Non-thymomatous Patients Research Articles

Generalized myasthenia gravis with acetylcholine receptor antibodies: A guidance for treatment.

Generalized myasthenia gravis (MG) with antibodies against the acetylcholine receptor is a chronic disease causing muscle weakness. Access to novel treatments warrants authoritative treatment recommendations. The Nordic countries have similar, comprehensive health systems, mandatory health registers, and extensive MG research. MG experts and patient representatives from the five Nordic countries formed a working group to prepare treatment guidance for MG based on a systematic literature search and consensus meetings. Pyridostigmine represents the first-line symptomatic treatment, while ambenonium and beta adrenergic agonists are second-line options. Early thymectomy should be undertaken if a thymoma, and in non-thymoma patients up to the age of 50-65 years if not obtaining remission on symptomatic treatment. Most patients need immunosuppressive drug treatment. Combining corticosteroids at the lowest possible dose with azathioprine is recommended, rituximab being an alternative first-line option. Mycophenolate, methotrexate, and tacrolimus represent second-line immunosuppression. Plasma exchange and intravenous immunoglobulin are used for myasthenic crises and acute exacerbations. Novel complement inhibitors and FcRn blockers are effective and fast-acting treatments with promising safety profiles. Their use depends on local availability, refunding policies, and cost-benefit analyses. Adapted physical training is recommended. Planning of pregnancies with optimal treatment, information, and awareness of neonatal MG is necessary. Social support and adaptation of work and daily life activities are recommended. Successful treatment of MG rests on timely combination of different interventions. Due to spontaneous disease fluctuations, comorbidities, and changes in life conditions, regular long-term specialized follow-up is needed. Most patients do reasonably well but there is room for further improvement. Novel treatments are promising, though subject to restricted access due to costs.

Outcomes after robotic thymectomy in nonthymomatous versus thymomatous patients with acetylcholine-receptor-antibody-associated myasthenia gravis

The aim of this study was to investigate the surgical and long-term neurological outcomes of patients with acetylcholine-receptor-antibody-associated myasthenia gravis (AChR-MG) who underwent robotic thymectomy (RATS). We retrospectively analyzed the clinical-pathological data of all patients with AChR-MG who underwent RATS using the DaVinci® Robotic System at the MUMC+ between April 2004 and December 2018. Follow-up data were collected from 60 referring Dutch hospitals. In total, 230 myasthenic patients including 76 patients with a thymoma (33.0%) were enrolled in this study. Mean follow-up time, procedure time and hospitalization were, respectively 65.7 ± 43.1 months, 111±52.5 min and 3.3 ± 2.2 days. Thymomatous patients had significantly more frequently and more severe complications than nonthymomatous patients (18.4% vs. 3.9%, p<0.001). Follow up data was available in 71.7% of the included patients. The Myasthenia Gravis Foundation of America postintervention score showed any kind of improvement of MG-symptoms after RATS in 82.4% of the patients. Complete stable remission (CSR) or pharmacological remission (PR) of MG was observed in 8.4% and 39.4% of the patients, respectively. Mean time till CSR/PR remission after thymectomy was 26.2 ± 29.2 months. No statistical difference was found in remission or improvement in MGFA scale between thymomatous and nonthymomatous patients. RATS is safe and feasible in patients with MG. The majority of the patients (82.4%) improved after thymectomy. CSR and PR were observed in 8.4% and 39.4% of the patients, respectively, with a mean of 26.2 months after thymectomy. Thymomatous patients had more frequently and more severe complications compared to nonthymomatous patients.

