Anti-muscle Specific Tyrosine Kinase Research Articles

Clinical pitfalls and serological diagnostics of MuSK myasthenia gravis

BackgroundWe aimed to evaluate the diagnostic accuracy of enzyme-linked immunosorbent assay (ELISA) for anti-muscle specific tyrosine kinase (MuSK) antibody (Ab) in a large cohort of anti-acetylcholine receptor (AChR) Ab-negative generalized myasthenia gravis (MG), and also to investigate clinical contexts for the diagnosis of MuSK MG.MethodsA retrospective study of 160 patients with a clinical suspicion of AChR Ab-negative generalized MG was performed. The serum samples were tested for anti-clustered AChR Ab by cell-based assay (CBA), anti-MuSK Ab by ELISA, CBA and/or radioimmunoprecipitation assay (RIPA). Clinical data were compared between anti-MuSK Ab-positive MG and double seronegative (AChR and MuSK) MG groups.ResultsAfter excluding non-MG and clustered AChR Ab-positive patients, we identified 89 patients as a cohort of AChR Ab-negative generalized MG. Anti-MuSK Ab was positive by ELISA in 22 (24.7%) patients. While CBA identified five additional anti-MuSK Ab-positive patients, the results of ELISA were mostly consistent with CBA and RIPA with Cohen’s kappa of 0.80 and 0.90, respectively (p < 0.001). The most frequent differential diagnosis was motor neuron disease particularly of bulbar onset which showed remarkably overlapping clinical and electrophysiological features with MuSK MG at presentation.ConclusionWhile confirming the highest sensitivity of CBA for detecting anti-MuSK Ab, our results highlight the clinical pitfalls in making a diagnosis of MuSK MG and may support a diagnostic utility of MuSK-ELISA in clinical practice.

Disease severity and response to treatment in Iranian patients with myasthenia gravis.

Myasthenia gravis (MG) is a potentially fatal neuromuscular disorder if left untreated. In this study, we tried to address the possible demographic, clinical, and laboratory determinants of severity and outcome in Iranian MG patients over a follow-up period of more than 5years. Demographic and diagnostic data (age, age of onset, antibody status, thymus pathology, and duration of the disease) of the patients with MG were extracted. Maximal disease severity and post-intervention status were assessed according to the recommendations of the task force of the Myasthenia Gravis Foundation of America. In our series of 146 patients, MG was more severe in older, anti-muscle specific tyrosine kinase (MuSK) positive, and thymomatous patients. Seropositivity to the MuSK antibody and the presence of thymoma determined the need for immunosuppressive drugs. However, the number of patients requiring more than one immunosuppressive was not significantly different among various subtypes. The overall outcome was favorable in the majority of patients, despite differences in the disease course and severity. In contrary to the previous reports, anti-MuSK positive patients in our series did not need a more vigorous treatment regimen comparing other serologic subtypes of MG.

Longstanding and Refractory Anti-Muscle Specific Tyrosine Kinase Antibody-Associated Myasthenia Gravis (Anti-MuSK-MG) in a Child Successfully Treated with Rituximab

ABSTRACTAnti-muscle specific tyrosine kinase antibody-associated myasthenia gravis (MuSK-MG) is a rare subtype of MG characterized by more frequent relapses and a clinical course that is refractory to standard treatments. Rituximab, a monoclonal antibody targeting CD20+ B cells, has been used effectively in the adult population to achieve stable remission. We describe a pediatric patient with MuSK-MG who demonstrated an excellent response to rituximab after failing standard therapy.

Ocular myasthenia gravis: an update on diagnosis and treatment.

Myasthenia gravis is an autoimmune disease that commonly affects the palpebral and extraocular muscles. Ocular myasthenia gravis (OMG) is a variant of the disease that is confined to the ocular muscles but frequently becomes generalized over time. The diagnosis of OMG is often challenging but both clinical and laboratory findings are helpful in confirming the clinical suspicion. This review provides an update on the diagnostic approach and therapeutic options for OMG. Antimuscle-specific tyrosine kinase and LDL-related receptor-related protein 4 are newly available serologic testing for myasthenia gravis that can help in increasing the diagnostic sensitivity of OMG. They should be included to the diagnostic algorithm of OMG in appropriate clinical situations. OMG remains a primarily clinical diagnosis, but recent advances in laboratory testing can improve the diagnostic accuracy and should be used in appropriate clinical settings. The mainstay of treatment for OMG has not significantly changed over the past years, but the increasing availability of steroid-sparing agents improved the disease control while minimizing steroid-induced complications.

English

Myasthenia gravis is a neuro-muscular junction disorder characterized by skeletal muscle weakness and fatiguability. It is due to a decrease in the number of available acetylcholine receptors at the neuromuscular junction as a result of antibody mediated autoimmune attack. Weakness of muscles may involve cranial and somatic musculatures. Weakness resembling myasthenia gravis may occur in other conditions as a result of drug, endocrine disease of thyroid, certain malignancies, bacterial toxins and also by non-autoimmune mechanisms involving the neuromuscular junction. The weakness may involve all the skeletal muscles of the body but the distribution of weakness has a characteristic pattern and there is a diurnal variation of symptoms. If the weakness of respiratory muscles becomes so severe as to require respiratory assistance, then it is called myasthenic crisis. The myasthenia may be generalized one involving all the groups of muscles or it may involve the extra ocular muscles and facial muscles. Sometimes the bulbar muscles alone may be involved and the condition is called bulbar myasthenia gravis. In some of the patients, (anti-AchR) Acetyl choline receptor antibodies may be positive and in some it will be negative. In some of the patients, anti-muscle specific tyrosine kinase antibodies will be positive and negative in some of the patients. CONCLUSION : 1. In our study, the commonest age group of presentation of myasthenic crisis is the fourth decade (36%). 2. Male predominance (56%) was noted in our study. 3. The most common predisposing factor is the respiratory infection (28%). 4. In three patients, the presenting symptoms of myasthenia gravis was crisis itself. 5. The mean duration of onset of myasthenia gravis to the onset of crisis was 439.36 days. 6. The duration of myasthenia gravis does not influence the occurrence of myasthenic crisis. 7. Our patients presented with predominant bulbar symptoms with respiratory distress. 8. Ventilator associated pneumonia and other respiratory complications influenced the outcome of treatment of myasthenic crisis. 9. 32% of thymectomised patients had myasthenic crisis. 10. Higher age is a risk factor and younger age is a favourable factor for good outcome. 11. Duration of myasthenia gravis have no role on the outcome of crisis. 12. The better survival rate in ventilated patients outweigh the preventable ventilator related complications.

Association of HLA class II (DRB1, DQA1, DQB1) alleles and haplotypes with myasthenia gravis and its subgroups in the Iranian population

Heterogenic pattern of HLA associations with myasthenia gravis (MG) among different ethnicities and also among different MG subgroups has been the subject of debate in large series of many studies. One hundred and sixty Iranian MG patients were investigated for HLA class II (DRB1, DQA1, DQB1) associations compared to two hundred healthy controls from the same ethnic population. DRB1*11 DQA1*0501 DQB1*0301 haplotype was found to be protective for total (ocular plus generalized) MG (Pc=0.005, OR=0.49) and generalized MG (Pc=0.008, OR=0.49). DRB1*04 DQA1*0301 DQB1*0302 haplotype (Pc=0.03, OR=2.25) was predisposing for anti-acetylcholine receptor (AChR) antibody-positive MG, while DRB1*16 DQA1*0102 DQB1*05 (Pc=0.013, OR=4.28) was predisposing for anti-muscle specific tyrosine kinase (MuSK) antibody-positive MG. There was also a trend of positive association for DRB1*14 DQA1*0104 DQB1*05 haplotype with MuSK-positive MG (Pc=0.054, OR=3.97). Among other MG subgroups and with less significance, DRB1*0101 DQA1*0101 DQB1*05 haplotype (P=0.016, OR=3.68) had positive association with pure ocular MG, and DRB1*03 DQA1*0501 DQB1*0201 haplotype (P=0.024) had negative association with thymomatous MG. This study highlights the importance of appropriate MG subgrouping according to clinical and paraclinical characteristics in HLA studies among MG patients.

