Inter-alpha-trypsin inhibitor heavy chain H3 is a potential biomarker for disease activity in myasthenia gravis.

Myasthenia gravis is a chronic antibody-mediated autoimmune disease disrupting neuromuscular synaptic transmission. Informative biomarkers remain an unmet need to stratify patients with active disease requiring intensified monitoring and therapy; their identification is the primary objective of this study. We applied mass spectrometry-based proteomic serum profiling for biomarker discovery. We studied an exploration and a prospective validation cohort consisting of 114 and 140 anti-acetylcholine receptor antibody (AChR-Ab)-positive myasthenia gravis patients, respectively. For downstream analysis, we applied a machine learning approach. Protein expression levels were confirmed by ELISA and compared to other myasthenic cohorts, in addition to myositis and neuropathy patients. Anti-AChR-Ab levels were determined by a radio receptor assay. Immunohistochemistry and immunofluorescence of intercostal muscle biopsies were employed for validation in addition to interactome studies of inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3). Machine learning identified ITIH3 as potential serum biomarker reflective of disease activity. Serum levels correlated with disease activity scores in the exploration and validation cohort and were confirmed by ELISA. Lack of correlation between anti-AChR-Ab levels and clinical scores underlined the need for biomarkers. In a subgroup analysis, ITIH3 was indicative of treatment responses. Immunostaining of muscle specimens from these patients demonstrated ITIH3 localization at the neuromuscular endplates in myasthenia gravis but not in controls, thus providing a structural equivalent for our serological findings. Immunoprecipitation of ITIH3 and subsequent proteomics lead to identification of its interaction partners playing crucial roles in neuromuscular transmission. This study provides data on ITIH3 as a potential pathophysiological-relevant biomarker of disease activity in myasthenia gravis. Future studies are required to facilitate translation into clinical practice.

Comparison of juvenile and adult myasthenia gravis in a French cohort with focus on thymic histology.

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle fatigability due to acetylcholine receptor (AChR) autoantibodies. To better characterize juvenile MG (JMG), we analyzed 85 pre- and 132 post-pubescent JMG (with a cutoff age of 13) compared to 721 adult MG patients under 40 years old using a French database. Clinical data, anti-AChR antibody titers, thymectomy, and thymic histology were analyzed. The proportion of females was higher in each subgroup. No significant difference in the anti-AChR titers was observed. Interestingly, the proportion of AChR+ MG patients was notably lower among adult MG patients aged between 30 and 40 years, at 69.7%, compared to over 82.4% in the other subgroups. Thymic histological data were examined in patients who underwent thymectomy during the year of MG onset. Notably, in pre-JMG, the percentage of thymectomized patients was significantly lower (32.9% compared to more than 42.5% in other subgroups), and the delay to thymectomy was twice as long. We found a positive correlation between anti-AChR antibodies and germinal center grade across patient categories. Additionally, only females, particularly post-JMG patients, exhibited the highest rates of lymphofollicular hyperplasia (95% of cases) and germinal center grade. These findings reveal distinct patterns in JMG patients, particularly regarding thymic follicular hyperplasia, which appears to be exacerbated in females after puberty.

Type B thymomas in patients with myasthenia gravis display a distinctive pattern of αß TCR and IL-7 receptor α expression on CD4+CD8+ thymocytes.