Immunological and Structural Characterization of Titin Main Immunogenic Region; I110 Domain Is the Target of Titin Antibodies in Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction (NJ) of skeletal muscles. The major MG autoantigen is nicotinic acetylcholine receptor. Other autoantigens at the NJ include MuSK, LRP4 and agrin. Autoantibodies to the intra-sarcomeric striated muscle-specific gigantic protein titin, although not directed to the NJ, are invaluable biomarkers for thymoma and MG disease severity. Thymus and thymoma are critical in MG mechanisms and management. Titin autoantibodies bind to a 30 KDa titin segment, the main immunogenic region (MIR), consisting of an Ig-FnIII-FnIII 3-domain tandem, termed I109-I111. In this work, we further resolved the localization of titin epitope(s) to facilitate the development of more specific anti-titin diagnostics. For this, we expressed protein samples corresponding to 8 MIR and non-MIR titin fragments and tested 77 anti-titin sera for antibody binding using ELISA, competition experiments and Western blots. All anti-MIR antibodies were bound exclusively to the central MIR domain, I110, and to its containing titin segments. Most antibodies were bound also to SDS-denatured I110 on Western blots, suggesting that their epitope(s) are non-conformational. No significant difference was observed between thymoma and non-thymoma patients or between early- and late-onset MG. In addition, atomic 3D-structures of the MIR and its subcomponents were elucidated using X-ray crystallography. These immunological and structural data will allow further studies into the atomic determinants underlying titin-based autoimmunity, improved diagnostics and how to eventually treat titin autoimmunity associated co-morbidities.

Dynamic nomogram for predicting generalized conversion in adult-onset ocular myasthenia gravis

PurposeTo explore the factors and risk mapping model of progression from ocular myasthenia gravis (OMG) to generalized myasthenia gravis (GMG) in adult-onset patients.MethodsA retrospective, observational cohort study was performed for 435 OMG patients with onset age older than 14 years old. Multivariate Cox regression was used to identify the independent factors affecting generalized conversions that then were incorporated into the construction of the nomogram.ResultsTwo hundred thirty-seven patients (54.5%) had transformed into GMG after a median of 1.1 years (range 0.1-–9.1 years). The 6-, 12-, and 24-month generalized conversion rates were 31.7%, 49.8%, and 65.4%, respectively. Multivariable analysis showed that the early-onset age, male sex, concomitant autoimmune diseases (AID), positive results of anti-acetylcholine receptor antibodies, repetitive nerve stimulation abnormalities, the presence of thymoma, and prednisone treatment were significantly associated with the generalized conversions (hazard ratio [HR] = 0.598, 0.686, 1.554, 1.541, 2.020, 2.510, and 0.556, respectively). A nomogram was established to predict the possibility of generalization-free survival (GFS) in adult-onset OMG patients, and the model demonstrated good predictive performance with a C-index of 0.736 (95% confidence interval 0.703 ~ 0.769). Moreover, subgroup analyses were performed based on the presence or absence of prednisone therapy, and the results indicated that prednisone therapy has better prevention of generalized conversions in male, non-thymoma patients, and patients without other AID.ConclusionA new predictive nomograph and web-based survival calculator we developed show favorable applicability and accuracy in predicting long-term GFS in adult-onset OMG patients.

Clinical characteristics and outcomes of thymoma-associated myasthenia gravis.

Prognosis of myasthenia gravis (MG) in patients with thymoma is not well established. Moreover, it is not clear whether thymoma recurrence or unresectable lesions entail a worse prognosis of MG. This multicenter study was based on data from a Spanish neurologist-driven MG registry. All patients were aged >18years at onset and had anti-acetylcholine receptor antibodies. We compared the clinical data of thymomatous and nonthymomatous patients. Prognosis of patients with recurrent or nonresectable thymomas was assessed. We included 964 patients from 15 hospitals; 148 (15.4%) had thymoma-associated MG. Median follow-up time was 4.6years. At onset, thymoma-associated MG patients were younger (52.0 vs. 60.4 years, p<0.001), had more generalized symptoms (odds ratio [OR]: 3.02, 95% confidence interval [CI]: 1.95-4.68, p<0.001) and more severe clinical forms according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR: 1.6, 95% CI: 1.15-2.21, p=0.005). Disease severity based on MGFA postintervention status (MGFA-PIS) was higher in thymomatous patients at 1year, 5years, and the end of follow-up. Treatment refractoriness and mortality were also higher (OR: 2.28, 95% CI: 1.43-3.63, p=0.001; hazard ratio: 2.46, 95% CI: 1.47-4.14, p=0.001). Myasthenic symptoms worsened in 13 of 27 patients with recurrences, but differences in long-term severity were not significant. Fifteen thymomatous patients had nonresectable thymomas with worse MGFA-PIS and higher mortality at the end of follow-up. Thymoma-associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long-term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG.

