RESUMEN
BACKGROUND: An observational study has suggested that relapsing-remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients. OBJECTIVE: To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS. METHODS: The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24-55) years, disease duration 9 (4-34) years, Expanded Disability Status Scale score 2.5 (1-5.0), and number of relapses within the last two years 3 (2-5). Four patients received no disease modifying therapy, while six patients received IFN-ß. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes. RESULTS: Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change. CONCLUSIONS: In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect.
Asunto(s)
Esclerosis Múltiple Recurrente-Remitente/terapia , Terapia con Helmintos/efectos adversos , Terapia con Helmintos/métodos , Trichuris/inmunología , Adulto , Animales , Progresión de la Enfermedad , Eosinofilia/parasitología , Femenino , Tracto Gastrointestinal/parasitología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/inmunología , Recurrencia , Adulto JovenRESUMEN
BACKGROUND: Cladribine is a synthetic deoxyadenosine analogue in development as an oral multiple sclerosis (MS) therapy. OBJECTIVE: To report in detail the safety findings from the 96-week, phase III, double-blind CLARITY study, which evaluated treatment with cladribine tablets in relapsing-remitting MS. METHODS: A total of 1,326 patients were randomized 1:1:1 to two short-course regimens of cladribine tablets (3.5 or 5.25 mg/kg cumulative dose over 96 weeks) or placebo. Safety assessments included monitoring for adverse events (AEs), routine physical and neurologic examinations and frequent laboratory parameter assessments. RESULTS: Of the randomized patients, 88.6% completed treatment with cladribine tablets versus 86.3% with placebo. Lymphopenia was the most commonly reported AE in patients treated with cladribine tablets and was anticipated based on the mechanism of action. The incidence of infections was 48.3% with cladribine tablets and 42.5% with placebo, with 99.1% and 99.0% rated mild-to-moderate by investigators. Herpes zoster infections developed in 20 (2.3%) cladribine-treated patients; all cases were dermatomal. There were no herpes zoster infections in the placebo group. Nine (1.0%) patients experienced events related to uterine leiomyomas in the cladribine tablets groups versus one (0.2%) with placebo. Three isolated cases of malignancy were reported in cladribine-treated patients during the study; a fourth was reported during post-study surveillance. A pre-malignant cervical carcinoma in situ was also reported. The incidence of malignancies during the study did not exceed the expected rate in a population standardized for country, gender and age. CONCLUSION: The safety and tolerability profile observed in the CLARITY study together with the reported efficacy support the potential for cladribine tablets as an MS therapy.
Asunto(s)
Cladribina/efectos adversos , Inmunosupresores/efectos adversos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Administración Oral , Adulto , Cladribina/administración & dosificación , Evaluación de la Discapacidad , Método Doble Ciego , Europa (Continente) , Herpes Zóster/inducido químicamente , Humanos , Inmunosupresores/administración & dosificación , Linfopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Neoplasias/inducido químicamente , Examen Neurológico , Examen Físico , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: In patients with multiple sclerosis (MS), neutralizing antibodies (NAbs) appearing during treatment with interferon (IFN) beta reduce or in high concentrations abolish bioactivity and therapeutic efficacy. In vivo MxA induction by IFNbeta is used as a marker of biologic response to IFNbeta. It has been argued that despite absence of MxA induction measured by PCR, some bioactivity might be preserved. In a cohort study, we measured gene expression by gene chip analysis in NAb-negative and NAb-positive patients to test that hypothesis. METHODS: The effect of IFNbeta was studied by comparing samples collected before and 9-12 hours after an injection. The cohort consisted of 12 NAb-positive patients without MxA response and 12 NAb-negative patients with preserved response. MxA in vivo response was determined in whole blood using real-time PCR. Screening for IFNbeta-regulated genes in mononuclear cells was done using gene chips. False discovery rate (FDR) analysis was used as statistical tool. RESULTS: Of 8,793 genes, 5,593 were detectable in at least one patient in both groups. Of these, calculation of FDR revealed 1,077 IFNbeta-regulated genes at a 5% level in NAb-negative patients. The corresponding number of IFNbeta-regulated genes in NAb-positive patients was zero. CONCLUSION: In neutralizing antibody (NAb)-positive patients without an MxA response, we were not able to detect differential expression of any of the 1077 interferon (IFN) beta-regulated genes identified in NAb-negative patients. Lack of MxA in vivo response in patients with multiple sclerosis with NAbs is a reliable marker of a completely blocked biologic response to IFNbeta, with no indication of residual bioactivity.
