Antibody-positive Myasthenia Gravis Research Articles

Does Surgical Removal of the Thymus Have Deleterious Consequences?

The role of immunosenescence, particularly the natural process of thymic involution during aging, is increasingly acknowledged as a factor contributing to the development of autoimmune diseases and cancer. Recently, a concern has been raised about deleterious consequences of the surgical removal of thymic tissue, including for patients who undergo thymectomy for myasthenia gravis (MG) or resection of a thymoma. This review adopts a multidisciplinary approach to scrutinize the evidence concerning the long-term risks of cancer and autoimmunity postthymectomy. We conclude that for patients with acetylcholine receptor antibody-positive MG and those diagnosed with thymoma, the removal of the thymus offers prominent benefits that well outweigh the potential risks. However, incidental removal of thymic tissue during other thoracic surgeries should be minimized whenever feasible.

Muscle-Specific Receptor Tyrosine Kinase Antibody Positive Myasthenia Gravis

Reportedly, patients with muscle-specific kinase (MuSK) antibody-positive myasthenia gravis (MG) account for approximately 3.0% of all patients with MG in Japan. Compared with patients who have acetylcholine receptor antibody-positive MG, those with MuSK antibody-positive MG show young-onset disease with female predominance, a low rate of ocular involvement (5.9%), and greater severity of dysphagia. The aforementioned types of MG are indistinguishable based on clinical symptoms and electrophysiological tests, and measurement of MuSK antibodies is essential for diagnosis. Thymectomy and complement inhibitors are not indicated for treatment, and acetylcholinesterase inhibitors, steroids, immunosuppressants, plasma exchange, intravenous immunoglobulin therapy, and neonatal Fc receptor inhibitors are used.

AChR Antibody-Positive Myasthenia Gravis

Herein, we describe the mechanisms, diagnostic procedures, and treatment options for acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG). The upstream pathomechanism of this condition involves AChR-sensitized T cell-dependent B cell proliferation and the subsequent production of pathogenic autoantibodies. Downstream molecules include AChR antibodies that activate complement pathways, resulting in the destruction of motor endplates. We further introduce newly-developed molecular targeted drugs for the treatment of MG that aims to secure patients' health-related quality of life.

Gut microbiota-derived butyrate restores impaired regulatory T cells in patients with AChR myasthenia gravis via mTOR-mediated autophagy

More than 80% of patients with myasthenia gravis (MG) are positive for anti-acetylcholine receptor (AChR) antibodies. Regulatory T cells (Tregs) suppress overproduction of these antibodies, and patients with AChR antibody-positive MG (AChR MG) exhibit impaired Treg function and reduced Treg numbers. The gut microbiota and their metabolites play a crucial role in maintaining Treg differentiation and function. However, whether impaired Tregs correlate with gut microbiota activity in patients with AChR MG remains unknown. Here, we demonstrate that butyric acid-producing gut bacteria and serum butyric acid level are reduced in patients with AChR MG. Butyrate supplementation effectively enhanced Treg differentiation and their suppressive function of AChR MG. Mechanistically, butyrate activates autophagy of Treg cells by inhibiting the mammalian target of rapamycin. Activation of autophagy increased oxidative phosphorylation and surface expression of cytotoxic T-lymphocyte-associated protein 4 on Treg cells, thereby promoting Treg differentiation and their suppressive function in AChR MG. This observed effect of butyrate was blocked using chloroquine, an autophagy inhibitor, suggesting the vital role of butyrate-activated autophagy in Tregs of patients with AChR MG. We propose that gut bacteria derived butyrate has potential therapeutic efficacy against AChR MG by restoring impaired Tregs.

Clinical Features and Prognostic Analysis of MuSK-Antibody-Positive Myasthenia Gravis versus Double-Seropositive Myasthenia Gravis: A Single-Center Study from Central South China.

