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BACKGROUND: Disease-modifying therapies (DMT) are increasingly used for children with multiple sclerosis (MS) even though most double-blinded randomized controlled trials evaluating efficacy, safety and dosing strategy of a specific drug have included adults. OBJECTIVE: To investigate predictors of treatment outcomes in patients with paediatric onset MS treated with DMTs. METHODS: Prospective cohort study from the nationwide Danish Multiple Sclerosis Registry including all patients with a MS diagnosis who initiated treatment with an approved DMT before the age of 18 (N = 137) and followed until their 25th birthday. Selected baseline predictors were tested in univariate and multivariate regression models. RESULTS: Multivariate analyses showed that being female and having disease duration for 2 or more years prior to DMT initiation predicted a higher relapse rate. In addition, disease duration and baseline expanded disability status scale (EDSS) predicted both confirmed disability worsening and improvement. We found no difference in treatment outcome between children with MS onset before and after the age of 13 years. CONCLUSIONS: The efficacy of DMT in paediatric onset MS patients is comparable to that seen in adult onset MS patients. Earlier treatment start is associated with a beneficial prognosis in the paediatric cohort.
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Progressão da Doença , Intervenção Médica Precoce , Fatores Imunológicos/administração & dosagem , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Sistema de Registros , Adolescente , Adulto , Idade de Início , Dinamarca , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Recidiva , Fatores Sexuais , Adulto JovemRESUMO
Treatment of multiple sclerosis (MS) has become increasingly multifaceted and comprises not only a variety of disease-modifying drugs with different mechanism of action but also a wide range of symptomatic therapies. Today, it is not possible for the family physician or even many general neurologists to master the current treatment algorithm, and this calls for the establishment of multidisciplinary MS Care Units. The core of the MS Care Unit would, in addition to MS neurologists and nurses, typically comprise neuropsychologists, clinical psychologists, physiotherapists, occupational therapists and secretaries, and will work together with a group of different specialists on formalized diagnostic workup procedures, protocols for initiation and follow-up of disease-modifying therapies. It is obvious that the terms of performance of different MS Care Units will vary across regions and need to be balanced with clinical practice according to local conditions. Although the main objective for establishment of MS Care Units will be to offer the single MS patient seamless and correct management of the disease to increase patient satisfaction and quality of life, it may even be cost-effective for the society by maintaining the working ability and reducing the costs of home help and custodial care by keeping people with MS resourceful.
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Atenção à Saúde , Esclerose Múltipla/tratamento farmacológico , Assistência ao Paciente , Qualidade de Vida , Análise Custo-Benefício/estatística & dados numéricos , Atenção à Saúde/legislação & jurisprudência , Gerenciamento Clínico , Humanos , Esclerose Múltipla/reabilitaçãoRESUMO
BACKGROUND: Neurofilament light chain (NFL) and chitinase-3-like-1 (CHI3L1) concentrations in cerebrospinal fluid (CSF) may have prognostic value in clinically isolated syndromes (CIS) and relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To compare the prognostic value of CSF concentrations of NFL and CHI3L1 in newly diagnosed CIS and RRMS patients. METHODS: NFL and CHI3L1 were measured in CSF in 177 newly diagnosed patients with CIS or RRMS who were followed clinically for a mean of 5.7 years. RESULTS: At baseline CSF concentrations of NFL correlated with CSF concentrations of CHI3L1, relapses in the previous year, time from last relapse, and the Expanded Disability Status Scale (EDSS) score. CSF concentrations of NFL and CHI3L1 were both associated with increased relapse risk during the first 2 years in univariate analyses, but only the CSF concentration of NFL was independently associated with relapse risk in a multivariable analysis. There was no relationship between CSF concentrations of NFL or CHI3L1 and risk of conversion to secondary progressive MS or development of disability. CONCLUSION: CSF concentrations of NFL are associated with 2-year relapse risk but not with disease progression or clinical worsening in newly diagnosed CIS and RRMS patients. This may be due to confounding by the effect of disease-modifying therapies.
