Nuevas reactividades antigénicas en neuropatías inmunomediadas

La descripción de correlaciones clínico-inmunológicas en las enfermedades autoinmunes es importante para caracterizar distintos fenotipos dentro de una enfermedad, establecer grupos diagnósticos y pronósticos y para escoger las terapias en función del perfil inmunológico de cada paciente. Las neuropatías inflamatorias constituyen un grupo de enfermedades raras del sistema nervioso periférico de probable etiología autoinmune. Este grupo incluye neuropatías agudas como el síndrome de Guillain-Barré (SGB) y neuropatías crónicas como la Poliradiculoneuropatía Inflamatoria Desmielinizante Crónica (CIDP). En todas ellas ha sido propuesto un papel prominente de los autoanticuerpos en su patogenia. Sin embargo, las reactividades antigénicas y los mecanismos patogénicos de estas enfermedades son desconocidos en su mayor parte. El SGB es una neuropatía aguda post-infecciosa en la que los anticuerpos antigangliósido juegan un papel importante. Existen diversos fenotipos dentro del SGB, incluyendo variantes sensitivo-motoras, atáxicas, sensitivas y variantes loco-regionales. Cada variante ha sido asociada a diferentes patrones de reactividad antigangliósido. El síndrome de Miller-Fisher (SMF) es una variante de SGB caracterizada por la presencia de ataxia, arreflexia y oftalmoparesia. Se asocia con la presencia de anticuerpos dirigidos contra gangliósidos que contienen el epítopo Neu NAcNeuNAcGal, como GQ1b y GT1a. En el SGB atáxico los pacientes presentan ataxia con signo de Romberg negativo y sin oftalmoparesia aparente. También se asocia a anticuerpos contra GQ1b. Por otro lado una forma sensitiva pura de SGB asociada a anticuerpos contra GD1b y conocida como neuropatía aguda sensitivo-atáxica (ASAN) puede presentarse también con ataxia de origen periférico. Distinguir el ASAN del SMF o el SGB atáxico puede ser difícil desde el punto de vista clínico. Además, la presencia de desmielinización, un criterio diagnóstico en el SGB sensitivo, es rara en ASAN y , por tanto, es controvertida su inclusión como variante de SGB. Considerando lo anterior, diseñamos un estudio para describir las características clínica e inmunológicas del ASAN. Todos los pacientes incluidos en una base de datos conteniendo los resultados de test rutinarios de anticuerpos antigangliósido y que cumplían criterios de ASAN fueron analizados en cuanto a sus características epidemiológicas, clínicas, electrofisiológicas y de reactividad anti-gangliósido. De los 12 pacientes que cumplían criterios en primer lugar, siete presentaban anticuerpos contra gangliósidos con epítopo disialosil (GQ1b, GD1b, GD2, GD3). Todos los pacientes con anticuerpos contra disialosil comenzaron con síntomas sensitivos e inestabilidad de la marcha y manifestaban haber presentado una infección de vías respiratorias altas en los días previos. Cinco de los 7 pacientes presentaron ptosis palpebral. Todos ellos tuvieron un buen pronóstico, bien tras tratamiento con IVIg o bien espontáneamente. Teniendo en cuenta lo anterior concluimos que el ASAN es, de hecho, una variante del SGB y que constituye un síndrome diferente al SMF o el SGB atáxico. La CIDP es una neuropatía crónica autoinmune en la que se ha propuesto un papel importante en su patogenia de los autoanticuerpos. En estudios previos habían sido descritos anticuerpos contra proteínas de la mielina mediante ELISA o western-blot, pero los resultados no se reprodujeron usando ensayos basados en células que mantuvieran la conformación de la proteína sin desnaturalizar y ninguno de esos autoanticuerpos se demostró útil como biomarcador. Más recientemente el descubrimiento en biopsias del nervio sural de pacientes con CIDP de que la estructura del nodo de Ranvier está desorganizada ha llevado a buscar antígenos candidatos en el nodo de Ranvier y estructuras relacionadas. Nosotros, usando una aproximación no sesgada, diseñamos un estudio que utilizaba técnicas de inmunocitoquímica en neuronas, inmunoprecipitación y confirmación de antígenos en células transfectadas para tratar de encontrar autoanticuerpos que pudieran servir de biomarcadores en la práctica clínica diaria. De 46 pacientes con una CIDP bien caracterizada, encontramos 7 que reaccionaban contra neuronas. Dos de estos pacientes precipitaron la proteína contactin-1 (CNTN1) y otro precipitó CNTN1 y contactin-associated protein-1 (CASPR1). La reactividad contra dichas proteínas fue confirmada con inmunocitoquímica, inmunohistoquímica y experimentos de absorción. Ninguno de los 104 controles fue positivo. Los tres pacientes que reaccionaban contra CNTN1 compartían un fenotipo específico que incluía avanzada edad, inicio agresivo, predominio motor, degeneración axonal marcada de inicio y respuesta pobre a las IVIg. Estas características clínicas definen un subgrupo de CIDP con fenotipo homogéneo. Por tanto, los anticuerpos contra CNTN1 son el primer biomarcador con utilidad clínica identificado en CIDP. En resumen, estos resultados refuerzan la noción de que las neuropatías autoinmunes constituyen un grupo muy heterogéneo de enfermedades en las que la descripción de autoanticuerpos y sus correlatos clínicos puede tener importantes implicaciones diagnósticas, pronósticas y terapéuticas.The description of clinical-immunological correlations in autoimmune diseases is of paramount importance to characterize disease phenotypes, diagnostic and prognostic subgroups and to choose therapies depending on the immunological profile of patients. Inflammatory neuropathies constitute a group of infrequent diseases of the peripheral nerves of presumed autoimmune pathogenesis. It includes acute neuropathies such as Guillain-Barré syndrome (GBS) and chronic neuropathies such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In all of them it has been postulated a prominent role of autoantibodies in their pathogenesis. However, the antigenic reactivities and the pathogenic mechanisms of these diseases remain largely unknown. GBS is a post-infectious acute neuropathy in which antibodies against gangliosides play an important role. There are various phenotypes of GBS, including sensory-motor, ataxic, sensory-ataxic and loco-regional variants. Each variant has been associated to different antiganglioside antibody patterns. Miller-Fisher syndrome (MFS) is a GBS variant characterized by ataxia, arreflexia and ophtalmoparesis. It associates with antiganglioside antibodies bearing the NeuNAcNeuNAcGal epitope, such as GQ1b and GT1a. In ataxic GBS patients present with ataxia and negative Romberg sign and there is no apparent ophtalmoparesis. It is also associated to GQ1b antibodies. On the other hand, a pure sensory form of GBS associated to GD1b antibodies known as acute sensory-ataxic neuropathy (ASAN) can also present with ataxia of peripheral origin. Distinguishing ASAN, MFS and ataxic GBS can be difficult from a clinical perspective. Moreover, demyelinating features, a diagnostic criteria in sensory GBS, are usually absent in ASAN and the inclusion of this form in the GBS spectrum is controversial. We designed a study to describe the clinical and immunological features of ASAN. All patients from a database including sera sent for routine antiganglioside-antibody testing and fulfilling ASAN criteria were collected and their epidemiological, clinical and electrophysiological features analyzed. Of 12 patients fulfilling criteria for ASAN, 7 had antibodies against gangliosides bearing disialosyl epitopes (GQ1b, GD2, GD3, GD1b). All ASAN patients with positive disialosyl antibodies presented with gait unsteadiness and sensory symptoms and reported an upper respiratory tract infection before disease onset. Five of the 7 patients presented eyelid ptosis. All patients had a good recovery with IVIg treatment or spontaneously. Considering these features we concluded that ASAN is, in fact, a GBS variant, and constitutes a specific phenotype different from ataxic GBS or MFS. CIDP is a chronic inflammatory neuropathy in which antibodies are thought to play an important role. Antibodies against myelin proteins had been described using ELISA and western-blot assays, but results were not reproduced in cell-based assays preserving protein conformation and none proved useful as biomarker. Recently, studies on sural nerve biopsies of CIDP patients have shown disorganization of node of Ranvier and the search of autoantibodies focused on proteins of the node of Ranvier. We used an unbiased approach with neuron immunocytochemistry, immunoprecipitation and confirmation of relevant antigens with transfected cells to find autoantibodies that could be useful in everyday practice. Starting with 46 well-characterized CIDP patients we found 7 patients reacting against neurons. Two patients precipitated contactin-1 (CNTN1) and one CNTN1 and contactin-associated protein-1 (CASPR1). Reactivity was confirmed with immunocytochemistry, inmmunohistochemistry and absorption studies. None of the 104 controls tested positive. All three patients shared old age, aggressive onset, motor predominance, prominent axonal degeneration at onset and poor response to IVIg. These features identify a subgroup of CIDP with homogeneous phenotype. Anti-CNTN1 antibodies are the first biomarker identified in CIDP with diagnostic, prognostic and therapeutic implications. These results strengthen the idea that autoimmune neuropathies are a very heterogeneous group of diseases in which autoantibody discovery and the definition of clinical-immunological correlations can have diagnostic, prognostic and therapeutic implication

