RESUMEN
Multiple sclerosis (MS) is a chronic disease affecting the central nervous system (CNS) due to an autoimmune attack on axonal myelin sheaths. Epigenetics is an open research topic on MS, which has been investigated in search of biomarkers and treatment targets for this heterogeneous disease. In this study, we quantified global levels of epigenetic marks using an ELISA-like approach in Peripheral Blood Mononuclear Cells (PBMCs) from 52 patients with MS, treated with Interferon beta (IFN-ß) and Glatiramer Acetate (GA) or untreated, and 30 healthy controls. We performed media comparisons and correlation analyses of these epigenetic markers with clinical variables in subgroups of patients and controls. We observed that DNA methylation (5-mC) decreased in treated patients compared with untreated and healthy controls. Moreover, 5-mC and hydroxymethylation (5-hmC) correlated with clinical variables. In contrast, histone H3 and H4 acetylation did not correlate with the disease variables considered. Globally quantified epigenetic DNA marks 5-mC and 5-hmC correlate with disease and were altered with treatment. However, to date, no biomarker has been identified that can predict the potential response to therapy before treatment initiation.
Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Acetato de Glatiramer/uso terapéutico , Interferón beta/uso terapéutico , Leucocitos Mononucleares , Metilación de ADN , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológicoRESUMEN
BACKGROUND: Immunotherapy dramatically changed the natural history of multiple sclerosis (MS), which was classically associated with severe disability. Treatment strategies advocate that early control of disease activity is crucial to avoid progressive disability, and the use of high efficacy drugs may be beneficial, but safety is a concern. Choosing the disease-modifying therapy is challenging in clinical practice and should be further discussed. OBJECTIVE: To discuss the state of art of selecting the initial therapy for relapsing MS patients. METHODS: We used a case-based approach followed by clinical discussion, exploring therapeutic options in different MS settings. RESULTS: We presented clinical cases profile compatible with the use of MS therapies, classified into moderate and high efficacy. In the moderate efficacy group, we discussed interferons, glatiramer acetate, teriflunomide and dimethyl fumarate, while in the high efficacy group we discussed fingolimod, cladribine, natalizumab, ocrelizumab, alemtuzumab and ofatumumab. CONCLUSION: Advances in MS treatment are remarkable. Strong evidence supports the use of early high efficacy therapy. However, biomarkers, clinical and radiologic prognostic factors, as well as patients' individual issues, should be valued and considered for a personalized treatment decision.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Clorhidrato de Fingolimod/uso terapéutico , Acetato de Glatiramer/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológicoRESUMEN
Mild cognitive impairment (MCI) is a prodromal stage of memory impairment that may precede dementia. MCI is classified by the presence or absence of memory impairment into amnestic or non-amnestic MCI, respectively. More than 90% of patients with amnestic MCI who progress towards dementia meet criteria for Alzheimer's disease (AD). A combination of mechanisms promotes MCI, including intracellular neurofibrillary tangle formation, extracellular amyloid deposition, oxidative stress, neuronal loss, synaptodegeneration, cholinergic dysfunction, cerebrovascular disease, and neuroinflammation. However, emerging evidence indicates that neuroinflammation plays an important role in the pathogenesis of cognitive impairment. Unfortunately, there are currently no Food and Drug Administration (FDA)-approved drugs for MCI. Copolymer-1 (Cop-1), also known as glatiramer acetate, is a synthetic polypeptide of four amino acids approved by the FDA for the treatment of relapsing-remitting multiple sclerosis. Cop-1 therapeutic effect is attributed to immunomodulation, promoting a switch from proinflammatory to anti-inflammatory phenotype. In addition to its anti-inflammatory properties, it stimulates brain-derived neurotrophic factor (BDNF) secretion, a neurotrophin involved in neurogenesis and the generation of hippocampal long-term potentials. Moreover, BDNF levels are significantly decreased in patients with cognitive impairment. Therefore, Cop-1 immunization might promote synaptic plasticity and memory consolidation by increasing BDNF production in patients with MCI.