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Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Adulto , Biomarcadores/líquido cefalorraquidiano , Doenças Desmielinizantes/líquido cefalorraquidiano , Doenças Desmielinizantes/fisiopatologia , Progressão da Doença , Feminino , Humanos , Masculino , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , PrognósticoRESUMO
BACKGROUND: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study, Cladribine Tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis. OBJECTIVE: Describe two clinically relevant definitions for patients with high disease activity (HDA) at baseline of the CLARITY study (utility verified in patients receiving placebo) and assess the treatment effects of Cladribine Tablets 3.5 mg/kg compared with the overall study population. METHODS: Outcomes of patients randomised to Cladribine Tablets 3.5 mg/kg or placebo were analysed for subgroups using HDA definitions based on high relapse activity (HRA; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not) or HRA plus disease activity on treatment (HRA + DAT; patients with ⩾2 relapses during the year prior to study entry, whether on DMD treatment or not, PLUS patients with ⩾1 relapse during the year prior to study entry while on therapy with other DMDs and ⩾1 T1 Gd+ or ⩾9 T2 lesions). RESULTS: In the overall population, Cladribine Tablets 3.5 mg/kg reduced the risk of 6-month-confirmed Expanded Disability Status Scale (EDSS) worsening by 47% vs placebo. A risk reduction of 82% vs placebo was seen in both the HRA and HRA + DAT subgroups (vs 19% for non-HRA and 18% for non-HRA + DAT), indicating greater responsiveness to Cladribine Tablets 3.5 mg/kg in patients with HDA. There were consistent results for other efficacy endpoints. The safety profile in HDA patients was consistent with the overall CLARITY population. CONCLUSION: Patients with HDA showed clinical and MRI responses to Cladribine Tablets 3.5 mg/kg that were generally better than, or at least comparable with, the outcomes seen in the overall CLARITY population.
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Cladribina/farmacologia , Progressão da Doença , Imunossupressores/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Adulto , Cladribina/administração & dosagem , Cladribina/efeitos adversos , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Smoking has been associated with increased multiple sclerosis (MS) risk, disease worsening, and progression in MS patients. Furthermore, interactions between smoking and human leukocyte antigen (HLA) genes have been shown for MS risk. Recently, we found that smoking was associated with an increased relapse rate in interferon-beta-treated relapsing-remitting multiple sclerosis (RRMS) patients. OBJECTIVES: We examined the association between smoking and relapses in natalizumab-treated RRMS patients. Second, we investigated if an interaction between smoking and HLA-DRB1*15:01 or HLA-A*02:01 affected the number of relapses during treatment. METHODS: In this observational cohort study, 355 natalizumab-treated RRMS patients were assessed. Prespecified criteria excluded 62 patients. Clinical data from the starting of treatment to the two-year follow-up visit were collected. Smoking status was obtained by a questionnaire survey. TaqMan allelic discrimination was used for genotyping of tag single-nucleotide polymorphisms (SNPs) for HLA-DRB1*15:01 and HLA-A*02:01. Negative binomial regression analysis was used to analyze the association between relapse rate and smoking intensity and HLA. RESULTS: One pack of cigarettes (20 cigarettes) per day during natalizumab treatment increased the relapse rate during treatment with 38% (incidence rate ratio (IRR) = 1.38, 95% confidence interval (CI): 1.08-1.77, p = 0.01). No association or interaction was found between smoking and HLA-DRB1*15:01 or HLA-A*02:01, respectively. CONCLUSION: Smoking intensity was significantly associated with the number of relapses during natalizumab treatment.
