Development and Feasibility Assessment of a Multimodal Digital Health Technology for Remote Monitoring of Symptoms in Myasthenia Gravis

Myasthenia gravis: do not forget the patient perspective

Evidence for a Central Cholinergic Deficit in Myasthenia Gravis

PurposeWith the adjustment of prevention strategies in December 2022, coronavirus disease 2019 (COVID-19) became widely prevalent in China. This study is aimed to describe the clinical characteristics of myasthenia gravis (MG) patients with COVID-19 and identify risk factors of exacerbation in MG patients with COVID-19 in Guangxi.Patients and MethodsA total of 489 MG patients and 587 control subjects in Guangxi during the COVID-19 pandemic were enrolled in this case–control study. After contacting the participants, the clinical data of MG patients and the control group were analyzed. The clinical characteristics of MG patients with COVID-19 were described. Multivariable logistic regression analysis was used for discovering independent risk factors of MG exacerbation in the patients with MG and COVID-19.ResultsA total of 311 (75.30%) MG patients and 428 (72.91%) control subjects were infected with COVID-19, and 64.31% of MG patients with COVID-19 were women. The median age at the time of interview was 41 (IQR: 28, 54) years old, and median onset age was 36 (IQR: 24, 51), both of which were lower than those in MG patients without COVID-19. MG duration was 24 (IQR: 9, 72) months. About 44.69% of patients were generalized MG (GMG). About 11.90% of MG patients with COVID-19 showed severe COVID-19 symptoms and the duration of symptomatic COVID-19 was 9.57 ± 6.79 days, higher than those in the control group. About 35.69% MG patients with immunosuppressive drugs were infected with COVID-19, which is higher than those in the non-infected MG patients (21.57%). A total of 120 (38.59%) MG patients with COVID-19 had comorbidities. About 21 (20.19%) of the 104 MG patients without vaccination showed severe COVID-19 symptoms. Multivariable logistic regression analysis showed that baseline MG activities of daily living profile (MG-ADL, OR 1.280, 95% CI: 1.010–1.621, p = 0.041), duration of COVID-19 (OR 1.158, 95% CI: 1.100–1.220, p < 0.001), GMG (OR 2.331, 95% CI: 1.228, 4.426, p = 0.010), and lack of COVID vaccination (OR 2.075, 95% CI: 1.152, 3.738, p = 0.015) were independent factors of exacerbation in MG patients with COVID-19.ConclusionMG patients with immunosuppressive drugs, younger onset, longer MG duration, or comorbidities are more susceptible to COVID-19. The baseline MG-ADL, duration of symptomatic COVID-19, GMG, and lack of COVID-19 vaccination are independent risk factors of exacerbation in MG patients with COVID-19.

Increased Toll-Like Receptor 4 Expression in Thymus of Myasthenic Patients with Thymitis and Thymic Involution

Effect of low-dose rituximab treatment on T- and B-cell lymphocyte imbalance in refractory myasthenia gravis

