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1.
Acta Neurol Scand ; 141(1): 77-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31657006

RESUMO

OBJECTIVES: Low circulating vitamin D levels are associated with an increased risk of active MRI lesions and relapses in several cohorts with relapsing remitting multiple sclerosis (RRMS). Randomized controlled supplementation trials are, however, negative on their primary endpoints, while secondary MRI endpoints suggest anti-inflammatory effects. Circulating levels of neurofilament light chain (NfL) are a biomarker of disease activity in RRMS. We explored whether 48-week high-dose vitamin D3 supplements were associated with lower circulating NfL levels. MATERIALS & METHODS: Of N = 40 Dutch interferon beta-treated participants with RRMS of the SOLAR trial, plasma samples at baseline and 48-week follow-up were available. Of these participants, N = 24 were supplemented with 14 000 IU/d vitamin D3 and N = 16 with placebo. Twenty-five hydroxyvitamin D3 (25(OH)D3 ) levels were measured with LC-MS/MS, and NfL levels were measured in duplicate with Simoa. RESULTS: Serum 25(OH)D3 levels at 48 weeks were increased in the vitamin D3 when compared to placebo group (median level 281 [IQR 205-330] vs 72 [39-88] nmol/L; P < .01). NfL levels at 48 weeks did not differ between the treatment groups (median level 25.4 [IQR 19.6-32.2] vs 25.3 [17.9-30.1] pg/mL; P = .74). Higher week 48 NfL level showed a trend toward association with a higher risk of combined unique active lesions on the week 48 MRI scan (OR 2.39 [95% CI 0.93-6.12] for each 10 pg/mL increase; P = .07). CONCLUSIONS: Supplementation of high-dose vitamin D3 for 48 weeks was not associated with lower NfL levels. This study does not support an effect of vitamin D3 on this biomarker of neuro-axonal injury.


Assuntos
Colecalciferol/uso terapêutico , Suplementos Nutricionais , Esclerose Múltipla Recidivante-Remitente/sangue , Proteínas de Neurofilamentos/sangue , Vitamina D/sangue , Adjuvantes Imunológicos/uso terapêutico , Adulto , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Humanos , Interferon beta-1a/uso terapêutico , Masculino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico
2.
BMC Neurol ; 19(1): 287, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729968

RESUMO

BACKGROUND: Fingolimod (Gilenya®) is approved for relapsing forms of multiple sclerosis in the USA. Owing to transient heart-rate effects when initiating fingolimod, eligible patients undergo precautionary baseline assessment and first-dose observation (FDO) for ≥6 h. Prior to 2014, FDO was undertaken only in clinics. As the FDO period is short, and fingolimod has accumulated evidence of a positive benefit:risk ratio, an in-home treatment-initiation program, Gilenya@Home, was developed to offer a convenient alternative. METHODS: Cardiac parameters and adverse events (AEs) were recorded by healthcare professionals performing fingolimod FDOs in the US Gilenya@Home program or in US Gilenya Assessment Network clinics. Anonymized data were collated retrospectively from the first 34 months in the home setting and from 78 months in clinics; data are reported descriptively. Satisfaction with Gilenya@Home was rated by patients using a 7-item questionnaire that considered aspects such as ease of scheduling, courtesy, and competency. RESULTS: Data were captured as part of standard care from 5573 patients initiating fingolimod in-home (October 2014 to July 2017) and from 15,025 patients initiating in-clinic (July 2010 to December 2016). In the Gilenya@Home questionnaire, 91.7% of 1848 respondents rated their overall satisfaction as "very good," and 7.6% rated their satisfaction as "good." AEs were reported for 30.7 and 32.6% of in-home and in-clinic patients, respectively. In total, 557 in-home (10.0%) and 398 in-clinic (2.6%) patients were monitored for > 6 h; 15 (0.3%) in-home and 129 (0.9%) in-clinic patients were transferred to an emergency room for overnight monitoring. The mean (standard deviation) heart rate (HR; bpm) pre-FDO was 74.8 (12.2) in-home and 74.2 (11.3) in-clinic; reduction in HR at 6 h postdose was 10.6 (12.0) and 6.3 (9.6), respectively. New-onset first-degree atrioventricular block was experienced by 132 (2.4%) in-home and 74 (0.5%) in-clinic patients, and Wenckebach (Mobitz type I) second-degree atrioventricular block by four (0.07%) and nine (0.1%) patients, with no cases of third-degree atrioventricular block. CONCLUSIONS: A substantial number of patients have initiated fingolimod at home, reporting very high levels of satisfaction. Gilenya@Home was as rigorous as the clinic setting in detecting cardiovascular events. Overall, FDO safety outcomes were similar with Gilenya@Home and in-clinic.