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Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/uso terapêutico , Fumar Tabaco/efeitos adversos , Adolescente , Adulto , Feminino , Seguimentos , Antígeno HLA-A2/genética , Cadeias HLA-DRB1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/genética , Polimorfismo de Nucleotídeo Único , Recidiva , Adulto JovemRESUMO
In the past 20 years the treatment scenario of multiple sclerosis has radically changed. The increasing availability of effective disease-modifying therapies has shifted the aim of therapeutic interventions from a reduction in relapses and disability accrual, to the absence of any sign of clinical or MRI activity. The choice for therapy is increasingly complex and should be driven by an appropriate knowledge of the mechanisms of action of the different drugs and of their risk-benefit profile. Because the relapsing phase of the disease is characterised by inflammation, treatment should be started as early as possible and aim to re-establish the normal complex interactions in the immune system. Before starting a treatment, neurologists should carefully consider the state of the disease, its prognostic factors and comorbidities, the patient's response to previous treatments, and whether the patient is likely to accept treatment-related risks in order to maximise benefits and minimise risks. Early detection of suboptimum responders, thanks to accurate clinical monitoring, will allow clinicians to redesign treatment strategies where necessary.
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Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Administração Oral , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Esquema de Medicação , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Injeções Intravenosas , Prevenção SecundáriaRESUMO
BACKGROUND: In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To assess the safety and efficacy of cladribine treatment in a 2-year Extension study. METHODS: In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained. RESULTS: A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0-1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension. CONCLUSION: Cladribine tablets treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.
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Cladribina/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Linfopenia/induzido quimicamente , Linfopenia/epidemiologia , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Multiple sclerosis (MS) is an inflammatory and neurodegenerative demyelinating disease of the central nervous system (CNS), most likely autoimmune in origin, usually beginning in early adulthood. The aetiology of the disease is not well understood; it is viewed currently as a multifactorial disease which results from complex interactions between genetic predisposition and environmental factors, of which a few are potentially modifiable. Improving our understanding of these factors can lead to new and more effective approaches to patient counselling and, possibly, prevention and management of the disease. The 2016 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) addressed the topic of environmental, modifiable risk factors for MS, gathering experts from around the world, to collate experimental and clinical research into environmental factors that have been associated with the disease onset and, in a few cases, disease activity and progression. A number of factors, including infections, vitamin D deficiency, diet and lifestyle factors, stress and comorbidities, were discussed. The meeting provided a forum to analyse available evidence, to identify inconsistencies and gaps in current knowledge and to suggest avenues for future research.
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BACKGROUND: Natalizumab and fingolimod were approved for treatment of active relapsing-remitting multiple sclerosis (RRMS) in Denmark in 2006 and 2011, respectively. There have been no randomized head-to-head studies comparing the two drugs. OBJECTIVE: To compare the clinical efficacy of natalizumab and fingolimod. METHODS: Data on all Danish RRMS patients who started their first second-line treatment with natalizumab or fingolimod from July 2011 to March 2015 were prospectively recorded in the Danish Multiple Sclerosis (MS) Treatment Register. The two treatment arms were 1:1 propensity score matched by baseline covariates using 'nearest neighbour' method. RESULTS: Propensity score matching left 928 of 1309 RRMS cases, 464 in each treatment group. The on-treatment annualized relapse rate was 0.296 (95% confidence interval (CI): 0.26-0.34) for natalizumab and 0.307 (95% CI: 0.27-0.35) for fingolimod. The adjusted relapse rate ratio was 0.93 (95% CI: 0.74-1.17; p = 0.53). Mean time to first relapse was 2.55 and 2.56 years, respectively ( p = 0.76). There was no difference in change of Expanded Disability Status Scale (EDSS). CONCLUSION: We found no differences in clinical disease activity between natalizumab- and fingolimod-treated RRMS patients in this real-life observational study. However, the lack of magnetic resonance imaging (MRI) data for the propensity score matching may conceal a higher efficacy of natalizumab.