Clinical characteristics and outcomes of thymoma-associated myasthenia gravis

[Background and purpose] Prognosis of myasthenia gravis (MG) in patients with thymoma is not well established. Moreover, it is not clear whether thymoma recurrence or unresectable lesions entail a worse prognosis of MG.[Methods] This multicenter study was based on data from a Spanish neurologist-driven MG registry. All patients were aged >18 years at onset and had anti-acetylcholine receptor antibodies. We compared the clinical data of thymomatous and nonthymomatous patients. Prognosis of patients with recurrent or nonresectable thymomas was assessed.[Results] We included 964 patients from 15 hospitals; 148 (15.4%) had thymoma-associated MG. Median follow-up time was 4.6 years. At onset, thymoma-associated MG patients were younger (52.0 vs. 60.4 years, p < 0.001), had more generalized symptoms (odds ratio [OR]: 3.02, 95% confidence interval [CI]: 1.95–4.68, p < 0.001) and more severe clinical forms according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR: 1.6, 95% CI: 1.15–2.21, p = 0.005). Disease severity based on MGFA postintervention status (MGFA-PIS) was higher in thymomatous patients at 1 year, 5 years, and the end of follow-up. Treatment refractoriness and mortality were also higher (OR: 2.28, 95% CI: 1.43–3.63, p = 0.001; hazard ratio: 2.46, 95% CI: 1.47–4.14, p = 0.001). Myasthenic symptoms worsened in 13 of 27 patients with recurrences, but differences in long-term severity were not significant. Fifteen thymomatous patients had nonresectable thymomas with worse MGFA-PIS and higher mortality at the end of follow-up.[Conclusions] Thymoma-associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long-term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG.This work is supported by Fondo de Investigaciones Sanitarias (FIS) grant FIS19/01774, Instituto de Salud Carlos III and cofunded by the European Union (ERDF/ESF, A Way to Make Europe/Investing in Your Future). Rodrigo Álvarez-Velasco was supported by a PhD for Medical Doctors grant from the Pla Estratègic de Recerca i Innovació en Salut (PERIS), Generalitat de Catalunya (SLT008/18/00207). Elena Cortés-Vicente was supported by a Juan Rodés grant (JR19/00037) from the Fondo de Investigación en Salud, Instituto de Salud Carlos III, Ministry of Health (Spain).Peer reviewe

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

Nuevas reactividades antigénicas en neuropatías inmunomediadas

La descripción de correlaciones clínico-inmunológicas en las enfermedades autoinmunes es importante para caracterizar distintos fenotipos dentro de una enfermedad, establecer grupos diagnósticos y pronósticos y para escoger las terapias en función del perfil inmunológico de cada paciente. Las neuropatías inflamatorias constituyen un grupo de enfermedades raras del sistema nervioso periférico de probable etiología autoinmune. Este grupo incluye neuropatías agudas como el síndrome de Guillain-Barré (SGB) y neuropatías crónicas como la Poliradiculoneuropatía Inflamatoria Desmielinizante Crónica (CIDP). En todas ellas ha sido propuesto un papel prominente de los autoanticuerpos en su patogenia. Sin embargo, las reactividades antigénicas y los mecanismos patogénicos de estas enfermedades son desconocidos en su mayor parte. El SGB es una neuropatía aguda post-infecciosa en la que los anticuerpos antigangliósido juegan un papel importante. Existen diversos fenotipos dentro del SGB, incluyendo variantes sensitivo-motoras, atáxicas, sensitivas y variantes loco-regionales. Cada variante ha sido asociada a diferentes patrones de reactividad antigangliósido. El síndrome de Miller-Fisher (SMF) es una variante de SGB caracterizada por la presencia de ataxia, arreflexia y oftalmoparesia. Se asocia con la presencia de anticuerpos dirigidos contra gangliósidos que contienen el epítopo Neu NAcNeuNAcGal, como GQ1b y GT1a. En el SGB atáxico los pacientes presentan ataxia con signo de Romberg negativo y sin oftalmoparesia aparente. También se asocia a anticuerpos contra GQ1b. Por otro lado una forma sensitiva pura de SGB asociada a anticuerpos contra GD1b y conocida como neuropatía aguda sensitivo-atáxica (ASAN) puede presentarse también con ataxia de origen periférico. Distinguir el ASAN del SMF o el SGB atáxico puede ser difícil desde el punto de vista clínico. Además, la presencia de desmielinización, un criterio diagnóstico en el SGB sensitivo, es rara en ASAN y , por tanto, es controvertida su inclusión como variante de SGB. Considerando lo anterior, diseñamos un estudio para describir las características clínica e inmunológicas del ASAN. Todos los pacientes incluidos en una base de datos conteniendo los resultados de test rutinarios de anticuerpos antigangliósido y que cumplían criterios de ASAN fueron analizados en cuanto a sus características epidemiológicas, clínicas, electrofisiológicas y de reactividad anti-gangliósido. De los 12 pacientes que cumplían criterios en primer lugar, siete presentaban anticuerpos contra gangliósidos con epítopo disialosil (GQ1b, GD1b, GD2, GD3). Todos los pacientes con anticuerpos contra disialosil comenzaron con síntomas sensitivos e inestabilidad de la marcha y manifestaban haber presentado una infección de vías respiratorias altas en los días previos. Cinco de los 7 pacientes presentaron ptosis palpebral. Todos ellos tuvieron un buen pronóstico, bien tras tratamiento con IVIg o bien espontáneamente. Teniendo en cuenta lo anterior concluimos que el ASAN es, de hecho, una variante del SGB y que constituye un síndrome diferente al SMF o el SGB atáxico. La CIDP es una neuropatía crónica autoinmune en la que se ha propuesto un papel importante en su patogenia de los autoanticuerpos. En estudios previos habían sido descritos anticuerpos contra proteínas de la mielina mediante ELISA o western-blot, pero los resultados no se reprodujeron usando ensayos basados en células que mantuvieran la conformación de la proteína sin desnaturalizar y ninguno de esos autoanticuerpos se demostró útil como biomarcador. Más recientemente el descubrimiento en biopsias del nervio sural de pacientes con CIDP de que la estructura del nodo de Ranvier está desorganizada ha llevado a buscar antígenos candidatos en el nodo de Ranvier y estructuras relacionadas. Nosotros, usando una aproximación no sesgada, diseñamos un estudio que utilizaba técnicas de inmunocitoquímica en neuronas, inmunoprecipitación y confirmación de antígenos en células transfectadas para tratar de encontrar autoanticuerpos que pudieran servir de biomarcadores en la práctica clínica diaria. De 46 pacientes con una CIDP bien caracterizada, encontramos 7 que reaccionaban contra neuronas. Dos de estos pacientes precipitaron la proteína contactin-1 (CNTN1) y otro precipitó CNTN1 y contactin-associated protein-1 (CASPR1). La reactividad contra dichas proteínas fue confirmada con inmunocitoquímica, inmunohistoquímica y experimentos de absorción. Ninguno de los 104 controles fue positivo. Los tres pacientes que reaccionaban contra CNTN1 compartían un fenotipo específico que incluía avanzada edad, inicio agresivo, predominio motor, degeneración axonal marcada de inicio y respuesta