To decipher the discrepancies between muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG) and double-seropositive myasthenia gravis (DSP-MG), and to determine prognostic factors for minimal manifestation status (MMS) achievement in MG patients with MuSK autoantibodies (MuSK-Ab). A total of 34 MG patients seropositive for MuSK-Ab were enrolled in this study. The demographic and clinical features were compared between MuSK-MG (n = 28) and DSP-MG (n = 6) patients, and factors affecting MMS induction in all patients with MuSK-Ab were identified using Cox regression analysis. Compared to MuSK-MG patients, those with DSP-MG had similar clinical characteristics, except that they had a lower frequency of bulbar muscle involvement at nadir (50% vs 92.9%; P = 0.029) and higher proportions of comorbidities with diabetes mellitus (33.3% vs 0%; P = 0.027) and thymic abnormalities (33.3% vs 0%; P = 0.027). Higher MG Activities of Daily Living (MG-ADL) scores (HR = 0.16, 95% CI: 0.037-0.7, P = 0.015) and axial muscle involvement at nadir (HR = 0.39, 95% CI: 0.16-0.94, P = 0.035) were negative prognostic factors for MMS achievement in patients with MuSK-Ab regardless of acetylcholine receptor antibody (AChR-Ab) positivity. Multivariable Cox regression analysis further established higher MG-ADL scores at the nadir (HR = 0.19, 95% CI: 0.04-0.94; P = 0.042) as an independent risk factor for MMS achievement. DSP-MG was comparable to MuSK-MG and could be considered a single entity in our cohort. In all MG patients with MuSK-Ab, a higher MG-ADL score at nadir may herald a lower chance of MMS achievement, with no observed potential effect of AChR-Ab presence.

Markedly upregulated serum semaphorin 4A as a novel activity marker of myasthenia gravis.

Myasthenia gravis (MG) is an autoantibody-mediated disease of the neuromuscular junction. Semaphorin 4A (Sema4A) is involved in the activation of T cells in various inflammatory disorders. In this study, we aimed to investigate whether Sema4A is involved in the pathogenesis of MG. We measured serum Sema4A concentrations in 30 treatment-naïve MG patients with acetylcholine receptor (AChR) antibodies, 7 with muscle-specific tyrosine kinase (MuSK) antibodies and 21 normal controls. As a result, serum Sema4A levels were significantly higher in patients with AChR antibody-positive MG and MuSK antibody-positive MG than in controls (p ≤ 0.0001 for both MG groups). Serum Sema4A levels were correlated with AChR antibody levels (Spearman's ρ = 0.39, p = 0.03) and MG Foundation of America clinical classification classes (Spearman's ρ = 0.38, p = 0.04) in patients with AChR antibody-positive MG. In conclusion, high serum Sema4A levels may reflect T-cell activation, and this molecule could be a potential marker of disease activity in MG.

Evidence for genetic causal relationships between gut microbiome, metabolites, and myasthenia gravis: a bidirectional Mendelian randomization study.

Myasthenia gravis (MG) is an autoimmune disease observed to have connections with gut microbiome. We aimed to systematically assess the causal relationships between gut microbiome, gut microbiome-derived metabolites, and MG using Mendelian randomization (MR) approach. Summary-level genetic datasets from large-scale genome-wide association studies regarding 196 gut microbial taxa from the MiBioGen consortium (n=18,340), 72 derived metabolites from the TwinsUK and KORA studies (n=7,824), and antiacetylcholine receptor (AChR) antibody-positive MG (case=1,873, control=36,370) were employed for MR causal estimates. The inverse-variance weighted (IVW) method was utilized as the main analysis with MR-Egger, maximum likelihood, simple mode, and weighted median as complements. The tests of Cochran's Q, MR-Egger intercept, Steiger, MR-PRESSO and leave-one-out were implemented for sensitivity analyses. The forward MR estimates of IVW revealed significant causal associations of the abundance of phylum Actinobacteria, class Gammaproteobacteria, family Defluviitaleac, family Family XIII, and family Peptococcaceae with a reduced risk of MG. Conversely, the abundance of phylum Lentisphaerae, order Mollicutes RF9, order Victivallales, and genus Faecalibacterium was causally associated with an increased risk of MG. The reversed MR analysis proved negative causal correlations between the MG and the abundance of family Peptostreptococcaceae, genus Romboutsia, and genus Subdoligranulum. Regarding the derived metabolites, the IVW estimates revealed that elevated levels of beta-hydroxyisovalerate and methionine were causally associated with a decreased risk of MG, while increased levels of choline and kynurenine were linked to an increased risk of MG. Furthermore, genetically predicted MG was associated with a decreased level of cholesterol. The results obtained from complementary MR methods were similar. These findings remained robust in all sensitivity analyses. Our MR findings support the causal effects of specific gut microbiome taxa and derived metabolites on AChR antibody-positive MG, and vice versa, yielding novel insights into prevention and therapy targets of MG. Future studies may be warranted for validation and pursuing the precise mechanisms.