Thymoma is closely associated with myasthenia gravis (MG). However, due to the heterogeneity of thymoma and the intricate pathogenesis of MG, it remains unclear why some patients with thymoma develop MG and others do not. In this study, we conducted a comparative phenotype analysis of thymocytes in type B thymomas in patients with MG (MG (+) thymomas) and without MG (MG (-) thymomas) via fluorescence-activated cell sorting (FACS). Our results show that the developmental stages defined by the expression of CD3, CD4, and CD8 were largely maintained in both MG (+) and MG (-) thymomas, with CD4+CD8+ cells constituting the majority of thymocytes in type B thymoma, and no significant difference between this cell population was observed in MG (+) and MG (-) thymomas.We discovered that CD4+CD8+ thymocytes in MG (+) thymomas expressed low levels of αß TCR and high levels of IL-7 receptor α (IL-7Rα), whereas in MG (-) thymomas, CD4+CD8+ thymocytes exhibited the opposite pattern of αß TCR and IL-7Rα expression. These results suggest that the positive and negative selection processes of CD4+CD8+ thymocytes might differ between MG (+) thymomas and MG (-) thymomas. The expression of the Helios transcription factor is induced during negative selection and marks a group of T cells that have undergone negative selection and are likely to be deleted due to strong TCR binding with self-peptides/MHC ligands. We observed that the percentage of Helios-positive CD4SP T cells was greater in MG (-) than in MG (+) thymomas. Thus, the differentially regulated selection process of CD4+CD8+ thymocytes, which involves TCR and IL-7/IL-7Rα signaling, is associated with the presence of MG in type B thymomas.

Thymic gene expression analysis reveals a potential link between HIF-1A and Th17/Treg imbalance in thymoma associated myasthenia gravis.

Myasthenia gravis (MG) is an immune-mediated disease frequently associated with thymic changes. Increased T helper 17 (Th17) cell activity and dysfunctional regulatory T (Treg) cells have been demonstrated in subgroups of MG. On the other hand, hypoxia-inducible factor 1 (HIF-1) has been shown to regulate the Th17/Treg balance by inducing Th17 differentiation while attenuating Treg development. To identify the underlying mechanisms of different thymic pathologies in MG development, we evaluated thymic samples from thymoma-associated myasthenia gravis (TAMG), MG with hyperplasia (TFH-MG) and thymoma without MG (TOMA) patients. Differential gene expression analysis revealed that TAMG and TFH-MG cells are associated with different functional pathways. A higher RORC/FOXP3 ratio provided evidence for Th17/Treg imbalance in TAMG potentially related to increased HIF1A. The hypoxic microenvironment in thymoma may be a driver of TAMG by increasing HIF1A. These findings may lead to new therapeutic approaches targeting HIF1A in the development of TAMG.

Mendelian randomization and colocalization analysis reveal novel drug targets for myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is a complex autoimmune disease affecting the neuromuscular junction with limited drug options, but the field of MG treatment recently benefits from novel biological agents. We performed a drug-targeted Mendelian randomization (MR) study to identify novel therapeutic targets of MG. METHODS: Cis-expression quantitative loci (cis-eQTL), which proxy expression levels for 2176 druggable genes, were used for MR analysis. Causal relationships between genes and disease, identified by eQTL MR analysis, were verified by comprehensive sensitivity, colocalization, and protein quantitative loci (pQTL) MR analyses. The protein-protein interaction (PPI) analysis was also performed to extend targets, followed by enzyme-linked immunosorbent assay (ELISA) to explore the serum level of drug targets in MG patients. A phenome-wide MR analysis was then performed to assess side effects with a clinical trial review assessing druggability. RESULTS: The eQTL MR analysis has identified eight potential targets for MG, one for early-onset MG and seven for late-onset MG. Further colocalization analyses indicated that CD226, CDC42BPB, PRSS36, and TNFSF12 possess evidence for colocalization with MG or late-onset MG. pQTL MR analyses identified the causal relations of TNFSF12 and CD226 with MG and late-onset MG. Furthermore, PPI analysis has revealed the protein interaction between TNFSF12-TNFSF13(APRIL) and TNFSF12-TNFSF13B(BLyS). Elevated TNFSF13 serum level of MG patients was also identified by ELISA experiments. This study has ultimately proposed three promising therapeutic targets (TNFSF12, TNFSF13, TNFSF13B) of MG. CONCLUSIONS: Three drug targets associated with the BLyS/APRIL pathway have been identified. Multiple biological agents, including telitacicept and belimumab, are promising for MG therapy.

Paraneoplastic myopathies.

This chapter reviews the association between cancer and the idiopathic inflammatory myopathies (IIM), which includes dermatomyositis (DM), antisynthetase syndrome (ASyS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Accumulating evidence shows that the risk of a coexisting malignancy is high in patients with DM, especially among those with anti-Tif1γ autoantibodies. Patients with IMNM and no defined autoantibodies also have an increased risk of malignancy. Recent evidence demonstrates that many IBM patients have increased numbers of circulating CD57+ CD8+ T cells, consistent with a diagnosis of large granular lymphocytic leukemia. In contrast, IMNM patients with anti-SRP or anti-HMGCR autoantibodies as well as patients with ASyS syndrome do not have a definitively increased risk of cancer. Patients who have a cancer treated with one of the immune checkpoint inhibitors can develop myositis (ICI-myositis), sometimes along with myasthenia gravis and/or myocarditis.

Defective autophagy and autophagy activators in myasthenia gravis: a rare entity and unusual scenario.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ) that results from autoantibodies against nicotinic acetylcholine receptors (nAchRs) at NMJs. These autoantibodies are mainly originated from autoreactive B cells that bind and destroy nAchRs at NMJs preventing nerve impulses from activating the end-plates of skeletal muscle. Indeed, immune dysregulation plays a crucial role in the pathogenesis of MG. Autoreactive B cells are increased in MG due to the defect in the central and peripheral tolerance mechanisms. As well, autoreactive T cells are augmented in MG due to the diversion of regulatory T (Treg) cells or a defect in thymic anergy leading to T cell-mediated autoimmunity. Furthermore, macroautophagy/autophagy, which is a conserved cellular catabolic process, plays a critical role in autoimmune diseases by regulating antigen presentation, survival of immune cells and cytokine-mediated inflammation. Abnormal autophagic flux is associated with different autoimmune disorders. Autophagy regulates the connection between innate and adaptive immune responses by controlling the production of cytokines and survival of Tregs. As autophagy is involved in autoimmune disorders, it may play a major role in the pathogenesis of MG. Therefore, this mini-review demonstrates the potential role of autophagy and autophagy activators in MG.Abbreviations: Ach, acetylcholine; Breg, regulatory B; IgG, immunoglobulin G; MG, myasthenia gravis; NMJ, neuromuscular junction; ROS, reactive oxygen species; Treg, regulatory T; Ubl, ubiquitin-like.

Unexpected fibrous mediastinitis in a patient with myasthenia gravis - a case report.

BACKGROUND: Fibrous mediastinitis (FM) is a rare mediastinal lesion characterized by proliferation of fibrous tissue within the mediastinum. Previous reports have shown that this lesion can be caused by histoplasmosis and tuberculosis. In extremely rare cases, FM can also be caused by autoimmune diseases such as antineutrophil cytoplasmic antibody-associated vasculitis and large-vessel arteritis. CASE PRESENTATION: In our case, we report unexpected fibrous mediastinitis found after robotic thymectomy in a patient with myasthenia gravis (MG). The preoperative imaging indicated no obvious lesion in the mediastinum and the patient denied histories of both histoplasmosis and tuberculosis. After the operation, both proliferation of fibrous tissue and ectopic germinal centres (GCs) could be found in the thymus. CONCLUSION: This rare case might enrich our knowledge of the relationship between FM and autoimmune diseases.

Outcomes of extended resection for locally advanced thymic malignancies.

BACKGROUND: Thymic malignancies are rare tumors about which data are limited. Our objective here was to evaluate the outcomes and risk factors for complications and death in patients who underwent extended surgery to remove thymic malignancies. METHODS: We retrospectively included patients who underwent extended resection of locally advanced, nonmetastatic thymic malignancies at our institution. Patients were deemed eligible for resection by a multidisciplinary team. During surgery, priority was given to achieving complete resection rather than to sparing organs. RESULTS: The 108 patients had a mean age of 53 ± 15 years (range, 9-83); among them, 91 had thymoma, 12 thymic carcinoma, and 5 neuroendocrine tumor. The Masaoka stage was III or higher in 86 patients; examination of operative specimens resulted in downstaging of 22 patients. Tumor-free resection margins were achieved in 98 patients. Overall 5- and 10-year survival rates were 80% and 68%, respectively. Myasthenia gravis, present in 36 patients, was the only independent significant risk factor for major postoperative complications. Age older than 70 years, thymic carcinoma or neuroendocrine tumor, pT3 or pT4 stage, and R1 or R2 resection margins independently predicted death. The number of resected structures was not associated with survival. Thymic carcinoma or neuroendocrine tumor was independently associated with shorter disease-free survival. CONCLUSION: In an expert center, extended resection targeting complete resection rather than organ preservation provided good outcomes in patients with locally advanced thymic malignancies. The risk/benefit ratio of surgery should be assessed with special care in patients who are elderly or have myasthenia gravis.

The value of postoperative radiotherapy in thymoma patients with myasthenia gravis.

INTRODUCTION: Surgery is the first-line treatment for patients with thymoma associated with myasthenia gravis (MG); however, the value of radiotherapy among these patients remains debatable. Herein, we examined the impact of postoperative radiotherapy (PORT) on the efficacy and prognosis of patients with thymoma and MG. METHODS: This retrospective cohort study included 126 patients with thymoma and MG who were enrolled in the Xiangya Hospital clinical database between 2011 and 2021. Demographic and clinical data were collected including sex, age, histologic subtype, Masaoka-Koga staging, primary tumor, lymph node, metastasis (TNM) staging, and therapeutic modalities. To evaluate short-term MG symptom improvement following PORT, we examined changes in the quantitative myasthenia gravis (QMG) scores within 3 months post-treatment. Minimal manifestation status (MMS) was the main endpoint for assessing long-term improvement in MG symptoms. Overall survival (OS) and disease-free survival (DFS) were primary endpoints to determine the impact of PORT on prognosis. RESULTS: Effects of PORT on MG symptoms: QMG scores significantly differed between the non-PORT and PORT groups (χ2 = 6.300, p = 0.012). The median time to achieve MMS was significantly shorter in the PORT group than that in the non-PORT group (2.0 years vs. 4.4 years; p = 0.031). Multivariate analysis revealed that radiotherapy was associated with a reduced time to achieve MMS (hazard ratio [HR] 1.971, 95% confidence interval [CI]:1.102-3.525, p = 0.022). Effects of PORT on DFS and OS: The 10-year OS rate of the entire cohort was 90.5%, whereas OS rates for the PORT and non-PORT groups were 94.4 and 85.1%, respectively. The 5-year DFS rates for the whole cohort, PORT group, and non-PORT group were 89.7, 95.8, and 81.5%, respectively. PORT was associated with improved DFS (HR 0.139, 95% CI: 0.037-0.533, p = 0.004). In the high-risk histologic subgroup (type B2, B3), patients who received PORT had better OS (p = 0.015) and DFS (p = 0.0053) than those who did not receive PORT. PORT was associated with improved DFS (HR 0.232, 95% CI: 0.069-0.782, p = 0.018) in Masaoka-Koga stages II, III, and IV disease. CONCLUSIONS: Overall, our findings indicate that PORT positively impacts thymoma patients with MG, particularly those with a higher histologic subtype and Masaoka-Koga staging.

Comparison of Short-Term Post-Thymectomy Outcomes by Time-Weighted Dosages of Drug Requirements between Thymoma and Non-Thymoma Myasthenia Gravis Patients.

(1) Background: Early thymectomy is suggested in all clinically indicated myasthenia gravis (MG) patients. However, short-term clinical response after thymectomy in MG patients has been limitedly described in the literature. This study aimed to compare the 5-year post-thymectomy outcomes between thymoma (Th) and non-thymoma (non-Th) MG patients. (2) Methods: MG patients aged ≥18 years who underwent transsternal thymectomy and had tissue histopathology reports in Songklanagarind Hospital between 2002 and 2020 were enrolled in a retrospective review. The differences in the baseline demographics and clinical characteristics between ThMG and non-Th MG patients were studied. We compared the time-weighted averages (TWAs) of daily required dosages of pyridostigmine, prednisolone or azathioprine to efficiently maintain daily living activities and earnings between the MG patient groups during 5 consecutive years following thymectomy. Post-thymectomy clinical status, exacerbations or crises were followed. Descriptive statistics were used for analysis with statistical significance set at p < 0.05. (3) Results: ThMG patients had significantly older ages of onset and shorter times from the MG diagnosis to thymectomy. Male gender was the only significant factor associated with ThMG. TWAs of the daily MG treatment drug dosages required showed no differences between the groups. Additionally, the rates of exacerbations and crises were not different, but decremental trends were shown in both groups after the thymectomies. (4) Conclusions: The daily dosage requirements of MG treatment drugs were not different. There was a trend of decreasing adverse event rates despite no statistically significant differences during the first 5 years after thymectomy in ThMG and non-ThMG patients.