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Factor Neurotrófico Derivado del Encéfalo , Proteína Coat de Complejo I , Progresión de la Enfermedad , Acetato de Glatiramer/uso terapéutico , Humanos , Trastornos de la Memoria , Pruebas NeuropsicológicasRESUMEN
Experimental autoimmune encephalomyelitis (EAE) is a relevant animal model of multiple sclerosis (MS). Oxidative stress and chronic inflammation play a major role in the pathogenesis of MS and EAE. Melatonin, a neurohormone, has potent anti-inflammatory properties. The aim of our study was to assess the therapeutic properties of melatonin alone or in combination with interferon ß-1b (IFNß-1b) or glatiramer acetate (GA) on EAE. EAE was induced in male Sprague-Dawley rats with an intraperitoneal injection of a homogenate of spinal cord and pig brain. At day 10 post immunization, rats were euthanized, and their brains were immediately excised and processed to measure oxidative stress markers and membrane fluidity. In addition, proinflammatory cytokines were quantified in plasma. Melatonin alone or in combination with GA and IFNß-1b inhibited the disease process of EAE and the synthesis of proinflammatory cytokines, caused a significant decrement in oxidative stress markers, and preserved the membrane fluidity in the motor cortex, midbrain, and spinal cord. The cumulative index score was significantly reduced in EAE rats treated with melatonin alone or in combination with GA and IFNß-1b. In conclusion, our findings provide preclinical evidence for the use of melatonin as an adjuvant therapeutic treatment for MS.
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Encefalomielitis Autoinmune Experimental , Melatonina , Esclerosis Múltiple , Animales , Biomarcadores , Citocinas , Encefalomielitis Autoinmune Experimental/patología , Acetato de Glatiramer/farmacología , Acetato de Glatiramer/uso terapéutico , Interferon beta-1b/uso terapéutico , Interferón beta , Masculino , Melatonina/farmacología , Melatonina/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , PorcinosRESUMEN
INTRODUÇÃO: A Esclerose Múltipla (EM) é uma doença imunogênica, inflamatória, desmielinizante e neurodegenerativa que acomete a substância branca e a cinzenta do sistema nervoso central (SNC). O quadro clínico se manifesta, na maior parte das vezes, por surtos ou ataques agudos, podendo entrar em remissão de forma espontânea ou com o uso de medicamentos. Denomina-se esclerose múltipla recorrente (EMR) o agrupamento das formas clínicas ativas esclerose múltipla remitente recorrente (EMRR); esclerose múltipla secundária progressiva (EMSP) e síndrome clinicamente isolada (Clinically Isolated Syndrome - CIS), com presença de recorrências ou sinais radiológicos de atividade de doença, ou seja, as formas que são caracterizadas pela ocorrência de surtos inflamatórios. O tratamento da EM pode ser complexo, com o uso de condutas medicamentosas e não medicamentosas. O objetivo do tratamento medicamentoso é a melhora clínica, o aumento da capacidade funcional, a redução de comorbidades e a atenuação de sintomas. As terapias modificadoras do curso da doença (TMCD) visam a reduzir as células imunogênicas circulantes, suprimir a adesão destas ao epitélio e, consequentemente, reduzir a sua migração para o parênquima e a resposta inflamatória decorrente. As seguint
Asunto(s)
Humanos , Inmunoglobulina G/uso terapéutico , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Clorhidrato de Fingolimod/uso terapéutico , Dimetilfumarato/uso terapéutico , Acetato de Glatiramer/uso terapéutico , Natalizumab/uso terapéutico , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economíaRESUMEN