Human Leukocyte Antigen Class II associations in late-onset Myasthenia Gravis.

ObjectiveGenetic factors predisposing to late‐onset myasthenia gravis (LOMG) have not been clearly defined yet. However, genome‐wide association studies identified Human Leukocyte Antigen (HLA) Class II alleles as a hotspot in this disease subtype. The aim of this study was to analyze the correlations of HLA Class II alleles with clinical data and titin antibodies in this patient subgroup.MethodsThis study consecutively enrolled anti‐acetylcholine receptor antibody‐positive, non‐thymoma patients with generalized LOMG. All patients were of Italian ancestry. HLA‐DRB1 and ‐DQB1 genotyping and serum titin antibody testing were performed in this population.ResultsA total of 107 patients (females: 28/107, 26.2%; median age of onset: 68 years, range: 50‐92) were included. We found a positive association with HLA‐DRB1*07 (P = 1.1 × 10‐5), HLA‐DRB1*14 (P = 0.0251) and HLA‐DQB1*02 (P = 0.0095). HLA‐DRB1*03, HLA‐DRB1*11, and HLA‐DQB1*03 were protective alleles (P = 7.9 × 10‐5, P = 0.0104, and P = 0.0067, respectively). By conditional haplotype analysis, HLA‐DRB1*07‐DQB1*02 was found to be the major risk haplotype (OR = 4.10; 95% C.I.: 2.80‐5.99; P = 6.01 × 10‐11). The mean age at onset was 73.4 years in DRB1*07 homozygotes, 69.7 years in heterozygotes, and 66.6 in non‐carriers (P = 0.0488). DRB1*07 carriers and non‐carriers did not differ in disease severity and response to therapy. Titin antibodies were detected in 61.4% of the cases, having no association with HLA alleles or specific clinical characteristics.InterpretationIn our study, we identified the HLA DRB1*07‐DQB1*02 haplotype as a predisposing factor for the development of generalized LOMG in the Italian population.

Late-Onset Myasthenia Gravis

Objective: The increase in the average life expectancy of humans has resulted in an increased occurrence of late-onset myasthenia gravis (LOMG). It is noticeable that the clinical, immunologic, and prognostic features of patients with LOMG are different than those of the patients with early-onset myasthenia gravis (EOMG). The present study aimed to establish the dissimilar features of patients with EOMG and LOMG. Subjects and Methods: The study retrospectively compared 93 patients with EOMG and LOMG in terms of clinical and immunologic features and response to medical treatment and thymectomy. Results: Of the 93 patients with MG, 56 had EOMG and 37 had LOMG. The EOMG group was dominated by female patients and generalized MG, whereas male patients and ocular MG were predominant in the LOMG group. Both groups tested positive for acetyl choline receptors antibodies. The number of patients undergoing thymectomy was higher in the EOMG group than in LOMG group. Responses to thymectomy and immunosuppressive treatment in LOMG group were lower compared with the EOMG group. Conclusion: The present study concludes that the clinical prognosis of patients with LOMG is better, and thymectomy may not be quite necessary for patients in this group who do not have thymomas (nonthymomatous patients).

Controversies in Ocular Myasthenia Gravis.

Myasthenia gravis (MG) with symptoms limited to eye muscles [ocular MG (OMG)] is a rare disease. OMG incidence varies according to ethnicity and age of onset. In recent years, both an increase in incidence rate, particularly in the elderly, and a lower risk for secondary generalization may have contributed to the growing disease prevalence in Western countries. OMG should be considered in patients with painless ptosis and extrinsic ophthalmoparesis. Though asymmetric muscle involvement and symptom fluctuations are typical, in some cases, OMG can mimic isolated cranial nerve paresis, internuclear ophthalmoplegia, and conjugate gaze palsy. Diagnostic confirmation can be challenging in patients negative for anti-acetylcholine receptor and anti-muscle-specific tyrosine kinase antibodies on standard radioimmunoassay. Early treatment is aimed at relieving symptoms and at preventing disease progression to generalized MG. Despite the absence of high-level evidence, there is general agreement on the efficacy of steroids at low to moderate dosage; immunosuppressants are considered when steroid high maintenance doses are required. The role of thymectomy in non-thymoma patients is controversial. Prolonged exposure to immunosuppressive therapy has a negative impact on the health-related quality of life in a proportion of these patients. OMG is currently excluded from most of the treatments recently developed in generalized MG.