Expression of Programmed Cell Death 1 Ligand 2 in Patients With Thymoma and Thymomatous Myasthenia Gravis.

OBJECTIVES: This study aimed to examine the expression of programmed cell death 1 ligand 2 (PD-L2) in thymoma and thymomatous myasthenia gravis (MG). METHODS: The records of 70 patients with thymoma receiving surgical resection between January 2017 and December 2018 were retrospectively reviewed. Thymoma PD-L2 expression was evaluated by immunohistochemistry staining. Associations between PD-L2 expression and clinicopathologic features were examined. RESULTS: PD-L2 expression was positive in 41 patients (58.6%) and negative in 29 patients (41.4%). Of them, 33 had thymomatous MG. Patients with MG were more likely to be 50 years of age or younger (69.70% vs 35.14%); have more World Health Organization (WHO) type B thymomas (84.85% vs 64.86%); have tumors of smaller size (4.09 ± 2.33 cm vs 6.47 ± 2.42 cm); have positive PD-L2 expression (78.79% vs 40.54%); and have a higher percentage of PD-L2-positive cells, higher PD-L2 expression intensity, and score (all P < .05). Positive PD-L2 expression was associated with more type B thymomas, higher Masaoka-Koga stage, smaller tumor size, ectopic thymus, and MG (all P < .05). Factors significantly associated with MG were age under 50 years, tumor size less than 5 cm, and positive PD-L2 expression (all P < .05). CONCLUSIONS: Thymoma PD-L2 expression is significantly associated with thymomatous MG and WHO histologic types B2 and B3.

Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities.

Myasthenia gravis is an autoimmune disorder defined by muscle weakness and fatigability associated with antibodies against proteins of the neuromuscular junction (NMJ). The most common autoantibody target is the acetylcholine receptor (AChR). Three mechanisms have been postulated by which autoantibodies might interfere with neurotransmission: direct antagonism of the receptor, complement-mediated destruction of the postsynaptic membrane, and enhanced internalization of the receptor. It is very likely that more than one of these mechanisms act in parallel. Dissecting the mechanisms of autoantibody-mediated pathology requires patient-derived, monoclonal antibodies. Using membrane antigen capture activated cell sorting (MACACS), we isolated AChR-specific B cells from patients with myasthenia gravis, and produced six recombinant antibodies. All AChR-specific antibodies were hypermutated, including isotypes IgG1, IgG3, and IgG4, and recognized different subunits of the AChR. Despite clear binding, none of the individual antibodies showed significant antagonism of the AChR measured in an in vitro neuromuscular synapse model, or AChR-dependent complement activation, and they did not induce myasthenic signs in vivo. However, combinations of antibodies induced strong complement activation in vitro, and severe weakness in a passive transfer myasthenia gravis rat model, associated with NMJ destruction and complement activation in muscle. The strongest complement activation was mediated by combinations of antibodies targeting disparate subunits of the AChR, and such combinations also induced the formation of large clusters of AChR on the surface of live cells in vitro. We propose that synergy between antibodies of different epitope specificities is a fundamental feature of this disease, and possibly a general feature of complement-mediated autoimmune diseases. The importance of synergistic interaction between antibodies targeting different subunits of the receptor can explain the well-known discrepancy between serum anti-AChR titers and clinical severity, and has implications for therapeutic strategies currently under investigation.

