Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial

Background: The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. Methods: We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. Findings: Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. Interpretation: At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further suppo

Inmunoglobulina endovenosa en enfermedades neuromusculares. Guía para su utilización

La Inmunoglobulina Endovenosa (IgEV) ha mostrado eficacia en varias enfermedades inmunomediadas del Sistema Nervioso Periférico. Los mecanismos postulados son: inhibir la producción de autoanticuerpos, neutralizarlos y aumentar su catabolismo, inducir bloqueo sobre monocitos y células T, interferir con el Complemento e interactuar con diversas citoquinas. La IgEV es elaborada a partir de la purificación y concentración del plasma de individuos sanos; aplicando diversas metodologías, como tratamiento a pH ácido con trazas de pepsina, cromatografía de intercambio iónico y precipitación con polietilenglicol, para eliminar los polímeros de alto peso molecular. Las entidades en las cuales se evaluó la IgEV más frecuentemente son: Neuropatías inmunomediadas Agudas (Síndrome Guillain-Barré y sus variedades: Síndrome de Miller-Fisher, Neuropatía Axonal Aguda Motora y Neuropatía Axonal Aguda Motora y Sensitiva) y Crónicas (Polineuropatía Inflamatoria Desmielinizante Crónica, Neuropatía Multifocal Motora, Neuropatía Desmielinizante Multifocal Sensitiva y Motora, Neuropatías Asociadas a Paraproteinemia y Neuropatías Atáxicas Crónicas Predominantemente Sensitivas), Enfermedades de la Unión Neuromuscular (Miastenia Gravis y Síndrome de Eaton-Lambert), Miopatías Inflamatorias (Dermatomiositis, Polimiositis y Miositis por Cuerpos de Inclusión) Ganglionopatías Sensitivas y Síndrome de Persona Rígida. La IgEV es fácilmente administrable y generalmente bien tolerada. Los efectos adversos raramente son serios, frecuentemente escalofríos, náuseas, cefalea, mialgias, fatiga y fiebre entre otros, controlables con tratamiento sintomático, y raramente falla renal, infartos miocárdicos, accidentes cerebrovasculares, reacción anafiláctica y meningitis aséptica. La IgEV se contraindica en hipersensibilidad a Inmunoglobulinas y en pacientes con déficit congénito de IgA. La dosis es de 2 g/kg, Clásicamente se distribuye a lo largo de 2-5 días con velocidad de infusión de 40-80 ml/hora.Fil: Figueredo, Alejandra. Sociedad Neurológica Argentina; ArgentinaFil: Altamirano, Lorena. Sociedad Neurológica Argentina; ArgentinaFil: Amores, Mirtha Graciela. Sociedad Neurológica Argentina; ArgentinaFil: Bertotti, Alicia Cristina. Sociedad Neurológica Argentina; ArgentinaFil: Cueto, Alicia. Sociedad Neurológica Argentina; ArgentinaFil: Díaz Livadiotis, Guillermo. Sociedad Neurológica Argentina; ArgentinaFil: Di Egidio, Mariana. Sociedad Neurológica Argentina; ArgentinaFil: Doumic, Javier. Sociedad Neurológica Argentina; ArgentinaFil: Dubrovsky, Alberto. Sociedad Neurológica Argentina; ArgentinaFil: Fulgenzi, Ernesto. Sociedad Neurológica Argentina; ArgentinaFil: Lautre, Andrea. Sociedad Neurológica Argentina; ArgentinaFil: Losavio, Adriana Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Marchesone, Cintia. Sociedad Neurológica Argentina; ArgentinaFil: Martinez Alvarez, Mariana. Sociedad Neurológica Argentina; ArgentinaFil: Mazia, Claudio Gabriel. Sociedad Neurológica Argentina; ArgentinaFil: Melano, Raúl. Sociedad Neurológica Argentina; ArgentinaFil: Orellano, Anabel. Sociedad Neurológica Argentina; ArgentinaFil: Pagano, Miguel Angel. Sociedad Neurológica Argentina; ArgentinaFil: Pardal, Ana Maria. Sociedad Neurológica Argentina; ArgentinaFil: Pirra, Laura. Sociedad Neurológica Argentina; ArgentinaFil: Politei, Juan. Sociedad Neurológica Argentina; ArgentinaFil: Reisin, Ricardo. Sociedad Neurológica Argentina; ArgentinaFil: Rey, Roberto. Sociedad Neurológica Argentina; ArgentinaFil: Rodriguez, Gabriel. Sociedad Neurológica Argentina; ArgentinaFil: Rugiero, Marcelo. Sociedad Neurológica Argentina; ArgentinaFil: Yorio, Alberto. Sociedad Neurológica Argentina; Argentin

Multicentric epidemiological study in amyotrophic lateral sclerosis in the Autonomous City of Buenos Aires

