Four-year safety and effectiveness data from patients with multiple sclerosis treated with fingolimod: The Spanish GILENYA registry

Esclerosis múltiple; Reacciones adversas; Infecciones respiratoriasEsclerosi múltiple; Reaccions adverses; Infeccions respiratòriesMultiple sclerosis; Adverse reactions; Respiratory infectionsObjective To describe the profile of patients with multiple sclerosis (MS) treated with fingolimod in Spain and to assess the effectiveness and safety of fingolimod after 4 years of inclusion in the Spanish Gilenya Registry. Methods An observational, retrospective/prospective, multicenter case registry, including all patients with relapsing-remitting MS (RRMS) starting treatment with fingolimod in 43 centers in Spain. Analyses were performed in the overall population and in subgroups according to prior disease-modifying therapy (DMT): glatiramer acetate/interferon beta-1 (BRACE), natalizumab, other treatment, or naïve. Results Six hundred and sixty-six evaluable patients were included (91.1% previously treated with at least one DMT). The mean annualized relapse rate (ARR) prior to fingolimod was 1.12, and the mean EDSS at fingolimod initiation was 3.03. Fingolimod reduced the ARR by 71.4%, 75%, 75.5%, and 80.3%, after 1, 2, 3 and 4 years, respectively (p<0.001). This significant reduction in the ARR continued to be observed in all subgroups. After 4 years, the EDSS showed a minimal deterioration, with the EDSS scores from year 1 to year 4 remaining mostly stable. The percentage of patients without T1 Gd+ lesions progressively increased from 45.6% during the year prior to fingolimod initiation to 88.2% at year 4. The proportion of patients free from new/enlarged T2 lesions after 4 years of fingolimod treatment was 80.3%. This trend in both radiological measures was also observed in the subgroups. Adverse events (AEs) were experienced by up to 41.6% of patients (most commonly: lymphopenia [12.5%] and urinary tract infection [3.7%]). Most AEs were mild in severity, 3.6% of patients had serious AEs. Conclusions The patient profile was similar to other observational studies. The results obtained from the long-term use of fingolimod showed that it was effective, regardless of prior DMT, and it had adequate safety results, with a positive benefit-risk balance.The study was funded by the Academia Española de Esclerosis Múltiple y Otras Enfermedades Autoinmunes (ACADEM), with a restricted investigational grant form Novartis. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

CLIPPERS syndrome with atypical distribution of lesions in magnetic resonance imaging of the brain

Introducción. El síndrome CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) es un proceso inflamatorio del sistema nervioso central cuyo rasgo distintivo son las lesiones puntiformes en el troncoencéfalo captantes en los estudios de resonancia magnética. Clínicamente, cursa con disartria, ataxia y diplopía, y suele responder a corticoides. Anatomopatológicamente, aparecen infiltrados de linfocitos T en los espacios perivasculares troncoencefálicos. Caso clínico. Mujer de 40 años con cuadro de instauración subaguda de diplopía binocular, ataxia y disartria. En la resonancia magnética cerebral presentó lesiones puntiformes hipertintensas en secuencia T2 en el tronco, cerebelo, diencéfalo y áreas córtico-subcorticales bihemisféricas, que realzaron con contraste. Se realizó un estudio etiológico para descartar un origen infeccioso, neoplásico o inflamatorio subyacente, que resultó negativo. La paciente recibió tratamiento en dos ocasiones con metilprednisolona, con descenso progresivo de la dosis, con buena respuesta. Conclusiones. La diplopía y la ataxia, como en nuestro caso, están presentes prácticamente siempre. Los hallazgos en la RM consisten en lesiones captantes puntiformes localizadas en la protuberancia con extensión hacia el cerebelo, ganglios basales y cuerpo calloso, con gradiente de captación menor conforme se alejan rostralmente hacia la corteza, y caudalmente hacia la médula. En el caso de nuestra paciente, este gradiente no se respeta, encontrándose una densidad similar de las lesiones a nivel supratentorial. El diagnóstico diferencial es amplio y justifica un estudio diagnóstico extenso, y en casos seleccionados la biopsia cerebral. El curso de la enfermedad es remitente-recurrente, y el pronóstico mejora cuanto más precoz y prolongado es el tiempo de corticoterapiaIntroduction. CLIPPERS syndrome (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is an inflammatory process of the central nervous system whose distinguishing features are the enhancing punctiform lesions in the brainstem that appear in the magnetic resonance images. Clinically, it is accompanied by dysarthria, ataxia and diplopia, and usually responds to treatment with corticoids. Pathologically, T lymphocytes appear infiltrated in the perivascular spaces of the brainstem. Case report. We report the case of a 40-year-old woman with an initial subacute clinical picture of binocular diplopia, ataxia and dysarthria. The magnetic resonance brain scan revealed T2 hyperintense punctiform lesions in the stem, cerebellum, diencephalons and cortico-subcortical areas of both hemispheres, which were enhanced with contrast. An aetiological study was performed to rule out any underlying infectious, neoplastic or inflammatory origin, the results being negative. The patient was treated on two occasions with methylprednisolone, with a gradual lowering of the dosage, the response being favourable. Conclusions. Diplopia and ataxia, as in our case, are practically always present. The MR findings consist of punctiform enhancing lesions located in the pons extending towards the cerebellum, basal ganglia and corpus callosum, the enhancement gradient becoming lower as the distance increases rostrally away from the cortex, and caudally towards the spinal cord. In the case of our patient, this gradient is not respected, and the density found was similar to that of lesions at the supratentorial level. The differential diagnosis is wide-ranging and justifies an extensive diagnostic study with, in certain cases, a biopsy study of brain tissue. The disease courses in a relapsing-remitting pattern and the earlier steroid therapy is established and the more prolonged it is, the better the prognosis will b