Inflammatory myopathy with myasthenia gravis: Thymoma association and polymyositis pathology.

ObjectiveTo provide evidence that idiopathic inflammatory myopathy (IM) with myasthenia gravis (MG) frequently shows thymoma association and polymyositis (PM) pathology and shares clinicopathologic characteristics with IM induced by immune checkpoint inhibitors (ICIs).MethodsWe analyzed the clinicopathologic features of 10 patients with idiopathic IM and MG identified in 970 consecutive patients with biopsy-proven IM.ResultsSeven patients (70%) had thymoma. IM and MG were diagnosed with more than 5-year time difference in 6 thymomatous patients and within 1 year in 1 thymomatous and 3 nonthymomatous patients. Seven thymomatous patients showed rhabdomyolysis-like features with respiratory failure (4/7), dropped head (3/7), cardiac involvement (2/7), and positive anti–acetylcholine receptor (anti-AChR) and anti-titin antibodies (7/7 and 4/6, respectively) but rarely showed ocular symptoms (2/7) or decremental repetitive nerve stimulation (RNS) responses (1/7) at IM diagnosis. Three nonthymomatous patients showed acute cardiorespiratory failure with rhabdomyolysis-like features (1/3), positive anti-AChR and anti-titin antibodies (3/2 and 2/2, respectively), and fluctuating weakness of the skeletal muscle without ocular symptoms (3/3). Muscle pathology showed a PM pathology with infiltration of CD8-positive CD45RA-negative T-lymphocytes (9/9), scattered endomysial programmed cell death 1 (PD-1)–positive cells (9/9), and overexpression of programmed cell death ligand 1 (PD-L1) on the sarcolemma of muscle fibers around the infiltrating PD-1–positive cells (7/9).ConclusionRhabdomyolysis-like features, positive anti-AChR antibody without decremental RNS responses, and PD-L1 overexpression are possible characteristics shared by ICI-induced IM. Frequent thymoma association in patients with idiopathic IM and MG may suggest thymoma-related immunopathogenic mechanisms, including dysregulation of the immune checkpoint pathway.

Comparative study of video-assisted thoracoscopic surgery versus open thymectomy for thymoma and myasthenia gravis.

IntroductionThymectomy is the preferred standard treatment in younger non-thymoma patients with myasthenia gravis as well as in patients with early stage thymoma. Total thymectomy by median sternotomy has been the surgical approach since resection of the thymus with video-assisted thoracoscopic surgery (VATS).AimTo compare the clinical outcomes of VATS thymectomy with conventional open thymectomy for neoplastic and non-neoplastic thymic diseases.Material and methodsForty patients underwent thymectomy between October 2012 and January 2016. Fifteen patients were male and 25 patients were female. The mean age was 40.3 ±17.7 years. Seventeen (55%) patients underwent VATS thymectomy and 23 (45%) patients underwent an open procedure. We retrospectively reviewed the data of the patients and compared these two techniques.ResultsThe mean tumor size was 5.17 ±3.2 cm in the thymoma group (VATS 2.5 ±2.4 cm vs. open access 4.7 ±3.7 cm). None of the patients experienced a myasthenic crisis. Conversion to thoracotomy was required in 1 patient in the VATS group due to bleeding from the right internal mammary artery; therefore, the conversion rate was 2.5% among all the patients. No mortality occurred in either group. No significant difference was found in the perioperative blood loss, operative time or pain visual analogue scale scores. On the other hand, regarding postoperative drainage, duration of chest tube drainage and length of hospital stay, VATS thymectomy yielded better results and the differences were significant.ConclusionsVideo-assisted thoracoscopic surgery thymectomy can be performed for both neoplastic and non-neoplastic thymic diseases with minimal morbidity and mortality.

PTPN22 R620W Polymorphism is Associated with Myasthenia Gravis Risk: A Systematic Review and Meta-Analysis.

