Documento del Grupo de Consenso de la Sociedad Española de Neurología sobre el uso de medicamentos en esclerosis múltiple / Consensus Statement on medication use in multiple sclerosis by the Spanish Society of Neurology's study group for demyelinating diseases

La terapia de la esclerosis múltiple está en rápida evolución. En un plazo próximo, se prevé la incorporación de nuevos fármacos que pueden modificar las pautas actuales de tratamiento. Mientras tanto, el Grupo de Enfermedades Desmielinizantes de la Sociedad Española de Neurología encargado del consenso sobre la utilización de medicamentos para la EM, ha considerado necesaria una puesta al día de las indicaciones actuales y de los principios de tratamiento de esta enfermedad (AU)

Treatments for multiple sclerosis therapy are rapidly evolving. It is believed that new drugs will be approved in the near future, thereby changing current indications for treatment. In this context, the Spanish Society of Neurology's study group on demyelinating diseases, which evaluates medication use in MS, has decided to draw up a consensus statement on the current indications and guidelines for multiple sclerosis treatment (AU)

Consensus Statement on medication use in multiple sclerosis by the Spanish Society of Neurology's study group for demyelinating diseases.

Treatments for multiple sclerosis therapy are rapidly evolving. It is believed that new drugs will be approved in the near future, thereby changing current indications for treatment. In this context, the Spanish Society of Neurology's study group on demyelinating diseases, which evaluates medication use in MS, has decided to draw up a consensus statement on the current indications and guidelines for multiple sclerosis treatment.

Consenso español sobre la utilización de natalizumab (Tysabri ®) - 2011 / Spanish consensus on the use of natalizumab (Tysabri ®) - 2011

Introducción: Natalizumab es un tratamiento que ha demostrado ser muy eficaz en los pacientes con esclerosis múltiple recurrente-remitente (EMRR) en cuanto a la reducción del número de brotes y al enlentecimiento de la progresión de la enfermedad. Sin embargo, el fármaco se ha asociado con el riesgo de desarrollar leucoencefalopatía multifocal progresiva (LMP). El objetivo de este artículo es proporcionar una posición consensuada sobre la valoración y estratificación de este riesgo y mejorar el manejo de los pacientes tratados con natalizumab.Desarrollo: En una reunión inicial de expertos en EM (los autores de este consenso), se perfilaron los temas de interés que fueron asignados a los asistentes para su desarrollo ulterior. Los temas incluían cómo establecer el beneficio y el riesgo en general, la estratificación para el riesgo de LMP, cómo informar a los pacientes de los beneficios y riesgos, cómo realizar el seguimiento del paciente en tratamiento y tras la suspensión del fármaco. Durante la fase de redacción, se revisó toda la información disponible, publicada o presentada en reuniones internacionales. Después de varios ciclos de revisión y de reuniones, se produjo el borrador final.Conclusiones: A pesar de ser un fármaco muy eficaz, la decisión de prescribir natalizumab debe ser tomada con cuidado por los posibles efectos adversos y en particular, el riesgo de LMP. El neurólogo debe explicar al paciente en detalle los riesgos y beneficios del tratamiento, en términos comprensibles para el paciente. Antes de empezar el tratamiento, deben estar disponibles las pruebas de laboratorio y las imágenes de resonancia magnética (RM) que permitan comparaciones en el futuro, en caso de sospecha de LMP. El riesgo de LMP debe estratificarse en alto, medio y bajo de acuerdo con la presencia o ausencia de anticuerpos frente al virus JC, antecedente de tratamiento inmunosupresor y duración del tratamiento (AU)