OBJECTIVE: Escalation (ES) and early high-efficacy (EHE) therapies have been the main treatment strategies adopted in multiple sclerosis (MS) in recent years. The aim of this study was to compare the effectiveness and safety of EHE versus ES strategies in MS patients from Argentina. METHODS: This is a retrospective multicenter cohort study in Argentina. Eligible patients were categorized into 2 groups as follows: EHE if received natalizumab, ocrelizumab, rituximab, alemtuzumab, mitoxantrone, or cladribine; and ES if received interferon ß, glatiramer acetate, teriflunomide, dimethyl fumarate, or fingolimod as initial therapy. The primary outcome was confirmed disability progression (Expanded Disability Status Scale [EDSS] increase). Additional outcomes included the proportion of patients and time to: EDSS 6; new relapses; new T2-magnetic resonance imaging (MRI) lesions; no evidence of disease activity; and specific adverse events. Propensity score-based nearest-neighbor matching (without replacement) was applied to homogenize the sample, and Cox regression model stratified by matched pairs was used for the analysis. RESULTS: After propensity score matching, 193 and 112 patients were retained in the ES and EHE groups, respectively. The EHE significantly decreased the risk of EDSS progression (hazard ratio [HR], 0.62; 95% confidence interval [95% CI], 0.40-0.98; P = 0.04), relapses (HR, 0.66; 95% CI, 0.49-0.89; P = 0.006), and new MRI activity during follow-up (HR, 0.55; 95% CI, 0.40-0.75; P < 0.001). No significant differences were observed in specific adverse events between groups. CONCLUSIONS: Our study shows that EHE therapies prevent disease progression, relapses, and new MRI lesions and demonstrated no increased risk of specific adverse events when compared with ES therapy. These data should be considered when selecting a specific treatment for MS patients.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Argentina , Estudios de Cohortes , Clorhidrato de Fingolimod , Acetato de Glatiramer/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , RecurrenciaRESUMEN
TnP is a family of patented synthetic peptides which is in a preclinical development stage with valuable potential therapeutic indication for multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS). The use of a preclinical animal model, such as experimental autoimmune encephalomyelitis (EAE) has deepened our knowledge of the immunomodulatory functions of TnP as a drug. We have shown that TnP possesses a disease suppressive function in EAE, ameliorating disease severity by 40% and suppressing the accumulation of T helper (Th)1- and Th17-producing lymphocytes (by 55% and 60%, respectively) in CNS along with activated microglia/macrophages populations (by 33% and 50%, respectively), and also conferred a protective effect anticipating the remyelination process to day 66 compared to day 83 of untreated cuprizone-mice. Here we expanded our knowledge about its effects compared with current first-line disease-modifying therapies (DMT). We demonstrated that prophylactic treatment with TnP generated similar protection to betaseron (30%) or was more effective than glatiramer (44% versus 6%) or fingolimod (50% versus 19%) against the development of clinical symptoms. Although TnP controlled the leukocyte infiltration (87% versus 82%) into demyelinated areas of the spinal cord in the same way as betaseron and fingolimod, it was more effective (72% to 78% decrease) in the long-term control of neuronal degeneration compared to them. Also, when compared to glatiramer, TnP was more efficient in reversing leukocytes infiltration into the spinal cord (55% versus 24%), as well as induced a higher percentage of regulatory cells in spleen (2.9-fold versus 2.3-fold increase over vehicle-treated EAE mice) an in the spinal cord (8-fold versus 6-fold increase over vehicle-treated EAE mice). This specialized TnP profile for inducing immune tolerance and neuronal regeneration has significant therapeutic potential for the treatment of MS and other autoimmune diseases.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Clorhidrato de Fingolimod/uso terapéutico , Acetato de Glatiramer/uso terapéutico , Interferon beta-1b/efectos adversos , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Péptidos/uso terapéuticoRESUMEN