BackroundThe association between PTPN22 R620W polymorphism and risk of myasthenia gravis (MG) remains controversial. Therefore, we did this meta-analysis to investigate this association.Material/MethodsWe did a comprehensive search in PubMed, Medline, Embase, CNKI (China National Knowledge Infrastructure), and Wanfang electronic databases to retrieve relevant articles. The overall effect was measured by odds ratios (ORs) with its 95% confidence intervals (CIs). Statistical analyses were conducted with STATA software.ResultsOverall, a total of 7 case-control studies with 2802 cases and 3730 controls were finally included in this review. PTPN22 R620W polymorphism was significantly associated with an increased risk of MG (OR=1.57; 95% CI, 1.34–1.82; I2=31%). In the subgroup analysis, thymoma patients were significantly associated with risk of MG (OR=1.59; 95% CI, 1.28–1.98; I2=0%). However, non-thymoma patients with this polymorphism did not have increased MG risk (OR=1.36; 95% CI, 0.86–2.15; I2=77%). In addition, PTPN22 R620W polymorphism showed increased early-onset myasthenia gravis (EOMG) risk (OR=2.38; 95% CI, 1.52–3.71; I2=0%).ConclusionsThis meta-analysis shows a significant association between PTPN22 R620W polymorphism and MG risk.

Extended transcervical thymectomy with partial upper sternotomy: results in non-thymomatous patients with myasthenia gravis.

Thymectomy is a recognized treatment for myasthenia gravis (MG), but the optimal surgical approach is yet to be determined. This study analysed the results in non-thymomatous MG patients treated at our institution using an extended transcervical access with partial upper sternotomy (TC-US), in order to describe cumulative incidence of remission and its predictors. In the period 1988-2012, 215 non-thymomatous MG patients underwent thymectomy using the TC-US approach. There were 61 males and 154 females (median age: 33 years). Primary end points were complete stable remission (CSR) and pharmacological remission (PR). Clinico-pathological predictors of CSR/PR were analysed including age, gender, preoperative MG symptom duration, preoperative immunosuppression therapy and disease severity. The median follow-up period was 127 months. The median preoperative duration of MG symptoms was 9 months (interquartile range 4-13). The median operative time was 65 min (range: 45-135). There was no postoperative death. Morbidity rate was 7% (14 patients, no major complication). Ten patients died at the follow-up (3 of MG). MG symptoms improved in 85% (150/176) of the patients. CSR rate was 34%, PR rate was 4%. Cumulative incidence of CSR/PR was 27, 37 and 46% at 5, 10 and 15 years, respectively. Independent predictors of increased CSR/PR rate were age (P = 0.028) and MG symptom duration <6 months (P = 0.013). Our data suggest that in patients with non-thymomatous MG, thymectomy by TC-US has a remission rate not inferior to those reported after trans-sternal or video-assisted thoracic surgery techniques. The short duration of MG symptoms before thymectomy is a predictor of remission. The technique strikes a reasonable balance between the extent of thymic resection, operative and anaesthesia time, patient acceptance, neurological outcome and costs.

Modified Maximal Thymectomy for Myasthenia Gravis: Effect of Maximal Resection on Late Neurologic Outcome and Predictors of Disease Remission

Although thymectomy is a standard practice of care in patients with myasthenia gravis, the best approach to thymic resection remains controversial. This study was conducted to assess the effect of maximal resection on neurologic outcome and identify predictors of disease remission. Data of 78 myasthenic patients who underwent modified maximal thymectomy during a 17-year period were retrospectively analyzed. The primary study end point was the achievement of complete remission. Separate analysis was performed for thymoma and nonthymoma patients regarding the factors predicting the neurologic outcome. No patients died perioperatively. Surgical morbidity was 7.7%. The rate of postoperative myasthenic crisis was 3.8%. Thymoma and nonthymoma patients experienced comparable complete stable remission prediction (74.5% vs 85.7% at 15 years; p = 0.632). The absence of steroids in the preoperative medical treatment was statistically related to the prediction for complete stable remission in both thymoma (95% confidence interval [CI], 2.687 to 339.182, p = 0.006) and nonthymoma patients (95% CI, 1.607 to 19.183; p = 0.007) in multivariate analysis. In thymomatous myasthenia gravis, there was a statistically significant association between disease remission and the World Health Organization (WHO) histologic classification (95% CI, 0.262 to 0.827; p = 0.009). Maximal resections are recommended in myasthenic patients. Disease severity represents the prime determinant of the neurologic outcome after thymectomy. The neurologic outcome in patients after thymectomy may be statistically associated with the WHO classification subtypes but not necessarily with the aggressiveness of these tumors.