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Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Natalizumab/uso terapêutico , Adulto , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: Little is known about the consequences of parental multiple sclerosis (MS) on offspring's socioeconomic circumstances. OBJECTIVE: To investigate employment, disability pension and income in offspring of parents with MS compared with matched reference persons in a nationwide register-based cohort study. METHODS: All Danish-born persons with onset of MS during 1950-1986 were retrieved from the Danish Multiple Sclerosis Registry. Their offspring were identified using the Civil Registration System. One random offspring from each sibship was matched by sex and year of birth with eight random reference persons. RESULTS: We included 2456 MS offspring and 19,648 reference persons. At age 30, employment was lower among MS offspring than reference children (odds ratio (OR): 0.89; 95% confidence interval (CI): 0.84-0.95; p = 0.0003), and they more often received disability pension (OR: 1.31; 95% CI: 1.15-1.50; p < 0.0001) at ages 30 and 40 but not at age 50. Although the mean income was not significantly lower for the MS offspring cohort, most of them attained an annual personal income below 250,000 DKK (Danish krone), that is, ~33,650 EUR (OR: 0.91; 95% CI: 0.84-0.99; p = 0.04). CONCLUSION: Having had a parent with MS may affect employment and increase the risk of disability pension and low income in adult life.
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Pessoas com Deficiência/estatística & dados numéricos , Esclerose Múltipla/economia , Pais , Adulto , Criança , Estudos de Coortes , Emprego , Feminino , Humanos , Renda/estatística & dados numéricos , Masculino , Esclerose Múltipla/terapia , Pensões/estatística & dados numéricos , Sistema de Registros , Fatores de RiscoRESUMO
BACKGROUND: Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS). OBJECTIVE: To evaluate a treatment effect of EPO on progressive MS. METHODS: This was a single-center, randomized, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6.5 and clinical progression without relapses in the 2 preceding years. The primary outcome was the change in a composite measure of maximum gait distance, hand dexterity, and cognition from baseline to 24 weeks. RESULTS: A total of 50 patients completed the study. Venesection was performed often but no thromboembolic events occurred. We found no difference in the primary outcome between the EPO and the placebo group using the intention-to-treat principle ( p = 0.22). None of the secondary outcomes, neither clinical nor magnetic resonance imaging (MRI) measures showed any significant differences. CONCLUSION: This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS.
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Encéfalo/efeitos dos fármacos , Eritropoetina/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Adulto , Encéfalo/patologia , Avaliação da Deficiência , Progressão da Doença , Método Duplo-Cego , Eritropoetina/administração & dosagem , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Resultado do TratamentoRESUMO
BACKGROUND: It is unknown whether disease activity according to consensus criteria (magnetic resonance imaging activity or clinical relapses) associate with cerebrospinal fluid (CSF) changes in progressive multiple sclerosis (MS). OBJECTIVE: To compare CSF biomarkers in active and inactive progressive MS according to consensus criteria. METHODS: Neurofilament light chain (NFL), myelin basic protein (MBP), IgG-index, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), chemokine CXCL13, terminal complement complex, leukocyte counts and nitric oxide metabolites were measured in primary ( n = 26) and secondary progressive MS ( n = 26) and healthy controls ( n = 24). RESULTS: Progressive MS patients had higher CSF cell counts, IgG-index, CHI3L1, MMP-9, CXCL13, NFL and MBP concentrations. Active patients were younger and had higher NFL, CXCL13 and MMP-9 concentrations than inactive patients. Patients with active disease according to consensus criteria or detectable CXCL13 or MMP-9 in CSF were defined as having combined active progressive MS. These patients had increased CSF cell counts, IgG-index and MBP, NFL and CHI3L1 concentrations. Combined inactive patients only had increased IgG-index and MBP concentrations. CONCLUSION: Patients with combined active progressive MS show evidence of inflammation, demyelination and neuronal/axonal damage, whereas the remaining patients mainly show evidence of active demyelination. This challenges the idea that neurodegeneration independent of inflammation is crucial in disease progression.