Introduction: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease of unknown cause, characterized by the simultaneous involvement of the upper and lower motor neurons. Epidemiological studies have estimated its annual incidence between 0.31 and 3.2 and its prevalence between 0.8 and 8.5 cases per 100,000 inhabitants. The epidemiological information in our country is limited to specialized centers. The present study presents the results of an epidemiological study in ELA performed in the Autonomous City of Buenos Aires (CABA). Methods: A multicentric retrospective study was conducted. Patients with defined and probable ALS according to the El Escorial Criteria, evaluated between January 1, 2012 and December 31, 2013, who lived in the CABA at the onset of symptoms, were included. The calculation of the incidence was based on the 2010 census. Results: We included 103 patients (55 men), with a mean age of 64 years. The onset of symptoms was in the lower limbs at 39%, upper extremities at 25% and bulbar at 26%. The initial symptom was weakness in 58% and dysarthria in 20%; 9% had dementia associated with ALS. The mean time to diagnosis was 14.5 months. Thirty new cases/patients were diagnosed between 01/06/2012 and 01/06/2013, with an incidence rate of 1.04 per 100,000 inhabitants. Conclusions: The epidemiological characteristics of ALS in CABA are similar to those reported in the universal literature. Further studies are needed to determine if these findings are applicable to the rest of the Argentine population.Introduction: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease of unknown cause, characterized by the simultaneous involvement of the upper and lower motor neurons. Epidemiological studies have estimated its annual incidence between 0.31 and 3.2 and its prevalence between 0.8 and 8.5 cases per 100,000 inhabitants. The epidemiological information in our country is limited to specialized centers. The present study presents the results of an epidemiological study in ELA performed in the Autonomous City of Buenos Aires (CABA). Methods: A multicentric retrospective study was conducted. Patients with defined and probable ALS according to the El Escorial Criteria, evaluated between January 1, 2012 and December 31, 2013, who lived in the CABA at the onset of symptoms, were included. The calculation of the incidence was based on the 2010 census. Results: We included 103 patients (55 men), with a mean age of 64 years. The onset of symptoms was in the lower limbs at 39%, upper extremities at 25% and bulbar at 26%. The initial symptom was weakness in 58% and dysarthria in 20%; 9% had dementia associated with ALS. The mean time to diagnosis was 14.5 months. Thirty new cases/patients were diagnosed between 01/06/2012 and 01/06/2013, with an incidence rate of 1.04 per 100,000 inhabitants. Conclusions: The epidemiological characteristics of ALS in CABA are similar to those reported in the universal literature. Further studies are needed to determine if these findings are applicable to the rest of the Argentine population.Fil: Pérez Akly, Manuel. Sociedad Neurológica; ArgentinaFil: Schiava, Marianela. Unidad Asistencial Doctor César Milstein; ArgentinaFil: Melcom, Mario. Fundación para la Investigación en Neuroepidemiología; ArgentinaFil: Rodríguez, Gabriel. Sociedad Neurológica; ArgentinaFil: Gargiulo Monachelli, Gisella Mariana. Sociedad Neurológica; ArgentinaFil: Bettini, Mariela. Sociedad Neurológica; ArgentinaFil: Reisin, Ricardo. Sociedad Neurológica; ArgentinaFil: Bendersky, Mariana. Sociedad Neurológica; ArgentinaFil: Barroso, Fabio. Sociedad Neurológica; ArgentinaFil: Brand, Patricio. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas "Raúl Carrea"; ArgentinaFil: de Ambrosi, Bruno. Sociedad Neurológica; ArgentinaFil: Di Egidio, Marianna. Sociedad Neurológica; ArgentinaFil: Fiorotto, Luis. Sociedad Neurológica; ArgentinaFil: Jáuregui, Agustín. Sociedad Neurológica; ArgentinaFil: Landriscina, Paula. Sociedad Neurológica; ArgentinaFil: Marchesoni, Cintia. Sociedad Neurológica; ArgentinaFil: Mazia, Claudio. Sociedad Neurológica; ArgentinaFil: Rey, Roberto. Sociedad Neurológica; ArgentinaFil: Rugiero, Marcelo. Sociedad Neurológica; ArgentinaFil: Salutto, Valeria Luján. Sociedad Neurológica; ArgentinaFil: Tillard, Belén. Sociedad Neurológica; ArgentinaFil: Fulgenzi, Ernesto. Sociedad Neurológica; Argentin

Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial

© 2019 Elsevier Ltd Background: The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. Methods: We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years\u27 duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. Findings: Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. Interpretation: At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. Funding: National Institutes of Health, National Institute of Neurological Disorders and Stroke

Eculizumab in refractory generalized myasthenia gravis previously treated with rituximab: subgroup analysis of REGAIN and its extension study

Introduction/Aims: Individuals with refractory generalized myasthenia gravis (gMG) who have a history of rituximab use and experience persistent symptoms represent a population with unmet treatment needs. The aim of this analysis was to evaluate the efficacy and safety of eculizumab in patients with refractory anti-acetylcholine receptor antibody-positive (AChR+) gMG previously treated with rituximab. Methods: This post hoc subgroup analysis of the phase 3 REGAIN study (NCT01997229) and its open-label extension (OLE; NCT02301624) compared baseline characteristics, safety, and response to eculizumab in participants who had previously received rituximab with those who had not. Rituximab use was not permitted within the 6 months before screening or during REGAIN/OLE. Results: Of 125 REGAIN participants, 14 had received rituximab previously (7 received placebo and 7 received eculizumab). In the previous-rituximab group, 57% had used at least four other immunosuppressants compared with 16% in the no-previous-rituximab group. Myasthenia Gravis Activities of Daily Living total scores from eculizumab baseline to week 130 of eculizumab treatment improved in both the previous-rituximab and no-previous-rituximab groups (least-squares mean −4.4, standard error of the mean [SEM] 1.0 [n = 9] and least-squares mean −4.6, SEM 0.3 [n = 67], respectively; difference = 0.2, 95% confidence interval −1.88 to 2.22). In addition, in both groups, most patients who were treated with eculizumab for 130 weeks achieved a Myasthenia Gravis Foundation of America post-intervention status of minimal manifestations (66.7% and 65.0%, respectively). The eculizumab safety profile was similar between groups and consistent with its established profile. Discussion: Eculizumab is an effective therapy for patients with refractory AChR+ gMG, irrespective of whether they had received rituximab treatment previously

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56.6 [SEM 4.5] vs 68.3 [4.5]; rank-based treatment difference -11.7, 95% CI -24.3 to 0.96; p=0.0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed