RESUMEN
BACKGROUND: Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy. OBJECTIVE: To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo. METHODS: POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo. RESULTS: Recruitment was stopped prematurely due to slow inclusions (n = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58-1.39), placebo = 0.97 (0.63-1.50) (p = 0.79)). CONCLUSION: POPARTMUS failed showing efficacy of a NOMAc-E2 combination in preventing post-partum relapses.
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Estradiol , Esclerosis Múltiple , Femenino , Humanos , Megestrol , Esclerosis Múltiple/tratamiento farmacológico , Norpregnadienos , Periodo Posparto , Embarazo , RecurrenciaRESUMEN
BACKGROUND: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses. OBJECTIVE: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy. METHODS: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992-1995 and 2005-2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis. RESULTS: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78). CONCLUSION: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.
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Anestesia de Conducción/efectos adversos , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple/fisiopatología , Complicaciones del Embarazo/inducido químicamente , Complicaciones del Embarazo/fisiopatología , Adulto , Femenino , Estudios de Seguimiento , Humanos , Periodo Posparto , Embarazo , Recurrencia , Estudios RetrospectivosRESUMEN
Increasing evidence supports the anti-inflammatory role of estrogens in Multiple Sclerosis (MS), originating from the observation of reduction in relapse rates among women with MS during pregnancy, but the molecular mechanisms are still not completely understood. Using an integrative data analysis, we identified T helper (Th) 17 and T regulatory (Treg) cell-type-specific regulatory regions (CSR) regulated by estrogen receptor alpha (ERα). These CSRs were validated in polarized Th17 from healthy donors (HD) and in peripheral blood mononuclear cells, Th17 and Treg cells from relapsing remitting (RR) MS patients and HD during pregnancy. 17ß-estradiol induces active histone marks enrichment at Forkhead Box P3 (FOXP3)-CSRs and repressive histone marks enrichment at RAR related orphan receptor C (RORC)-CSRs in polarized Th17 cells. A disease-associated epigenetic profile was found in RRMS patients during pregnancy, suggesting a FOXP3 positive regulation and a RORC negative regulation in the third trimester of pregnancy. Altogether, these data indicate that estrogens act as immunomodulatory factors on the epigenomes of CD4+ T cells in RRMS; the identified CSRs may represent potential biomarkers for monitoring disease progression or new potential therapeutic targets.
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Esclerosis Múltiple Recurrente-Remitente/sangre , Embarazo/sangre , Linfocitos T Reguladores/fisiología , Células Th17/fisiología , Transcriptoma , Adolescente , Adulto , Análisis de Varianza , Polaridad Celular , Ensamble y Desensamble de Cromatina/genética , Epigénesis Genética , Estradiol/metabolismo , Receptor alfa de Estrógeno/metabolismo , Femenino , Factores de Transcripción Forkhead/genética , Voluntarios Sanos , Código de Histonas/genética , Humanos , Persona de Mediana Edad , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Polimorfismo de Nucleótido Simple , Tercer Trimestre del Embarazo/sangre , Secuencias Reguladoras de Ácidos Nucleicos/genética , Adulto JovenRESUMEN
Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab.
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Alemtuzumab/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/patología , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Femenino , HumanosRESUMEN
INTRODUCTION: Natalizumab is a humanized monoclonal antibody highly effective in relapsing-remitting multiple sclerosis (MS). Important concerns about its safety have been pointed out mainly because of the risk of progressive multifocal leukoencephalopathy (PML), caused by the opportunistic John-Cunningham virus (JCV). Areas covered: This review analyzes all the safety aspects related to the use and safety of natalizumab in MS patients. Other than PML, post-marketing, safety red-flags have been reported, as liver or haematological serious adverse events. Pregnancy evidences will be pointed out. The risk of PML depends on: concomitant or previous immunosuppression, exposure duration, anti-JCV antibody level. In natalizumab-related PML the average survival is 77%; prognostic features and information for the earliest identification of PML have been identified to maximally reduce its incidence, mortality and morbidity. Expert opinion: Natalizumab is a highly effective drug for MS patients but its safety issues represent a relevant limitation and impose strict clinical surveillance of treated patients. Some post-marketing safety red-flags have been pointed out, with higher attention to severe liver failures and limphoma cases. If PML and its consequences are considered the most relevant issues, a continuous surveillance must be maintained also regarding other possible SAEs like liver diseases and malignancies.