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Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Crônica Progressiva/patologia , Adulto , Biomarcadores/líquido cefalorraquidiano , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND OBJECTIVES: Treatment of spasticity poses a major challenge given the complex clinical presentation and variable efficacy and safety profiles of available drugs. We present a systematic review of the pharmacological treatment of spasticity in multiple sclerosis (MS) patients. METHODS: Controlled trials and observational studies were identified. Scientific evidence was evaluated according to pre-specified levels of certainty. RESULTS: The evidence supports the use of baclofen, tizanidine and gabapentin as first-line options. Diazepam or dantrolene could be considered if no clinical improvement is seen with the previous drugs. Nabiximols has a positive effect when used as add-on therapy in patients with poor response and/or tolerance to first-line oral treatments. Despite limited evidence, intrathecal baclofen and intrathecal phenol show a positive effect in severe spasticity and suboptimal response to oral drugs. CONCLUSION: The available studies on spasticity treatment offer some insight to guide clinical practice but are of variable methodological quality. Large, well-designed trials are needed to confirm the effectiveness of antispasticity agents and to produce evidence-based treatment algorithms.
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Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Relaxantes Musculares Centrais/uso terapêutico , Espasticidade Muscular/tratamento farmacológico , Aminas/uso terapêutico , Analgésicos/uso terapêutico , Baclofeno/uso terapêutico , Canabidiol/uso terapêutico , Clonidina/análogos & derivados , Clonidina/uso terapêutico , Ácidos Cicloexanocarboxílicos/uso terapêutico , Dantroleno/uso terapêutico , Diazepam/uso terapêutico , Dronabinol/uso terapêutico , Combinação de Medicamentos , Gabapentina , Humanos , Injeções Espinhais , Esclerose Múltipla/complicações , Espasticidade Muscular/etiologia , Fenol/uso terapêutico , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
BACKGROUND: Multiple sclerosis (MS) is a debilitating disease that negatively impacts patients' lives. OBJECTIVE: ENABLE assessed the effect of long-term prolonged-release (PR) fampridine (dalfampridine extended release in the United States) treatment on patient-perceived health impact in patients with MS with walking impairment. METHODS: ENABLE was a 48-week, open-label, Phase 4 study of PR-fampridine 10 mg twice daily. Patients who showed any improvement in Timed 25-Foot Walk walking speed at weeks 2 and 4 and any improvement in 12-item MS Walking Scale score at week 4 remained on treatment. The primary endpoint was change from baseline in 36-Item Short-Form Health Survey (SF-36) physical component summary (PCS) score. RESULTS: At week 4, 707/901 (78.5%) patients met the criteria to remain on treatment. Patients on treatment demonstrated significant and clinically meaningful improvements in SF-36 PCS scores from baseline (mean change (95% confidence interval)) to week 12 (4.30 (3.83, 4.78); p < 0.0001), week 24 (3.75 (3.23, 4.27); p < 0.0001), week 36 (3.46 (2.95, 3.97); p < 0.0001), and week 48 (3.24 (2.72, 3.77); p < 0.0001). Significant improvements from baseline were also demonstrated in secondary health measures in patients on treatment. CONCLUSION: PR-fampridine improved patient-perceived physical and psychological health impact of MS measured in a real-life setting.
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4-Aminopiridina/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Bloqueadores dos Canais de Potássio/uso terapêutico , 4-Aminopiridina/efeitos adversos , Adolescente , Adulto , Idoso , Austrália , Preparações de Ação Retardada , Avaliação da Deficiência , Europa (Continente) , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Marcha , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/psicologia , Bloqueadores dos Canais de Potássio/efeitos adversos , Qualidade de Vida , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Caminhada , Adulto JovemRESUMO
BACKGROUND: Evidence is accumulating supporting a beneficial effect of vitamin D in multiple sclerosis (MS). Genome-wide association studies (GWAS) have shown significant associations between 25-hydroxyvitamin D (25(OH)D) and single nucleotide polymorphisms (SNPs) in key genes in the vitamin D metabolism. OBJECTIVE: To examine the association between 25(OH)D and six GWAS SNPs and environmental factors in 1497 MS patients. METHODS: Blood samples and lifestyle questionnaires were collected between 2009 and 2012. Genotyping of GC-, CYP2R1- and NADSYN1-SNPs was performed by TaqMan allelic discrimination (Life Technologies). RESULTS: We found significant associations between 25(OH)D and SNPs in GC (rs7041, p = 0.01 and rs2282679, p = 0.03) and CYP2R1 (rs10741657, p =1.8 × 10(-4)). Season of blood sampling (p = 2.8 × 10(-31)), sex (p = 1.9 × 10(-5)), BMI (p = 2.3 × 10(-5)), vitamin supplements (p = 7.0 × 10(-22)), and fish intake (p = 0.02) also had significant effects on 25(OH)D. CONCLUSION: In this cross-sectional study, we found significant effects of environmental factors and SNPs in GC and CYP2R1 on 25(OH)D in MS patients. Since 25(OH)D might have protective effects in MS, and vitamin D supply is a modifiable factor, it may be important to include this in the MS treatment regimen.