Assuntos
Bloqueio Atrioventricular/induzido quimicamente , Cloridrato de Fingolimode/efeitos adversos , Serviços Hospitalares de Assistência Domiciliar , Imunossupressores/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Bloqueio Atrioventricular/diagnóstico , Eletroencefalografia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Estudos Retrospectivos
3.
Neurology ; 93(20): e1906-e1916, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31594857

RESUMO

OBJECTIVE: In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS. METHODS: Eligible patients with RRMS treated with SC interferon-ß-1a (IFN-ß-1a) 44 µg 3 times weekly and serum 25(OH)D levels <150 nmol/L were included. From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-ß-1a plus placebo (n = 116) or SC IFN-ß-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113). The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48. RESULTS: At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80). Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: -0.074; p = 0.035). CONCLUSIONS: SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-ß-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS. CLINICALTRIALSGOV IDENTIFIER: NCT01285401. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS treated with SC IFN-ß-1a, 48 weeks of cholecalciferol supplementation did not promote NEDA-3 status.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Colecalciferol/administração & dosagem , Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Vitaminas/administração & dosagem , Adulto , Encéfalo/diagnóstico por imagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Resultado do Tratamento , Vitamina D/análogos & derivados , Vitamina D/sangue
4.
Neurology ; 93(19): e1778-e1786, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31484710

RESUMO

OBJECTIVE: To assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS). METHODS: Brain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) ß-1a (30 µg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN-ß-1a (44 µg). RESULTS: In patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-ß-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-ß-1a (both p < 0.001). In patients with RMS, ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-ß-1a within the first 8 weeks. CONCLUSION: Epoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Encéfalo/diagnóstico por imagem , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Adulto , Feminino , Humanos , Interferon beta-1a/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Recidiva , Fatores de Tempo , Resultado do Tratamento
5.
Int J Qual Stud Health Well-being ; 14(1): 1648946, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31390951

RESUMO

Purpose: In addition to becoming familiar with the life changing event of having a chronic illness and exploring its meaning in daily life, people with relapsing-remitting Multiple Sclerosis (RRMS) are faced with important decisions about immunomodulating treatment. Biomedical research on the use of Disease Modifying Therapies (DMTs) mostly focuses on adherence, conceptualized and understood as a behavioral act leading to a desired outcome. Less attention has been paid to the meaning for a person with RRMS of starting and continuing the use of DMTs. Studies on the experiences of people with RRMS taking orally administered DMTs are lacking. The aim of this phenomenological study was to examine the experiences of people with RRMS taking oral medication. Methods: The study was guided by Interpretative Phenomenological Analysis (IPA) and Phenomenology of Practice. 25 persons with RRMS participated in in-depth interviews. Results: In general, participants of this study find themselves in alternating phases that vary by degree of experienced unfamiliarity or familiarity with concern to one's illness, one's changing body, and one's new life. The meaning of taking medication is closely related to these phases. Conclusions: Adherence serves a purpose in the lifeworlds of participants. Medication is the embodiment of this purpose. The pill has inherent meaning.