pobre a las IVIg. Estas características clínicas definen un subgrupo de CIDP con fenotipo homogéneo. Por tanto, los anticuerpos contra CNTN1 son el primer biomarcador con utilidad clínica identificado en CIDP. En resumen, estos resultados refuerzan la noción de que las neuropatías autoinmunes constituyen un grupo muy heterogéneo de enfermedades en las que la descripción de autoanticuerpos y sus correlatos clínicos puede tener importantes implicaciones diagnósticas, pronósticas y terapéuticas.The description of clinical-immunological correlations in autoimmune diseases is of paramount importance to characterize disease phenotypes, diagnostic and prognostic subgroups and to choose therapies depending on the immunological profile of patients. Inflammatory neuropathies constitute a group of infrequent diseases of the peripheral nerves of presumed autoimmune pathogenesis. It includes acute neuropathies such as Guillain-Barré syndrome (GBS) and chronic neuropathies such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In all of them it has been postulated a prominent role of autoantibodies in their pathogenesis. However, the antigenic reactivities and the pathogenic mechanisms of these diseases remain largely unknown. GBS is a post-infectious acute neuropathy in which antibodies against gangliosides play an important role. There are various phenotypes of GBS, including sensory-motor, ataxic, sensory-ataxic and loco-regional variants. Each variant has been associated to different antiganglioside antibody patterns. Miller-Fisher syndrome (MFS) is a GBS variant characterized by ataxia, arreflexia and ophtalmoparesis. It associates with antiganglioside antibodies bearing the NeuNAcNeuNAcGal epitope, such as GQ1b and GT1a. In ataxic GBS patients present with ataxia and negative Romberg sign and there is no apparent ophtalmoparesis. It is also associated to GQ1b antibodies. On the other hand, a pure sensory form of GBS associated to GD1b antibodies known as acute sensory-ataxic neuropathy (ASAN) can also present with ataxia of peripheral origin. Distinguishing ASAN, MFS and ataxic GBS can be difficult from a clinical perspective. Moreover, demyelinating features, a diagnostic criteria in sensory GBS, are usually absent in ASAN and the inclusion of this form in the GBS spectrum is controversial. We designed a study to describe the clinical and immunological features of ASAN. All patients from a database including sera sent for routine antiganglioside-antibody testing and fulfilling ASAN criteria were collected and their epidemiological, clinical and electrophysiological features analyzed. Of 12 patients fulfilling criteria for ASAN, 7 had antibodies against gangliosides bearing disialosyl epitopes (GQ1b, GD2, GD3, GD1b). All ASAN patients with positive disialosyl antibodies presented with gait unsteadiness and sensory symptoms and reported an upper respiratory tract infection before disease onset. Five of the 7 patients presented eyelid ptosis. All patients had a good recovery with IVIg treatment or spontaneously. Considering these features we concluded that ASAN is, in fact, a GBS variant, and constitutes a specific phenotype different from ataxic GBS or MFS. CIDP is a chronic inflammatory neuropathy in which antibodies are thought to play an important role. Antibodies against myelin proteins had been described using ELISA and western-blot assays, but results were not reproduced in cell-based assays preserving protein conformation and none proved useful as biomarker. Recently, studies on sural nerve biopsies of CIDP patients have shown disorganization of node of Ranvier and the search of autoantibodies focused on proteins of the node of Ranvier. We used an unbiased approach with neuron immunocytochemistry, immunoprecipitation and confirmation of relevant antigens with transfected cells to find autoantibodies that could be useful in everyday practice. Starting with 46 well-characterized CIDP patients we found 7 patients reacting against neurons. Two patients precipitated contactin-1 (CNTN1) and one CNTN1 and contactin-associated protein-1 (CASPR1). Reactivity was confirmed with immunocytochemistry, inmmunohistochemistry and absorption studies. None of the 104 controls tested positive. All three patients shared old age, aggressive onset, motor predominance, prominent axonal degeneration at onset and poor response to IVIg. These features identify a subgroup of CIDP with homogeneous phenotype. Anti-CNTN1 antibodies are the first biomarker identified in CIDP with diagnostic, prognostic and therapeutic implications. These results strengthen the idea that autoimmune neuropathies are a very heterogeneous group of diseases in which autoantibody discovery and the definition of clinical-immunological correlations can have diagnostic, prognostic and therapeutic implication