Retrospective histopathology audit of thymectomy specimens: A clinicopathological study of 303 cases spanning the non-neoplastic, benign and malignant spectrum.

Aims: Thymectomy specimens are uncommon in routine histopathology practice. However, awareness of various pathologic entities and definite reporting of these specimens is paramount to optimal patient management. Our objective was to determine the histomorphologic spectrum of thymectomy specimens spanning the non-neoplastic, benign to malignant spectrum. Methods and Results: Thymectomies received over an 8-year period were retrospectively analyzed by reviewing clinical details and histologic findings in detail, incorporating the latest World Health Organization (WHO) 2015 histologic classification. A total of 303 thymectomy specimens (179 males/124 females, mean age 45.3 years [3-84 years]) were included. Around 51.2% (n = 155) patients had associated myasthenia gravis (MG), while 17.5% (n = 53) had incidentally detected anterior mediastinal mass (AMM). Non-neoplastic and benign pathologies comprised 31% (n = 94) cases and showed stronger association with MG (P = 0.009). Thymic follicular hyperplasia (TFH) was the commonest non-neoplastic pathology (n = 32), while the benign tumor group included thymic hemangioma/lymphangioma, thymolipoma, and ectopic parathyroid adenoma. Thymic epithelial tumors (TETs) comprised 64.7% cases, with majority being thymomas (185/303; 61.1%). Thymoma type B2 was the commonest histologic subtype and Stage I/T1 was the most frequent stage. Type A and AB thymomas affected older patients (P = 0.005) and were in lower stage (both Masaoka and American Joint Committee on Cancer [AJCC]) than type B thymomas (P = 0.007). No significant association between MG and thymoma subtype, patient sex or Masaoka stage was seen (P > 0.05). Thymic carcinomas comprised 11 cases and showed no association with MG (0/11, P < 0.001); squamous cell carcinoma was the commonest histologic type (8/11; 72.7%). Conclusion: TETs are the commonest thymic lesions; however, a diverse spectrum of pathologic processes can affect the thymus.

Ectopic germinal centers in the thymus accurately predict prognosis of myasthenia gravis after thymectomy.

The ability of thymic histopathology to predict the long-term impact of thymectomy in non-thymomatous myasthenia gravis (NTMG) is mainly uncharted. We applied digital pathology to quantitatively characterize differences of thymic histology between early-onset (EOMG) and late-onset MG (LOMG) and to investigate the role of thymic changes for thymectomy outcomes in MG. We analyzed 83 thymic H&E slides from thymectomized NTMG patients, of which 69 had EOMG and 14 LOMG, using digital pathology open-access software QuPath. We compared the results to the retrospectively assessed clinical outcome at two years after thymectomy and at the last follow-up visit where complete stable remission and minimal use of medication were primary outcomes. The automated annotation pipeline was an effective and reliable way to analyze thymic H&E samples compared to manual annotation with mean intraclass correlation of 0.80. The ratio of thymic tissue to stroma and fat was increased in EOMG compared to LOMG (p = 8.7e-07), whereas no difference was observed in the ratio of medulla to cortex between these subtypes. AChRAb seropositivity correlated with the number of ectopic germinal centers (eGC; p = 0.00067) but not with other histological areas. Patients with an increased number of eGCs had better post-thymectomy outcomes at two years after thymectomy (p = 0.0035) and at the last follow-up (p = 0.0267). ROC analysis showed that eGC area predicts thymectomy outcome in EOMG with an AUC of 0.79. Digital pathology can thus help in providing a predictive tool to the clinician, the eGC number, to guide the post-thymectomy treatment decisions in EOMG patients.

Partial Versus Complete Thymectomy in Non-Myasthenic Patients With Thymoma: A Systematic Review and Meta-Analysis of Clinical Outcomes.