Myasthénie séronégative et myasthénie avec anticorps anti-MuSK : une série rétrospective de 20 cas

Introduction Despite the fact that anti-muscle specific tyrosine kinase (MuSK) antibodies have been discovered for seven years, only a few studies have, until now, focused on myasthenia without acetylcholine-receptors antibodies (ab) (formerly known as “seronegative myasthenia”), and among them, anti-MuSK-antibody-positive and -negative patients. Method We retrospectively studied 20 patients with “seronegative” myasthenia gravis, eight of them being anti-MuSK-ab positive, the remaining twelve being negative. We searched for clinical, neurophysiological, and therapeutic differences between the two groups (anti-MuSK-ab positive: anti-MuSK+ versus anti-MuSK-ab negative: anti-MuSK−). Results Anti-MuSK+ patients had more predominantly bulbar involvement and had more severe disease (these patients required referral to intensive care more frequently). There was no difference between the two groups concerning treatment efficiency and tolerance. Most of our patients were treated with acetylcholinesterase-inhibitors, and immunomodulatory or immunosuppressive drugs that could indirectly reflect greater severity. However, there was no difference in treatments for anti-MuSK+ versus anti-MuSK− patients. Conclusion These results both confirm and complete the preexisting data on RACh-negative myasthenia, and especially on myasthenia associated with MuSK antibodies.

ＨＩＶ感染症を合併し，シクロスポリン投与を要した抗ＭｕＳＫ抗体陽性・重症筋無力症の１例

A-58-year old man presented with fluctuating ptosis and dysphagia. When he was 53 years old, he developed oral candidiasis and serum human immunodeficiency virus (HIV) RNA was detected. After starting highly active antiretroviral therapy, serum HIV RNA became undetectable. Neurological examination revealed ptosis and bulbar symptoms. Myasthenia gravis was comfirmed by a positive edrophonium test, showing 20% decrement of the compound muscle action potential on repetitive stimulation. Anti-acetylcholine receptor antibodies were negative and anti-muscle specific tyrosine kinase (MuSK) antibodies were positive. The chest CT scan was normal. He experienced transient clinical remission with pyridostigmine bromide and prednisolone. However relapse occurred after he returned to work. Persistent clinical remission was first observed after cyclosporin administration. There are eleven reports in which patients had concomitant myasthenia gravis and HIV infection. Most of those cases were benign in clinical course and required only anticholinesterase therapy. In our case, however, anti-MuSK antibodies were positive, and symptoms of myasthenia gravis remained despite prednisolone administration. Cyclosporin is directly active against HIV, and thus, cyclosporine therapy may be helpful in patients with concomitant myasthenia gravis and HIV infection.

High-dose intravenous immunoglobulin for the treatment of MuSK antibody-positive seronegative myasthenia gravis

We treated two patients with anti-muscle specific tyrosine kinase (MuSK)-antibody positive seronegative myasthenia gravis (MG) with high-dose intravenous gammaglobulin (IVIg) and evaluated their clinical courses. Both patients were Japanese women, MuSK-positive seronegative MG, and were unresponsive to conventional treatments, including thymectomy, steroids, and tacrolimus. The patients required frequent hospitalization for plasmapheresis. In case 1, a 45-year-old woman, it was difficult to obtain blood access for plasmapheresis. High-dose IVIg, 400 mg/kg per day for 5 days, was administered in cases 1 and 2. In both cases, clinical improvement was observed 3 days after the start of IVIg therapy and lasted for 2 to 3 months. We propose that IVIg therapy is an effective treatment for MuSK-positive seronegative MG, when conventional treatments have failed.