Clinical and therapeutic features of myasthenia gravis in adults based on age at onset

[Objective] To describe the characteristics of patients with very-late-onset myasthenia gravis (MG).[Methods] This observational cross-sectional multicenter study was based on information in the neurologist-driven Spanish Registry of Neuromuscular Diseases (NMD-ES). All patients were >18 years of age at onset of MG and onset occurred between 2000 and 2016 in all cases. Patients were classified into 3 age subgroups: early-onset MG (age at onset <50 years), late-onset MG (onset ≥50 and <65 years), and very-late-onset MG (onset ≥65 years). Demographic, immunologic, clinical, and therapeutic data were reviewed.[Results] A total of 939 patients from 15 hospitals were included: 288 (30.7%) had early-onset MG, 227 (24.2%) late-onset MG, and 424 (45.2%) very-late-onset MG. The mean follow-up was 9.1 years (SD 4.3). Patients with late onset and very late onset were more frequently men (p < 0.0001). Compared to the early-onset and late-onset groups, in the very-late-onset group, the presence of anti–acetylcholine receptor (anti-AChR) antibodies (p < 0.0001) was higher and fewer patients had thymoma (p < 0.0001). Late-onset MG and very-late-onset MG groups more frequently had ocular MG, both at onset (<0.0001) and at maximal worsening (p = 0.001). Although the very-late-onset group presented more life-threatening events (Myasthenia Gravis Foundation of America IVB and V) at onset (p = 0.002), they required fewer drugs (p < 0.0001) and were less frequently drug-refractory (p < 0.0001).[Conclusions] Patients with MG are primarily ≥65 years of age with anti-AChR antibodies and no thymoma. Although patients with very-late-onset MG may present life-threatening events at onset, they achieve a good outcome with fewer immunosuppressants when diagnosed and treated properly