Background A previous study on thymomas in myasthenia gravis (MG) patients indicated that OX40 expression may be upregulated in thymic tissues adjacent to germinal centers (GCs) and thymomas, and OX40 may interact with OX40L in GCs to enhance anti-acetylcholine receptor antibody production. However, little is known about the clinical significance of the expression of OX40 and OX40L in the peripheral blood of patients with MG. We aimed to characterize the expression of membrane-bound and soluble OX40 and OX40L in the peripheral blood of patients with MG and to identify their clinical significance. Methods For membrane molecules, we collected peripheral blood (PB) from 39 MG patients at baseline, 22 patients in relapse, and 42 patients in remission, as well as from 36 healthy participants as controls. For soluble molecules, plasma from 37 MG patients at baseline, 34 patients in relapse, and 30 patients in remission, as well as plasma from 36 healthy controls (HC), was retrospectively collected from the sample bank of the First Hospital of Soochow University. The expression of membrane-bound OX40 and OX40L (mOX40 and mOX40L) by immune cells was measured using flow cytometry. Plasma levels of soluble OX40 and OX40L (sOX40 and sOX40L) were measured by ELISA. Results (1) The expression of OX40 on CD4+ T cells and that of OX40L on B cells and monocytes were significantly increased, and the levels of sOX40 were significantly decreased in MG patients at baseline compared with HC, while the expression of sOX40L was not significantly different between the two groups. (2) Dynamic observation of the molecules showed significantly higher expression of OX40 on CD4+ T cells and higher levels of sOX40 in MG patients in relapse than in MG patients at baseline and MG patients in remission. Furthermore, the expression levels of sOX40 were significantly elevated in MG patients in remission compared with MG patients at baseline, and the expression of sOX40L was significantly lower in MG patients in remission than in MG patients at baseline and MG patients in relapse. (3) Plasma levels of sOX40 and sOX40L were significantly decreased in 13 patients with relapsed MG after immunosuppressive treatment compared with those before treatment. (4) Correlation analysis showed that the expression of OX40 on CD4+ T cells in patients with relapsed MG was positively correlated with the concentration of acetylcholine receptor antibodies (AchR-Ab), whereas the expression of OX40L on CD19+ B cells and CD14+ monocytes was negatively correlated with disease duration. (5) Binary regression analysis showed that patients with high CD4+ OX40 expression and high sOX40L levels had an increased risk of relapse. Conclusions OX40 and OX40L are abnormally expressed in the peripheral blood of patients with MG and may be closely associated with disease status and treatment. The OX40/OX40L pathway may be involved in the immunopathological process of MG and may play a role mainly in the later stage of MG.

Coronavirus disease 2019 (COVID-19), caused by the late 2019 outbreak of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a respiratory disease which could put myasthenia gravis patients at a greater risk of developing severe disease course. This paper presents a single-institution case series of hospitalized myasthenia gravis patients with COVID 19. We identified eight patients previously diagnosed with myasthenia gravis, four of whom presented with clear signs of myasthenia gravis symptom worsening on admission. No form of respiratory support was needed during the complete duration of stay for three patients, oxygen therapy was administered to two patients, while the remaining three patients required mechanical ventilation. Treatment was successful for seven patients, six of whom were discharged without any myasthenia gravis symptoms. One patient died after eleven days of intensive care unit treatment. Although treatment of patients with myasthenia gravis and COVID-19 patients is challenging, case series of myasthenia gravis patients with COVID-19 treated in our institution demonstrates relatively favorable treatment outcome. Our data seem to support the notion that immunosuppressive medication does not seem to result in worse outcomes. Our data also support the notion that intravenous immunoglobulin treatment is safe and should be administered to patients with myasthenia gravis and COVID-19 in case of myasthenia gravis worsening since benefits seem to greatly outweigh the risks.

Leflunomide and low-dose prednisone (0.25mg/kg/day) (LEF + Pred) rapidly improved the clinical symptoms of myasthenia gravis (MG) patients. Here, we aimed to analyze the long-term efficacy and safety of LEF + Pred in MG patients. This retrospective cohort study enrolled MG patients treated with LEF + Pred in our center between 2012 and 2020. We reviewed all the MG patients continuously treated with LEF + Pred for more than 1year. MG activities of daily living (MG-ADL) profile score and quantitative MG scale (QMG) score in each clinical follow-up visits were collected for the efficacy analysis. The laboratory testing results of MG patients, the relevant chief complain and physical examination results in each follow-up visits were collected for the safety evaluation. In total, 103 patients were examined. Effective treatment was achieved in 58.3% of patients after 1month and in 88.4% after 12months. Overall, 63 patients (61.2%) exhibited only minimal manifestations after 12months of treatment. The average MG-ADL score decreased from 6.0 to 1.0, while the average QMG score decreased from 10.0 to 4.0. The decrease in MG-ADL and QMG scores of patients with generalized MG was more pronounced than those of the ocular MG patients. Patients with MG who had a thymectomy had a smaller decrease in MG-ADL and QMG scores than those who did not have a thymectomy. Sixteen adverse effects associated with LEF + Pred were observed; none was severe. Long-term LEF + Pred therapy could considerably improve clinical symptoms in MG patients while being well tolerated with just few side effects.