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Meio Ambiente , Genótipo , Esclerose Múltipla , Vitamina D/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bancos de Espécimes Biológicos , Estudos Transversais , Dinamarca , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/etiologia , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Vitamina D/sangue , Adulto JovemRESUMO
BACKGROUND: Neurofilament light chain (NFL) is a biomarker for monitoring disease activity and treatment response in multiple sclerosis (MS). However, while most agree that NFL levels predict disease activity and worsening, the predictive value of NFL on future relapse risk remains uncertain. OBJECTIVE: The primary aim was to evaluate the predictive value of age-corrected serum NFL (sNFL) ratio on relapse risk in highly active relapsing-remitting MS patients (RRMS) treated with natalizumab. A secondary aim was to investigate the predictive value of sNFL ratios for MRI activity. METHODS: From January 1, 2006, to December 31, 2010, 355 patients initiated natalizumab treatment at the Danish Multiple Sclerosis Center. 305 patients were anti-natalizumab antibodies negative and had at least one blood sample available for sNFL analysis using single molecule array analysis at baseline, three, six, or 12 months. The patients were either treatment-naïve (n = 8), switching from interferon-ß or glatiramer acetate (n = 253), or switching from mitoxantrone (n = 44). An age-corrected ratio was calculated for sNFL. Time to first relapse was calculated from baseline and after re-baseline at 90 days. Data were collected from baseline until the two-year follow-up or end of treatment and included disease duration, expanded disability status scale, previous treatments, relapses 12 months prior to natalizumab initiation, smoking intensity, body mass index, and body weight. In addition, the patients underwent annual MRI of the brain. RESULTS: The sNFL ratio was increased in 173 of 287 samples (60.3 %) at baseline, in 119 of 246 samples (48.8 %) at month three, in 109 of 287 samples (38.0 %) at month six, and in 82 of 270 samples (30.4 %) at month 12. The sNFL ratio continuously declined over 12 months with significant decreases for every measuring timepoint: baseline vs. three months p = 3.0 × 10-6; three months vs. six months p = 3.2 × 10-5; six months vs. 12 months p = 0.002. Univariate Cox regression analysis showed that time to first relapse from 1) natalizumab initiation and from 2) re-baseline was associated with the number of relapses in the previous 12 months (hazard ratio 1.31 per relapse, 95 % CI = 1.2-1.5, p = 2.0 × 10-6; and 1.21 per relapse, 95 % CI = 1.1-1.4, p = 0.002, respectively). sNFL ratio at re-baseline was negatively associated with relapse risk (hazard ratio 0.82 per unit; 95 % CI = 0.7-1.0; p = 0.049). A multivariable Cox regression analysis of relapse risk from re-baseline showed that the number of relapses in the 12 months prior to natalizumab treatment (hazard ratio 1.29; 95 % CI = 1.1-1.5; p = 6.0 × 10-4) and smoking (hazard ratio 1.51 per 20 cigarettes per day; 95 % CI = 1.0-2.2; p = 0.030) were associated with increased risk of relapse; sNFL ratio was associated with a lower risk of relapse (hazard ratio = 0.736 per unit; 95 % CI = 0.6-0.9 p = 0.007). In univariate logistic regression analyses, the sNFL ratio at 12 months and values above the 75th and the 90th percentile predicted MRI activity in the following year (odds ratio [OR] = 2.0, 95 % CI = 1.2-3.6, p = 0.012; OR = 2.2, 95 % CI = 1.2-4.1, p = 0.014; and OR = 2.8, 95 % CI = 1.1-6.7, p = 0.026). CONCLUSION: In this highly active RRMS cohort, high sNFL ratios reflected previous relapse activity and decreased after initiation of treatment but were not associated with increased relapse risk in the following two years. Pre-treatment relapses and smoking on treatment were predictors of relapse risk after re-baselining at 90 days. MRI activity in year two was predicted by sNFL ratios at month 12.