The autoimmunity-related polymorphism PTPN22 1858C/T is associated with anti-titin antibody-positive myasthenia gravis

Genetic variation in the intracellular tyrosine phosphatase PTPN22 has been recently associated with susceptibility to various autoimmune diseases. Myasthenia gravis (MG) is a complex genetic disease with a distinct clinical and pathological heterogeneity. We conducted a case–control association study for the PTPN22 1858C/T polymorphism in Hungarian and German MG patients ( n = 282) and regional controls ( n = 379). We detected an association of the PTPN22 1858T allele with MG in the subgroup of nonthymoma patients with anti-titin antibodies present ( n = 50; T allele frequency 21% vs 11% in controls; p = 0.005, odds ratio 2.1, 95% confidence interval 1.23–3.58). This overrepresentation was reported independently in both Hungarian and German MG patients compared with regional controls. We conclude that the common autoimmune polymorphism PTPN22 1858C/T may account for disease susceptibility in a subset of nonthymoma MG patients with anti-titin antibodies present.

Current and Future Standards in Treatment of Myasthenia Gravis

Myasthenia gravis (MG) is a prototypic antibody-mediated neurological autoimmune disorder. Herein we characterize modern treatment algorithms that are adapted to disease severity, and introduce the current principles of escalating strategies for MG treatment. In non-thymoma patients younger than about 50 years of age and with generalized weakness, a complete early (but not urgent) thymectomy is considered as state-of-the-art on the basis of circumstantial evidence and expert opinion. In up to 10% of patients, MG is associated with a thymoma (i.e., is of paraneoplastic origin). The best surgical type of procedure is still under debate. Myasthenic crisis is best treated by plasmapheresis, mostly combined with immunoabsorption techniques. Intravenous immunoglobulins are a reasonable alternative, but a shortage in supplies and high prices limit their use. In generalized MG, a wide array of immunosuppressive treatments has been established, although not formally tested in double-blind, prospective trials. With regard to immunosuppression, azathioprine is still the standard baseline treatment, often combined with initial corticosteroids. In rare patients with an inborn hepatic enzyme deficiency of thiomethylation, azathioprine may be substituted by mycophenolate mofetil. Severe cases may benefit from combined immunosuppression with corticosteroids, cyclosporine A, and even with moderate doses of methotrexate or cyclophosphamide. Tacrolimus is under investigation. In refractory cases, immunoablation via high-dose cyclophosphamide followed by trophic factors such as granulocyte colony-stimulating factor has also been suggested. In the future we may face an increased use of novel, B-cell, or T-cell-directed monoclonal antibodies.