Background: Emerging evidence of antibody-independent functions, as well as the clinical efficacy of anti-CD20 depleting therapies, helped to reassess the contribution of B cells during multiple sclerosis (MS) pathogenesis. Objective: To investigate whether CD19+ B cells may share expression of the serine-protease granzyme-B (GzmB), resembling classical cytotoxic CD8+ T lymphocytes, in the peripheral blood from relapsing-remitting MS (RRMS) patients. Methods: In this study, 104 RRMS patients during different treatments and 58 healthy donors were included. CD8, CD19, Runx3, and GzmB expression was assessed by flow cytometry analyses. Results: RRMS patients during fingolimod (FTY) and natalizumab (NTZ) treatment showed increased percentage of circulating CD8+GzmB+ T lymphocytes when compared to healthy volunteers. An increase in circulating CD19+GzmB+ B cells was observed in RRMS patients during FTY and NTZ therapies when compared to glatiramer (GA), untreated RRMS patients, and healthy donors but not when compared to interferon-ß (IFN). Moreover, regarding Runx3, the transcriptional factor classically associated with cytotoxicity in CD8+ T lymphocytes, the expression of GzmB was significantly higher in CD19+Runx3+-expressing B cells when compared to CD19+Runx3- counterparts in RRMS patients. Conclusions: CD19+ B cells may exhibit cytotoxic behavior resembling CD8+ T lymphocytes in MS patients during different treatments. In the future, monitoring "cytotoxic" subsets might become an accessible marker for investigating MS pathophysiology and even for the development of new therapeutic interventions.
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Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Antígenos CD19/uso terapéutico , Antígenos CD20 , Linfocitos B/metabolismo , Femenino , Clorhidrato de Fingolimod/uso terapéutico , Acetato de Glatiramer/uso terapéutico , Humanos , Interferón beta/uso terapéutico , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab/uso terapéutico , Péptidos , Linfocitos TAsunto(s)
Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/terapia , Metilprednisolona/uso terapéutico , Protocolos Clínicos/normas , Interferones/uso terapéutico , Terapia Ocupacional/instrumentación , Modalidades de Fisioterapia , Fonoaudiología/instrumentación , Clorhidrato de Fingolimod/uso terapéutico , Acetato de Glatiramer/uso terapéutico , Natalizumab/uso terapéuticoRESUMEN
Neurodegenerative diseases (NDD) are disorders characterized by the progressive loss of neurons affecting motor, sensory, and/or cognitive functions. The incidence of these diseases is increasing and has a great impact due to their high morbidity and mortality. Unfortunately, current therapeutic strategies only temporarily improve the patients' quality of life but are insufficient for completely alleviating the symptoms. An interaction between the immune system and the central nervous system (CNS) is widely associated with neuronal damage in NDD. Usually, immune cell infiltration has been identified with inflammation and is considered harmful to the injured CNS. However, the immune system has a crucial role in the protection and regeneration of the injured CNS. Nowadays, there is a consensus that deregulation of immune homeostasis may represent one of the key initial steps in NDD. Dr. Michal Schwartz originally conceived the concept of "protective autoimmunity" (PA) as a well-controlled peripheral inflammatory reaction after injury, essential for neuroprotection and regeneration. Several studies suggested that immunizing with a weaker version of the neural self-antigen would generate PA without degenerative autoimmunity. The development of CNS-related peptides with immunomodulatory neuroprotective effect led to important research to evaluate their use in chronic and acute NDD. In this review, we refer to the role of PA and the potential applications of active immunization as a therapeutic option for NDD treatment. In particular, we focus on the experimental and clinical promissory findings for CNS-related peptides with beneficial immunomodulatory effects.