This cross-sectional study was undertaken to evaluate the existence and distribution of comorbid disorders among myasthenia gravis (MG) patients according to subgroups and to identify the effects of the comorbid diseases of MG patients on clinical outcomes. The patients were divided into six subgroups according to serum antibodies, age at onset, and thymoma presence. All patients were treated in line with the International Consensus Guidance for Management of Myasthenia Gravis. To assess the clinical outcome after treatment for MG, we used the MGFA Post-intervention Status. In generalized MG patients, the good prognosis group included patients who were classified as having minimal-manifestation status or better. In ocular MG patients, the remission subgroup included patients who were classified as having complete stable remission or pharmacological remission status. Our study included 168 MG patients, 85 were female while 83 were male. Comorbid diseases were present in 124 (73.8%) MG cases. After at least 1year of follow-up, 106 (86.8%) of the generalized MG patients were in the good prognosis group and 16 (13.2%) generalized MG patients were in the poor prognosis group. 27 (58.6%) ocular MG patients were in the remission group and 19 (41.3%) ocular MG patients were in the non-remission group. Hypertension increased the risk of poor prognosis by 3.55-fold among patients with generalized MG and type 2 DM increased the risk of not achieving remission by 9.32-fold among patients with ocular MG. Hypertension and type 2 DM had negative effects on the clinical outcomes of MG.

The aim of this study was to analyze the prevalence and clinical features of myasthenia gravis (MG) patients with and without autoimmune thyroid disease (ATD). Between 1999 and 2009, we reviewed a total of 1482 patients with MG. On the basis of thyroid evaluations, as well as neurological, clinical, and serological findings, the patients were divided into group A (MG patients with ATD) or group B (MG patients without ATD). The patients were categorized as having ocular myasthenia when symptoms restricted to the ocular system were present for 2 years or more. Of the 1482 MG patients, 121 (8.2%) patients were classified into group A. Graves' disease was more predominant (5.7%) than Hashimoto's thyroiditis (1.1%) and antibody-positive thyroid disease (1.4%). MG patients with ATD were predominantly female, were younger at the onset of MG symptoms, had a higher frequency of mild MG (ocular and mild generalized MG) and thymic hyperplasia, and had lower levels of seropositive anti-acetylcholine receptor antibodies. Compared to patients without thyroid eye disease, ATD patients with thyroid eye disease had a higher frequency of ocular MG. This is the largest review of the clinical features of MG patients with and without ATD to date. We found that compared to ocular MG, mild MG is more commonly associated with ATD. Furthermore, we observed that thymic hyperplasia is more common in MG patients with ATD, while thymoma is more common in MG patients without ATD.

Introduction Different autoimmune conditions have been described in human immunodeficiency virus (HIV) patients on antiretroviral therapy (ART), but muscle-specific kinase (MuSK) myasthenia gravis (MG) coexisting with HIV is rare. We report a case of a Chinese patient with an asymptomatic HIV infection who presented with newly-onset MuSK MG and was managed successfully with the acetylcholinesterase inhibitor pyridostigmine. Case report A 71-year-old Chinese male from Zhejiang province had an established HIV infection and was on ART since 2014. He presented to the outpatient clinic stating that for the last 5 days he had been experiencing double ptosis, weakness in the neck, and difficulty to hold up his head, which were all worsening in the evening. He had been on ART consisting of Zidovudine 300 mg BID, Lamivudine 300 mg QD, and Nevirapine 200 mg BID. Although he was diagnosed and started on ART in 2014, he was subsequently followed up and had undetected viral loads with CD4 counts of 100–150 cells/μL in 2017. So, the highly active antiretroviral therapy (HAART) was changed in October 2017, and subsequently consisted of Tenofovir 300 mg QD, Lamivudine 300 mg QD, and Efavirenz 600 mg QD. His CD4 counts had increased to 183 cells/μL by April 2018. He had hypertension since 1999 and was treated with L-amlodipine and irbesartan. He had type 2 diabetes since 1999 and was treated with insulin aspartate and insulin glargine. Review of other systems was negative. On examination, he had bilateral ptosis with serious left ptosis covering the inferior margin of the pupil, and cervical extensors were at 4-strength. Fatigue tests of bilateral palpebral muscles were positive and the bilateral tendon reflex was positive. Other cranial nerves were intact. Motor, sensory, coordination, and other deep-tendon reflexes were normal. Routine blood tests, creatinine kinase, anti-nuclear antibody, anti-neutrophil cytoplasmic antibodies, rheumatoid factor, thyroid function, and anti-thyroid antibodies were normal. Total IgG titers were mildly elevated (1878 mg/dL, reference range 800–1800 mg/dL, and IgA, IgM, C3, and C4 were within normal limits. Hepatitis C antibodies were negative. Brain magnetic resonance imaging did not show any neurological abnormalities and computerized tomographic scanning of the chest did not show any significant enlargement of the thymus. His acetylcholine receptor (AChR) antibodies were negative, while MuSK antibodies were 12.00 U/mL (MuSK autoantibody titer along with cutoff 0.40 U/mL). Repetitive nerve stimulation tests (3 Hz) showed normal findings. He received oral pyridostigmine therapy (360 mg daily) soon after diagnosis of MuSK antibody-positive MG in September 2018, which resulted in resolution of ptosis and bulbar symptoms and incomplete improvement of neck weakness. However, he experienced double ptosis and weakness in the neck again when pyridostigmine was reduced to a daily dosage of 180 mg in February 2019. So, the dose of oral pyridostigmine was reduced slowly and he responded to oral pyridostigmine therapy with daily dosages of 240–180 mg from February to June 2019. By July 2019, all his symptoms had improved dramatically and pyridostigmine was stopped. He experienced continuous improvement of CD4+ T cells (202 cells/μL) with undetectable HIV viral loads. Up to January 2020, none of his symptoms reappeared. Discussion MG is an autoimmune disease that is associated with antibodies affecting the postsynaptic membrane at the neuromuscular junction.1,2 80% of MG patients have detectable antibodies against AChR, while a minority has antibodies against MuSK and lipoprotein-receptor-related protein 4.2 Overall, 1%–10% of the MG patients have serum MuSK antibodies.1 MuSK is a protein expressed in the postsynaptic muscle membrane and linked to AChR to maintain AChR function. MuSK MG is estimated to have a prevalence of 2.9 per million people in Europe.3 In China, MuSK MG is more common in the north.4 Although MG is one of the best-characterized and understood autoimmune disorders, comorbidity of HIV and MG is rare and mostly reported in incidental case reports.5 Hung et al.6 previously summarized the common characteristics of these comorbid HIV and MG patients: (1) MG develops in the early stage of HIV infection when the immune system is relatively intact; (2) the clinical course of MG appears to be benign and most patients show improvements along with advancing immunodeficiency; (3) serum anti-AChR antibodies are absent or show low titers; (4) there is little association of thymus hyperplasia as opposed to patients with AChR-Ab-positive myasthenia. Clinical features of MuSK MG resemble AChR-Ab MG, but MuSK MG patients show predominant involvement of cranial and bulbar muscles with increased incidence of ptosis, diplopia, and dysarthria, prominent with neck and respiratory muscle involvement and are less responsive to acetylcholinesterase inhibitors.7 MuSK MG may have a different cause and pathologic mechanism compared with AChR-Ab-positive MG.1,2 Comorbidity of HIV and MuSK MG is very rare, with only five cases previously reported, and very little is known about this association.8–12 These cases are summarized in Table 1. Among them, two are African Americans, while the other three are African, Japanese, and someone from Thailand. In our case, the MuSK MG patient with HIV infection came from Zhejiang province, in the south of China. One case report showed no MG relapse in an HIV-infected patient who was successfully treated with efavirenz-containing therapy.13 However, our patient, who was on Efavirenz-containing HAART, was just being diagnosed with MuSK MG. All these five case reports have described MuSK MG in HIV as part of immune reconstitution after antiretroviral treatment, in which MG was manifested as CD4 counts improved after HAART.8–12 A similar pattern was seen in the presentation of our patient, in whom the improvement of CD4 counts with changes of antiretroviral drug led to presentation of the symptoms. The following improvement of MG was accompanied with increasing CD4+ T cell counts. A consistent finding in patients with MuSK MG is that they have a much lower frequency of thymic pathology than patients with AChR-Ab-positive MG.14 This finding is consistent in all the aforementioned cases summarized in Table 1, including our patient. A possible explanation might be the normalization of immune regulation and the remount of CD4+ suppressor-inducer or regulatory T cells.Table 1: Comparison of case reports on MuSK myasthenia gravis and HIV.The management of patients with both HIV and MuSK MG is challenging. Immunosuppressants and immunomodulators have been used for the treatment of MuSK MG in HIV patient based on case reports, and was not entirely without risk.8–12 All of the five reported cases listed in Table 1 had similar findings along with positive MuSK antibodies and were subsequently treated with immunomodulators like cyclosporine, intravenous immunoglobulin, azathioprine, rituximab, and plasma exchange. Different from other cases of MG with worsening symptoms, our patient was managed with the acetylcholinesterase inhibitor pyridostigmine, which improved his symptoms successfully. Therefore, due to the lack of studies on treatment of MuSK MG in HIV patients, the use of steroids and immunomodulators should be cautiously evaluated in each patient. In conclusion, we propose that the relationship between HIV infection and MuSK MG is not just a coincidence. The Chinese old man with an established HIV infection developed new-onset MuSK MG when he was on Efavirenz-containing HAART. The improvement of MG was actually accompanied with increasing CD4+ T cell counts after changes of prescribed antiretroviral drugs and MG was successfully managed with the acetylcholinesterase inhibitor pyridostigmine. Further research is needed to identify the underlying immuno-pathogenesis and to prevent and treat MuSK MG in HIV patients.