Effectiveness of early glucocorticoids in myasthenia gravis: a retrospective cohort study.

This study aimed to clarify the effect of early glucocorticoid (GC) application on achieving minimal manifestation (MM) status or better in the treatment of myasthenia gravis (MG) in the early clinical phase. A retrospective analysis was performed using data from 336 patients with MG who received GC therapy from January 2015 to September 2022 in the Zhengzhou University Henan Institute of Medical and Pharmaceutical Sciences Myasthenia Gravis Biobank (ZMB). Patients were divided into two groups: the early mono-GC group (treated with GC within 6 months of MG onset) and the delayed mono-GC group. Kaplan-Meier analysis showed that the early mono-GC group achieved MM status earlier and more frequently than the delayed mono-GC group (log-rank test, p = 0.0082; hazard ratio [HR], 1.66; p = 0.011). The early mono-GC group had a lower maintenance oral GC dose than the delayed mono-GC group. In multivariate Cox regression analysis, early mono-GC (HR, 1.50; p = 0.043), early-onset MG (EOMG) (HR, 1.74; p = 0.034), and ocular MG (OMG) (HR, 1.90; p = 0.007) were associated with MM status or better. In conclusion, early mono-GC, EOMG, and OMG were positive predictors of treatment goals. In EOMG, OMG, and acetylcholine receptor antibody-positive MG (AChR-MG) subgroups, the maintenance oral GC doses in the early mono-GC group were significantly lower than the doses in the delayed mono-GC group (p < 0.05). Early intervention with GC led to better long-term outcomes and reduced the necessary maintenance dose of oral GC for patients with MG. EOMG and OMG were positive predictors of MM status or better with mono-GC.

Therapeutic effect of ofatumumab in patients with myasthenia gravis: immunoregulation of follicular T helper cells and T helper type 17 cells.

This study aimed to study the therapeutic effects of ofatumumab in patients with myasthenia gravis (MG) in addition to the immunomodulatory effects on peripheral follicular T helper (Tfh) cells and T helper type 17 (Th17) cells. Thirty-one patients with anti-acetylcholine receptor (AChR) antibody-positive MG were included in this study. At weeks 0, 1, 2, and 4, an initial dose of 20 mg of ofatumumab was injected subcutaneously, with a 2-month follow-up after completing this first cycle. At baseline, 1 month, and 3 months, we assessed the Quantitative MG (QMG), 15-item MG-Quality of Life (MG-QOL15), and MG-Activities of Daily Living (MG-ADL) scales and measured the frequencies of Tfh, Th17, and B cells and the levels of anti-AChR antibody, IL-6, IL-21, and IL-17 in the peripheral blood. At 1 month and 3 months, the QMG, MG-QOL15, and MG-ADL scores were all significantly reduced. At 3 months, doses of prednisone were reduced by an average of 37%. Decreased frequencies of Tfh and Th17 cells, depletion of B cells, and reduced levels of IL-6, IL-21, and IL-17 were all observed at 1 month or 3 months. Therefore, the therapeutic effect of ofatumumab could be detected after one cycle of treatment, which was maintained for 2 months. The immunomodulatory effect of ofatumumab during the observation period may involve depletion of B cells, reduction of Tfh and Th17 cells frequencies, and reduced levels of IL-6, IL-21, and IL-17. The findings provide novel data for the potential application of ofatumumab in MG.