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Autoantígenos/uso terapéutico , Autoinmunidad/inmunología , Factores Inmunológicos/uso terapéutico , Regeneración Nerviosa/inmunología , Enfermedades Neurodegenerativas/terapia , Neuroprotección/inmunología , Péptidos/uso terapéutico , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/terapia , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/terapia , Animales , Acetato de Glatiramer/uso terapéutico , Humanos , Inmunización Pasiva , Inmunomodulación , Proteína Básica de Mielina/uso terapéutico , Enfermedades Neurodegenerativas/inmunología , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/terapia , Fragmentos de Péptidos/uso terapéutico , Deficiencias en la Proteostasis , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/terapia , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/terapiaRESUMEN
BACKGROUND: Recent changes to the diagnostic criteria for multiple sclerosis (MS) and new medications have had a major impact on the way in which specialists manage the disease. OBJECTIVE: To investigate factors considered by Brazilian neurologists in managing MS, and to identify how these contribute to diagnosis and treatment. METHODS: Potential participants were selected by a steering committee (MS experts who developed this survey). Only MS specialists were included in the study (neurologists who had completed a neuroimmunology fellowship or who were treating more than 30 MS patients). Links to the online questionnaire were distributed between March 2019 and January 2020. This questionnaire was composed of sections with hypothetical MS scenarios. RESULTS: Neurologists from 13 Brazilian states responded to the survey (n = 94). In the clinically isolated syndrome (CIS) scenario, the respondents agreed to treat patients with a high risk of MS diagnosis, whereas in the radiologically isolated syndrome (RIS) half of the respondents opted not to treat, even among high-risk patients. In cases of low-activity relapsing-remitting MS (RRMS), the choice of treatment was distributed among interferon beta, glatiramer acetate and teriflunomide, which were changed to fingolimod and natalizumab, as RRMS severity increased. The topics in which disagreement was found included practices regarding use of disease-modifying therapy (DMT) for pregnant patients and the washout period required for some DMTs. CONCLUSIONS: This study enabled identification of areas of agreement and disagreement about MS treatment among Brazilian neurologists, which can be used to update future protocols and improve patient management.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Femenino , Acetato de Glatiramer , Humanos , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab/uso terapéutico , Neurólogos , EmbarazoRESUMEN
CARACTERIZAÇÃO DA TECNOLOGIA: As betainterferonas, produzidas por tecnologia de DNA recombinante ou engenharia genética, atuam na infrarregulação da expressão de MHC (do inglês, major histocompatibility complex) em células apresentadoras de antígeno, na diminuição das citocinas pró-inflamatórias, na inibição da proliferação de células T, e na limitação do trânsito de células inflamatórias no SNC. O acetato de glatirâmer, por sua vez, é um polipeptídeo randômico sintético que atua na indução de células T supressoras e no equilíbrio entre citocinas pró-inflamatórias. OBJETIVO: Avaliar o desempenho dos medicamentos de primeira linha disponíveis para o tratamento da EMRR fornecidos pelo SUS. MÉTODOS: Coorte aberta retrospectiva referente ao período de janeiro de 2000 a dezembro de 2015 de pacientes com EMRR com 18 anos ou mais, diagnosticados de acordo com CID-10 (G35) e com indicação de uso de um dos medicamentos de primeira linha, glatiraÌmer ou uma das três apresentações das betainterferonas. Para medir a efetividade, foi avaliada a falha do tratamento e a persistência no primeiro e segundo anos após a entrada da coorte. RESUMO DOS RESULTADOS: Foram analisados dados de 22.722 pacientes, sendo que a maioria iniciou tratamento com betainterferona 1a subcutâneo (35,6%), eram mulheres (73,3%), da região Sudeste (58,4%), e tinham idade mediana de 37 anos (29-46). Aproximadamente 25% dos pacientes experimentaram falha terapêutica durante o tempo de seguimento, sendo mais frequente em pacientes que utilizaram betainterferona intramuscular. O acetato de glatiraÌmer apresentou os melhores resultados de persistência. CONCLUSÃO: A análise de desempenho realizada sugere que o acetato de glatiraÌmer está associado a melhores resultados, quando comparado às betainterferonas, na redução de falha terapêutica e na maior persistência ao tratamento. Além disso, os resultados sugerem que a betainterferona 1a intramuscular está associada a maior falha terapêutica em relação aos demais medicamentos de primeira linha no tratamento da EMRR.