Assuntos
Imunomodulação , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Administração Oral , Adulto , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Medo , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Adulto Jovem
6.
BMC Neurol ; 19(1): 190, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399069

RESUMO

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare complication of patients treated with fingolimod. CASE PRESENTATION: Routine MRI eventually led to diagnosis of asymptomatic early PML that remained stable after discontinuation of fingolimod. As blood lymphocyte counts normalized, signs of immune reconstitution inflammatory syndrome (IRIS) and renewed MS activity developed. Both, advanced laboratory and ultrahigh field MRI findings elucidated differences between PML and MS. CONCLUSIONS: In our case, early discontinuation of fingolimod yielded a good outcome, lymphocyte counts reflected immune system activity, and paraclinical findings helped to differentiate between PML-IRIS and MS.


Assuntos
Cloridrato de Fingolimode/efeitos adversos , Síndrome Inflamatória da Reconstituição Imune/diagnóstico por imagem , Imunossupressores/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Adulto , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico
8.
BMC Res Notes ; 12(1): 497, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31405369

RESUMO

OBJECTIVE: Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality. RESULTS: We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment.


Assuntos
Agranulocitose/induzido quimicamente , Alemtuzumab/efeitos adversos , Hemorragia Cerebral/induzido quimicamente , Fatores Imunológicos/efeitos adversos , Listeriose/induzido quimicamente , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Pneumonia/induzido quimicamente , Adulto , Agranulocitose/mortalidade , Agranulocitose/patologia , Alemtuzumab/administração & dosagem , Hemorragia Cerebral/mortalidade , Hemorragia Cerebral/patologia , Evolução Fatal , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Listeriose/microbiologia , Listeriose/mortalidade , Listeriose/patologia , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/mortalidade , Insuficiência de Múltiplos Órgãos/patologia , Esclerose Múltipla Recidivante-Remitente/patologia , Pneumonia/microbiologia , Pneumonia/mortalidade , Pneumonia/patologia
9.
Expert Opin Drug Saf ; 18(10): 925-948, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31429602

RESUMO

Introduction: In the last 20 years the armamentarium for multiple sclerosis (MS) treatment has been enriched from an increasingly wider variety of new drugs in order to reach a better control of the disease with a better patient compliance. Areas covered: With this great variety of therapeutic options, physicians may face new and major challenges. The huge amount of data from pilot studies and real-life settings showed that the first-line therapies have a better safety profile. On the other hand, the risks associated with newer drugs, with more selective mechanism of action and targeting specific pathways of MS pathophysiology, are not yet fully established. In particular, real-life use of these advanced drugs has raised important safety issues as long-term effects and potential risks are not yet known and remain to be carefully evaluated. Expert opinion: No time like the present, the physician faces new and major challenges in order to choose the best available therapy for MS. With the increasing number of drugs for treating MS and the lack of safety data, observational studies and post-marketing surveillance activities are crucial in order to improve the knowledge about the safety profile of these drugs and the therapeutic management in clinical practice settings.


Assuntos
Fatores Imunológicos/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Vigilância de Produtos Comercializados , Animais , Desenho de Drogas , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Adesão à Medicação , Esclerose Múltipla Recidivante-Remitente/fisiopatologia
10.
BMC Neurol ; 19(1): 159, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299922

