Predictive factors for a severe course of COVID-19 infection in myasthenia gravis patients with an overall impact on myasthenic outcome status and survival.

BACKGROUND AND PURPOSE: Myasthenia gravis (MG) patients could be a vulnerable group in the pandemic era of coronavirus 2019 (COVID-19) mainly due to respiratory muscle weakness, older age and long-term immunosuppressive treatment. We aimed to define factors predicting the severity of COVID-19 in MG patients and risk of MG exacerbation during COVID-19. METHODS: We evaluated clinical features and outcomes after COVID-19 in 93 MG patients. RESULTS: Thirty-five patients (38%) had severe pneumonia and we recorded 10 deaths (11%) due to COVID-19. Higher forced vital capacity (FVC) values tested before COVID-19 were shown to be protective against severe infection (95% CI 0.934-0.98) as well as good control of MG measured by the quantified myasthenia gravis score (95% CI 1.047-1.232). Long-term chronic corticosteroid treatment worsened the course of COVID-19 in MG patients (95% CI 1.784-111.43) and this impact was positively associated with dosage (p = 0.005). Treatment using azathioprine (95% CI 0.448-2.935), mycophenolate mofetil (95% CI 0.91-12.515) and ciclosporin (95% CI 0.029-2.212) did not influence the course of COVID-19. MG patients treated with rituximab had a high risk of death caused by COVID-19 (95% CI 3.216-383.971). Exacerbation of MG during infection was relatively rare (15%) and was not caused by remdesivir, convalescent plasma or favipiravir (95% CI 0.885-10.87). CONCLUSIONS: As the most important predictors of severe COVID-19 in MG patients we identified unsatisfied condition of MG with lower FVC, previous long-term corticosteroid treatment especially in higher doses, older age, the presence of cancer, and recent rituximab treatment.

Methylome and transcriptome profiling in Myasthenia Gravis monozygotic twins.

OBJECTIVE: To identify novel genetic and epigenetic factors associated with Myasthenia gravis (MG) using an identical twins experimental study design. METHODS: The transcriptome and methylome of peripheral monocytes were compared between monozygotic (MZ) twins discordant and concordant for MG, as well as with MG singletons and healthy controls, all females. Sets of differentially expressed genes and differentially methylated CpGs were validated using RT-PCR for expression and target bisulfite sequencing for methylation on additional samples. RESULTS: >100 differentially expressed genes and ∼1800 differentially methylated CpGs were detected in peripheral monocytes between MG patients and controls. Several transcripts associated with immune homeostasis and inflammation resolution were reduced in MG patients. Only a relatively few genes differed between the discordant healthy and MG co-twins, and both their expression and methylation profiles demonstrated very high similarity. INTERPRETATION: This is the first study to characterize the DNA methylation profile in MG, and the expression profile of immune cells in MZ twins with MG. Results suggest that numerous small changes in gene expression or methylation might together contribute to disease. Impaired monocyte function in MG and decreased expression of genes associated with inflammation resolution could contribute to the chronicity of the disease. Findings may serve as potential new predictive biomarkers for disease and disease activity, as well as potential future targets for therapy development. The high similarity between the healthy and the MG discordant twins, suggests that a molecular signature might precede a clinical phenotype, and that genetic predisposition may have a stronger contribution to disease than previously assumed.

Two-year outcome of thymectomy with or without immunosuppressive treatment in nonthymomatous myasthenia gravis and its effect on regulatory T cells.

