Efgartigimod improves muscle weakness in a mouse model for muscle-specific kinase myasthenia gravis.

Myasthenia gravis is hallmarked by fatigable muscle weakness resulting from neuromuscular synapse dysfunction caused by IgG autoantibodies. The variant with muscle-specific kinase (MuSK) autoantibodies is characterized by prominent cranial and bulbar weakness and a high frequency of respiratory crises. The majority of MuSK MG patients requires long-term immunosuppressive treatment, but the result of these treatments is considered less satisfactory than in MG with acetylcholine receptor antibodies. Emergency treatments are more frequently needed, and many patients develop permanent facial weakness and nasal speech. Therefore, new treatment options would be welcome. The neonatal Fc receptor protects IgG from lysosomal breakdown, thus prolonging IgG serum half-life. Neonatal Fc receptor antagonism lowers serum IgG levels and thus may act therapeutically in autoantibody-mediated disorders. In MuSK MG, IgG4 anti-MuSK titres closely correlate with disease severity. We therefore tested efgartigimod (ARGX-113), a new neonatal Fc receptor blocker, in a mouse model for MuSK myasthenia gravis. This model involves 11 daily injections of purified IgG4 from MuSK myasthenia gravis patients, resulting in overt myasthenic muscle weakness and, consequently, body weight loss. Daily treatment with 0.5 mg efgartigimod, starting at the fifth passive transfer day, reduced the human IgG4 titres about 8-fold, despite continued daily injection. In muscle strength and fatigability tests, efgartigimod-treated myasthenic mice outperformed control myasthenic mice. Electromyography in calf muscles at endpoint demonstrated less myasthenic decrement of compound muscle action potentials in efgartigimod-treated mice. These substantial in vivo improvements of efgartigimod-treated MuSK MG mice following a limited drug exposure period were paralleled by a tendency of recovery at neuromuscular synaptic level (in various muscles), as demonstrated by ex vivo functional studies. These synaptic improvements may well become more explicit upon longer drug exposure. In conclusion, our study shows that efgartigimod has clear therapeutic potential in MuSK myasthenia gravis and forms an exciting candidate drug for many autoantibody-mediated neurological and other disorders.

NMO-IgG and AQP4 Peptide Can Induce Aggravation of EAMG and Immune-Mediated Muscle Weakness.

Neuromyelitis optica (NMO) and myasthenia gravis (MG) are autoimmune diseases mediated by autoantibodies against either aquaporin 4 (AQP4) or acetylcholine receptor (AChR), respectively. Recently, we and others have reported an increased prevalence of NMO in patients with MG. To verify whether coexisting autoimmune disease may exacerbate experimental autoimmune MG, we tested whether active immunization with AQP4 peptides or passive transfer of NMO-Ig can affect the severity of EAMG. Injection of either AQP4 peptide or NMO-Ig to EAMG or to naive mice caused increased fatigability and aggravation of EAMG symptoms as expressed by augmented muscle weakness (but not paralysis), decremental response to repetitive nerve stimulation, increased neuromuscular jitter, and aberration of immune responses. Thus, our study shows increased disease severity in EAMG mice following immunization with the NMO autoantigen AQP4 or by NMO-Ig, mediated by augmented inflammatory response. This can explain exacerbation or increased susceptibility of patients with one autoimmune disease to develop additional autoimmune syndrome.

Fatigue and muscle atrophy in a mouse model of myasthenia gravis is paralleled by loss of sarcolemmal nNOS.

Myasthenia Gravis (MG) patients suffer from chronic fatigue of skeletal muscles, even after initiation of proper immunosuppressive medication. Since the localization of neuronal nitric oxide synthase (nNOS) at the muscle membrane is important for sustained muscle contraction, we here study the localization of nNOS in muscles from mice with acetylcholine receptor antibody seropositive (AChR+) experimental autoimmune MG (EAMG). EAMG was induced in 8 week-old male mice by immunization with AChRs purified from torpedo californica. Sham-injected wild type mice and mdx mice, a model for Duchenne muscular dystrophy, were used for comparison. At EAMG disease grade 3 (severe myasthenic weakness), the triceps, sternomastoid and masseter muscles were collected for analysis. Unlike in mdx muscles, total nNOS expression as well as the presence of its binding partner syntrophin α-1, were not altered in EAMG. Immunohistological and biochemical analysis showed that nNOS was lost from the muscle membrane and accumulated in the cytosol, which is likely the consequence of blocked neuromuscular transmission. Atrophy of all examined EAMG muscles were supported by up-regulated transcript levels of the atrogenes atrogin-1 and MuRF1, as well as MuRF1 protein, in combination with reduced muscle fiber diameters. We propose that loss of sarcolemmal nNOS provides an additional mechanism for the chronic muscle fatigue and secondary muscle atrophy in EAMG and MG.

Miastenia grave en edad pediátrica / Miasthenia gravis in pediatric age

La miastenia grave es una enfermedad autoinmune que se caracteriza por presentar debilidad muscular fluctuante y fatiga de distintos grupos musculares secundaria a una alteración de la transmisión sináptica causada por la destrucción y el bloqueo de los receptores de acetilcolina en la unión neuromuscular. Se realizó un estudio retrospectivo mediante una revisión de las historias clínicas de los cinco casos de miastenia gravis diagnosticados en esta institución. Se encontró que son trastornos poco frecuentes en nuestra especialidad, su diagnóstico precoz es fundamental para controlar los síntomas y retardar el avance de la enfermedad, pues las crisis pueden poner en peligro la vida de los pacientes. Nuestra serie incluye cinco pacientes con miastenia. Tres de ellas de debut generalizadas y dos de forma ocular. El diagnóstico se realizó en edades muy variables desde los cuatro hasta los 16 años. Tres niños presentaron hiperplasia tímica; fueron intervenidos quirúrgicamente dos de ellos después de los nueve años, pero ambos requirieron continuar tratamiento inmunosupresor; tuvo menor éxito la cirugía del paciente con la miastenia ocular, que era el más joven de los dos. Consideramos que la timectomía está indicada en aquellos niños con miastenia generalizada inmunológica sin respuesta a los esteroides o a la gammaglobulina y que se debe evitar la realización temprana de la misma para impedir el riesgo de inmunodeficiencia(AU)

An experimental model of myasthenia myopathy.

Normal and thymectomised rabbits been have immunized by means of a thymic extract emulsified with Freund's Complete Adjuvant. The experiment was conducted over a three month period, in order to reproduce an experimental model of chronic myasthenia. During this period immunological, electromyographic and histologic studies were undertaken. Typical findings of partial neuromuscular block were invariably obtained from all the non thymectomized animals, while such signs were constantly absent both in non-treated control rabbits and in the immunized thymectomized ones. This neuromuscular block was intermittent. The compromised neuromuscular conduction was associated to an histological pattern of autoimmune myopathy. Evidence was put on antibodies directed against the thymus, muscular and nervous tissue. The results indicate the important role of the thymus gland both in altering conduction at the neuromuscular junction level and causing histopathologic muscle lesions.