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Humanos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Acetato de Glatiramer/uso terapéutico , Interferón beta-1a/uso terapéutico , Interferon beta-1b/uso terapéutico , Sistema Único de Salud , Brasil , Eficacia , Análisis Costo-BeneficioRESUMEN
INTRODUCTION: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, which occurs in up to 85% of cases as relapsing remitting (RR), with episodes of neurological dysfunction partially forwarded. Its treatment in Chile is financially protected by the Explicit Health Guarantees (GES) and Law 20,850 on high-cost diseases. The Regional Hospital of Talca (HRT) has 25 patients benefiting from Law 20,850 in treatment with second-line biologic therapy. Adverse reactions (RAM) to the use of these drugs have been described and to date there are no case reports or studies of significant adverse events in Chile. Objectives: To present the experience of the use of biologic therapy in EMRR in HRT, in relation to adverse events. METHODS: A review of the current guidelines in Chile for the treatment of relapsing-remitting multiple sclerosis and the protocol of law 20,850 was carried out, the clinical records of 25 patients benefiting from the law in the HRT were reviewed, with emphasis on the adverse events presented before First and second line therapies and the con sequences of these events on the continuity of therapy. RESULTS: Half of the patients who started their treatment with first-line drugs had adverse effects, of which 28% involved a change in therapy, the remaining changed from therapy due to failure to treatment. Of the 26 patients included in the sample, 24 are currently using second-line drugs. The profile of adverse effects should be a variable to consider when indicating a therapy for MS.
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Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/tratamiento farmacológico , Chile , Interferón beta/administración & dosificación , Interferón beta/efectos adversos , Guías de Práctica Clínica como Asunto , Acetato de Glatiramer/efectos adversos , Inmunosupresores , Esclerosis Múltiple/complicacionesRESUMEN
BACKGROUND: Relapsing-remitting multiple sclerosis (RRMM) is a chronic, progressive, inflammatory and immune-mediated disease that affects the central nervous system and is characterized by episodes of neurological dysfunction followed by a period of remission. The pharmacological strategy aims to delay the progression of the disease and prevent relapse. Interferon beta and glatiramer are commonly used in the Brazilian public health system and are available to patients who meet the guideline criteria. The scenario of multiple treatments available and in development brings the need for discussion and evaluation of the technologies already available before the incorporation of new drugs. This study analyses the effectiveness of first-line treatment of RRMS measured by real-world evidence data, from the Brazilian National Health System (SUS). METHODS AND FINDINGS: We conducted a non-concurrent national cohort between 2000 and 2015. The study population consisted of 22,722 patients with RRMS using one of the following first-line drugs of interest: glatiramer or one of three presentations of interferon beta. Kaplan-Meier analysis was used to estimate the time to treatment failure. A univariate and multivariate Cox proportional hazard model was used to evaluate factors associated with treatment failure. In addition, patients were propensity score-matched (1:1) in six groups of comparative first-line treatments to evaluate the effectiveness among them. The analysis indicated a higher risk of treatment failure in female patients (HR = 1.08; P = 0,01), those with comorbidities at baseline (HR = 1.20; P<0,0001), in patients who developed comorbidities after starting treatment (i.e., rheumatoid arthritis-HR = 1.65; P<0,0001), those exclusive SUS patients (HR = 1.31; P<0,0001) and among patients using intramuscular interferon beta (IM ßINF-1a) (28% to 60% compared to the other three treatments; P<0,0001). Lower risk of treatment failure was found among patients treated with glatiramer. CONCLUSIONS: This retrospective cohort suggests that glatiramer is associated with greater effectiveness compared to the three presentations of interferon beta. When evaluating beta interferons, the results suggest that the intramuscular presentation is not effective in the treatment of multiple sclerosis.