Promising efficacy of Low-Dose rituximab in Muscle specific kinase antibody positive Myasthenia Gravis

AimsThe study aims to evaluate the efficacy of low dose rituximab (RTX) in patients with muscle-specific kinase antibody positive myasthenia gravis (MuSK-MG). MethodsThis is a single-center, retrospective study. A total of 10 patients with MuSK-MG were admitted to the Department of Neurology, First Hospital, Shanxi Medical University, between April 2021 to April 2023. Of them, 9 patients had been treated with low dose RTX (500 mg every 6 month) and recruited in this study. The clinical information, including the severity before and after RTX treatment, were collected from the medical records. Clinical effectiveness was assessed by Myasthenia Gravis Foundation of America (MGFA)-postintervention status (PIS), MG-related activities of daily living (MG-ADL), Quantitative Myasthenia Gravis (QMG) scores, Myasthenia Gravis Quality of Life 15-item revised (MG-QOL15r), dosage of steroid at the end of follow up. ResultsAll nine patients showed clinical improvement at the final follow-up after low-dose RTX treatment. The mean dose of prednisolone decreased significantly from 50 mg at baseline to 18.33 mg at the last follow-up (z = -3.417, p = 0.001). The administration of low-dose RTX treatment led to significant improvements in ADL levels (Z = -2.675, P < 0.01), QMG score levels (Z = -2.371, P < 0.05) and QOL-15r levels (Z = -2.547, P < 0.01) at last visit. ConclusionLow-dose RTX is effective for treating MuSK-MG patients. Longer-term follow-up and larger-scale studies are needed to provide further evidence.

Clinical features and outcomes of patients with muscle-specific kinase antibody-positive myasthenia gravis in Japan

This study included 51 patients with muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG) from a Japanese multicenter survey to examine clinical features and outcomes. Median onset age was 37 years and female predominance was observed. All patients developed generalized symptoms and almost all (50/51) patients had bulbar symptoms. About half of the patients met the criteria for refractory MG. The refractory group had a lower age of onset, higher severity scores, and higher maximum daily doses of oral prednisolone compared to the nonrefractory group. The outcomes for MuSK-MG patients in Japan are not favorable, indicating the need for more aggressive treatment.

Remission of severe myasthenia gravis after autologous stem cell transplantation.

Myasthenia gravis (MG) is an autoantibody-mediated neuromuscular junction disorder involving the acetylcholine receptors on the motor endplate. The safety and response to high-dose chemotherapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were assessed in a patient with severe refractory MG. As part of a pilot study of HDIT/HCT for patients with treatment-resistant autoimmune neurological disorders, a patient with severe refractory MG underwent treatment. After mobilization of hematopoietic stem cells with rituximab, prednisone, and G-CSF, the patient had HDIT consisting of carmustine, etoposide, cytarabine, melphalan, and rabbit antithymocyte globulin, followed by autologous HCT. The effect of treatment on the autoantibody to the acetylcholine receptor (AChR) was assessed. The patient had been diagnosed with AChR antibody-positive MG 14 years before HDIT/HCT and had failed thymectomy, therapeutic plasma exchange, and multiple immunomodulatory agents. The Myasthenia Gravis Foundation of America (MGFA) clinical classification was IVb before HDIT/HCT. She tolerated HDIT/HCT well and started to improve clinically within days of treatment. At both 1 and 2 years after HDIT/HCT, patients remained symptom-free. After HDIT/HCT, AChR-binding autoantibodies persisted, and the relative frequency of immune cell subtypes shifted. HDIT/HCT induced a complete response of disease activity in a patient with severe refractory MG. This response may suggest that a cell-mediated etiology may be a significant contributing factor in refractory MG cases. A phase 2 clinical trial is warranted to establish if HDIT/HCT can be an effective therapy for severe refractory MG and to gain a further understanding of disease pathogenesis.

Advancements in Targeted Therapies for Generalized Acetylcholine Receptor Antibody Positive Myasthenia Gravis: Beginnings of a Paradigm Shift.

In recent years, a new era of biologic therapeutics has emerged for the treatment of generalized myasthenia gravis (gMG). Compared to traditional immune modulatory therapies (steroids, non-steroidal immunosuppressive agents), these agents have more specific target engagement via inhibition of complement activation (eculizumab, ravulizumab, zilucoplan) or blockade of IgG recycling via the neonatal Fc receptor (FcRn; efgartigimod, rozanolixizumab). Phase 3 trials with each of these agents have shown rapid clinical improvement and good safety and tolerability. B-cell targeting with rituximab was safe and well-tolerated but with less impressive efficacy in two phase 2 studies. As a result, four new therapies are now approved for use (eculizumab, ravulizumab, efgartigimod, rozanolixizumab), another (zilucoplan) is in regulatory approval process and several others are in pivotal trials. A paradigm shift is afoot. The challenge is figuring out where these therapies may fit in gMG treatment algorithms.