Review: Progress in the treatment of myasthenia gravis

Substantial therapeutic progress has been made in myasthenia gravis (MG) even before the era of molecular medicine. Here we characterize modern treatment algorithms that are adapted to disease severity and introduce the principle of escalating treatment strategies for MG. In very mild cases and in some ocular forms of MG, treatment with acetylcholinesterase inhibitors may be sufficient, at least temporarily, but commonly some kind of immunologically active treatment is needed. In generalized MG, a wide array of immunosuppressive treatments has been established through observational studies, some prospective, but most of them have never been tested in a double-blind, prospective and randomized trial. Within the immunologically active drugs, glucocorticosteroids (GCS) and the immunosuppressive drug azathioprine (Aza) have been studied the longest. Aza is still the standard base-line treatment, in particular in cases where high doses of GCS would be needed to maintain remission. If Aza is not tolerated, several alternatives are available including cyclosporine A (Cic A), mycophenolate mofetil, cyclophosphamide, and methotrexate, all of them off-label in most western countries. Tacrolimus is under investigation. More severe cases may profit from drug combinations in which compounds with more rapidly acting drugs (GCS, Cic A) are combined with others showing a more delayed action (Aza). All such combination therapies need to be supervised by an experienced neuroimmunological center because of potentially serious adverse reactions. Serial measurements of anti-acetylcholine receptor antibodies, once these are elevated, is a useful adjunct for monitoring long-term treatment success and may help in weaning from higher to lower doses or to single drugs rather than combinations. For very severe and treatment-resistant cases, co-treatment with intravenous immunoglobulins or different modalities of plasmapheresis may be considered on the short term while the humanized monoclonal anti-CD 20 antibody (rituximab) is a candidate for the long term. In highly refractory cases also immuno-ablation via high-dose cyclophosphamide, followed by hematologic trophic factors such as G-CSF, has been tried successfully. Future developments may include other immunologically active monoclonal antibodies (e.g., anti-CD 52, Campath-1). Up to 10% of patients with MG are associated with a malignant thymoma, often referred to as paraneoplastic MG, as detected by CT scan or MRI, and these patients require thymomectomy and sometimes postsurgical chemotherapy and radiation treatment. In nonthymoma patients with generalised MG, including older children and adults up to the 5th decade, a complete transsternal thymectomy is recommended based on available open trials and expert opinion, preferentially during the first year of disease. Endoscopic surgery may also be effective. Before surgery, pretreatment with immunosuppressive medication or plasmapheresis is usually recommended to ameliorate MG and subsequently reduce perioperative morbidity and mortality which is now near zero in experienced centers. Myasthenic crisis is the life-threatening exacerbation of MG and is best treated by plasmapheresis, mostly combined with immunoadsorption techniques. Intravenous immunoglobulins are a reasonable alternative, but a shortage in supplies and high prices limit its use.

Antibodies to acetylcholine receptors in myasthenia gravis. In vitro synthesis by peripheral blood lymphocytes before and after thymectomy

Pokeweed mitogen (PWM)-driven in vitro synthesis of antibodies to the acetylcholine receptor (PSA) was studied in non-thymoma patients with myasthenia gravis. In a group of 46 patients, the occurrence of PSA was related to the presence of the thymus or, in operated patients, the absence of a clinical effect of thymectomy. Sixteen patients were followed before and soon after thymectomy. PSA disappeared in all patients, at least temporarily, between 6 weeks and 1 year afterwards, independent of the clinical course and eventual clinical effect of the operation. A recurrence was found only in one of the five patients who derived no benefit from the operation. These findings support the hypothesis that the therapeutic effect of thymectomy can be explained by removal of a source of autoreactive lymphocytes. There was no correlation between the changes in serum levels of a-AChR and clinical improvement, suggesting a minor role of circulating peripheral blood lymphocytes (PBL) and the thymus in the total production of a-AChR.

Treatment of myasthenia gravis

Myasthenia gravis is a prototypic antibody-mediated neurological autoimmune disorder. Its pathogenesis is much better understood than that of multiple sclerosis or immune neuropathies. Currently two targets in the endplate membrane are considered as autoantigens, the acetylcholine receptor (in up to 90%) and the muscle-specific kinase (MuSK, in about 5%). Fortunately, substantial therapeutic progress has been made even before the era of molecular and translational medicine. In this review we characterise modern treatment algorithms that are adapted to disease severity and introduce the principle of escalating treatment strategies for myasthenia gravis. In mild cases and ocular forms of myasthenia gravis treatment with acetylcholine esterase inhibitors may be sufficient, at least temporarily. In generalised myasthenia gravis a wide array of immunosuppressive treatments have been established but most have never been tested in a full-size prospective randomised trial. Up to 10% of patients with myasthenia gravis are associated with a thymoma, i.e. of paraneoplastic origin, and this has to be looked for by CAT scan or MRI. In non-thymoma patients younger than about 50 years of age and with generalised weakness a complete early (but not urgent) thymectomy is considered as state of the art based on circumstantial evidence and expert opinion; the best type of procedure is still under debate. Usually, pretreatment with immunosuppressive medication or plasma-pheresis is recommended. Myasthenic crisis is best treated by plasma-pheresis, mostly combined with immunoadsorption techniques. Intravenous immunoglobulins are a reasonable therapeutic alternative, but a shortage in supply and high prices limit its use. With regard to immunosuppression azathioprine is still the standard base-line treatment, often combined with initial corticosteroids. In rare patients with inborn hepatic enzyme deficiency of thiomethylation azathioprine it is not well tolerated and may be substituted by mycophenolate mofetil. Severe cases may profit from combined immunosuppression with corticosteroids, cyclosporine A and even moderate doses of methotrexate or cyclophosphamide. Tacrolimus is under investigation. All such combination therapies need to be supervised by an experienced academic neuroimmunological centre. Serial measurements of anti-acetylcholine receptor antibodies, once these are elevated, or MuSK antibodies are a useful adjunct for monitoring treatment success. In escalating therapy for very severe cases one may employ monoclonal anti-CD 20 antibodies (rituximab). In highly refractory cases also immunoablation via high-dose cyclophosphamide, followed by trophic factors such as G-CSF has been suggested.