Introduction: Natalizumab is very effective at reducing relapses and delaying disease progression in patients with relapsing-remitting multiple sclerosis (RRMS). However, treatment has also been associated with a risk of progressive multifocal leukoencephalopathy (PML). The aim of this article is to provide a consensus view on the assessment and stratification of these risks, and to improve the management of natalizumab-treated patients.Development: At an initial meeting of experts on multiple sclerosis (the authors of this consensus), the relevant topics of the consensus were determined and assigned for further elaboration. Topics included how to establish benefit and risk in general, stratification for risk of PML, informing patients of benefits/risks, and how to monitor patients during treatment and after discontinuing treatment. During the drafting phase, all available information published or presented at international meetings was reviewed. After a series of review sessions and meetings, the final draft was produced. Conclusions: Although natalizumab is a very effective drug, its use needs to be considered carefully in view of possible adverse effects and the risk of PML in particular. The neurologist should carefully explain the risks and benefits of treatment in terms the patient can best understand. Before starting treatment, baseline laboratory tests and magnetic resonance imaging (MRI) should be available for future comparisons in the event of suspected PML. The risk of PML should be stratified into high, medium and low risk groups according to presence or absence of anti-JC virus antibodies, prior immunosuppressive therapy, and treatment duration. The follow-up, and frequency of MRI scans in particular, should depend on the risk group to which patient belongs. As our understanding of the risk factors for PML develops, it should be possible to offer patients increasingly individualised therapy (AU)

Spanish consensus on the use of natalizumab (Tysabri(®))--2011.

INTRODUCTION: Natalizumab is very effective at reducing relapses and delaying disease progression in patients with relapsing-remitting multiple sclerosis (RRMS). However, treatment has also been associated with a risk of progressive multifocal leukoencephalopathy (PML). The aim of this article is to provide a consensus view on the assessment and stratification of these risks, and to improve the management of natalizumab-treated patients. DEVELOPMENT: At an initial meeting of experts on multiple sclerosis (the authors of this consensus), the relevant topics of the consensus were determined and assigned for further elaboration. Topics included how to establish benefit and risk in general, stratification for risk of PML, informing patients of benefits/risks, and how to monitor patients during treatment and after discontinuing treatment. During the drafting phase, all available information published or presented at international meetings was reviewed. After a series of review sessions and meetings, the final draft was produced. CONCLUSIONS: Although natalizumab is a very effective drug, its use needs to be considered carefully in view of possible adverse effects and the risk of PML in particular. The neurologist should carefully explain the risks and benefits of treatment in terms the patient can best understand. Before starting treatment, baseline laboratory tests and magnetic resonance imaging (MRI) should be available for future comparisons in the event of suspected PML. The risk of PML should be stratified into high, medium and low risk groups according to presence or absence of anti-JC virus antibodies, prior immunosuppressive therapy, and treatment duration. The follow-up, and frequency of MRI scans in particular, should depend on the risk group to which patient belongs. As our understanding of the risk factors for PML develops, it should be possible to offer patients increasingly individualised therapy. This is a consensus that establishes general recommendations, but neurologists must use their clinical expertise to monitor patients individually.

El diagnóstico precoz de esclerosis múltiple en urgencias: una necesidad con importantes implicaciones terapéuticas / Early diagnosis of multiple sclerosis in the emergency department: necessary for its important therapeutic implications

Numerosos estudios internacionales han concluido que los pacientes que inician el tratamiento para la esclerosis múltiple (EM) en las fases tempranas de la enfermedad experimentan una notable reducción en el número e intensidad de los brotes y, como consecuencia, tienen mayor probabilidad de permanecer durante más tiempo activos e independientes. Así pues, podemos afirmar que la detección precoz de la EM puede resultar el método más efectivo para combatir esta enfermedad degenerativa, que actualmente afecta en España a unas 40.000 personas. La primera fuente de diagnóstico de estos pacientes es el servicio de urgencias de los hospitales y representa casi un tercio de los diagnosticados de EM. En este contexto, los urgenciólogos cobran especial relevancia y deben ser capaces de sospechar que un paciente sin clínica previa neurológica puede presentar un primer brote de EM. En esta revisión se muestran las claves para poder detectar a estos enfermos lo antes posible, para evitar así demoras que puedan causar una pérdida de los efectos beneficiosos de los tratamientos actualmente disponibles (AU)

Numerous international studies have shown that patients who start treatment for multiple sclerosis (MS) early havemarkedly fewer outbreaks and the episodes are less intense. Consequently, they are likely to stay active and independentlonger. We might say that early detection of MS is the most effective way to fight this degenerative disease, which presently affects some 40 000 persons in Spain. Hospital emergency departments are often the first place MS is recognized, and nearly a third of all MS diagnoses are made there. Emergency physicians therefore play an importantrole and should be able to suspect the debut of this disease in patients without a prior history of neurological symptoms. This review discusses the keys for identifying MS as early as possible to avoid delays that may diminish the effectiveness of currently available treatments (AU)

Association of HLA-DRB1*15 allele and CSF oligoclonal bands in a Spanish multiple sclerosis cohort.