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Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Resultado del Tratamiento , Adyuvantes Inmunológicos/uso terapéutico , Adulto , Brasil/epidemiología , Estudios de Cohortes , Análisis Costo-Beneficio , Femenino , Acetato de Glatiramer/uso terapéutico , Humanos , Interferón beta/uso terapéutico , Estimación de Kaplan-Meier , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Modelos de Riesgos Proporcionales , Estudios RetrospectivosAsunto(s)
Conductas Relacionadas con la Salud , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Cuarentena , Adulto , Alemtuzumab/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Betacoronavirus , COVID-19 , Chile/epidemiología , Infecciones por Coronavirus/epidemiología , Toma de Decisiones , Femenino , Clorhidrato de Fingolimod/uso terapéutico , Acetato de Glatiramer/uso terapéutico , Adhesión a Directriz , Guías como Asunto , Humanos , Interferones/uso terapéutico , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Natalizumab/uso terapéutico , Pandemias , Neumonía Viral/epidemiología , SARS-CoV-2 , Organización Mundial de la Salud , Adulto JovenRESUMEN
Identity is a critical quality attribute that must be determined before releasing batches of medicinal and dietary products. However, the identities of peptide-derived products composed of a large number of diverse molecules is challenging since most analytical techniques cannot analyze multiple molecules simultaneously. Here, we proposed the determination of the weight-average molecular weight (Mw) and polydispersity index (PDI) by mass spectrometry for control quality for the batch release of complex products, namely, glatiramer acetate (Copaxone), collagen hydrolysate (Colagenart), and a human dialyzable leucocyte extract (Transferon). The Mw and PDI values were orthogonally determined by PFG-STE-H2O(presaturation)-DOSY-NMR analysis. To the best of our knowledge, this is the first time that MS and NMR spectra have been combined to determine the PDI of complex products derived from protein hydrolysis that are not monodisperse. The performance of each method was evaluated by comparing the obtained results to those reported for glatiramer acetate using MALLS, the technique commonly employed to determine PDI. This combined approach demonstrates the ability of these techniques to separate peptide populations from complex mixtures to establish their identity through their mass distribution profiles.
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Colágeno/química , Acetato de Glatiramer/química , Inmunosupresores/química , Leucocitos/química , Espectrometría de Masas/métodos , Humanos , Hidrólisis , Espectroscopía de Resonancia Magnética/métodos , Peso MolecularRESUMEN
It is currently unknown how genetic factors may influence the clinical course of multiple sclerosis (MS). OBJECTIVE: We examined the impact of CIITA polymorphisms -168A/G (rs3087456) and +1614G/C (rs4774) on the risk of disability progression, severity and on responses to first-line immunomodulator treatments. METHODS: Genomic DNA was extracted from blood samples. We used ABI3730xl and GeneMapper v.4.0 software to identify genotype variations. All patients were followed up and clinically reassessed at three-month intervals. Disability progression was measured by the Expanded Disability Status Scale and disease severity by the Multiple Sclerosis Spasticity Scale (MSSS). RESULTS: We included 37 men and 80 women. We found no evidence regarding the influence of the single nucleotide polymorphisms studied in the Expanded Disability Status Scale or therapeutic response of the evaluated drugs. We performed a logistic regression analysis with the MSSS and found that a less severe MS course was associated with wild type CIITA -168AA and CIITA +1614GG, as the chance of the patient progressing to MSSS2 and MSSS3 decreased in 61% and 75% with CIITA -168AA and 66% and 75% with CIITA +1614GG, respectively (p < 0.0001). Although less significant, the CIITA +1614 GC also pointed to a less severe MS course and the chance of the patient progressing to MSSS3 decreased 79% (p = 0.015). We also observed that the CIITA -168GG genotype was more frequent in MSSS2 and MSSS3 and had 40% lower odds ratio to becoming more severe MS. CONCLUSION: These data suggest that CIITA -168AA, CIITA +1614GG and CIITA +1614 GC polymorphisms may be associated with a better MS clinical course. This knowledge may be useful for a better understanding of MS and its therapeutic management.