Four-year safety and effectiveness data from patients with multiple sclerosis treated with fingolimod : The Spanish GILENYA registry

Objective To describe the profile of patients with multiple sclerosis (MS) treated with fingolimod in Spain and to assess the effectiveness and safety of fingolimod after 4 years of inclusion in the Spanish Gilenya Registry. Methods An observational, retrospective/prospective, multicenter case registry, including all patients with relapsing-remitting MS (RRMS) starting treatment with fingolimod in 43 centers in Spain. Analyses were performed in the overall population and in subgroups according to prior disease-modifying therapy (DMT): glatiramer acetate/interferon beta-1 (BRACE), natalizumab, other treatment, or naïve. Results Six hundred and sixty-six evaluable patients were included (91.1% previously treated with at least one DMT). The mean annualized relapse rate (ARR) prior to fingolimod was 1.12, and the mean EDSS at fingolimod initiation was 3.03. Fingolimod reduced the ARR by 71.4%, 75%, 75.5%, and 80.3%, after 1, 2, 3 and 4 years, respectively (p<0.001). This significant reduction in the ARR continuedto be observed in all subgroups. After 4 years, the EDSS showed a minimal deterioration, with the EDSS scores from year 1 to year 4 remaining mostly stable. The percentage of patients without T1 Gd+ lesions progressively increased from 45.6% during the year prior to fingolimod initiation to 88.2% at year 4. The proportion of patients free from new/enlarged T2 lesions after 4 years of fingolimod treatment was 80.3%. This trend in both radiological measures was also observed in the subgroups. Adverse events (AEs) were experienced by up to 41.6% of patients (most commonly: lymphopenia [12.5%] and urinary tract infection [3.7%]). Most AEs were mild in severity, 3.6% of patients had serious AEs. Conclusions The patient profile was similar to other observational studies. The results obtained from the long-term use of fingolimod showed that it was effective, regardless of prior DMT, and it had adequate safety results, with a positive benefit-risk balance

Baseline Inflammatory Status Reveals Dichotomic Immune Mechanisms Involved In Primary-Progressive Multiple Sclerosis Pathology

