Antibody Positive Myasthenia Gravis Patients Research Articles

Elevated serum levels of C-terminal agrin fragment in acetylcholine receptor antibody-positive myasthenia gravis

Agrin is essential for neuromuscular junction (NMJ) formation and maintenance. The C-terminal agrin fragment (CAF), generated by neurotrypsin-mediated cleavage of agrin, has been gaining attention as a potential biomarker for sarcopenia. We investigated serum CAF levels in myasthenia gravis (MG), a NMJ disorder. Compared to healthy controls, serum CAF levels were significantly elevated in acetylcholine receptor antibody-positive MG (AChR-MG) patients, but not in muscle-specific kinase antibody-positive MG patients. In AChR-MG, baseline and post-treatment CAF levels inversely correlated with post-treatment MG activities of daily living scores, suggesting that elevated CAF levels may reflect protective mechanisms against AChR-MG pathogenesis, such as improved NMJ regeneration.

Clinical characteristics and treatment outcomes in patients with double-seronegative myasthenia gravis.

Double-seronegative myasthenia gravis (dSNMG) is defined as myasthenia gravis (MG) without detectable or low affinity antibodies to acetylcholine receptor (AChR) and muscle-specific kinase (MuSK). There are limited data on detailed clinical features and outcomes after treatment in dSNMG patients. The aim was to describe the clinical characteristics and outcomes in dSNMG patients based on MG scales. A retrospective study was performed of patients diagnosed with MG who had negative AChR or MuSK antibodies and they were compared with an AChR-positive MG cohort. Correlations were made with data from the first and last clinic visits, between demographics, clinical characteristics, treatment and disease severity, based on the Myasthenia Gravis Foundation of America category, Myasthenia Gravis Impairment Index (MGII), Patient Acceptable Symptom State and simple single question (SSQ). Eighty patients met the inclusion criteria for dSNMG. The baseline MGII and SSQ scores in the dSNMG cohort showed no significant differences from the AChR group (p = 0.94 and p = 0.46). The dSNMG cohort MGII and SSQ scores improved significantly at the last clinical evaluation (p = 0.001 and p = 0.047). The MGII improvement in the AChR cohort was significantly better (p = 0.003). The initial severity of dSNMG based on clinical scores is similar to antibody-positive MG patients. There is significant clinical improvement in dSNMG patients after therapy, measured in the last clinical evaluation. This supports an immune pathophysiology of many dSNMG patients.

Complement Activation Profile in Myasthenia Gravis Patients: Perspectives for Tailoring Anti-Complement Therapy.

The complement system plays a key role in myasthenia gravis (MG). Anti-complement drugs are emerging as effective therapies to treat anti-acetylcholine receptor (AChR) antibody-positive MG patients, though their usage is still limited by the high costs. Here, we searched for plasma complement proteins as indicators of complement activation status in AChR-MG patients, and potential biomarkers for tailoring anti-complement therapy in MG. Plasma was collected from AChR-MG and MuSK-MG patients, and healthy controls. Multiplex immunoassays and ELISA were used to quantify a panel of complement components (C1Q, C2, C3, C4, C5, Factor B, Factor H, MBL, and properdin) and activation products (C4b, C3b, C5a, and C5b-9), of classical, alternative and lectin pathways. C2 and C5 levels were significantly reduced, and C3, C3b, and C5a increased, in plasma of AChR-MG, but not MuSK-MG, patients compared to controls. This protein profile was indicative of complement activation. We obtained sensitivity and specificity performance results suggesting plasma C2, C3, C3b, and C5 as biomarkers for AChR-MG. Our findings reveal a plasma complement “C2, C3, C5, C3b, and C5a” profile associated with AChR-MG to be further investigated as a biomarker of complement activation status in AChR-MG patients, opening new perspectives for tailoring of anti-complement therapies to improve the disease treatment.

Serum irisin levels in patients with myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disorder whose main symptoms are muscle weakness and fatigue. Irisin is a novel skeletal muscle-derived myokine participating in several physiological and pathological processes. The initial objective of the project was to explore serum levels of irisin in patients with MG, as well as its correlation with disease severity. We retrospectively evaluated serum levels of irisin in 77 MG patients and 57 healthy controls (HCs) by enzyme-linked immunosorbent assay. Further, clinical parameters were measured properly. Serum irisin levels were significantly elevated in MG patients compared with HCs (p < 0.001). Furthermore, serum irisin levels were associated with the myasthenia gravis activities of daily living score in ocular myasthenia gravis (OMG) patients (r = 0.476, p = 0.004), but there was no relationship to be considered of any relevant value in generalized myasthenia gravis (GMG) patients. Acetylcholine receptor antibody-positive MG patients had higher serum irisin levels compared with HCs. Thymoma, endotracheal intubation, or intensive care unit treatments subsequently were not found to have effect on serum levels of irisin, but tendencies of increase were observed in negative ones. Serum irisin levels were elevated in patients with MG, suggesting its possible involvement in MG. And irisin is expected to be a signal to evaluate the activities of daily living of OMG patients, while its effect needs further study.