BACKGROUND: Myasthenia gravis (MG) is the autoimmune disorder in which the thymus is considered the pathogenic organ. Thymectomy (TE) is a therapeutic option for MG and often ameliorates clinical symptoms. METHODS: We evaluated clinical features and outcomes after TE in patients without thymoma and the influence of TE with or without concomitant immunotherapy on the CD4(+)CD25(+) regulatory T cell subpopulation of lymphocytes in peripheral blood in defined followed groups of nonthymomatous MG patients. RESULTS: A total of 46 patients with generalized MG who underwent transsternal TE were identified. Neurologic outcomes after TE were favorable for the majority of patients mainly from the group treated with corticosteroids or combined immunosuppressive treatment. TEs with immunosuppressive treatment in MG patients were associated with increased percentages of CD4(+)CD25(+) cells (p<0.001). No significant change in the postoperative levels of CD4(+)CD25(+) cells was observed in thymectomized patients who preoperatively only received pyridostigmine. Also their clinical response to TE after 2 years of follow-up was worst of all followed groups. CONCLUSIONS: The exact mechanism by which TE ameliorates symptoms of MG is yet not clear. These observations indicate that increased percentages of CD4(+)CD25(+) T cells in MG may be related to disease stability and that TE and synergistic effect with concomitant, continuing immunotherapy augmented the proportion of CD4(+)CD25(+) T cells. On the basis of our observations TE alone is not enough to increase the number of circulating CD4(+)CD25(+) regulatory T cells and to establish complete stable remission.

Myasthenia gravis, Castleman disease, pemphigus, and anti-phospholipid syndrome.

INTRODUCTION: Myasthenia gravis is an autoimmune disease marked by neuromuscular transmission failure at the neuromuscular junction. Castleman disease is a rare lymphoproliferative disease characterized by non-cancerous angiofolicular hyperplasia of lymphatic tissue. METHODS AND RESULTS: We describe a young man with rapid, successive manifestations of myasthenia gravis, a solitary form of Castleman disease, pemphigus vulgaris, and anti-phospholipid syndrome, which resulted in 2 ischemic cerebrovascular events that caused a severe central neurological deficit. DISCUSSION: We were unable to find a similar case in the literature, but we hypothesize that the temporal concidence of these clinical entities may be related to a common immunological pathway, such as B-cell activation. Therefore, we treated the patient with an immunosuppressant and anticoagulant treatment, as well as rituximab, a monoclonal antibody therapy against CD20+.

Experience with extracorporeal elimination therapy in myasthenia gravis.

We describe our experience with plasma exchange (PE) and immunoadsorption in patients with myasthenia gravis. The group of 27 patients consists of 21 patients treated with PE and 6 patients who received immunoadsorption. PE therapy led to stabilization in 20 patients. In patients treated with immunoadsorption, therapy could be discontinued in 2 patients after 13 months of therapy, and the other 4 patients were stabilized without myasthenic crises after 6-9 years of therapy. Extracorporeal elimination therapy through PE or immunoadsorption is effective and sometimes life saving and is safe in the hands of an experienced team (6% complication rate).

Atrophy of type II fibres in myasthenia gravis muscle in thymectomized patients: steroid-induced change with prognostic impact.

Selective atrophy of type II muscle fibres has been long recognized as an enigmatic but consistent feature of myasthenia gravis (MG) muscle; however, the pathophysiology and the mechanism of that change have remained obscure. In the present study, the results of histomorphometric analysis performed on muscle biopsies from 207 thymectomized seropositive MG patients were correlated with clinical features of MG to demonstrate possible pathophysiological associations and potential prognostic impact. The atrophy of type II fibres was verified in 35 cases (16.9%), being more pronounced in fibres of IIB subtype. It was neither significantly associated with the duration and severity of MG nor with the age of the patients. On the other hand, we demonstrated that the atrophy associated with long-term treatment with corticosteroids, and correlated with increasing doses. Thus, we suppose that the atrophy of type II muscle fibres in seropositive MG is steroid induced rather than MG-associated event. Although the MG patients with atrophy of type II fibres did not differ from the remaining MG cases in terms of improvement in the disease during the follow-up period, our analysis provides clear evidence that they presented a significantly slower tendency to reach an asymptomatic state after thymectomy. Therefore, the steroid-induced atrophy of type II fibres in MG muscle might be considered to be an unfavourable prognostic factor.

Muscle lymphocytic infiltrates in thymoma-associated myasthenia gravis are phenotypically different from those in polymyositis.