BACKGROUND AND OBJECTIVE: The HLA-DRB1*15 allele is consistently associated with multiple sclerosis (MS) susceptibility in most studied populations. This study investigated the association between HLA-DRB1 alleles and the presence of oligoclonal immunoglobulin G bands (OCB) in the cerebrospinal fluid (CSF) in a Spanish population with MS. METHODS: The HLA-DRB1 typing was performed in 268 patients with sporadic MS and the detection of OCB in CSF. HLA-DRB1 allelic frequencies were compared between OCB-positive and OCB-negative patients, and both groups were also compared with 1088 unrelated healthy controls. Moreover, we correlated the various HLA-DRB1 genotypes, considering all the combinations of both parental alleles found with the presence or absence of OCB. RESULTS: We found 206 OCB-positive and 62 OCB-negative patients. The HLA-DRB1*15 allele in OCB-positive patients had a higher frequency when compared with OCB-negative patients (39.3% in OCB-positive vs. 16.1% in OCB-negative, OR = 1.38 95% CI = 1.18-1.61, P < 0.001). The other alleles did not show differences. When we compared with controls, the HLA-DRB1*15 allele was associated with the disease only in the OCB-positive patients group. None of the 55 genotypes found showed any association with the presence or absence of OCB. CONCLUSIONS: HLA-DRB1*15 allele is associated with OCB-positive patients with MS when studying a Spanish MS population.

Multiple sclerosis and cognitive decline: is ApoE-4 a surrogate marker?

BACKGROUND - The role of the apolipoprotein E (ApoE) polymorphism has been well demonstrated in neurodegenerative disorders such as Alzheimer. However, its role in multiple sclerosis (MS) remains unclear. AIMS - The aims of our study were as follows: (i) to assess whether ApoE-4 might be a surrogate marker of cognitive decline in MS; (ii) to confirm the presence of cognitive impairment in mildly disabled patients treated with interferon-beta; and (iii) to analyse the correlation between cognitive disturbances and clinical variables. MATERIAL AND METHODS - Fifty relapsing-remitting MS patients underwent a battery of neuropsychological tests and were genotyped for ApoE. Their scores were compared with those of 35 controls. RESULTS - No association was found between ApoE-4 and cognitive impairment. Significant differences in most domains were observed between MS and the control group. Cognitive decline was not related to disability progression. CONCLUSION - No association between cognitive impairment and ApoE-4 or clinical markers was detected in our MS patients.

HLA-DRB1: genetic susceptibility and disability progression in a Spanish multiple sclerosis population.

BACKGROUND AND OBJECTIVE: The association of HLA-DRB1*15 with susceptibility to multiple sclerosis (MS) has been consistently reported although its effect on the clinical phenotype is still controversial. The objectives of this study are to investigate the influence of the HLA-DRB1 alleles on the genetic susceptibility to MS and to study their impact on disability progression in a Spanish population. METHODS: HLA-DRB1 typing was performed by PCR-SSP in 380 patients with sporadic MS and 1088 unrelated healthy controls. Allelic frequencies were compared between groups. We studied the correlation between the different alleles and the progression of MS. RESULTS: The HLA-DRB1*15 allele in patients with MS had a statistically significant higher frequency when compared with controls (18.9% in patients vs. 10.1% in controls, Odds ratio (OR)=2.07, 95% CI=1.64-2.60, P<0.001). In the univariate analysis, the DRB1*01 and DRB1*04 alleles were associated with a worse prognosis when considering the time to reach an EDSS of 6, whereas the DRB1*03 was correlated with a better outcome. In the multivariate analysis, the alleles*01 and *04 were demonstrated to be independent factors to have a worse prognosis. CONCLUSIONS: HLA-DRB1*15 is associated with MS when comparing patients with unrelated healthy controls in a Spanish population. The HLA-DRB1*01 and HLA-DRB1*04 alleles are related to a worse prognosis when considering the time taken to reach severe disability.

Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study.

BACKGROUND: Laquinimod, an oral novel immunomodulator, was shown to reduce MRI-measured disease activity in relapsing-remitting MS (RRMS) patients. OBJECTIVES: To determine whether the safety and efficacy profile of laquinimod, as shown in a placebo-controlled 36-week trial (LAQ/5062), is sustained and reproducible. METHODS: Two hundred and fifty seven patients entered the extension phase in which MRI was performed at the beginning and at the end of the active extension phase. Clinical assessments were performed at weeks 4, 12 and every 12 weeks thereafter. RESULTS: Two hundred and thirty nine (93%) patients completed the extension phase and 222 (86.3%) had a final scan available. Gadolinium-enhanced (GdE) T1 lesions were significantly reduced for patients switching from placebo to 0.3/ 0.6 mg doses (52%, p = 0.0006). In patients initially randomized to 0.6 mg in LAQ/5062 the reduction of MRI activity observed in the placebo-controlled phase was maintained in the extension. The proportion of GdE-free patients for those who switched from placebo increased from a baseline of 31% to 47% at the end of the extension phase (p = 0.01). The most prominent safety signal was elevations of liver enzymes, reversible in all cases. CONCLUSIONS: The good efficacy and the excellent safety and tolerability profiles of laquinimod 0.6 mg/day are confirmed in this extension study.

[Spanish Neurology Society consensus document on the use of drugs in multiple sclerosis: escalating therapy]. / Documento de consenso de la Sociedad Española de Neurología sobre el uso de medicamentos en esclerosis múltiple: escalado terapéutico.

INTRODUCTION: Treatment of multiple sclerosis has advanced considerably in the last few years, at the same time as its complexity has increased. The purpose of this consensus document is to provide specific recommendations and rules on the strategy to follow in the treatment of multiple sclerosis in order to modify its course. MATERIAL AND METHODS: Experts on the treatment and clinical research on multiple sclerosis proposed by the Demyelinating Diseases Group of the Spanish Neurology Society (SEN) prepared an initial document with recommendations for the treatment of this disease. The final version of this document was submitted to members of the Demyelinating Diseases Group of the SEN, who were able to make modifications and suggest changes to the final manuscript. RESULTS AND CONCLUSIONS: A review has been made of the evidence levels and indications for the treatment of the different clinical forms of multiple sclerosis, and recommendations made for the use of drugs. As well as authorised drugs, a review has also been made of other occasionally used products, as well as combined therapy, therapeutic response criteria, levels of treatment changes, and finally a proposal is made on therapeutic escalation.

Documento de consenso de la Sociedad Española de Neurología sobre el uso de medicamentos en esclerosis múltiple: escalado terapéutico / Spanish Neurology Society consensus document on the use of drugs in multiple sclerosis: escalating therapy

Introducción: La terapéutica de la esclerosis múltiple ha avanzado notablemente en los últimos an ̃os al tiempo que ha aumentado su complejidad. El propósito de este documento de consenso es presentar recomendaciones y pautas concretas sobre la estrategia a seguir en el tratamiento para modificar el curso de la esclerosis múltiple. Material y métodos: expertos en el tratamiento y en investigación clínica en esclerosis múltiple propuestos por el grupo de enfermedades desmielinizantes de la Sociedad Española de Neurología (SEN) elaboraron un documento inicial con recomendaciones para el tratamiento de esta enfermedad. La versión final de este documento fue remitida a los miembros del grupo de enfermedades desmielinizantes de la SEN, quienes pudieron realizar modificaciones y sugerir cambios al manuscrito final. Tras considerar estas enmiendas, el comité de expertos validó el documento final. Resultados y conclusiones: se revisan los niveles de evidencia y las indicaciones para el tratamiento de las diferentes formas clínicas de esclerosis múltiple y se hacen recomendaciones de uso de los medicamentos. Además de los fármacos autorizados, se revisan también otros productos ocasionalmente empleados, así como la terapia combinada, los criterios de respuesta terapéutica, los niveles de cambio de tratamiento y finalmente se hace una propuesta de escalado terapéutico (AU)