Silencing of FCRLB by shRNA ameliorates MuSK-induced EAMG in mice

IntroductionMuscle specific kinase (MuSK) antibody positive myasthenia gravis (MG) often presents with a severe disease course and resistance to treatment. Treatment-refractory patients may respond to B cell depleting treatment methods. Our aim was to investigate whether inhibition of Fc receptor–like B (FCRLB) could effectively suppress autoimmunity without diminishing B cell counts in animal model of MG, a classical antibody-mediated autoimmune disease. MethodsExperimental autoimmune MG was induced in Balb/C mice with two s.c. immunizations with recombinant human MuSK in complete Freund's adjuvant. FCRLB was silenced with a lentiviral particle transported shRNA in myasthenic mice with a single i.p. injection during second MuSK-immunization. Control immunized mice received scrambled shRNA or saline. Mice were observed for clinical parameters for 28 days and at termination, anti-MuSK IgG, neuromuscular junction (NMJ) deposits, muscle AChR expression and lymph node B and T cell ratios were assessed by ELISA, immunofluorescence, immunoblotting and flow cytometry, respectively. ResultsFCRLB shRNA-treated mice showed no muscle weakness or weight loss at termination. Also, they exhibited higher grip strength and muscle AChR levels, lower anti-MuSK IgG and NMJ IgG/C3 levels than control mice. Flow cytometry analysis showed that ratios of major effector lymph node B and T cell populations were not altered by FCRLB silencing. However, regulatory T and CD19 + CD5+ B cell ratios were decreased in FCRLB shRNA-group. ConclusionOur results provide evidence regarding involvement and therapeutic value of FCRLB in MuSK-MG. Silencing of FCRLB appears to substantially inhibit antibody production without interfering with survival of major lymphocyte populations.

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.

P.035 Autologous hematopoietic stem cell transplant for the treatment of refractory myasthenia gravis with anti-muscle specific kinase antibodies

Background: Several case series describe patients with refractory acetylcholine receptor antibody-positive (AChR) myasthenia gravis (MG) treated with hematopoietic stem cell transplant (HSCT). In this report, we describe four patients with anti-muscle-specific kinase (MuSK)MG treated with HSCT. Methods: We reviewed the records of all patients undergoing HSCT for MG in the Alberta Blood and Bone Marrow Transplant Program and identified 4 patients with anti-MuSK MG. Results: All 4 patients had severe disease (Myasthenia Gravis Foundation of America score IVb-V) and were refractory to multiple treatments, including rituximab. 3 patients improved with no clinical manifestations or mild symptoms and remained as such for 2, 3.5, and 5.5 years. In these 3 patients, adverse events ranged from treatable infections and transient dyspnea to persistent fatigue and premature menopause. The average worst Myasthenia Gravis Activities of Daily Living (MG-ADL) scores improved from 14.7 before to 0.3 after HSCT while their mean worst Myasthenia Gravis Quality of Life Questionnaire (MG-QoL15) scores improved from 26.7 to 0. The fourth patient developed pneumonia and passed away from respiratory failure 8 weeks post-transplant. Conclusions: In patients with severe refractory anti-MuSK MG, it may be reasonable to consider HSCT but with an appreciation of the associated risks.