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Factores Inmunológicos/administración & dosificación , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Natalizumab/administración & dosificación , Animales , Humanos , Factores Inmunológicos/efectos adversos , Virus JC/aislamiento & purificación , Leucoencefalopatía Multifocal Progresiva/virología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Natalizumab/efectos adversos , Infecciones Oportunistas/virología , Pronóstico , Riesgo , Tasa de SupervivenciaRESUMEN
Natalizumab is a monoclonal antibody highly effective in the treatment of relapsing remitting multiple sclerosis (RRMS) patients. Despite its effectiveness, there are growing concerns regarding the risk of progressive multifocal leukoencephalopathy (PML), a brain infection caused by John Cunningham virus (JCV), particularly after 24 doses and in patients who previously received immunosuppressive drugs. Long-term natalizumab treated, immunosuppressive-pretreated, and JCV antibody-positive patients are asked to rediscuss natalizumab continuation or withdrawal after 24 doses. Until now, there has not been a clear strategy that should be followed to avoid PML risk and in parallel reduce clinical and radiological rebound activity. In this review, we analyzed the results of clinical trials and case reports in relation to the following situations: natalizumab continuation, natalizumab discontinuation followed by full therapeutic suspension or switch to other first or second line MS treatments. Quitting all MS treatment after natalizumab increases MS activity occurrence. The results regarding the therapeutic switch are not homogeneous, so at the moment there are no established guidelines regarding natalizumab treatment after 24 administrations; the choice is currently based on the professional experience of the neurologist, and on patients' clinical features and preferences.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab/uso terapéutico , Corticoesteroides/uso terapéutico , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Virus JC/aislamiento & purificación , Leucoencefalopatía Multifocal Progresiva/diagnóstico , Leucoencefalopatía Multifocal Progresiva/etiología , Natalizumab/administración & dosificación , Natalizumab/efectos adversosRESUMEN
Alemtuzumab is a humanized monoclonal antibody targeting the surface molecule CD52, resulting in a rapid depletion of innate and adaptive immune cells. Infection rates in multiple sclerosis (MS) treatment trials were higher in alemtuzumab than in interferon beta-treated patients. We report two MS patients who developed cytomegalovirus disease within 1 month after the first 5-day cycle of alemtuzumab. Upon identification and appropriate treatment of the infection, each recovered completely. Neurologists should be aware of this serious but treatable complication.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Infecciones por Citomegalovirus/etiología , Factores Inmunológicos/efectos adversos , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Alemtuzumab , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/tratamiento farmacológico , Femenino , HumanosRESUMEN
Neurological diseases can be complicated by sialorrhea, an excessive flow of saliva. Patients suffering from moderate to severe sialorrhea have an impaired quality of life, often worsened by correlated complications such as aspiration pneumonia, oral infections, dental caries, and maceration of the skin. Diverse therapeutic approaches have been proposed for the treatment of sialorrhea, including surgery and the use of anticholinergic agents, with limited results and the possible occurrence of serious adverse events. Recently, botulinum toxin (BoNT) injection within the major salivary glands has been proposed in patients refractory to anticholinergic therapy, with the aim of inhibiting local acetylcholine release and gland activity. In order to obtain a better outcome in terms of reduction of saliva production, efficacy, duration, and avoidance of major adverse events, we developed an ultrasound-guided BoNT-type A injection technique accurately described in the text. Here we present a method of treating sialorrhea with bilateral parotid and submandibular gland BoNT-type A injections under ultrasound guidance. Four quadrants of the parotid gland and two quadrants of the submandibular gland are visualized and injected using two accesses and one access, respectively. The ultrasound-guided procedure provides a simple, non-invasive, real-time visualization of the muscular and glandular tissues and their surrounding structures, optimizing treatment efficacy and safety.