To ascertain the role of inflammation in the response to ocrelizumab in primary-progressive multiple sclerosis (PPMS).Multicenter prospective study including 69 patients with PPMS who initiated ocrelizumab treatment, classified according to baseline presence [Gd+, n=16] or absence [Gd-, n=53] of gadolinium-enhancing lesions in brain MRI. Ten Gd+ (62.5%) and 41 Gd- patients (77.4%) showed non-evidence of disease activity (NEDA) defined as no disability progression or new MRI lesions after 1 year of treatment. Blood immune cell subsets were characterized by flow cytometry, serum immunoglobulins by nephelometry, and serum neurofilament light-chains (sNfL) by SIMOA. Statistical analyses were corrected with the Bonferroni formula.More than 60% of patients reached NEDA after a year of treatment, regardless of their baseline characteristics. In Gd+ patients, it associated with a low repopulation rate of inflammatory B cells accompanied by a reduction of sNfL values 6 months after their first ocrelizumab dose. Patients in Gd- group also had low B cell numbers and sNfL values 6 months after initiating treatment, independent of their treatment response. In these patients, NEDA status was associated with a tolerogenic remodeling of the T and innate immune cell compartments, and with a clear increase of serum IgA levels.Baseline inflammation influences which immunological pathways predominate in patients with PPMS. Inflammatory B cells played a pivotal role in the Gd+ group and inflammatory T and innate immune cells in Gd- patients. B cell depletion can modulate both mechanisms.Copyright © 2022 Fernández-Velasco, Monreal, Kuhle, Meca-Lallana, Meca-Lallana, Izquierdo, Oreja-Guevara, Gascón-Giménez, Sainz de la Maza, Walo-Delgado, Lapuente-Suanzes, Maceski, Rodríguez-Martín, Roldán, Villarrubia, Saiz, Blanco, Diaz-Pérez, Valero-López, Diaz-Diaz, Aladro, Brieva, Íñiguez, González-Suárez, Rodríguez de Antonio, García-Domínguez, Sabin, Llufriu, Masjuan, Costa-Frossard and Villar

Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis : APLIOS, a randomized phase-2 study

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed. Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion

Recommendations for vaccination in patients with multiple sclerosis who are eligible for immunosuppressive therapies: Spanish consensus statement

Background: The recent development of highly effective treatments for multiple sclerosis (MS) and the potential risk of infectious complications require the development of prevention and risk minimisation strategies. Vaccination is an essential element of the management of these patients. This consensus statement includes a series of recommendations and practical scenarios for the vaccination of adult patients with MS who are eligible for highly effective immunosuppressive treatments. Methodology: A formal consensus procedure was followed. Having defined the scope of the statement, we conducted a literature search on recommendations for the vaccination of patients with MS and specific vaccination guidelines for immunosuppressed patients receiving biological therapy for other conditions. The modified nominal group technique methodology was used to formulate the recommendations. Development: Vaccination in patients who are candidates for immunosuppressive therapy should be considered before starting immunosuppressive treatment providing the patient's clinical situation allows. Vaccines included in the routine adult vaccination schedule, as well as some specific ones, are recommended depending on the pre-existing immunity status. If immunosuppressive treatment is already established, live attenuated vaccines are contraindicated. For vaccines with a correlate of protection, it is recommended to monitor the serological response in an optimal interval of 1-2 months from the last dose.Antecedentes: La reciente aparición de terapias de alta efectividad para el tratamiento de la esclerosis múltiple (EM), con potencial riesgo de complicaciones infecciosas, obliga plantear estrategias de prevención y minimización de riesgos. La vacunación constituye una parte esencial del manejo de estos pacientes. Este consenso recoge una serie de pautasy escenarios prácticos de vacunación en pacientes adultos con EM candidatos a tratamiento inmunosupresor. Metodología: Se llevó a cabo un consenso de tipo formal. Tras definir el alcance del documento, se realizó una búsqueda bibliográfica de vacunación en pacientes con EM, así como guías de vacunación específicas de pacientes inmunosuprimidosy en tratamiento biológico con otras enfermedades.Para la formulación de las recomendaciones se empleó la metodología de Modified Nominal Group Technique. Desarrollo: La vacunación en pacientes candidatos a tratamiento inmunosupresor se debe plantear antes de iniciar un tratamiento inmunosupresor siempre que la situación clínica del paciente lo permita. Se recomendarán tanto aquellas indicadas en el calendario vacunal del adulto, como algunas específicas, en función de la inmunidad previa. Si ya está instaurado el tratamiento inmunosupresor las vacunas vivas atenuadas estarán contraindicadas.Para aquellas vacunas que dispongan de un correlato de protección se recomienda monitorizar la respuesta serológica transcurridos de uno a2 meses de la última dosi