The treatment effect on peripheral B cell markers in antibody positive myasthenia gravis patients

B cells play a major role in the pathophysiology of myasthenia gravis (MG) with their ability to produce disease specific, pathogenic antibodies. However, their status during disease development and follow-up stages of the disease in the peripheral blood may need further studies to determine useful markers. In this study, we aimed to detect B cell associated factors concerning immunosuppressive treatment in generalized non-thymomatous MG patients. Although CD19+ B cell distribution did not vary among disease subgroups, expressions of both CD38 and BAFFR were altered on B cells in MG patients under immunosuppressive therapy. Serum levels of BAFF were elevated in untreated MG patients as compared to treated MG patients and healthy controls. B cell activation factors may show profound alterations due to immunosuppression.

Use of rituximab in muscle-specific tyrosine kinase antibody-positive myasthenia gravis: Preliminary observations from a tertiary care center in Northern India.

OBJECTIVES:Approximately 10%–15% of patients with myasthenia gravis (MG) are refractory to standard treatment. A sizable chunk of these patients is due to muscle-specific tyrosine kinase (MuSK) antibody-positive MG which often runs a severe course with frequent relapses and poor response to conventional treatment. We report six patients with refractory MuSK-positive MG who responded well to the treatment with rituximab.PATIENTS AND METHODS:In this prospective institute-based observational study, we report six MuSK antibody-positive MG patients, who did not achieve remission with standard treatment and were later started on rituximab infusion.RESULTS:There was a significant clinical improvement in all patients after starting rituximab.CONCLUSION:Rituximab is an effective immunomodulatory therapy in MuSK antibody-positive MG patients who are not responding to the standard treatment.

Robotic-Extended Rethymectomy for Refractory Myasthenia Gravis: A Case Series

To assess the safety and efficacy of robotic-extended rethymectomy in selected refractory myasthenia gravis (MG) patients with suspected residual thymic tissue. Robotic-extended rethymectomy was performed in 6 MG patients with seropositive acetylcholine receptors (AChR) antibody who had undergone a previous thymectomy (1 cervicotomy, 2 video-assisted thoracoscopic surgeries, and 3 sternotomies). The median observation time before robotic rethymectomy was 108 (24-171) months. The main outcomes were perioperative morbidity, mortality, conversion to open surgery, and clinical outcomes according to the Myasthenia Gravis Foundation of America Post-Intervention Status (MGFA-PIS). Before rethymectomy, all patients required immunosuppressants and 5 patients (83.3%) required intravenous immune globulin and/or plasma exchange to control the symptoms. The median specimen weight was 24.5 (14-144) g after rethymectomy, and residual thymic tissue was found in 5 patients (83.3%). No conversion to open surgery or perioperative morbidity and mortality was observed. With a median follow-up time of 46.5 (13-155) months, 3 patients (50%) achieved "improved" and 3 (50%) were "unchanged" according to the MGFA-PIS. Compared with preoperative use, the median daily dose of corticosteroids statistically decreased (25 [7.5-60] vs 0 [0-5] mg, P = 0.002) without significant change in azathioprine use (100 [0-200] vs 50 [0-150] mg, P = 0.360). AChR antibody positive MG patients with a treatment refractory long-term course after thymectomy might have remaining thymic tissue with the 2 commonly associated thymus pathologies, thymoma, and follicular hyperplasia. Robotic-extended rethymectomy might be considered as a safe and beneficial treatment option in these patients.

Myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disorder caused by antibodies against acetylcholine receptors (AChR) or other structural proteins of the neuromuscular junction. This diminishes cholinergic transmission, thus leading to exercise-induced fatigue and sometimes manifest muscle weakness, including the bulbar and ocular musculature. Whereas ocular MG is as a rule initially symptomatically treated with acetylcholine esterase inhibitors, generalized MG requires long-term immunosuppression. The thymus plays aparticular role in the pathophysiology of AChR antibody-positive MG, which can also manifest as aparaneoplastic disorder in the context of athymoma. This article reviews the basic and advanced treatment options of the different disease subtypes including plasma exchange and immunoglobulins for treatment in a myasthenic crisis. Recently, clinical approval of eculizumab, acomplement inhibitor, enriched the pharmacological armamentarium for AChR antibody-positive MG patients not appropriately responding to immunosuppression alone.

3,4-Diaminopyridine for the treatment of myasthenia gravis with electrophysiological patterns of Lambert-Eaton myasthenic syndrome

3,4-Diaminopyridine (34DAP) is a presynaptic transmission enhancer. Its efficacy for Lambert-Eaton myasthenic syndrome (LEMS) and myasthenia gravis (MG) was demonstrated. However, there are cases sharing the characteristics of both disease and the effect of 34DAP in “gray zone” patients is sparse. Recently, we prescribed 34DAP to five anti-acetylcholine receptor antibody-positive MG patients with electrophysiological LEMS patterns and three LEMS patients, and carefully monitored the responses. Sero-positive MG patients exhibited more favorable responses than LEMS patients. The combination of 34DAP and pyridostigmine resulted in the best outcomes. No significant side effects were recorded during the follow-up period. In conclusion, this study results provide evidence that 34DAP could be effective in sero-positive MG patients with pre-synaptic dysfunction.

Evaluation of immunoglobulin G and immunoglobulin G subclass levels in serum of antimuscle specific kinase and anti-acetylcholine receptor antibody positive myasthenia gravis patients

Due to policy boundaries, the results and conclusions of my thesis cannot be disclosed in this paper. Instead this paper will provide background information about myasthenia gravis (MG) and the role of immunoglobulin G (IgG) antibodies in autoimmune MG. Additionally, previous literature will be discussed to elucidate the aim and relevance of my internship project. During the internship, total IgG and IgG subclass (IgG1, IgG2, IgG3, and IgG4) concentrations were evaluated in serum of anti-muscle specific kinase antibody positive MG (MuSK-MG), anti-acetylcholine receptor antibody positive MG (AChR-MG) patients and compared with the total IgG and IgG subclass levels in healthy control serum.

Ocular myasthenia gravis induced by human acetylcholine receptor ϵ subunit immunization in HLA DR3 transgenic mice

Extraocular muscles (EOM) are preferentially involved in myasthenia gravis (MG) and acetylcholine receptor (AChR) antibody positive MG patients may occasionally present with isolated ocular symptoms. Although experimental autoimmune myasthenia gravis (EAMG) induced by whole AChR immunization closely mimics clinical and immunopathological aspects of MG, EOM are usually not affected. We have previously developed an EAMG model, which imitates EOM symptoms of MG by immunization of human leukocyte antigen (HLA) transgenic mice with α or γ-subunits of human AChR (H-AChR). To investigate the significance of the ϵ-subunit in ocular MG, we immunized HLA-DR3 and HLA-DQ8 transgenic mice with recombinant H-AChR ϵ-subunit expressed in Escherichia coli. HLA-DR3 transgenic mice showed significantly higher clinical ocular and generalized MG severity scores and lower grip strength values than HLA-DQ8 mice. H-AChR ϵ-subunit-immunized HLA-DR3 transgenic mice had higher serum anti-AChR antibody (IgG, IgG1, IgG2b, IgG2c and IgM) levels, neuromuscular junction IgG and complement deposit percentages than ϵ-subunit-immunized HLA-DQ8 transgenic mice. Control mice immunized with E. coli extract or complete Freund adjuvant (CFA) did not show clinical and immunopathological features of ocular and generalized EAMG. Lymph node cells of ϵ-subunit-immunized HLA-DR3 mice showed significantly higher proliferative responses than those of ϵ-subunit-immunized HLA-DQ8 mice, crude E. coli extract-immunized and CFA-immunized transgenic mice. Our results indicate that the human AChR ϵ-subunit is capable of inducing myasthenic muscle weakness. Diversity of the autoimmune responses displayed by mice expressing different HLA class II molecules suggests that the interplay between HLA class II alleles and AChR subunits might have a profound impact on the clinical course of MG.

Mycophenolate mofetil in AChR‐antibody‐positive myasthenia gravis: Outcomes in 102 patients

Two recent randomized, controlled trials failed to demonstrate a benefit of mycophenolate mofetil (MMF) over prednisone in the treatment of myasthenia gravis (MG). We reviewed our experience with MMF in MG to determine whether these trials may have been unsuccessful because of their short duration and the unpredicted benefit of prednisone. We reviewed outcomes and prednisone dosage for all our acetylcholine-receptor (AChR)-antibody positive MG patients treated with MMF alone or with prednisone for at least 3 months. The percentage of patients with a desirable outcome (MG-specific Manual Muscle Test score <4 or Myasthenia Gravis Foundation of America post-invention status of minimal manifestations or better) began to increase after 6 months; 80% of those followed for >24 months had a desirable outcome. Prednisone dose decreased after 12 months; after 25 months, 54.5% of patients took no prednisone and 75% took <7.5 mg/day. This retrospective analysis provides class IV evidence that MMF begins to improve AChR-positive MG after 6 months, both with prednisone and as monotherapy.