Asunto(s)
Toxinas Botulínicas Tipo A/uso terapéutico , Sialorrea/terapia , Ultrasonografía Intervencional/métodos , Caries Dental , Humanos , Inyecciones/efectos adversos , Calidad de Vida , Glándula Submandibular , Resultado del TratamientoRESUMEN
OBJECTIVE: To analyze changes in T-helper (Th) subsets, T-regulatory (Treg) cell percentages and function, and mRNA levels of immunologically relevant molecules during a 24-month follow-up after alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Multicenter follow-up of 29 alemtuzumab-treated patients with RRMS in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and CARE-MS II trials. Peripheral blood (PB) samples were obtained at months 0, 6, 12, 18, and 24. We evaluated (1) mRNA levels of 26 immunologic molecules (cytokines, chemokines, chemokine receptors, and transcriptional factors); (2) Th1, Th17, and Treg cell percentages; and (3) myelin basic protein (MBP)-specific Treg suppressor activity. RESULTS: We observed 12 relapses in 9 patients. mRNA levels of the anti-inflammatory cytokines interleukin (IL)-10, IL-27, and transforming growth factor-ß persistently increased whereas those of proinflammatory molecules related to the Th1 or Th17 subsets persistently decreased after alemtuzumab administration throughout the follow-up period. PB CD4+ cell percentage remained significantly lower than baseline while that of Th1 and Th17 cells did not significantly change. A significant increase in Treg cell percentage was observed at month 24 and was accompanied by an increase in Treg cell suppressive activity against MBP-specific Th1 and Th17 cells. CONCLUSIONS: The long-lasting therapeutic benefit of alemtuzumab in RRMS may involve a shift in the cytokine balance towards inhibition of inflammation associated with a reconstitution of the PB CD4+ T-cell subsets that includes expansion of Treg cells with increased suppressive function.
RESUMEN
Literature provides reports only of a limited follow-up single injection of botulinum toxin-A (BoNT-A) in patients with sialorrhea. The aim of our study is to evaluate the long-lasting efficacy and safety of ultrasound-guided BoNT-A injections for severe sialorrhea secondary to neurological dysphagia. We enrolled 38 severe adult sialorrhea patients referred consecutively to the neurology unit and performed bilateral parotid and submandibular gland BoNT-A injections under ultrasound guidance. The outcomes of the study were reduction of sialorrhea, duration of therapeutic effect, and subjective patient- and caregiver-reported satisfaction. A total of 113 BoNT-A administrations were given during the study period with a mean duration of follow-up of 20.2 ± 4.4 months. We observed a significant decrease from baseline in mean number of daily aspirations and a significant improvement in patient- and caregiver-reported outcomes following ultrasound-guided BoNT-A injections (p < 0.001 vs baseline for all comparisons) and the mean duration of the efficacy was 5.6 ± 1 months. No major treatment-related adverse events occurred and a low incidence of minor adverse events was reported. This study confirms the long-lasting efficacy and safety of ultrasound-guided BoNT-A injections for sialorrhea, regardless of the causative neurological disorder. These results should encourage the use of BoNT-A in the treatment of severe sialorrhea and highlight the role of ultrasound guidance to obtain optimal results in terms of safety and reproducible outcomes.
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Toxinas Botulínicas Tipo A/farmacología , Trastornos de Deglución/complicaciones , Neurotoxinas/farmacología , Evaluación de Resultado en la Atención de Salud , Sialorrea/tratamiento farmacológico , Ultrasonografía Intervencional/métodos , Anciano , Anciano de 80 o más Años , Toxinas Botulínicas Tipo A/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , Neurotoxinas/administración & dosificación , Glándula Parótida , Sialorrea/etiología , Glándula SubmandibularRESUMEN
Th1 and Th17 cells have been considered as effectors in mouse EAE and in the human counterpart, MS. Recently, IL-22, a Th17-related, proinflammatory cytokine, has been associated with a new Th cell subset, defined as Th22, involved in chronic inflammatory conditions, such as psoriasis; the role of IL-22 in MS has not yet been elucidated. Here, we report that similar to Th17 cells, the number of Th22 cells increased in the PB and the CSF of RR MS patients, especially during the active phases of the disease. However, as opposed to Th17 cells, the expansion of Th22 cells occurred before the active phases of the disease. Th22 cells were found to be specific for the autoantigen MBP and also expressed high levels of CCR6 and T-bet, as for Th17 cells, indicating that Th22 self-reactive cells could have CNS-homing properties and be pathogenic in active RRMS patients. Conversely to Th17 cells, Th22 cells displayed lower levels of IFNAR1 and were insensitive to IFN-ß inhibition. These data suggest that expansion of Th22 cells in MS could be one of the factors that critically influence resistance to IFN-ß therapy.