Seeing Double: a Case of a Massive Type B2 Thymoma Presenting with Pseudo-Internuclear Ophthalmoplegia (P9-13.004)

<h3>Objective:</h3> NA <h3>Background:</h3> Thymomas are rare, malignant epithelial cell tumors usually diagnosed in the 5th decade. Median tumor size is approximately 5 cm. An estimated 20 – 25% present as paraneoplastic myasthenia gravis (MG) with positive acetylcholine receptor antibodies (AChR Ab). A rarely described presentation of MG is pseudo-internuclear ophthalmoplegia (p-INO). This presents a diagnostic conundrum as INO is discretely localizable to the brainstem and more commonly associated with cerebrovascular disease or demyelination. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 27-year-old man presented with a three-month history of binocular horizontal diplopia, night sweats, weight loss and generalized weakness. The rapid progression of weakness occurred almost immediately following the COVID-19 vaccine. Examination demonstrated bilateral INO, worrisome for central nervous system inflammatory demyelination. An MRI of brain and cervical spine showed no evidence of demyelination, but the thoracic MRI showed a large soft tissue mass in the right hemithorax. A chest CT demonstrated a massive multilobulated mass encompassing almost the entirety of the right thoracic cavity. Given the mass in conjunction with the neurological symptoms, AchR Ab was obtained demonstrating positivity (51.2 nmol/L) for MG. Biopsy revealed thymoma type B2 and positron emission tomography showed metastatic disease, stage IVa. The patient was treated with four cycles of cisplatin, cyclophosphamide, and doxorubicin with prednisone, as well as a thymus gland resection. He was additionally started on pyridostigmine 60mg every 4 hours which improved his p-INO and generalized weakness. <h3>Conclusions:</h3> This case represents a rare presentation of myasthenia gravis in a young patient with p-INO. The incidental finding of a large thymoma (measuring ~30cm) discovered on thoracic spine imaging for work-up of demyelinating disease prompts alternative diagnostic consideration when presented with MRI-negative INO. It also evokes the question, should there be more emphasis on expediting CT chest imaging to evaluate for thymoma in patients with antibody positive MG. <b>Disclosure:</b> Dr. Hart has nothing to disclose. Maja Ostojic has nothing to disclose. Dr. Farrell has nothing to disclose. Dr. Esch has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen.

Epidemiology of Antibody-positive Myasthenia Gravis in Sardinia, Italy (P2-5.027)

<h3>Objective:</h3> To determine the incidence and prevalence of myasthenia gravis (MG) associated with acetylcholine receptor (AchR)-IgG and muscle tyrosine kinase (MuSK)-IgG in the district of Sassari (Sardinia; Italy). <h3>Background:</h3> The global mean incidence and prevalence of MG have been assessed at ≈15 (range, 4–29)/million and 20 (range, 2–37)/100,000, respectively. The island of Sardinia is a recognized area at higher risk for different immune-mediated disorders (<i>e.g</i>., multiple sclerosis), but the epidemiology of MG remains unclear. <h3>Design/Methods:</h3> From the Neurochemistry Laboratory of the University-Hospital of Sassari (reference laboratory for AchR-IgG/MuSK-IgG testing in the island since 1998) we retrospectively identified patients with: 1) AchR-IgG (titer ≥0.5 nmol/L) and/or MuSK-IgG (titer ≥100 pg/ml) positivity by radioimmunoprecipitation assay; 2) available medical records; and 3) residence within the district of Sassari. Incidence (January 2010-December 2019) and prevalence (on January 1, 2020; population 325,288) were calculated. <h3>Results:</h3> Among 517 antibody-positive patients identified, 183 were included (incident, 97; prevalent, 165). We excluded 334 patients due to: 1) missing clinical information (n=65); 2) residency outside the Sassari district (n=168); 3) not classifiable as incident or prevalent (n=56); and 4) clinical phenotype not consistent with MG (n=45; median AchR-IgG titer, 0.7 [range, 0.5–5.5] nmol/L). The crude MG prevalence was 50.7/100,000 (95% CI, 43.4–58.9), whereas incidence was 29.8/1,000,000 person-years (95% CI, 24.3–36.2). Antibody specificities were AchR in 170 (92.9%; median titer 5.7 [range, 0.5–22]) and MuSK in 13 (7.1%; median titer 1,255 [range, 136–1,730]). Among incidence cases, age at disease onset was distributed as: &lt;18 years (n=2; 2%); 18–50 years (n=14; 14.4%); 51–65 years (n=25; 25.8%); and &gt;65 years (n=56; 57.7%). In 45 (46.4%) incident cases, MG was initially restricted to ocular muscles. <h3>Conclusions:</h3> We report the highest incidence and prevalence of MG worldwide. The environmental and genetic determinants of MG risk in the Sardinian population need to be investigated. <b>Disclosure:</b> Dr. Zara has nothing to disclose. Dr. DEIANA has nothing to disclose. Prof. Sotgiu has nothing to disclose. Dr. Ortu has nothing to disclose. Stefano Sotgiu has nothing to disclose. Gregorio Spagni has nothing to disclose. Dr. Damato has nothing to disclose. Dr. Solla has nothing to disclose. Dr. Sechi has nothing to disclose.