OBJECTIVE: The optimal extent of surgical resection for non-myasthenic patients with thymoma is controversial. The objective of this meta-analysis was to compare complete to partial thymectomy in non-myasthenic patients for oncological and postoperative clinical outcomes. METHODS: We performed a PubMed and EMBASE search (from inception to January 2020) for English-language studies directly comparing partial thymectomy (thymomectomy) to complete thymectomy for thymoma resection. Clinical endpoints studied included overall and disease-free survival, Masaoka and World Health Organization staging, adjuvant therapy, postoperative complications, postoperative drainage, length of hospital stay, thymoma-related deaths, postresection development of myasthenia gravis, incomplete resection, and recurrence. Random effects meta-analyses across all clinical endpoints was done. RESULTS: There was no statistically significant difference between the two approaches with regard to recurrence (odds ratio [OR], 1.22; 95% confidence interval [CI], 0.78-1.92), completeness of resection (OR, 1.17; 95% CI, 0.66-2.10), adjuvant therapy (OR, 0.71; 95% CI, 0.40-1.26), or thymoma-related deaths (OR, 0.76; 95% CI, 0.12-4.66). There was a statistically significant decrease in postoperative complications (OR, 0.61; 95% CI, 0.39-0.97), drainage (mean difference [MD], -0.99; 95% CI, -1.98 to -0.01), and length of hospital length (MD, -1.88; 95% CI, -3.39 to -0.36) with partial thymectomy. CONCLUSIONS: The evidence appeared to suggest that partial thymectomy is oncologically equivalent to complete thymectomy for non-myasthenic patients with early-stage thymoma. There is an additional advantage of reduced postoperative complications and decreased length of hospital stay with partial thymectomy.

Case Report: The first reported case of pulmonary alveolar proteinosis with myasthenia gravis in a 27-year-old patient.

Background: Pulmonary alveolar proteinosis is a very rare diffuse lung disease characterized by the accumulation of amorphous and periodic acid Schiff-positive lipoproteinaceous material in the alveolar spaces due to impaired surfactant clearance by alveolar macrophages. Three main types were identified: Autoimmune, secondary and congenital. Pulmonary alveolar proteinosis has been previously reported to be associated with several systemic auto-immune diseases. Accordingly, we present the first case report of pulmonary alveolar proteinosis associated with myasthenia gravis. Case: A 27-year-old female patient, ex-smoker, developed a dyspnea on exertion in 2020. The chest X-ray detected diffuse symmetric alveolar opacities. Pulmonary infection was ruled out, particularly COVID-19 infection. The chest scan revealed the "crazy paving" pattern. The bronchoalveolar lavage showed a rosy liquid with granular acellular eosinophilic material Periodic acid-Schiff positive. According to the lung biopsy results, she was diagnosed with pulmonary alveolar proteinosis. The granulocyte macrophage colony-stimulating factor autoantibodies were negative. Nine months later, she was diagnosed with bulbar seronegative myasthenia gravis, confirmed with the electroneuromyography with repetitive nerve stimulation showing significant amplitude decrement of the trapezius and spinal muscles. She was treated with pyridostigmine, oral corticosteroids and azathioprine. Given the worsening respiratory condition of the patient, a bilateral whole lung lavage was performed with a partial resolution of symptoms. Thus, this previously unreported association was treated successfully with rituximab, including improvement of dyspnea, diplopia and muscle fatigability at six months of follow-up. Conclusions: This case emphasizes on the possible association of auto-immune disease to PAP, which could worsen the disease course, as the specific treatment does not exist yet. Hence, further studies are needed to establish clear-cut guidelines for PAP management, particularly when associated to auto-immune diseases.

A Review on the Role of Non-Coding RNAs in the Pathogenesis of Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune condition related to autoantibodies against certain proteins in the postsynaptic membranes in the neuromuscular junction. This disorder has a multifactorial inheritance. The connection between environmental and genetic factors can be established by epigenetic factors, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). XLOC_003810, SNHG16, IFNG-AS1, and MALAT-1 are among the lncRNAs with a possible role in the pathoetiology of MG. Moreover, miR-150-5p, miR-155, miR-146a-5p, miR-20b, miR-21-5p, miR-126, let-7a-5p, and let-7f-5p are among miRNAs whose roles in the pathogenesis of MG has been assessed. In the current review, we summarize the impact of miRNAs and lncRNAs in the development or progression of MG.