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Interferón beta/farmacología , Interleucinas/biosíntesis , Esclerosis Múltiple Recurrente-Remitente/inmunología , Receptores de Quimiocina/biosíntesis , Receptores de Citocinas/biosíntesis , Subgrupos de Linfocitos T/patología , Factores de Transcripción/metabolismo , Adulto , Autoantígenos/inmunología , División Celular , Células Cultivadas , Células Clonales/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Ensayos de Liberación de Interferón gamma , Interleucinas/genética , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Proteína Básica de Mielina/inmunología , Cultivo Primario de Células , Receptores CCR6/biosíntesis , Receptores CCR6/genética , Receptores de Quimiocina/genética , Receptores de Citocinas/genética , Proteínas de Dominio T Box/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th17/inmunología , Adulto Joven , Interleucina-22RESUMEN
OBJECTIVE: To investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients. METHODS: We used a human FRDA neuronal cell model, derived from patient induced pluripotent stem cells, to determine the efficacy of a 2-aminobenzamide HDACi (109) as a modulator of FXN gene expression and chromatin histone modifications. FRDA patients were dosed in 4 cohorts, ranging from 30mg/day to 240mg/day of the formulated drug product of HDACi 109, RG2833. Patients were monitored for adverse effects as well as for increases in FXN mRNA, frataxin protein, and chromatin modification in blood cells. RESULTS: In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered. INTERPRETATION: Drug exposure inducing epigenetic changes in neurons in vitro is comparable to the exposure required in patients to see epigenetic changes in circulating lymphoid cells and increases in gene expression. These findings provide a proof of concept for the development of an epigenetic therapy for this fatal neurological disease.
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Ataxia de Friedreich/tratamiento farmacológico , Ataxia de Friedreich/genética , Regulación de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/uso terapéutico , Proteínas de Unión a Hierro/genética , Administración Oral , Adolescente , Adulto , Aminocaproatos/farmacología , Aminocaproatos/uso terapéutico , Área Bajo la Curva , Benzamidas/farmacología , Benzamidas/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular Transformada , Inmunoprecipitación de Cromatina , Estudios de Cohortes , Estudios Transversales , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Ataxia de Friedreich/patología , Regulación de la Expresión Génica/genética , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Células Madre Pluripotentes , Expansión de Repetición de Trinucleótido/genética , Adulto Joven , FrataxinaRESUMEN
IMPORTANCE: The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS). OBJECTIVE: To evaluate the effect of therapeutic choices on the mean annualized relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS: The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centers (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab. INTERVENTIONS: Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod. MAIN OUTCOMES AND MEASURES: The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year. RESULTS: No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery. CONCLUSIONS AND RELEVANCE: This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug. TRIAL REGISTRATION: Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.
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Anticuerpos Monoclonales Humanizados/farmacología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Humanos , Italia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Natalizumab , Estudios Prospectivos , Recurrencia , Resultado del TratamientoRESUMEN
IFN-ß inhibits the expansion of Th17 cells in active multiple sclerosis (AMS), and this might contribute to improve the clinical symptoms. The effectiveness of this inhibition, however, requires intact IFN-γ signaling in T cells. In this study, we report that both mRNA and cell surface expression of the signaling chain of the IFN-γ receptor (IFN-γR2) and its cognate tyrosine kinase JAK2 are enhanced in peripheral blood Th17 cells and clones from patients with AMS compared with those with inactive multiple sclerosis (IMS) or healthy subjects (HS). IFN-γ decreased the frequency of Th17 peripheral cells and proliferation of Th17 clones from AMS patients. Stimulation of PBMCs from HS in Th17-polarizing conditions resulted in the enhancement of JAK2 expression and accumulation of cell surface IFN-γR2. The role of JAK2 in the modulation of IFN-γR2 was demonstrated as its transduction prevented rapid internalization and degradation of IFN-γR2 in JAK2-deficient γ2A cells. In conclusion, these data identify JAK2 as a critical factor that stabilizes IFN-γR2 surface expression in Th17 cells from AMS patients, making them sensitive to IFN-γ. These data may have clinical implications for a better use of IFNs in multiple sclerosis and possibly other inflammatory diseases.