Assuntos
Fatores Imunológicos , Imageamento por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente , Natalizumab , Proteínas de Neurofilamentos , Recidiva , Humanos , Natalizumab/administração & dosagem , Natalizumab/farmacologia , Proteínas de Neurofilamentos/sangue , Feminino , Masculino , Adulto , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/sangue , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Biomarcadores/sangue , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing-remitting multiple sclerosis. METHODS: We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks. RESULTS: Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (hazard ratio for the 3.5-mg group, 0.67; 95% confidence interval [CI], 0.48 to 0.93; P=0.02; and hazard ratio for the 5.25-mg group, 0.69; 95% CI, 0.49 to 0.96; P=0.03), and significant reductions in the brain lesion count on magnetic resonance imaging (MRI) (P<0.001 for all comparisons). Adverse events that were more frequent in the cladribine groups included lymphocytopenia (21.6% in the 3.5-mg group and 31.5% in the 5.25-mg group, vs. 1.8%) and herpes zoster (8 patients and 12 patients, respectively, vs. no patients). CONCLUSIONS: Treatment with cladribine tablets significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks. The benefits need to be weighed against the risks. (ClinicalTrials.gov number, NCT00213135.)
Assuntos
Cladribina/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Análise de Variância , Encéfalo/patologia , Cladribina/efeitos adversos , Avaliação da Deficiência , Progressão da Doença , Método Duplo-Cego , Feminino , Herpes Zoster/etiologia , Humanos , Imunossupressores/efeitos adversos , Análise de Intenção de Tratamento , Linfopenia/induzido quimicamente , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/patologia , Adulto JovemRESUMO
BACKGROUND: Ofatumumab, a fully human anti-CD20 monoclonal antibody indicated for the treatment of relapsing forms of multiple sclerosis (RMS), binds to a unique conformational epitope, thereby depleting B cells very efficiently and allowing subcutaneous administration at lower doses. OBJECTIVES: The aims were to characterize the relationship between ofatumumab concentration and B cell levels, including the effect of covariates such as body weight, age, or baseline B cell count, and use simulations to confirm the chosen therapeutic dose. METHODS: Graphical and regression analyses previously performed based on data from a dose-range finding study provided the B cell depletion target used in the present work. All available adult phase 2/3 data for ofatumumab in RMS patients were pooled to develop a population pharmacokinetics (PK)-B cell count model, using nonlinear mixed-effects modeling. The population PK-B cell model was used to simulate B cell depletion and repletion times and the effect of covariates on PK and B cell metrics, as well as the dose response across a range of subcutaneous ofatumumab monthly doses. RESULTS: The final PK-B cell model was developed using data from 1486 patients. The predetermined B cell target was best achieved and sustained with the 20-mg dose regimen, with median B cell count reaching 8 cells/µL in 11 days and negligible repletion between doses. Only weight had a significant effect on PK, which did not translate into any clinically relevant effect on B cell levels. CONCLUSION: The PK-B cell modeling confirms the dose chosen for the licensed ofatumumab regimen and demonstrates no requirement for dose adjustment based on adult patient characteristics.