RESUMO

BACKGROUND: Glatiramer acetate (GA) is one of the first therapies approved for multiple sclerosis (MS). We prospectively included and monitored drug-naïve and pre-treated MS patients who had been prescribed GA for 1 year, to investigate reasons for GA prescription, its effectiveness and safety in real life clinical practice. METHODS: One year, prospective, multicentre, observational study performed between 2010 and 2015 in consecutive MS and clinically isolated syndrome patients starting GA as a first ("naïve") or second ("switcher") line therapy. Primary endpoint was the annualized relapse rate (ARR) over 1 year of GA treatment (from baseline, V1, to 12 months, V2) in naïve and switchers compared to previous 24 months. Secondary endpoints were: EDSS changes between V1 and V2, frequency of adverse events, and reasons for prescribing and discontinuing GA. Baseline demographics and clinical characteristics were retrieved from medical records, and outcome measures were documented at V1 and V2, and in case of clinical worsening. RESULTS: One hundred ninety-four consecutive patients were monitored over 12 months (N = 64 naïve, N = 130 switchers). Side effect profile (naïve = 36%, switchers = 28%) and comorbidities (naïve = 31%, switchers = 15%) were the most frequent reasons to start GA. The ARR was reduced in both naïve and switchers during V1-2 as compared to the 24 months preceding V1 [naïve: 0.0 (0.0-0.0) vs 0.5 (0.5-1.0, p = 2.9e-10); switchers: 0.0 (0.0-0.0) vs 0.5 (0.0-0.5, p = 0.022)]. EDSS at V2 was significantly reduced only in naïve [(1.5 (1.0-2.5) vs 2.0 (1.5-2.5), p = 0.003)]. Naïve status and EDSS at V1 were negatively associated with EDSS change between V1-V2 in multivariable analysis (regression coefficient = - 0.436, p = 0.008, and regression coefficient = - 0.263, p = 6.18e-05, respectively). No new unexpected AE was reported. CONCLUSION: In our Swiss cohort, GA was prescribed mainly to naïve or switcher MS patients fearing interferon related side effects, with various comorbidities or considering pregnancy, and showed effectiveness and safety comparable with data of previous GA studies.


Assuntos
Acetato de Glatiramer/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla , Gravidez , Estudos Prospectivos , Recidiva
11.
J Neuroinflammation ; 16(1): 134, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266527

RESUMO

BACKGROUND: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are related to several acquired demyelinating syndromes in adults, but the therapeutic approach is currently unclear. We aimed to describe the response to different therapeutic strategies in adult patients with relapsing MOG-Ab-associated disease. METHODS: This is a retrospective study conducted in France and Spain including 125 relapsing MOG-Ab patients aged ≥ 18 years. First, we performed a survival analysis to investigate the relapse risk between treated and non-treated patients, performing a propensity score method based on the inverse probability of treatment weighting. Second, we assessed the annualised relapse rates (ARR), Expanded Disability Status Scale (EDSS) and visual acuity pre-treatment and on/end-treatment. RESULTS: Median age at onset was 34.1 years (range 18.0-67.1), the female to male ratio was 1.2:1, and 96% were Caucasian. At 5 years, 84% (95% confidence interval [CI], 77.1-89.8) patients relapsed. At the last follow-up, 66 (52.8%) received maintenance therapy. Patients initiating immunosuppressants (azathioprine, mycophenolate mophetil [MMF], rituximab) were at lower risk of new relapse in comparison to non-treated patients (HR, 0.41; 95CI%, 0.20-0.82; p = 0.011). Mean ARR (standard deviation) was reduced from 1.05(1.20) to 0.43(0.79) with azathioprine (n = 11; p = 0.041), from 1.20(1.11) to 0.23(0.60) with MMF (n = 11; p = 0.033), and from 1.08(0.98) to 0.43(0.89) with rituximab (n = 26; p = 0.012). Other immunosuppressants (methotrexate/mitoxantrone/cyclophosphamide; n = 5), or multiple sclerosis disease-modifying drugs (MS-DMD; n = 9), were not associated with significantly reduced ARR. Higher rates of freedom of EDSS progression were observed with azathioprine, MMF or rituximab. CONCLUSION: In adults with relapsing MOG-Ab-associated disease, immunosuppressant therapy (azathioprine, MMF and rituximab) is associated with reduced risk of relapse and better disability outcomes. Such an effect was not found in the few patients treated with MS-DMD.


Assuntos
Autoanticorpos/sangue , Imunossupressores/uso terapêutico , Glicoproteína Mielina-Oligodendrócito/sangue , Neuromielite Óptica/sangue , Neuromielite Óptica/tratamento farmacológico , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Neuromielite Óptica/diagnóstico , Estudos Retrospectivos , Rituximab/uso terapêutico , Resultado do Tratamento , Adulto Jovem
12.
PLoS One ; 14(7): e0218453, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31276502