The aim of the study is to provide evidence that the lymphocytic infiltration of myasthenia gravis (MG) muscle do not represent a true autoimmune myositis, rather an infiltration by naive lymphocytes derived from lymphocyte-rich thymomas. Muscle biopsies from 179 patients with pure MG, 6 thymoma patients without MG and 15 patients with definite polymyositis were analyzed. In 18 patients with MG (all associated with lymphocyte-rich thymomas) and in two thymoma patients without MG, lymphocytic infiltrates were identified in muscles. By use of immunohistochemistry, we demonstrated that the lymphocytes in MG differ from those in polymyositis, being mature but in contrast to polymyositis naive CD45RA+ T lymphocytes. We suggest that the lymphocytic infiltrates in patients with MG and thymoma represent an infiltration of muscle by thymoma-derived mature but naive T cells. The finding of CD8+CD45RA+ lymphocytes in muscle may signify an underlying thymoma and should not be misdiagnosed as polymyositis.

Opsoclonus-myoclonus-dysequilibrium syndrome: cytological and immunological dynamics in the serial cerebrospinal fluid in two patients.

A peculiar clinical presentation characterized by the triad of opsoclonus,myoclonus and ataxia, mainly in a form of dysequilibrium, is usually associated with infectious or paraneoplastic processes. Serial cerebrospinal fluid (CSF) analysis in two patients with opsoclonus-myoclonus-dysequilibrium syndrome suggestive of viral encephalitis were performed from disease onset for up to 8 months. A cell count, cytology, total protein and glucose concentrations in CSF, the blood-CSF barrier function, intrathecal synthesis of immunoglobulins (Ig) in class M, G and A expressed as IgM, IgG and IgA indices and oligoclonal IgG bands were monitored. Cellular and humoral alterations in both patients were slight at the onset becoming more pronounced a month later. The kinetics of the CSF changes mirrored the subacute clinical deterioration and subsequent recovery. The delayed response in the CSF measures and the gradual clinical deterioration suggest the development of subacute brain inflammation. A mononuclear pleocytosis, including macrophages and plasma cells, increased within the first month and then normalized during the following weeks. Intrathecally synthesized IgM occurred only transiently after one month of illness, whereas intrathecal IgG production increased during the first month and persisted for at least eight months. An increasing number of oligoclonal IgG bands during the course, indicative of expanding local intrathecal synthesis, was noted. The dynamics of these CSF changes supports the hypothesis that opsoclonus-myoclonus syndrome is a post-infectious immune- mediated condition.

Augmentation cystoplasty in patients with multiple sclerosis.

INTRODUCTION: Augmentation cystoplasty is an effective approach to the detrusor hyperreflexia which is refractory to conservative treatment. Sporadic data have been published in patients with progressive diseases such as multiple sclerosis (MS). MATERIALS AND METHODS: Augmentation ileocystoplasty (Goodwin 'cup-patch') was performed in 9 patients (7 females, 2 males). The average Expanded Disability Status Scale score was 4.1 (range 3.0-6.5); 7 patients had relapse-remitting MS and 2 patients secondary-progressive MS. The indication was a detrusor hyperreflexia refractory to conservative treatment in 8 patients and a detrusor hyperrefluxia with third degree bilateral vesico-ureteral reflux and renal insufficiency in 1 patient. Pre- and postoperative objective parameters were evaluated by urodynamic examination, imaging methods and laboratory examination. Subjective evaluation was performed using a questionnaire on micturition symptoms (score 0-5) and on quality of life (score 0-6). RESULTS: With a follow-up of 6-19 months, we recorded an average increase of the maximum detrusor capacity from 105 to 797 ml and decrease of maximum detrusor pressure from 53 to 30 cm H(2)O. Postmicturition residual urine >25% of the maximum capacity was present in 6 patients who performed clear intermittent autocatheterization postoperatively (2 patients preoperatively). In all patients there was a significant improvement in the irritation micturition symptomatology (pollakisuria, nycturia, urgency and urge incontinence) and the quality of life score improved on average from 5 to 0.7. In the case of the patient with renal insufficiency, the creatinine level decreased from 286 to 150 micromol/l; in the other patients renal function remained normal. CONCLUSIONS: Augmentation cystoplasty is a safe and effective method for indicated patients, which significantly enhances their quality of life.