Asunto(s)
Anticuerpos/sangre , Proteínas de Unión al GTP/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Interferón beta/farmacología , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Biomarcadores/análisis , Biomarcadores/metabolismo , Estudios de Cohortes , Femenino , Proteínas de Unión al GTP/análisis , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/inmunología , Humanos , Interferón beta/inmunología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Proteínas de Resistencia a Mixovirus , Análisis de Secuencia por Matrices de Oligonucleótidos , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Several studies have reported a reduction of relapses after the long-term administration of IV immunoglobulin (IVIG) to patients with relapsing-remitting multiple sclerosis (RRMS), but they were mostly small and differed in terms of predefined outcome variables and treatment regimen. We therefore set out to test two different doses of a new formulation of immunoglobulin termed IGIV-C 10% for suppression of both clinical and MRI disease activity as well as safety. METHODS: One hundred twenty-seven patients with RRMS participated in this multicenter, randomized, double-blind, placebo-controlled trial. Forty-four and 42 patients received treatment with 0.2 and 0.4 g/kg of IGIV-C 10%, and 41 patients received an equal volume of placebo (0.1% albumin) every 4 weeks for 48 weeks. The primary endpoint was the proportion of relapse-free patients. The main secondary endpoint was lesion activity assessed by 6-weekly MRI. RESULTS: Baseline variables were similar in IVIG- and placebo-treated groups. After 1 year, the proportion of relapse-free patients did not differ statistically according to treatment (IVIG 0.2 g/kg: 57%; IVIG 0.4 g/kg: 60%; placebo: 68%), and there was no difference regarding the cumulative number of unique newly active MRI lesions (median numbers: IVIG 0.2 g/kg: 8.0; IVIG 0.4 g/kg: 5.0; placebo: 7.2) after 48 weeks. There were no significant between-group differences in the rates of adverse events. CONCLUSION: Although IV immunoglobulin (IVIG) treatment was well tolerated, this study did not substantiate a beneficial effect of IVIG in doses ranging from 0.2 to 0.4 g/kg. This result seriously questions the utility of IVIG for the treatment of relapsing-remitting multiple sclerosis.
Asunto(s)
Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoterapia/métodos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Adolescente , Adulto , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Evaluación de la Discapacidad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Infusiones Intravenosas/efectos adversos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Placebos , Prevención Secundaria , Resultado del TratamientoRESUMEN
We measured neutralizing antibodies (NABs) and the in vivo biologic response to interferon-beta on neopterin and beta(2)-microglobulin blood levels. All NAB-negative patients had an in vivo biologic response (full or partial), whereas all high-level positive patients had no response. High-level NAB patients had more MRI activity than NAB-negative patients (p = 0.031). Patients with a full response had less MRI activity than patients without biologic response (p = 0.032).
Asunto(s)
Anticuerpos/sangre , Resistencia a Medicamentos/inmunología , Interferón beta/antagonistas & inhibidores , Interferón beta/inmunología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Adulto , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Neopterin/sangre , Neopterin/inmunología , Resultado del TratamientoRESUMEN
Biomarkers that allow the identification of patients with multiple sclerosis (MS) with an insufficient response to immunomodulatory treatment would be desirable, as currently available treatments are only incompletely efficacious. Previous studies have shown that the expression of CD25, CD26 and CCR5 on T cells is altered in patients with active MS. We studied the expression of these molecules by flow cytometry in patients followed for six months during immunomodulatory treatment. In interferon (IFN)-beta-treated patients, we found that the hazard ratio for developing an attack was 28 in patients with CD26 + CD4 + T cell counts above median, and this risk was independent of the risk conferred by neutralizing anti-IFN-beta antibodies. CD26 + CD4 + T cell counts may identify patients with MS at increased risk of attack during treatment with IFN-beta.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Linfocitos T CD4-Positivos/citología , Interferón beta/administración & dosificación , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Adulto , Biomarcadores , Antígenos CD4/metabolismo , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Femenino , Citometría de Flujo , Humanos , Interferón beta-1a , Interferon beta-1b , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/epidemiología , Modelos de Riesgos Proporcionales , Receptores CCR5/metabolismo , Receptores de Interleucina-2/metabolismo , Factores de RiesgoRESUMEN
BACKGROUND: Neutralizing antibodies (NABs) occur frequently in patients receiving interferon (IFN)-beta for multiple sclerosis (MS), but it is unclear whether occurrence of NABs is predictive for the persistence of NABs during continued IFN-beta therapy. METHODS: The authors used an antiviral neutralization bioassay to measure NABs blindly from 6 months up to 78 months in patients with MS who were followed for at least 24 months during treatment with IFN-beta. Patients were classified into three groups: 1) persistently NAB-negative patients, defined as patients without any positive samples at any time; 2) definitely NAB-positive patients, defined as patients who had at least two consecutive positive samples; and 3) patients with fluctuating NAB-positive and NAB-negative samples. RESULTS: A total of 455 patients were included in the study. Overall, 52.3% of the patients were persistently NAB-negative, 40.9% became definitely NAB-positive, and the remaining 6.8% were fluctuating. More patients treated with IFN-beta-1a (Avonex) remained NAB-negative (p < 0.0001), whereas there was no difference between IFN-beta-1b (Betaferon) and IFN-beta-1a (Rebif). Patients who have remained NAB-negative during the first 24 months of therapy rarely developed NABs. On the contrary, the majority of patients, who had been NAB-positive from 12 through 30 months after start of therapy, remained NAB-positive. CONCLUSIONS: NABs should be measured in all patients treated with IFN-beta. If patients have been persistently NAB-negative for 24 months, measurements can be discontinued. Patients who have been NAB-positive for a period of 18 months or more usually remain NAB-positive for a long time.