Introduction: Treatment of multiple sclerosis has advanced considerably in the last few years, at the same time as its complexity has increased. The purpose of this consensus document is to provide specific recommendations and rules on the strategy to follow in the treatment of multiple sclerosis in order to modify its course. Material and methods: Experts on the treatment and clinical research on multiple sclerosis proposed by the Demyelinating Diseases Group of the Spanish Neurology Society (SEN) prepared an initial document with recommendations for the treatment of this disease. The final version of this document was submitted to members of the Demyelinating Diseases Group of the SEN, who were able to make modifications and suggest changes to the final manuscript. Results and conclusions: A review has been made of the evidence levels and indications for the treatment of the different clinical forms of multiple sclerosis, and recommendations made for the use of drugs. As well as authorised drugs, a review has also been made of other occasionally used products, as well as combined therapy, therapeutic response criteria, levels of treatment changes, and finally a proposal is made on therapeutic escalation (AU)

Anticipation of age at onset in multiple sclerosis: methodologic pitfalls.

BACKGROUND/AIM: There are several reports that claim anticipation in complex or polygenic diseases such as multiple sclerosis (MS), Crohn disease or schizophrenia. The aim of the present study was to assess age at onset of MS during the last 60 years in the region of Costa de Ponent (Barcelona, Spain) showing how apparent changes in age at onset between generations can be an artefact of analysis based on cohorts that have not been followed enough time. METHODS: The study comprised 1100 patients diagnosed of MS. The method used to correct for follow-up time bias involves constructing comparison cohorts that had been observed for the same amount of time. To ensure equal follow-up times, we restricted our analysis to patients whose onset was by 37 years of age (percentile 75) and were at least 37 years old. We analysed differences in age at onset using log-rank test to compare survival curves estimated by Kaplan-Meier method. RESULTS: Age at onset decreases progressively from older to younger generations. However, when adjustment to equal follow-up time was done, anticipation in age at onset was not found. CONCLUSION: Anticipation of age at onset is undetectable when adjusted for follow-up time.

Characteristics of multiple sclerosis at onset and delay of diagnosis and treatment in Spain (the Novo Study).

Multiple sclerosis (MS) is a disease supposedly of autoimmune origin, with reactivity directed against myelin antigens. From the neuropathological point of view, MS produces inflammation, demyelination and axonal and neuronal degeneration. Inflammatory phenomena are predominant in the initial phase of the disease, followed later by neurodegenerative processes. Over the last decade, early treatment, during the most inflammatory phase of the disease, has been considered the best strategy to treat MS. Accordingly, we decided to determine the periods of delay between the first symptoms and the time to the first medical visit, the time to referral to a specialised MS unit, the delay in undertaking clinical and paraclinical tests, the diagnostic criteria used and the overall delay in diagnosis and treatment. The median time from onset of first symptoms to the first visit to a physician was 19.2 months, which represented the greatest delay. The median time between this initial medical consultation and the confirmation of the diagnosis by a specialised MS unit was 5.7 months, and the overall time from symptom onset to diagnosis was 24.9 months (2.08 years). The median time between onset of the first symptoms and the decision to give the first treatment was 2 years. The most important delay was that from symptom onset to the first medical visit, with the other delays being less. Thus, it is during this initial period that greater effort is required in order to reduce the time to diagnosis, by increasing awareness of the problem of MS among the general population and primary care physicians.

Anticipation of age at onset in familial multiple sclerosis.

BACKGROUND AND OBJECTIVE: Anticipation of age at onset in the younger generations is a widely known characteristic of many diseases with genetic inheritance. This study was performed to assess whether there is anticipation of age at onset in younger generations of familial multiple sclerosis (MS) in a Spanish population and to compare clinical characteristics of familial and sporadic MS. METHODS: We studied a cohort of 1110 patients diagnosed with MS and followed-up in our MS Unit. Patients were considered as familial MS if they had in their family at least one relative of first or second degree diagnosed with MS. Otherwise, patients were considered to have sporadic MS. We compared the age at onset between relatives from different generations, and we also compared the age at onset of familial and sporadic MS. RESULTS: A lower age at onset in the younger generations was found (median 22 years vs. 30 years, P < 0.001) and a significant lower age at onset of the disease in familial MS comparing to sporadic MS (median 25 years vs. 29 years, P = 0.042). CONCLUSIONS: There is an anticipation of the age at onset of MS in the younger generations of patients with familial MS. There is also a lower age at onset in familial versus sporadic MS.

