Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis

Abstract

The term seronegative myasthenia gravis (SNMG) refers to the generalized disease without detectable anti-acetylcholine receptor (anti-AChR) antibodies. In these patients, IgG antibodies against the muscle-specific kinase (MuSK) have been described, which reduced agrin-induced AChR clustering in vitro. We have assayed anti-MuSK antibodies in 78 patients with SNMG, who have been followed for many years in our Institution. Here we describe the clinical phenotype of the 37 patients whose results were positive on this assay. MG with anti-MuSK antibodies was characterized by a striking prevalence of female patients (eight men and 29 women). Age of onset ranged from 6 to 68 years, with 56.8% of patients presenting under 40 years of age. All these patients shared a similar pattern of muscle weakness, with prevalent involvement of cranial and bulbar muscles and a high frequency of respiratory crises; the involvement of limb muscles was comparatively less severe and inconsistent. Single-fibre-EMG confirmed the most sensitive examination in the EMG diagnosis of MuSK-positive disease, while, owing to weakness topography, repetitive nerve stimulation in limb muscles was diagnostic in 56.8% of cases. The effect of edrophonium (or neostigmine) injection was equivocal or negative in 11 of 37 patients (29.7%), and the response to oral pyridostigmine was even more unsatisfactory, ranging from mild benefit to overt intolerance. In thymectomized patients, thymus was normal for age or atrophied, and no benefit from surgery was noticed. Thirty-five of 37 patients were given immunosuppressive therapy and 22 received plasma-exchange. The course of the disease was often characterized by periodic exacerbation phases requiring hospitalization and even assisted ventilation; plasma-exchange produced marked improvement in these cases. At the end of the observation period, most patients, although improved, were still symptomatic, having developed permanent facial and pharyngeal weakness together with some atrophy of facial muscles. MuSK-negative disease was comparatively more heterogeneous. Most patients were affected with mild to moderate symptoms and responded well to pharmacological treatment; however, a few subjects in this group had severe refractory disease, poorly responsive to both acetylcholinesterase inhibitors and immunosuppressants.

Autoimmune disorders of the neuromuscular junction

“…[52] MuSK-MG often presents with ocular involvement, but frequently evolves to include severe bulbar and facial weakness, sometimes with marked muscle atrophy in these muscles. [53,54] Antibodies to MuSK [55] were demonstrated in around 70% of patients without AChR antibodies, and in none of the AChR antibody positive patients. Subsequently radioimmunoprecipitation assays found the antibodies in varying proportions of patients and the incidence seems to vary throughout the northern hemisphere (there are insufficient data from the southern hemisphere).…”

Emerging patterns of risk factor make‐up enable subclassification of rheumatoid arthritis

“…Myasthenia gravis, which is also associated with HLA-DR3, is typically characterized by the presence of anti-acetylcholine receptor antibodies, but in 15% of patients with generalized myasthenia gravis (and in 50% of patients with ocular myasthenia gravis), these auto-antibodies are not detectable. Recently, it was demonstrated that a considerable portion of these patients harbor antibodies against muscle-specific kinase, and that these antibodies are not found in patients who were formerly classified as having seropositive myasthenia gravis (46,47). A similar scenario might apply to ACPAnegative, RF-negative RA, although at present there is no indication of the presence of autoantibodies in patients with RF-negative, ACPA-negative RA.…”

Myasthenia Gravis with Anti-MuSK Antibodies: Clinical Features and Histopathological Changes

“…This opinion is based on clinical reports and morphological studies. These studies [17,19], even if performed in small patient series and presenting potential confounding factors such as the effect of immunosuppressive treatment and the inclusion of patients with different disease severity and duration, have altogether failed to show a better outcome in thymectomised than in unthymectomised MuSK-positive patients, both in terms of remission rate and need for immunosuppressive therapy.…”

“…This impression is based on the remission rate. When comparing therapeutic results in MuSK-MG and AChR-MG in a meta-analysis, Evoli et al [17] found a significant difference in remission rates: 10%-35% in MuSK-MG versus 24%-58% in AChR-MG. Because of the disease severity and the poor response to acetyl-cholinesterase inhibitors, the majority of MuSK-positive patients require immunosuppressive therapy [22].…”