RESUMO

RebiQoL was a phase IV multicenter randomized study to assess the impact of a telemedicine patient support program (MSP) on health-related quality of life (HRQoL) in patients with relapsing-remitting MS (RRMS) being administered with Rebif with the RebiSmart device. The primary endpoint was to assess the impact of MSP compared to patients only receiving technical support for RebiSmart on HRQoL at 12 months, using the psychological part of Multiple Sclerosis Impact Scale (MSIS-29), in patients administered with Rebif. A total of 97 patients diagnosed with RRMS were screened for participation in the study of which 3 patients did not fulfill the eligibility criteria and 1 patient withdrew consent. Of the 93 randomized patients, 46 were randomized to MSP and 47 to Technical support only. The demographic characteristics of the patients were well-balanced in the two arms. There were no statistical differences (linear mixed model) in any of the primary (difference of 0.48, 95% CI: -8.30-9.25, p = 0.91) or secondary outcomes (p>0.05). Although the study was slightly underpowered, there was a trend towards better adherence in the MSP group (OR 3.5, 95% CI 0.85-14.40, p = 0.08) although not statistically significant. No unexpected adverse events occurred. This study did not show a statistically significant effect of the particular form of teleintervention used in this study on HRQoL as compared to pure technical support, for MS patients already receiving Rebif with the RebiSmart device. Trial Registration: ClinicalTrials.gov: NCT01791244.


Assuntos
Interferon beta-1a/administração & dosagem , Adesão à Medicação/psicologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/psicologia , Qualidade de Vida , Telemedicina , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Nat Commun ; 10(1): 3081, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300673

RESUMO

Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.


Assuntos
Fumarato de Dimetilo/uso terapêutico , Imunossupressores/uso terapêutico , Monócitos/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , NADPH Oxidases/genética , Adulto , Metilação de DNA/efeitos dos fármacos , Fumarato de Dimetilo/farmacologia , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/farmacologia , Contagem de Leucócitos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/imunologia , NADPH Oxidases/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
14.
Value Health ; 22(7): 772-776, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31277823

RESUMO

OBJECTIVES: Statistical methods to adjust for treatment switching are commonly applied to randomized controlled trials (RCTs) in oncology. Nevertheless, RCTs with extension studies incorporating nonrandomized dropout require consideration of alternative adjustment methods. The current study used a recognized method and a novel method to adjust for treatment switching in relapsing-remitting multiple sclerosis (MS). METHODS: The Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) RCT evaluated the efficacy of cladribine versus placebo over 96 weeks. Many (but not all) CLARITY participants enrolled in the 96-week CLARITY extension study; placebo-treated patients from CLARITY received cladribine (PP→LL), and cladribine-treated patients were re-randomized to placebo (LL→PP) or continued cladribine (LL→LL). End points were time to first qualifying relapse (FQR) and time to 3-month and 6-month confirmed disability progression (3mCDP, 6mCDP). We aimed to estimate the effectiveness of the LL→PP treatment strategy compared with a counterfactual (unobserved) PP→PP strategy. We applied the commonly used rank-preserving structural failure time model (RPSFTM) and a novel approach that combined propensity score matching (PSM) with inverse probability of censoring weights (IPCW). RESULTS: The RPSFTM resulted in LL→PP versus PP→PP hazard ratios (HRs) of 0.48 (95% confidence interval [CI] 0.36-0.62) for FQR, 0.62 (95% CI 0.46-0.84) for 3mCDP, and 0.62 (95% CI 0.44-0.88) for 6mCDP. The PSM+IPCW resulted in HRs of 0.47 (95% CI 0.38-0.63) for FQR, 0.61 (95% CI 0.43-0.86) for 3mCDP, and 0.63 (95% CI 0.40-0.87) for 6mCDP. CONCLUSIONS: The PSM+IPCW HRs were consistent with those from the RPSFTM, suggesting that the results were not substantially biased by informative dropout, assuming that all relevant confounders were controlled for. There was no statistical evidence of a reduction in the cladribine treatment effect during the extension period.