Resultado clínico a 6 años del trasplante autólogo de progenitores hematopoyéticos en la esclerosis múltiple / Clinical outcome 6 years after autologous hematopoietic stem cell transplantation in multiple sclerosis

Introducción. El trasplante autólogo de progenitoreshematopoyéticos (TAPH) es considerado un tratamiento experimentalpara formas de esclerosis múltiple (EM) de evoluciónagresiva. Describimos la evolución clínica de 14 pacientes incluidosen un protocolo de TAPH tras un seguimiento medianode 6 años.Métodos. Catorce pacientes con EM (cinco remitenterecidivantey nueve secundariamente progresiva) con unamediana de brotes el año previo de 3 (1-7), Expanded DisabilityStatus Scale (EDSS) de 6 (4,5-6,5) y decil de la MultipleSclerosis Severity Store (MSSS) 9 (7-10) fueron incluidos. Elprocedimiento consistió en carmustina, ciclofosfamida, globulinaantitimocítica y depleción de células T mediante selecciónpositiva de progenitores CD34+.Resultados. La supervivencia libre de progresión a los4,5 años fue del 71%. La probabilidad actuarial de estar librede progresión a los 6 años del 62,5% y la supervivencialibre de actividad de la enfermedad del 7,1%. La EDSS medianaera de 6 (4-8,5) y el MSSS 8 (5-10). Sólo dos pacientespresentaron lesiones captantes de gadolinio en la RM. No seobservaron complicaciones tóxicas a largo plazo.Conclusión. El TAPH no puede considerarse un tratamientocurativo, pero puede inducir una estabilización prolongadao cambiar el curso agresivo de la enfermedad (AU)

Introduction. Autologous hematopoietic stem celltransplantation (AHSCT) remains as an experimental treatmentfor severe forms of multiple sclerosis (MS). We describethe clinical outcome of 14 patients included in a protocolof AHSCT after a median follow-up period of 6 years.Methods. 14 patients (5 relapsing-remitting and 9secondary progressive) with a median number of relapsesin the year before of 3 (1-7), Expanded DisabilityStatus Scale (EDSS) of 6 (4.5-6.5) and decile of the MultipleSclerosis Severity Store (MSSS) 9 (7-10) were included.The procedure included carmustine, cyclophosphamide,antithymocyte globulin and T-cell depletion byCD34+ selection.Results. The 4.5-year progression-free survival was71%. The 6 year actuarial probability of progression-freesurvival was 62.5% and the disease activity-free survivalof 7.1%. The median EDSS was 6 (4-8.5) and the MSSS 8(5-10). Only 2 patients presented enhanced T1 lesions.No long-term complications related to the procedure wereobserved.Conclusion. AHSCT cannot be deemed a curativetreatment but may cause prolonged stabilisation or changethe aggressive course of the disease (AU)

Interferón-beta y hepatitis autoinmune en la esclerosis múltiple: ¿causa-efecto o asociación? / No disponible

No disponible

[Clinical outcome 6 years after autologous hematopoietic stem cell transplantation in multiple sclerosis]. / Resultado clínico a 6 años del trasplante autólogo de progenitores hematopoyéticos en la esclerosis múltiple.