Asunto(s)
Progresión de la Enfermedad , Esclerosis Múltiple/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , Transactivadores/genética , Adolescente , Adulto , Anciano , Evaluación de la Discapacidad , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Acetato de Glatiramer/uso terapéutico , Humanos , Factores Inmunológicos/uso terapéutico , Interferón beta/uso terapéutico , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/mortalidad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Adulto JovenRESUMEN
ABSTRACT It is currently unknown how genetic factors may influence the clinical course of multiple sclerosis (MS). Objective: We examined the impact of CIITA polymorphisms −168A/G (rs3087456) and +1614G/C (rs4774) on the risk of disability progression, severity and on responses to first-line immunomodulator treatments. Methods: Genomic DNA was extracted from blood samples. We used ABI3730xl and GeneMapper v.4.0 software to identify genotype variations. All patients were followed up and clinically reassessed at three-month intervals. Disability progression was measured by the Expanded Disability Status Scale and disease severity by the Multiple Sclerosis Spasticity Scale (MSSS). Results: We included 37 men and 80 women. We found no evidence regarding the influence of the single nucleotide polymorphisms studied in the Expanded Disability Status Scale or therapeutic response of the evaluated drugs. We performed a logistic regression analysis with the MSSS and found that a less severe MS course was associated with wild type CIITA −168AA and CIITA +1614GG, as the chance of the patient progressing to MSSS2 and MSSS3 decreased in 61% and 75% with CIITA −168AA and 66% and 75% with CIITA +1614GG, respectively (p < 0.0001). Although less significant, the CIITA +1614 GC also pointed to a less severe MS course and the chance of the patient progressing to MSSS3 decreased 79% (p = 0.015). We also observed that the CIITA −168GG genotype was more frequent in MSSS2 and MSSS3 and had 40% lower odds ratio to becoming more severe MS. Conclusion: These data suggest that CIITA −168AA, CIITA +1614GG and CIITA +1614 GC polymorphisms may be associated with a better MS clinical course. This knowledge may be useful for a better understanding of MS and its therapeutic management.
RESUMO Atualmente não se sabe como os fatores genéticos podem influenciar o curso clínico da esclerose múltipla (EM). Objetivo: Examinamos o impacto dos polimorfismos CIITA −168A/G (rs3087456) e CIITA +1614G/C (rs4774) no risco de progressão da incapacidade, gravidade e resposta aos tratamentos imunomoduladores de primeira linha. Métodos: O DNA genômico foi extraído de amostras de sangue. Utilizamos o software ABI3730xl e GeneMapper v.4.0 (Applied Biosystems) para identificar variações genotípicas. Todos os pacientes foram acompanhados e reavaliados clinicamente em intervalos de três meses. A progressão da incapacidade foi medida pela EDSS e a gravidade da doença pelo MSSS. Resultados: Incluímos 37 homens e 80 mulheres. Não encontramos evidências sobre a influência dos SNPs estudados no EDSS e na resposta terapêutica aos fármacos avaliados. Realizamos uma análise de regressão logística com o MSSS e observamos uma evolução menos grave da EM associada aos tipos selvagens CIITA −168AA e CIITA +1614GG, pois a chance do paciente atingir MSSS2 e MSSS3 diminuiu em 61%/75%, e 66/75% respectivamente (p < 0,0001). Embora menos significativo, o CIITA +1614GC também foi relacionado com evolução menos grave da EM e a chance do paciente atingir o MSSS3 diminuiu 79% (p = 0,015). Nós também observamos que o genótipo CIITA −168GG foi mais frequente no MSSS2 e MSSS3 e teve uma razão de chance 40% menor para atingir forma mais grave da EM. Conclusão: Estes dados sugerem que os polimorfismos CIITA −168AA, CIITA +1614GG e CIITA +1614GC podem estar associados a um melhor curso clínico da EM. Este conhecimento pode ser útil para uma melhor compreensão da EM e o seu manejo terapêutico.