Asunto(s)
Autoanticuerpos/inmunología , Interferón beta/efectos adversos , Interferón beta/inmunología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Adyuvantes Inmunológicos/efectos adversos , Adolescente , Adulto , Anciano , Autoanticuerpos/sangre , Bioensayo , Línea Celular , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Inmunoensayo/normas , Interferón beta-1a , Interferon beta-1b , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/epidemiología , Sistema de Registros/estadística & datos numéricosRESUMEN
BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.
Asunto(s)
Evaluación de la Discapacidad , Esclerosis Múltiple/diagnóstico , Índice de Severidad de la Enfermedad , Adulto , Edad de Inicio , Estudios de Cohortes , Estudios Transversales , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Francia/epidemiología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Modelos Neurológicos , Modelos Estadísticos , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/fisiopatología , Valor Predictivo de las Pruebas , Pronóstico , Recurrencia , Reproducibilidad de los ResultadosRESUMEN
The Multiple Sclerosis Impairment Scale (MSIS) is a measure of accumulated deficits assessed by means of a standard neurological examination. We compared the responsiveness of the MSIS with that of the Expanded Disability Status Scale (EDSS). We reviewed 4300 records collected systematically from 1995 to 2003 and identified 534 patients who had clinically definite multiple sclerosis and had had at least two clinical assessments with a time interval of 2-5 years. The rate of deterioration was significantly higher on the MSIS than on the EDSS. The annualized change in EDSS exhibited a maximum at baseline EDSS 4 and a subsequent rapid decline at higher baseline EDSS, while the annualized change in MSIS was fairly stable over a wide middle range of baseline MSIS. The variance of the annualized change in EDSS fluctuated markedly between the baseline EDSS categories, being highest at baseline EDSS 2, while the variance of the annualized change in MSIS was stable. The study indicates that the responsiveness of the MSIS is better than that of the EDSS in terms of both magnitude and stability over the range of measurement
Asunto(s)
Evaluación de la Discapacidad , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/fisiopatología , Índice de Severidad de la Enfermedad , Estudios de Evaluación como Asunto , Humanos , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: To investigate if IV immunoglobulins (IVIg) in combination with methylprednisolone make recovery from a relapse faster and more complete than methylprednisolone alone. Design/ METHODS: The authors studied 76 patients with multiple sclerosis (MS) who had an acute relapse with involvement of visual function, upper limb motor function, or gait, and with onset of symptoms between 24 hours and 14 days before. Patients were treated with either IVIg 1 g/kg or placebo (0.1% human albumin), given 24 hours before treatment with IV methylprednisolone 1 g on 3 consecutive days. RESULTS: Both groups improved, but the authors observed no significant difference between IVIg and placebo patients regarding the primary endpoint, the mean change in the Z-score of the individually chosen targeted neurologic deficit (the most affected system) from baseline to 12 weeks (p = 0.89). A slightly better, but not significant remission was seen in the IVIg group in global scores, i.e., Expanded Disability Status Scale (p = 0.23) and Multiple Sclerosis Impairment Scale (p = 0.24), and in time to next relapse (p = 0.22). CONCLUSIONS: The results do not justify routine application of IV immunoglobulins as add-on therapy to IV methylprednisolone in the treatment of acute multiple sclerosis attacks.