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Janus Quinasa 2/metabolismo , Esclerosis Múltiple/inmunología , Receptores de Interferón/metabolismo , Células Th17/metabolismo , Estudios de Casos y Controles , Proliferación Celular , Humanos , Interferones , Esclerosis Múltiple/patología , ARN Mensajero/análisis , Receptores de Interferón/análisis , Células Th17/inmunología , Receptor de Interferón gammaRESUMEN
It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS.
RESUMEN
Of 37 multiple sclerosis patients, 19 suboptimal responders were randomized to 375 (n=12) or 250µg (n=7) interferon (IFN)-ß-1b. mRNA levels of 23 cytokines, chemokines, and chemokine receptors were quantified by TaqMan low-density array (TLDA) real-time polymerase chain reaction. Better treatment responses or increased IFN-ß doses were associated with elevated IL-10 and TGF-ß and decreased CXCL10, IL-18, IFN-γ, and TNF-α transcript levels. Adjusting for dose, poor treatment responses resulted in a 4-fold increase in CXCL10 and IFN-γ expression (Mantel-Haenszel RR=3.74, p<0.0001). CXCL10 and IFN-γ mRNA levels were reliable indicators of treatment response. TLDA can be used to tailor IFN-ß-1b therapy.
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Citocinas/sangre , Citocinas/genética , Interferón beta/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , ARN Mensajero/sangre , Adulto , Citocinas/clasificación , Relación Dosis-Respuesta a Droga , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interferón beta/farmacología , Estudios Longitudinales , Masculino , Adulto JovenRESUMEN
OBJECTIVE: T-helper 1 (Th1) and Th17 lymphocytes are involved in experimental autoimmune encephalomyelitis, the model of multiple sclerosis (MS). We characterized the Th1/Th17 cell populations in peripheral blood (PB), their interferon (IFN) receptor expression sensitivity to IFN-beta in MS patients. METHODS: In 30 untreated patients with active MS (AMS) and 32 with inactive MS (IMS), and in 22 healthy subjects, we measured intracellular cytokine expression, interleukin-17-producing myelin basic protein-stimulated PB lymphocytes, surface IFN type I receptor chain1 (IFN-alphaR1) expression, IFN-beta-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation, and apoptosis of anti-CD3 monoclonal antibody-stimulated PB lymphocytes. RESULTS: Th17 cell percentage increased around sevenfold in AMS compared with IMS or healthy subjects, but there was no change in Th1 cells. Th17 cells in AMS were myelin basic protein specific. The longitudinal follow-up of 18 MS patients shifting between AMS and IMS showed that the percentage of Th17 but not Th1 cells always increased in AMS. IFN-alphaR1 expression, IFN-beta-induced STAT1 activation, and apoptosis were significantly greater in Th17 than Th1 cells. IFN-alphaR1 expression and IFN-beta-dependent STAT1 activation progressively increased in vitro with a highly significant positive correlation only in developing Th17 but not in Th0 or Th1 cells. INTERPRETATION: Evidence that an expansion of peripheral Th17 cells, a Th subset that can infiltrate brain parenchyma and damage cells, is associated with disease activity in MS. The greater IFN-alphaR1 level expressed by Th17 compared with Th1 cells might make them a selective target for IFN-beta therapy.
Asunto(s)
Factores Inmunológicos/farmacología , Interferón beta/farmacología , Interleucina-17/metabolismo , Esclerosis Múltiple/patología , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/metabolismo , Adulto , Anexina A5/metabolismo , Antígenos CD/metabolismo , Apoptosis/efectos de los fármacos , Diferenciación Celular/fisiología , Distribución de Chi-Cuadrado , Dactinomicina/análogos & derivados , Dactinomicina/metabolismo , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Citometría de Flujo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interferón beta/metabolismo , Leucocitos Mononucleares/patología , Masculino , Esclerosis Múltiple/sangre , Receptor de Interferón alfa y beta/metabolismo , Linfocitos T Colaboradores-Inductores/citología , Factores de TiempoRESUMEN
There is still uncertainty regarding risk factors for cancer occurrence in patients with myasthenia gravis (MG). The objective of this study is to determine the prevalence of extrathymic neoplasms in patients with MG and the factors associated with tumor occurrence. The archives of four tertiary MG centers were consulted and patients were interviewed on the main clinical features of the disease, the presence and type(s) of extrathymic neoplasms and other autoimmune disorders, and their symptomatic and immunosuppressant treatments (with detailed schedules). A retrospective cohort survey was undertaken comparing the demographic and clinical variables of patients with extrathymic neoplasms to those of the remaining MG population. 2,479 patients were traced and interviewed personally or through informants. The sample included 1,490 women and 989 men (mean age 54.7 years). Other autoimmune disorders were present in 216 cases (8.7%). Thymectomy was performed in 1,549 cases (62.5%), thymic hyperplasia and thymoma being the most common findings. Acetylcholinesterase-inhibitors were the most common treatment (93.5%), followed by steroids (64.3%), azathioprine (35.0%), plasma exchange (13.2%), immunoglobulins (7.5%), cyclosporine (5.3%), and cyclophosphamide (5.0%). 221 patients (8.9%) had one or more extrathymic tumors, 168 of which occurred after disease onset. Patients with and without extrathymic neoplasms were followed for 14.8 and 13.9 years, respectively. Variables shown by multivariate analysis to be associated with increased neoplastic risk included older age, thymoma and immunoglobulin use. Extrathymic tumors are a common finding in patients with MG and tend to be associated with age, thymoma, and immunoglobulin use.