Tacrolimus hydrate (FK506) reduces the symptoms of myasthenia gravis (MG) due to its immunosuppressive properties. A drug efflux pump P-glycoprotein (P-gp) actively transports FK506 out of target cells, thereby reducing their efficacy. We investigated the influence of FK506 therapy on the P-gp function of peripheral-blood mononuclear cells (PBMCs) in MG patients. Six MG patients treated with FK506 (MG(FK+)), four MG patients treated without FK506 administration (MG(FK-)), and 18 healthy subjects were included in this study. P-gp function was estimated by transporter activity that was inferred from a decrease in fluorescent P-gp substrate Rhodamine 123 (Rh123) and its inhibition by cyclosporine A (CsA). The P-gp efflux function in MG (FK+) patients assessed by the Kolmogorov-Smirnov (KS) statistic D was lower than in the healthy subjects (p=0.0084). However, PBMC sensitivity to FK506 in MG (FK+) patients was significantly higher compared to that of the healthy subjects (p=0.02). There was a significant correlation between the Rh123 efflux activity and PBMC sensitivity to FK506 in vitro (p=0.011). The data raise the possibility that FK506 treatment attenuated P-gp function in the PBMCs of the MG patients.

Does myasthenia gravis affect the brain?

BackgroundWe have previously reported using two-step cluster analysis to classify myasthenia gravis (MG) patients into the following five subtypes: ocular MG; thymoma-associated MG; MG with thymic hyperplasia; anti-acetylcholine receptor antibody (AChR-Ab)-negative MG; and AChR-Ab-positive MG without thymic abnormalities. The objectives of the present study were to examine the reproducibility of this five-subtype classification using a new data set of MG patients and to identify additional characteristics of these subtypes, particularly in regard to response to treatment.MethodsA total of 923 consecutive MG patients underwent two-step cluster analysis for the classification of subtypes. The variables used for classification were sex, age of onset, disease duration, presence of thymoma or thymic hyperplasia, positivity for AChR-Ab or anti–muscle-specific tyrosine kinase antibody, positivity for other concurrent autoantibodies, and disease condition at worst and current. The period from the start of treatment until the achievement of minimal manifestation status (early-stage response) was determined and then compared between subtypes using Kaplan-Meier analysis and the log-rank test. In addition, between subtypes, the rate of the number of patients who maintained minimal manifestations during the study period/that of patients who only achieved the status once (stability of improved status) was compared.ResultsAs a result of two-step cluster analysis, 923 MG patients were classified into five subtypes as follows: ocular MG (AChR-Ab-positivity, 77%; histogram of onset age, skewed to older age); thymoma-associated MG (100%; normal distribution); MG with thymic hyperplasia (89%; skewed to younger age); AChR-Ab-negative MG (0%; normal distribution); and AChR-Ab-positive MG without thymic abnormalities (100%, skewed to older age). Furthermore, patients classified as ocular MG showed the best early-stage response to treatment and stability of improved status, followed by those classified as thymoma-associated MG and AChR-Ab-positive MG without thymic abnormalities; by contrast, those classified as AChR-Ab-negative MG showed the worst early-stage response to treatment and stability of improved status.ConclusionsDifferences were seen between the five subtypes in demographic characteristics, clinical severity, and therapeutic response. Our five-subtype classification approach would be beneficial not only to elucidate disease subtypes, but also to plan treatment strategies for individual MG patients.

Serum amyloid A (SAA) is a clinically useful inflammatory marker involved in the pathogenesis of autoimmune diseases. This study aimed to explore the SAA levels in a cohort of patients with myasthenia gravis (MG) in relation to disease-related clinical parameters and myasthenic crisis (MC) and elucidate the effects of SAA on immune response. A total of 82 MG patients including 50 new-onset MG patients and 32 MC patients were enrolled in this study. Baseline data and laboratory parameters of all enrolled MG patients were routinely recorded through electronic medical systems. SAA levels were measured by enzyme-linked immunosorbent assay (ELISA) kit. CD4+ T and CD19+ B cell subsets were analyzed by flow cytometry. Invitro, human recombinant SAA (Apo-SAA) was applied to stimulate peripheral blood mononuclear cells (PBMCs) from MG patients to observe the effect on T and B cell differentiation. Our results indicated that SAA levels in new-onset MG patients were higher than those in controls and were positively correlated with QMG score, MGFA classification, plasmablast cells, IL-6, and IL-17 levels. Subgroup analysis revealed that SAA levels were increased in generalized MG (GMG) patients than in ocular MG (OMG), as well as elevated in late-onset MG (LOMG) than in early-onset MG (EOMG) and higher in MGFA III/IV compared with MGFA I/II. The ROC curve demonstrated that SAA showed good diagnostic value for MC, especially when combined with NLR. Invitro, Apo-SAA promoted the Th1 cells, Th17 cells, plasmablast cells, and plasma cells differentiation in MG PBMCs. The present findings suggested that SAA was increased in MG patients and promoted expansion of CD4+ T cell and CD19+ B cell subsets, which implicated in the severity of MG patients.