SARS-CoV-2 Infection in Multiple Sclerosis

To understand COVID-19 characteristics in people with multiple sclerosis (MS) and identify high-risk individuals due to their immunocompromised state resulting from the use of disease-modifying treatments. Retrospective and multicenter registry in patients with MS with suspected or confirmed COVID-19 diagnosis and available disease course (mild = ambulatory; severe = hospitalization; and critical = intensive care unit/death). Cases were analyzed for associations between MS characteristics and COVID-19 course and for identifying risk factors for a fatal outcome. Of the 326 patients analyzed, 120 were cases confirmed by real-time PCR, 34 by a serologic test, and 205 were suspected. Sixty-nine patients (21.3%) developed severe infection, 10 (3%) critical, and 7 (2.1%) died. Ambulatory patients were higher in relapsing MS forms, treated with injectables and oral first-line agents, whereas more severe cases were observed in patients on pulsed immunosuppressors and critical cases among patients with no therapy. Severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course, and higher disability. Fifteen of 33 patients treated with rituximab were hospitalized. Four deceased patients have progressive MS, 5 were not receiving MS therapy, and 2 were treated (natalizumab and rituximab). Multivariate analysis showed age (OR 1.09, 95% CI, 1.04-1.17) as the only independent risk factor for a fatal outcome. This study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19 but evidenced that people with MS with advanced age and disease, in progressive course, and those who are more disabled have a higher probability of severe and even fatal diseas

Consensus statement on the use of alemtuzumab in daily clinical practice in Spain

Introducción: Alemtuzumab es un fármaco de alta eficacia aprobado por la Agencia Europeade Medicamentos como tratamiento modificador de la enfermedad en pacientes con esclerosismúltiple remitente recurrente.Objetivo: Elaborar un documento de consenso sobre el manejo de alemtuzumab en la práctica clínica habitual, que sea de aplicación en el ámbito español.Desarrollo: Un grupo de expertos en esclerosis múltiple revisó las publicaciones disponibles hasta diciembre de 2017, de tratamiento con alemtuzumab y esclerosis múltiple. Se incluyeron trabajos sobre eficacia, efectividad y seguridad, despistaje de infecciones y vacunación, admi-nistración y monitorización. La propuesta inicial de recomendaciones fue desarrollada por un grupo coordinador con base en la evidencia disponible y en su experiencia clínica. El proceso de consenso se llevó a cabo en 2 etapas; se estableció como porcentaje inicial de acuerdo grupal el 80%. El documento final con todas las recomendaciones acordadas por el grupo de trabajo se sometió a revisión externa y los comentarios recibidos fueron considerados por el grupo coordinador. Conclusiones: El documento aportado pretende ser una herramienta útil para facilitar el manejo del fármaco en condiciones de práctica clínica habitualtIntroduction: Alemtuzumab is a highly effective drug approved by the European Medicines Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. Objective: A consensus document was drafted on the management of alemtuzumab in routineclinical practice in Spain. Development: A group of multiple sclerosis specialists reviewed articles addressing treatment with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug’s efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommendations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recom-mendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group. Conclusion: The present document is intended to be used as a tool for optimising the management of alemtuzumab in routine clinical practiceLa elaboración de este manuscrito ha sido financiada por Sanofi-Genzym

Consenso de expertos sobre el uso de alemtuzumab en la práctica clínica diaria en España

Introducción: Alemtuzumab es un fármaco de alta eficacia aprobado por la Agencia Europea de Medicamentos como tratamiento modificador de la enfermedad en pacientes con esclerosis múltiple remitente recurrente. Objetivo: Elaborar un documento de consenso sobre el manejo de alemtuzumab en la práctica clínica habitual, que sea de aplicación en el ámbito español. Desarrollo: Un grupo de expertos en esclerosis múltiple revisó las publicaciones disponibles hasta diciembre de 2017, de tratamiento con alemtuzumab y esclerosis múltiple. Se incluyeron trabajos sobre eficacia, efectividad y seguridad, despistaje de infecciones y vacunación, administración y monitorización. La propuesta inicial de recomendaciones fue desarrollada por un grupo coordinador con base en la evidencia disponible y en su experiencia clínica. El proceso de consenso se llevó a cabo en 2 etapas; se estableció como porcentaje inicial de acuerdo grupal el 80%. El documento final con todas las recomendaciones acordadas por el grupo de trabajo se sometió a revisión externa y los comentarios recibidos fueron considerados por el grupo coordinador. Conclusiones: El documento aportado pretende ser una herramienta útil para facilitar el manejo del fármaco en condiciones de práctica clínica habitual.Introduction: Alemtuzumab is a highly effective drug approved by the European Medicines Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. Objective: A consensus document was drafted on the management of alemtuzumab in routine clinical practice in Spain. Development: A group of multiple sclerosis specialists reviewed articles addressing treatment with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug's efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommendations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recommendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group. Conclusion: The present document is intended to be used as a tool for optimising the management of alemtuzumab in routine clinical practice