Anales del Instituto Español de Edafología, Ecología y Fisiología Vegetal Tomo 6

[Volumen 1] Mariano Claver Aliod / Contribución al estudio de los suelos salícico-húmicos de la Sierra de Guadarrama.-- Enrique Gutiérrez Ríos y Lorenzo Hernando / Yacimientos de hentonita en Marruecos Español.-- A. Hoyos de Castro y F. González García / Identificación y propiedades de un caolín español.-- A. Hoyos de Castro y J. M. Ahumada Buesa / Nota sobre materiales de alfarería.-- F. Pino y J. Acosta Rodríguez / Nota sobre la determinación de hierro (II) en silicatos y rocas.-- Isidoro Asensio Amor / Estudio comparativo de métodos de análisis granulométricos de suelos.-- Luis Cavanillas Rodríguez / Estudios de transpiración vegetal (experiencías en Iisímetros con cultivos de maíz).--José Mª Rodríguez de la Borbolla y Alcalá / La influencia del cloro sobre las plantas.-- J. A. Jiménez Salas / La mecánica del suelo, una nueva rama de la Edafología (II).-- Charles Thom / Control de la población microbiana del suelo.-- Libros publicados.-- Reseña[Volumen 2] Manuel Carlos Alvarez Querol / Variables que influyen sobre la razón molecular sílice/alúmina en los suelos graníticos españoles.-- Ángel Hoyos de Castro / Contribución al estudio de los suelos silícicos españoles.-- Arturo Caballero López / Estudios fisiológicos relacionados con las fitohormonas en Sterubergia Lutea Gawl. et Ker.-- Charles Thom / The Penicillia. Molds men meet everyday (Los Penicillium, mohos que vemos todos los días).-- José Mª Sierra de la Guerra / ¿Edafología o Geonomía?.-- Reseña[Volumen 3] Vicente Aleixandre Ferrandis / Caracterización de algunas arcillas españolas por cambio de bases y curvas de deshidratación.-- José Mª Albareda Herrera y Cruz Rodríguez Muñoz.-Fenómenos de ordenación y reoanisotropía de arcillas.-- Fernando Burriel Martí y Valentín Hernando Fernández / El fósforo en los suelos españoles : I. Contribución a la determinación colorimétrica del fósforo.-- Florencio Bustinza Lachiondo y Arturo Caballero López / Sobre el empleo de un excipiente hidrosoluble en las técnicas de aplicación de fitohormonas.-- Ernesto Vieitez Cortizo y José L. Blanco / Relaciones entre la condición genética del maíz y las características biométricas de su polen (Trabajo preliminar).-- José Mª Albareda Herrera y Vicente Aleixandre Ferrandis / Sobre la aditividad en las deshidrataciones de mezclas de los minerales de arcilla.-- Libros publicados.--ReseñaPeer reviewe

Consistent improvement with eculizumab across muscle groups in myasthenia gravis

Objective: To assess whether eculizumab, a terminal complement inhibitor, improves patient- and physician-reported outcomes (evaluated using the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale, respectively) in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis across four domains, representing ocular, bulbar, respiratory, and limb/gross motor muscle groups. Methods: Patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis were randomized 1:1 to receive either placebo or eculizumab during the REGAIN study (NCT01997229). Patients who completed REGAIN were eligible to continue into the open-label extension trial (NCT02301624) for up to 4 years. The four domain scores of each of the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale recorded throughout REGAIN and through 130 weeks of the open-label extension were analyzed. Results: Of the 125 patients who participated in REGAIN, 117 enrolled in the open-label extension; 61 had received placebo and 56 had received eculizumab during REGAIN. Patients experienced rapid improvements in total scores and all four domain scores of both the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale with eculizumab treatment. These improvements were sustained through 130 weeks of the open-label extension. Interpretation: Eculizumab treatment elicits rapid and sustained improvements in muscle strength across ocular, bulbar, respiratory, and limb/gross motor muscle groups and in associated daily activities in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis

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