Assuntos
Cladribina/administração & dosagem , Substituição de Medicamentos , Imunossupressores/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Pacientes Desistentes do Tratamento , Cladribina/efeitos adversos , Avaliação da Deficiência , Progressão da Doença , Humanos , Imunossupressores/efeitos adversos , Modelos Estatísticos , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Fatores de Tempo , Resultado do Tratamento
15.
Expert Opin Pharmacother ; 20(11): 1309-1320, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237780

RESUMO

Introduction: Multiple sclerosis (MS) is a demyelinating disease, causing axonal damage and disability. Dalfampridine (DAL) is an extended-release formulation of 4-aminopyridine (4AP) and broad-spectrum voltage-dependent potassium channel blocker that is reported to improve motor, visual and cognitive functions. Furthermore, it is presently the only approved drug for walking impairment in MS. Areas covered: Herein, the authors evaluate DAL as a relapsing-remitting MS treatment, reporting and commenting on all aspects of the drug including its chemistry, safety, pharmacokinetics, and cost-effectiveness. A bibliographic search was performed on PubMed using the terms 'dalfampridine OR fampridine OR 4-aminopyridine'. Expert opinion: Evidence from post-marketing studies suggests that DAL, consistent with the effects of 4AP, may not only improve walking speed, but also arm function, fatigue, mood and cognition through restored nerve conduction in central nervous system demyelinated areas. Long-term safety data confirm that the approved dose of 10 mg twice daily is generally well tolerated. However, despite the reported efficacy, the extent of the benefits is limited in real life activities, although significant improvements have been demonstrated in the clinical setting. Patients often complain of side effects (such as cramps and painful paraesthesia) or lack of efficacy. Also, its considerably higher pricing in comparison to 4AP represents an important limitation.


Assuntos
4-Aminopiridina/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , 4-Aminopiridina/efeitos adversos , 4-Aminopiridina/química , 4-Aminopiridina/farmacocinética , Ensaios Clínicos como Assunto , Disfunção Cognitiva/complicações , Análise Custo-Benefício , Bases de Dados Factuais , Fadiga/complicações , Meia-Vida , Humanos , Esclerose Múltipla Recidivante-Remitente/economia , Bloqueadores dos Canais de Potássio/efeitos adversos , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacocinética , Convulsões/etiologia , Resultado do Tratamento
16.
BMC Neurol ; 19(1): 116, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176355

RESUMO

BACKGROUND: STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS. METHODS: Patients aged 18-65 years had an RRMS diagnosis < 3 years prior to screening, an Expanded Disability Status Scale (EDSS) score ≤ 4.0, and anti-JCV antibody negative status. Magnetic resonance imaging was performed at baseline and yearly thereafter. Cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were evaluated at 2 years. NEDA (no 24-week-confirmed EDSS worsening, no relapses, no gadolinium-enhancing lesions, and no new/newly enlarging T2-hyperintense lesions) was evaluated over 2 years. The Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Score (MSIS-29) were assessed at baseline and 1 and 2 years. Statistical analysis used summary statistics and frequency distributions. RESULTS: The study population (N = 222) had early RRMS, with mean (standard deviation [SD]) time since diagnosis of 1.6 (0.77) years and mean (SD) baseline EDSS score of 2.0 (1.13). NEDA was achieved in 105 of 187 patients (56.1%) during year 1 and 120 of 163 (73.6%) during year 2. Over 2 years, 76 of 171 patients (44.4%) attained overall NEDA. Probabilities of 24-week-confirmed EDSS worsening and improvement were 14.1% and 28.4%, respectively. After 2 years, patients exhibited significant improvements from baseline in SDMT (n = 158; mean [SD]: 4.3 [11.8]; p < 0.001) and MSIS-29 physical (n = 153; mean [SD]: - 3.9 [14.7]; p = 0.001), psychological (n = 152; mean [SD]: - 2.0 [7.9]; p < 0.001), and quality-of-life (n = 153; mean [SD]: - 6.0 [21.3]; p < 0.001) scores. CONCLUSIONS: These results support natalizumab's effectiveness over 2 years, during which nearly half of early RRMS patients achieved NEDA. During year 2, nearly 75% of patients exhibited NEDA. Over 2 years, patients continued to experience significant cognitive and quality-of-life benefits. These results are limited by the lack of a comparator group to determine the extent of a placebo effect. TRIAL REGISTRATION: clinicaltrials.gov, NCT01485003 , registered 5 December 2011.