Two Cases of Anti-PD1 Antibody Associated Neurological Immune-Related Adverse Effects (P5-4.001)

<h3>Objective:</h3> We present two cases of neurological immune-related adverse events (irAEs) indefinitely triggered by pembrolizumab. <h3>Background:</h3> Recently, immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Programmed cell death protein 1 (PD-1) is a key immune checkpoint receptor expressed by activated T cells. PD-1/PD-L1 antibody therapy is used to treat multiple malignancies; however, it has been associated with an increasing number of irAEs. Neurological irAEs are highly significant complications of ICI therapy that can cause long-term disability and death. Most commonly, neurological irAEs are neuromuscular complications and occur within 4 months after immunotherapy initiation. The anti-PD-1 agent pembrolizumab is currently approved for treatment of several tumors and has been used increasingly due to its more favorable toxicity profile. <h3>Design/Methods:</h3> NA <h3>Results:</h3> NA <h3>Conclusions:</h3> <h3>Case 1:</h3> Our first case is an 84-year-old man with a history of metastatic colon cancer that was treated with pembrolizumab. This is thought to have elicited myositis with elevated CK as well as acetylcholine receptor antibody-positive myasthenia gravis, causing him diffuse and debilitating weakness and functional limitation. He had multiple exacerbations of these symptoms temporally associated with pembrolizumab administration. With the initiation of maintenance treatment and the cessation of pembrolizumab, he required no further admissions for neurologic irAEs, but ultimately he was transitioned to hospice care for cancer progression. <h3>Case 2:</h3> A 65-year-old man with a history of non-small cell carcinoma of the lung on pembrolizumab and zoledronic acid presented with altered mental status and agitation. He had mild pleocytosis on CSF, MRI brain with left mesial temporal T2 FLAIR hyperintensity and nonspecific encephalopathy markers on continuous EEG. He subsequently had complete recovery with IV high-dose steroids followed by plasmapheresis. His symptoms were therefore suspected to be secondary to autoimmune encephalitis elicited by pembrolizumab administration. His oncologist elected to transition to another treatment regimen, and he has had no relapses to date. <b>Disclosure:</b> Ms. Vitek has nothing to disclose. Dr. Hansra has nothing to disclose.

Autologous hematopoietic stem cell transplant for the treatment of refractory myasthenia gravis with anti-muscle specific kinase antibodies.

Up to 25% of patients with myasthenia gravis (MG) have refractory disease despite trials of multiple immunosuppressants. Several case series describe acetylcholine receptor antibody-positive (AChR) MG patients treated with autologous hematopoietic stem cell transplant (HSCT). In this report, we describe three patients with anti-muscle-specific kinase (MuSK) MG treated with HSCT. We included all patients who had undergone HSCT with anti-MuSK myasthenia gravis identified through the records of the Alberta Blood and Marrow Transplant Program. We collected demographic and clinical data including validated MG scales as well as questionnaire data. All 3 patients had severe disease (Myasthenia Gravis Foundation of America score IVb-V) and were refractory to multiple treatments, including rituximab. All patients improved with no clinical manifestations or mild symptoms and remained as such for 2, 3.5, and 5.5y. Adverse events ranged from treatable infections and transient dyspnea to persistent fatigue and premature menopause. The average worst Myasthenia Gravis Activities of Daily Living (MG-ADL) scores improved from 14.7 before to 0.3 after HSCT. The mean worst Myasthenia Gravis Quality of Life Questionnaire (MG-QoL15) scores improved from 26.7 to 0. All patients reported they would undergo transplant again for their MG. We describe three patients with anti-MuSK MG treated with HSCT, all of whom became symptom free from MG with a tolerable side effect profile. In patients with severe refractory anti-MuSK MG, it may be reasonable to consider HSCT.