Adult celiac disease with acetylcholine receptor antibody positive myasthenia gravis

Celiac disease has been associated with some autoimmune disorders. A 40-year-old competitive strongman with celiac disease responded to a gluten-free diet, but developed profound and generalized motor weakness with acetylcholine receptor antibody positive myasthenia gravis, a disorder reported to occur in about 1 in 5000. This possible relationship between myasthenia gravis and celiac disease was further explored in serological studies. Frozen stored serum samples from 23 acetylcholine receptor antibody positive myasthenia gravis patients with no intestinal symptoms were used to screen for celiac disease. Both endomysial and tissue transglutaminase antibodies were examined. One of 23 (or, about 4.3%) was positive for both IgA-endomysial and IgA tissue transglutaminase antibodies. Endoscopic studies subsequently showed duodenal mucosal scalloping and biopsies confirmed the histopathological changes of celiac disease. Celiac disease and myasthenia gravis may occur together more often than is currently appreciated. The presence of motor weakness in celiac disease may be a clue to occult myasthenia gravis, even in the absence of intestinal symptoms.

The role of complement in myasthenia gravis: serological evidence of complement consumption in vivo

Background Antibodies to the acetylcholine receptor (AChR) titin and the ryanodine receptor (RyR) occur in myasthenia gravis (MG). These antibodies are capable of complement activation in vitro. The involvement of the complement system should cause consumption of complement components such as C3 and C4 in vivo. Materials and methods Complement components C3 and C4 were assayed in sera from 78 AChR antibody-positive MG patients and 52 healthy controls. Forty-eight of the patient sera contained titin antibodies as well, and 20 were also RyR antibody-positive. Results MG patients with AChR antibody concentrations above the median (11.2 nmol/l) had significantly lower mean C3 and C4 concentrations in serum compared to those with AChR antibody concentrations below the median. Titin antibody-positive MG patients, titin antibody-negative early-onset MG patients, titin antibody-negative late-onset MG patients, and controls had similar C3 and C4 concentrations. Nor did mean C3 and C4 concentrations differ in MG patients with RyR antibodies. Patients with severe MG (grades 4 and 5) had similar C3 and similar C4 levels compared to those with mild MG (grades 1 and 2). Conclusion An increased in vivo complement consumption was detected in MG patients with high AChR antibody concentrations, unrelated to MG severity and non-AChR muscle antibodies.

Cell-mediated immune response against titin in myasthenia gravis: evidence for the involvement of Th1 and Th2 cells.

Myasthenia gravis (MG) patients may have circulating autoantibodies against titin. In this study, we have stimulated T cells from MG patients with a recombinant polypeptide containing the main immunogenic region of titin, MGT-30 (myasthenia gravis titin-30 kDa). In an ELISpot assay, MGT-30 reactive interferon (IFN)-gamma secreting cells (Th1 cells) were detected in six of 10 titin antibody positive MG patients. Such cells were not detected in any of the five titin antibody negative MG patients or in the seven blood donors. In three patients, the stimulated number of cells decreased when total remission of MG symptoms was achieved after thymectomy or following a period of intensive immunosuppressive medication. We detected MGT-30 interleukin (IL)-4 secreting cells (Th2 cells) in two of five titin antibody positive MG patients, but not in the two titin antibody negative patients or the five blood donors examined. We conclude that titin antibody positive MG patients have a combined Th1/Th2 cell mediated immunity against the muscle protein titin.

Titin antibody positive myasthenia gravis patients have a cellular immune response against the main immunogenic region of titin

Some myasthenia gravis (MG) patients have antibodies against non-acetylcholine receptor (AChR) epitopes of skeletal muscle including titin. Peripheral blood lymphocytes from 11 MG patients and 13 blood-donors were tested for lymphocyte proliferation after stimulation with the titin peptide MGT-30, which represents the main immunogenic region. Four out of seven titin antibody positive patients had significant stimulation defined as a stimulation index (SI) above 2. Neither of the four titin antibody negative patients nor the 13 blood-donors had SI above 2 (p = 0.001). Mean SI was significantly higher for T-cells from titin antibody positive MG patients, SI = 2.2 ± 0.8, compared to titin antibody negative patients, SI = 0.9 ± 0.2 (p = 0.01), and blood-donors, SI = 0.8 ±0.3 (p > 0.0005). After MGT-30 stimulation, IL-4 was detected in the blood lymphocyte culture supernatant from four of the five MG patients examined, but from none of the eight blood-donors. Thus, MG patients with anti-titin antibodies have a T-cell mediated immune reaction against titin.