linkage mapping and complementation testing, we identified the mutation as a single nucleotide insertion in the gene encoding zinc finger protein 191 (Zfp191), which is a widely expressed, nuclear-localized protein that belongs to a family whose members contain both DNA-binding zinc finger domains and protein-protein-interacting SCAN domains. Zfp191 mutants express an array of myelin-related genes at significantly reduced levels, and our in vitro and in vivo data indicate that mutant ZFP191 acts in a cell-autonomous fashion to disrupt oligodendrocyte function. Therefore, this study demonstrates that ZFP191 is required for the myelinating function of differentiated oligodendrocytes.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Alelos , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Células Cultivadas , Sistema Nervoso Central/embriologia , Embrião de Mamíferos/metabolismo , Camundongos , Camundongos Transgênicos , MutaçãoRESUMO
Monitoring pathology/regeneration in experimental models of de-/remyelination requires an accurate measure not only of functional changes but also of the amount of myelin. We tested whether X-ray diffraction (XRD), which measures periodicity in unfixed myelin, can assess the structural integrity of myelin in fixed tissue. From laboratories involved in spinal cord injury research and in studying the aging primate brain, we solicited "blind" samples and used an electronic detector to record rapidly the diffraction patterns (30 min each pattern) from them. We assessed myelin integrity by measuring its periodicity and relative amount. Fixation of tissue itself introduced +/-10% variation in periodicity and +/-40% variation in relative amount of myelin. For samples having the most native-like periods, the relative amounts of myelin detected allowed distinctions to be made between normal and demyelinating segments, between motor and sensory tracts within the spinal cord, and between aged and young primate CNS. Different periodicities also allowed distinctions to be made between samples from spinal cord and nerve roots and between well-fixed and poorly fixed samples. Our findings suggest that, in addition to evaluating the effectiveness of different fixatives, XRD could also be used as a robust and rapid technique for quantitating the relative amount of myelin among spinal cords and other CNS tissue samples from experimental models of de- and remyelination.