INTRODUCTION: Autologous hematopoietic stem cell transplantation (AHSCT) remains as an experimental treatment for severe forms of multiple sclerosis (MS). We describe the clinical outcome of 14 patients included in a protocol of AHSCT after a median follow-up period of 6 years. METHODS: 14 patients (5 relapsing-remitting and 9 secondary progressive) with a median number of relapses in the year before of 3 (1-7), Expanded Disability Status Scale (EDSS) of 6 (4.5-6.5) and decile of the multiple Sclerosis Severity Store (MSSS) 9 (7-10) were included. The procedure included carmustine, cyclophosphamide, antithymocyte globulin and T-cell depletion by CD34+ selection. RESULTS: The 4.5-year progression-free survival was 71%. The 6 year actuarial probability of progression-free survival was 62.5% and the disease activity-free survival of 7.1%. The median EDSS was 6 (4-8.5) and the MSSS 8 (5-10). Only 2 patients presented enhanced T1 lesions. No long-term complications related to the procedure were observed. CONCLUSION: AHSCT cannot be deemed a curative treatment but may cause prolonged stabilisation or change the aggressive course of the disease.

Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study.

BACKGROUND: A 24-week phase II trial has shown that 0.3 mg of laquinimod given daily to patients with relapsing-remitting multiple sclerosis was well tolerated and reduced the formation of active lesions. We assessed the effect of oral daily 0.3 and 0.6 mg laquinimod on MRI-monitored disease activity in a 36-week double-blind, placebo-controlled phase IIb study. METHODS: The study was done in 51 centres in nine countries. Inclusion criteria were one or more relapses in the year before entry and at least one gadolinium enhancing (GdE) lesion on screening MRI. Of 720 patients screened, 306 eligible patients were enrolled. Patients, aged 18-50 years, were randomly assigned to placebo (n=102), laquinimod 0.3 mg a day (n=98), or 0.6 mg a day (n=106). Brain MRI scans and clinical assessments were done at week -4, baseline, and monthly from week 12 to week 36. The primary outcome was the cumulative number of GdE lesions at weeks 24, 28, 32, and 36. The principal analysis of the primary endpoint was done on the intention-to-treat cohort. This study is registered with ClinicalTrials.gov, number NCT00349193. FINDINGS: Compared with placebo, treatment with laquinimod 0.6 mg per day showed a 40.4% reduction of the baseline adjusted mean cumulative number of GdE lesions per scan on the last four scans (simple means 4.2 [SD 9.2] vs 2.6 [5.3], p=0.0048); treatment with 0.3 mg per day showed no significant effects (3.9 [5.5] vs placebo, p=0.6740). Both doses of laquinimod were well tolerated, with some transient and dose-dependent increases in liver enzymes. A case of Budd-Chiari syndrome-ie, a thrombotic venous outflow obstruction of the liver-occurred after 1 month of exposure in a patient with underlying hypercoagulability who received 0.6 mg laquinimod. Anticoagulant treatment resulted in a decline of liver enzymes to normal without any clinical signs of hepatic decompensation. INTERPRETATION: In patients with relapsing-remitting multiple sclerosis, 0.6 mg per day laquinimod significantly reduced MRI-measured disease activity and was well tolerated.

An approach to estimating the intangible costs of multiple sclerosis according to disability in Catalonia, Spain.

Multiple sclerosis (MS) is a chronic demyelinating disease, which represents a great economic burden to society. Cost-of-illness studies of MS tend to underestimate the intangible costs related to pain, anxiety and helplessness. The purpose of this study was to estimate the intangible costs of MS, and determine whether these costs increase as disability progresses. We studied 211 consecutive patients with MS who attended our MS unit. Patients mean age was 41.6 (SD: 10.7) years, 69% were female, and their mean Expanded Disability Status Scale (EDSS) score was 2.47 (SD: 2.05). Quality-of-life was measured with the EuroQoL visual analogue scale. Quality-adjusted life year (QALY) was calculated for each patient. Patients were grouped into five disability stages according to their EDSS, and QALY was compared between patients and a group of healthy controls matched by age and sex. A benchmark value was ascribed to each QALY lost, and the intangible costs per patient-year were calculated as Euros 0 (EDSS =0), Euros 1100 (EDSS =1-3), Euros 8250 (EDSS =3.5-5.5), Euros 9900 (EDSS =6-7) and Euros 11,000 (EDSS >7.5). Sensitivity analysis showed a similar progression of costs. We conclude that intangible costs are relevant in MS, especially when disability increases. Although the method to calculate the costs remains controversial, we consider that they should be included in cost analysis of MS.