Asunto(s)
Miastenia Gravis/epidemiología , Neoplasias/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Comorbilidad , Femenino , Humanos , Inmunoglobulinas/efectos adversos , Terapia de Inmunosupresión/efectos adversos , Terapia de Inmunosupresión/métodos , Lactante , Masculino , Persona de Mediana Edad , Miastenia Gravis/inmunología , Miastenia Gravis/fisiopatología , Neoplasias/inmunología , Neoplasias/fisiopatología , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Timoma/epidemiología , Neoplasias del Timo/epidemiología , Adulto JovenRESUMEN
We aimed to evaluate the safety and MRI efficacy of interferon beta-1b (IFNbeta-1b) 375 microg (subcutaneously [sc] every other day [eod]) in relapsing-remitting multiple sclerosis (RRMS) patients with a suboptimal response to IFNbeta-1b 250 microg, i.e., with MRI activity or relapses. The OPTimization of Interferon for MS (OPTIMS) study was a prospective multicenter randomized phase 2 trial comprising a 6-month run-in phase (to identify suboptimal responders) and a 6-month randomized phase of open-label clinical and blinded MRI follow-up. During run-in all patients were treated with IFNbeta-1b 250 microg sc eod; during the study phase suboptimal treatment responders were randomized either to IFNbeta-1b 250 or 375 microg sc eod. Primary outcome was the proportion of patients without MRI activity during study Months 9-12 according to the intention-to-treat principle. 216 RRMS patients entered the study: 83 suboptimal responders were identified and randomized, 7 refused to continue treatment, 76 were included in the analysis. More patients treated with 375 microg had no MRI activity at Months 9-12 (30/36 vs.16/40; relative risk, 0.28; 95 % confidence interval, 0.08-0.47; p = 0.0001). Sensitivity analysis ("worst case scenario") confirmed the results. No new or unexpected adverse events were observed, but there was a trend towards more withdrawals in the 375 microg group. Increasing the dose of IFNbeta-1b from 250 microg to 375 microg is a successful strategy for reducing subclinical signs of disease activity in RRMS patients. Further studies are needed to show whether this dose may also improve clinical efficacy.
Asunto(s)
Interferón beta/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/efectos adversos , Adyuvantes Inmunológicos/uso terapéutico , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Estudios de Seguimiento , Humanos , Inyecciones Subcutáneas , Interferon beta-1b , Interferón beta/administración & dosificación , Interferón beta/efectos adversos , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Estudios Prospectivos , Método Simple Ciego , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Today many different drugs are available for treatment of multiple sclerosis (MS). Interferons, glatiramer acetate, mitoxantrone, and natalizumab have been approved by the regulatory authorities of many countries for the treatment of MS. Evidence based medicine (EBM) principles allow physicians to better address the correct treatment for patients. This article aimed to review all the clinical trials on immune-modulating and immunosuppressive drugs on the basis of the EBM principles. Based on the evidence to date interferon beta represents the best therapeutic option, particularly if given at high doses and with multiple injections per week. Due to its lower efficacy, glatiramer acetate should be used as a second choice in case of intolerable side effects or toxicity of interferon beta. Great efficacy has been demonstrated for mitoxantrone and natalizumab. These drugs should be, however, used with particular attention for their potential toxic effects.