Assuntos
Fatores Imunológicos/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/farmacologia , Adulto , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Natalizumab/administração & dosagem , Fatores de Tempo
17.
Mol Med Rep ; 20(1): 678-684, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180553

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system of autoimmune etiopathogenesis, and is characterized by various neurological symptoms. Glatiramer acetate and interferon­ß are administered as first­line treatments for this disease. In non­responsive patients, several second­line therapies are available, including natalizumab; however, a percentage of MS patients does not respond, or respond partially. Therefore, it is of the utmost importance to develop a diagnostic test for the prediction of drug response in patients suffering from complex diseases, such as MS, where several therapeutic options are already available. By a machine learning approach, the UnCorrelated Shrunken Centroid algorithm was applied to identify a subset of genes of CD4+ T cells that may predict the pharmacological response of relapsing­remitting MS patients to natalizumab, before the initiation of therapy. The results from the present study may provide a basis for the design of personalized therapeutic strategies for patients with MS.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/uso terapêutico , Biomarcadores Farmacológicos/análise , Linfócitos T CD4-Positivos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Aprendizado de Máquina , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/genética , Prognóstico , Transcriptoma/efeitos dos fármacos
18.
J Neurol ; 266(10): 2440-2446, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31209573

RESUMO

BACKGROUND: A high reactivation of multiple sclerosis (MS) was reported in patients treated with alemtuzumab after fingolimod. We aimed to understand whether this shift enhanced the risk for reactivation in a real-life cohort. METHODS: Subjects with relapsing MS, shifting from fingolimod to alemtuzumab were enrolled. We collected the following data: age, sex, disease duration, relapses after fingolimod withdrawal, new T2/gadolinium (Gd)-enhancing lesions in the last magnetic resonance imaging (MRI) during fingolimod and in the first, while on alemtuzumab, lymphocyte counts at alemtuzumab start, and Expanded Disability Status Scale (EDSS) before and after alemtuzumab. RESULTS: We enrolled 77 patients (women 61 (79%); mean age 36.2 years (SD 9.6), and disease duration 12.3 years (SD 6.8) at fingolimod discontinuation; median washout 1.8 months). The annualised relapse rate was 0.89 during fingolimod, 1.32 during washout, and 0.15 after alemtuzumab (p = 0.001). The EDSS changed from a median of 3 (IQR 2-4) at the end of fingolimod to 2.5 after alemtuzumab (IQR 1.5-4) (p = 0.013). The washout length and the lymphocyte count before alemtuzumab were not associated with EDSS change after alemtuzumab (p = 0.59 and p = 0.33, respectively). MRI activity decreased after alemtuzumab compared to that during fingolimod (p = 0.001). At alemtuzumab start, lymphocyte counts were < 0.8 × 103/mL in 21 patients. CONCLUSIONS: In our cohort, alemtuzumab reduced relapse, new T2/Gd-enhancing lesions, and EDSS score, as compared to the previous periods (fingolimod/washout). These results were not related to washout length or lymphocyte counts. Therefore, a rapid initiation of alemtuzumab after fingolimod does not seem to be a risk factor for MS reactivation.


Assuntos
Alemtuzumab/farmacologia , Cloridrato de Fingolimode/farmacologia , Fatores Imunológicos/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Alemtuzumab/administração & dosagem , Alemtuzumab/efeitos adversos , Feminino , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/efeitos adversos , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Estudos Retrospectivos , Índice de Gravidade de Doença
19.
Am J Health Syst Pharm ; 76(15): 1150-1157, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31201774