Effects of thymectomy on late-onset myasthenia gravis without thymoma

Objectives This study aims to investigate whether thymectomy is beneficial for late-onset (>50 years) myasthenia gravis patients with no thymoma, particularly for those with mild generalized weakness. Patients and methods A total of 34 patients were included in the study. The clinical course and long-term outcomes over 2 years were reviewed in 20 patients who underwent thymectomy and in 14 without thymectomy. Results Of the 34 patients, 20 (59%) underwent thymectomy. Thymectomized patients had more severe disability at entry than non-thymectomized patients, but outcome measures did not significantly differ between the two patient groups. Moreover, subgroup analyses including 22 patients with mild generalized weakness at entry showed that the thymectomized group ( n = 10) showed a greater percentage of clinical remission (no symptoms; 50% versus 17%; p = 0.11) and a lower frequency of the presence of generalized symptoms (30% versus 75%; p < 0.05) than the non-thymectomized group ( n = 12) at the end of follow-up (means 9.6 years after onset). Conclusions Thymectomy is a potentially effective treatment for late onset, non-thymomatous patients with mild generalized myasthenia gravis.

Experience with starting tacrolimus postoperatively after transsternal extended thymectomy in patients with myasthenia gravis

ABSTRACTBackground: Thymectomy is a standard treatment of myasthenia gravis (MG). Immunomodulating agents are frequently given during the postthymectomy latency period until complete remission is fully consolidated, but serious side effects is a relevant clinical problem for patients on long-term immunomodulating treatment.Objective: To assess the effectiveness of starting tacrolimus in the immediate postoperative period in MG patients undergoing transsternal extended thymectomy, with complete stable remission (CSR) as the primary outcome of the study.Methods: Forty-eight MG patients received tacrolimus, 0.1 mg/kg per day b.i.d. (started 24 h after thymectomy) and prednisone 1.5 mg/kg/day. Histologically, 34 patients had hyperplasia, 20 thymic involution, and 14 thymoma. Of the 48 patients, 40 completed 1 year of tacrolimus therapy, 38 completed 2 years, 27 completed 3 years, 21 completed 4 years, and 9 more than 5 years. Mean dose of tacrolimus was 4.9 mg/day (range 2–8 mg/day) with a mean plasma drug concentration of 7.6 ng/mL (range 7–9 ng/mL). Prednisone could be withdrawn after the first year in 93.7% of patients and at 2 years in 100%.Results: The mean follow-up was 24.4 months, SD 17.3 (range 6–60 months). Improvement of muscular strength and decrease of anti-AChR antibodies were statistically significant ( p < 0.001) shortly after operation. CSR was obtained in 33.4% of patients, pharmacological remission in 62.6%; 4% of patients had minimal symptoms. None of the patients with thymoma achieved CSR. The estimated median follow-up to obtain a CSR was 37.9 months (95% confidence interval [CI] 26.4–49.5 months). The overall crude CSR rate was 33.4%, with 47% for non-thymoma patients. The probability to achieve CSR at 3 years was 67% for the non-thymomatous group.Conclusions: Long-term immune-directed treatment with tacrolimus to improve the effectiveness of thymectomy in MG is feasible and was associated with a high rate of CSR in patients without thymoma.