Enrichment of serum IgG4 in MuSK myasthenia gravis patients.

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic autoantibodies are of the IgG4 subclass. The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1-3 autoantibodies. A dominant role for IgG4 in autoimmune disease is intriguing due to its anti-inflammatory characteristics. It is unclear why MuSK autoantibodies are predominantly IgG4. We hypothesized that MuSK MG patients have a general predisposition to generate IgG4 responses, therefore resulting in high levels of circulating IgG4. To investigate this, we quantified serum Ig isotypes and IgG subclasses using nephelometric and turbidimetric assays in MuSK MG and AChR MG patients not under influence of immunosuppressive treatment. Absolute serum IgG1 was increased in both MuSK and AChR MG patients compared to healthy donors. In addition, only MuSK MG patients on average had significantly increased and enriched serum IgG4. Although more MuSK MG patients had elevated serum IgG4, for most the IgG4 serum levels fell within the normal range. Correlation analyses suggest MuSK-specific antibodies do not solely explain the variation in IgG4 levels. In conclusion, although serum IgG4 levels are slightly increased, the levels do not support ubiquitous IgG4 responses in MuSK MG patients as the underlying cause of dominant IgG4 MuSK antibodies.

The effect of immunosuppression or thymectomy on the response to tetanus revaccination in myasthenia gravis.

OBJECTIVE: To determine the effect of tetanus toxoid (TT) revaccination on circulating B-, T- and NK-cell compartments in myasthenia gravis (MG) patients. METHODS: Lymphocyte (sub)populations and differentiation stages were assessed by flow cytometry in 50 TT revaccinated MG patients. TT-specific proliferative responses were explored in PBMC cultures. RESULTS: In patients treated with azathioprine B- and NK cell numbers were strongly decreased. Lymphocyte (sub)populations remained unaffected upon TT revaccination. t All patients showed a significant TT-induced proliferative response. CONCLUSION: TT revaccination is effective in MG patients with stable disease irrespective of their thymectomy status and medication and does not alter the composition of the lymphocyte compartment.

Accuracy of patient-reported data for an online patient registry of autoimmune myasthenia gravis and Lambert-Eaton myasthenic syndrome.

Disorders of the neuromuscular junction (NMJ) comprise a spectrum of rare diseases causing muscle fatigability and weakness, leading to life-long effects on quality of life. We established the Dutch-Belgian registry for NMJ disorders, based on a unique combination of patient- and physician-reported information. Information on natural course, disease burden, prevalence of complications and comorbidity is collected through patient-reported standardized questionnaires and verified using medical documentation. Currently, the registry contains information of 565 Myasthenia Gravis (MG) patients and 38 Lambert-Eaton myasthenic syndrome (LEMS) patients, constituting approximately 25% (MG) and 80% (LEMS) of patients in the Netherlands. This is a very large registry, with the highest participation rate per capita. In addition to confirming many disease characteristics previously described in the literature, this registry provides several novel insights. The reported rate of potentially corticosteroid-related comorbidity, including hypertension, heart disease, osteoporosis and type 2 diabetes was high, emphasizing the need to commence corticosteroid-sparing immune suppressive treatment as soon as possible. The reported rate of other auto-immune diseases is far higher than previously expected: 27% of MG and 38% of LEMS patients, and a surprisingly high number of MG patients (47%) is unaware of their antibody status. In conclusion, this registry provides a valuable collection of information regarding MG and LEMS disease course. Continuous collection of annual follow-up data will provide further longitudinal insights in disease burden, course and treatment effect.

A prospective, double-blind, randomized, placebo-controlled study on the efficacy and safety of influenza vaccination in myasthenia gravis.

OBJECTIVE: To investigate the efficacy and safety of an influenza vaccination in patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG). METHODS: An influenza vaccination or placebo was administered to 47 AChR MG patients. Before and 4 weeks after administration blood samples and clinical outcome scores were obtained. Antibodies to the vaccine strains A/California/7/2009 (H1N1)pdm09, A/Hong Kong/4801/14 (H3N2) and B/Brisbane/060/08 were measured using the hemagglutination-inhibition (HI) assay and disease-specific AChR antibody titers were measured with a radio-immunoprecipitation assay. Forty-seven healthy controls (HC) were vaccinated with the same influenza vaccine to compare antibody titers. RESULTS: A post-vaccination, seroprotective titer (HI ≥ 1:40) was achieved in 89.4% of MG patients vs. 93.6% in healthy controls for the H3N2 strain, 95.7% vs 97.9% for the H1N1 strain and 46.8 vs 51% for the B-strain. A seroprotective titer for all three strains of the seasonal influenza vaccine was reached in 40.4% (19/47) of the MG group and in 51% (24/47) of the HC group. Immunosuppressive medication did not significantly influence post geomean titers (GMT). The titers of disease-specific AChR antibodies were unchanged 4 weeks after vaccination. The clinical outcome scores showed no exacerbation of MG symptoms. CONCLUSION: The antibody response to an influenza vaccination in patients with AChR MG was not different from that in healthy subjects, even in AChR MG patients using immunosuppressive medication. Influenza vaccination does not induce an immunological or clinical exacerbation of AChR MG. CLINICAL TRIAL REGISTRY: The influenza trial is listed on clinicaltrialsregister.eu under 2016-003138-26.

Serum Acetylcholine Receptor Antibodies Before the Clinical Onset of Myasthenia Gravis.

A patient with autoimmune myasthenia gravis and a clinical and serological follow-up of 13 years is described. In this unique case, serum samples were available up to two years before the clinical onset of the myasthenia gravis and showed gradual increase of acetylcholine receptor antibodies, starting two years before onset of the clinical symptoms.

Translation and validation of the 15-item Myasthenia Gravis Quality of life scale in Dutch.

INTRODUCTION: The 15-item Myasthenia Gravis Quality of Life (MG-QOL15) scale has been developed to assess the health-related quality of life of patients with myasthenia gravis (MG). The aim of this study was to translate the original English version into Dutch and to test the test-retest reliability and construct validity. METHODS: Fifty patients with MG were included. Test-retest reliability and internal consistency were assessed using the intraclass correlation coefficient (ICC) and the Cronbach α. Construct validity was assessed by testing 5 predefined hypotheses. RESULTS: A good test-retest reliability was confirmed with an ICC of 0.866. The Cronbach α was 0.93. The predefined hypotheses were confirmed in 80% of cases, which points to good construct validity. DISCUSSION: The Dutch MG-QOL15 has good test-retest reliability and good construct validity. It can be used for research in a Dutch-speaking population. It is also suitable for monitoring individual patients in clinical practice. Muscle Nerve 57: 206-211, 2018.

A prospective, placebo controlled study on the humoral immune response to and safety of tetanus revaccination in myasthenia gravis.

OBJECTIVE: To investigate the humoral immune response to and safety of a tetanus revaccination in patients with myasthenia gravis or Lambert-Eaton myasthenic syndrome. METHODS: A tetanus revaccination was administered to 66 patients. Before and 4weeks after revaccination a blood sample and clinical outcome scores were obtained. Anti-tetanus IgG total, IgG1 and IgG4 titres were measured with an ELISA and disease-specific antibody titres (AChR, MuSK or VGCC) with a radio-immunoprecipitation assay. A historic healthy control group was used for comparing tetanus antibody titres with that of our patients. A placebo (saline) vaccination group was used to investigate the variability of clinical outcome scores with a 4weeks interval. RESULTS: In 60 of 65 patients, a significant increase of the anti-tetanus antibody response was measured. Thymectomy did not have an impact on this responsiveness. Patients with immunosuppressive medication had a significantly lower pre and post titre compared to healthy controls, but their response was still significant. The titres of disease-specific antibodies were unchanged 4weeks after revaccination. The clinical outcome scores showed no exacerbation of symptoms of the disease. CONCLUSION: A tetanus revaccination in patients with myasthenia gravis or Lambert-Eaton myasthenic syndrome is safe and induces a significant immune response, irrespectively of their immunosuppressive medication. We observed neither immunological nor clinical relevant exacerbations associated with the tetanus revaccination. CLINICAL TRIAL REGISTRY: The tetanus trial is listed on clinicaltrialsregister.eu under 2014-004344-35. The placebo AChR MG group was part of another clinical trial, investigating influenza vaccination in myasthenic patients. This trial is listed on clinicaltrialsregister.eu under 2016-003138-26.

Neuromuscular junction disorders.

Diseases of the neuromuscular junction comprise a wide range of disorders. Antibodies, genetic mutations, specific drugs or toxins interfere with the number or function of one of the essential proteins that control signaling between the presynaptic nerve ending and the postsynaptic muscle membrane. Acquired autoimmune disorders of the neuromuscular junction are the most common and are described here. In myasthenia gravis, antibodies to acetylcholine receptors or to proteins involved in receptor clustering, particularly muscle-specific kinase, cause direct loss of acetylcholine receptors or interfere with the agrin-induced acetylcholine receptor clustering necessary for efficient neurotransmission. In the Lambert-Eaton myasthenic syndrome (LEMS), loss of the presynaptic voltage-gated calcium channels results in reduced release of the acetylcholine transmitter. The conditions are generally recognizable clinically and the diagnosis confirmed by serologic testing and electromyography. Screening for thymomas in myasthenia or small cell cancer in LEMS is important. Fortunately, a wide range of symptomatic treatments, immunosuppressive drugs, or other immunomodulating therapies is available. Future research is directed to understanding the pathogenesis, discovering new antigens, and trying to develop disease-specific treatments.

[Paraneoplastic phenomena in patients with a thymoma]. / Paraneoplastische verschijnselen bij thymomen.

A thymoma arises from the epithelial cells of the thymus. Local tumour growth may cause symptoms like coughing, dyspnoea or chest pain. Paraneoplastic phenomena can also occur in patients with a thymoma; myasthenia gravis is a well-known example. Other neurological, dermatological, cardiological and haematological disorders are not always recognised as being paraneoplastic phenomena. There is no clear relationship between tumour activity and the clinical course of paraneoplastic phenomena. The three cases in this article illustrate how the clinical presentation of these phenomena can vary.