RESUMO

PURPOSE: The development and dissemination of a specialty pharmacy service to optimize fingolimod therapy management are described. SUMMARY: Fingolimod was the first oral therapy developed to counter relapsing-remitting multiple sclerosis. Pharmacovigilance measures and individualized support are strongly recommended due to associated safety concerns. The Fingolimod Patient Support Program (F-PSP) was developed and disseminated within a community pharmacy network. The F-PSP aims to ensure responsible use of fingolimod and patient empowerment by promoting medication adherence and patient safety through a person-centered and integrated care approach. It complements basic pharmacy services through 2 interventions: medication adherence support and pharmacovigilance tailored to fingolimod. The adherence intervention combines motivational interviewing with longitudinal electronic medication adherence monitoring. The pharmacovigilance component consists of informing patients of fingolimod recommendations, reminding patients of recommended medical tests, and tracking and monitoring symptoms, especially those of potential serious adverse fingolimod reactions. A secure Web platform guides the pharmacist in conducting interviews and enables collection of patient-reported outcome data. A transition care pharmacist proposes program participation to all patients initiated on fingolimod, performs enrollment, and coordinates transfers to patient-designated community pharmacies for ongoing care. CONCLUSION: The F-PSP enables support of individual patients, and also provides real-world data, helping to bridge the gap between practice and research. The F-PSP is intended to be a generic model of a specialty pharmacy service that is transferable to any other healthcare context, specialty drug or disease.


Assuntos
Serviços Comunitários de Farmácia/organização & administração , Cloridrato de Fingolimode/uso terapêutico , Conduta do Tratamento Medicamentoso/organização & administração , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Transferência de Pacientes/organização & administração , Administração Oral , Redes Comunitárias/organização & administração , Prestação Integrada de Cuidados de Saúde/organização & administração , Feminino , Humanos , Adesão à Medicação/psicologia , Entrevista Motivacional , Educação de Pacientes como Assunto , Segurança do Paciente , Farmacêuticos/organização & administração , Farmacovigilância , Desenvolvimento de Programas , Suíça
20.
BMC Neurol ; 19(1): 130, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202258

RESUMO

BACKGROUND: Interferon (IFN) beta drugs have been approved for the treatment of relapsing forms of multiple sclerosis (RMS) for more than 20 years and are considered to offer a favourable benefit-risk profile. In July 2014, subcutaneous (SC) peginterferon beta-1a 125 µg dosed every 2 weeks, a pegylated form of interferon beta-1a, was approved by the EMA for the treatment of adult patients with RRMS and in August 2014 by the FDA for RMS. Peginterferon beta-1a shows a prolonged half-life and increased systemic drug exposure resulting in a reduced dosing frequency compared to other available interferon-based products in MS. In the Phase 3 ADVANCE trial peginterferon beta-1a demonstrated significant positive effects on clinical and MRI outcome measures versus placebo after one year. Furthermore, in the ATTAIN extension study, sustained efficacy with long-term treatment for nearly 6 years was shown. MAIN TEXT: In July 2016, an interdisciplinary panel of German and Austrian experts convened to discuss the management of side effects associated with peginterferon beta-1a and other interferon beta-based treatments in MS in daily practice. The panel was composed of experts from university hospitals and private clinics comprised of neurologists, dermatologists, and an MS nurse. In this paper we report recommendations regarding best practices for adverse event management, focussing on peginterferon beta-1a. Injection site reactions (ISRs) and influenza-like illness are the most common adverse effects of interferon beta therapies and can present a burden for MS patients leading to non-adherence and discontinuation of therapy. Peginterferon beta-1a shows improved pharmacological properties. In clinical trials, the adverse event (AE) profile of peginterferon beta-1a was similar to other interferon beta formulations. The most common AEs were mild to moderate ISRs, influenza-like illness, pyrexia, and headache. Current information on the underlying cause of skin reactions associated with SC interferon treatment, and the management strategies for these AEs are limited. In pivotal trials, ISRs were mainly characterized and classified by neurologists, while dermatologists were only rarely consulted. CONCLUSIONS: This report addresses expert recommendations on the management of most relevant adverse effects related to peginterferon beta-1a and other interferon betas, based on literature and interdisciplinary experience.


Assuntos
Imunossupressores/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Adulto , Áustria , Dermatologistas , Feminino , Alemanha , Humanos , Masculino , Neurologistas
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