Refractory Myasthenia Gravis Patients Research Articles

Long-Term Efficacy and Safety of Low-Dose Rituximab in Patients with Refractory Myasthenia Gravis

Introduction: Rituximab is a monoclonal chimeric antibody against CD20⁺ B cells. We aimed to assess the long-term efficacy and safety of CD20⁺ B cell-guided treatment with low-dose rituximab in refractory myasthenia gravis patients. Methods: Patients with refractory myasthenia gravis treated with rituximab for more than 2 years were included. Rituximab was administered when CD20⁺ B cells were greater than 1%. We analysed the efficacy of rituximab, treatment interval, side effects, prognosis, and treatment course. Results: A total of 22 patients were included. All patients received 2–12 doses of rituximab, and the median follow-up time was 48.5 months. The scores of the Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Composite were significantly lower than those at baseline (p < 0.05). MGFA-PIS was significantly improved in 21 (95.45%) patients and 14 (63.64%) patients have reached MGFA-PIS minimal manifestations. The average daily dose of prednisone and pyridostigmine bromide and the proportion of immunosuppressants were significantly lower (p < 0.05). Seven patients suffered from 14 worsenings. Eight patients terminated rituximab due to good efficacy. Most patients tolerated rituximab well, although 1 patient had opportunistic infection and hypogammaglobulinemia, 1 patient had an intracranial mass. Conclusion: Long-term CD20⁺ B-cell-guided low-dose rituximab showed good efficacy and tolerance in patients with refractory myasthenia gravis.

Autoantibody profile in myasthenia gravis patients with a refractory phase

A subgroup of myasthenia gravis (MG) patients fail to respond adequately to recommended treatments, a condition referred to as refractory MG. During the refractory phase, patients experience persistent debilitating symptoms with potential life-threatening events or inability to reduce immunosuppressant dosages and minimize long-term toxicities. We conducted a retrospective, single-center study of 113 MG patients to investigate the autoantibody profile and clinical characteristics of refractory MG patients, compared with nonrefractory patients, based on predefined criteria. Fifteen patients (13.3%) were classified as refractory. Double-seronegative MG (DSNMG), without detectable nicotinic acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) antibodies, was identified in six refractory patients, significantly higher than those with nonrefractory MG (40% vs 16.3%; P=.031). None of the refractory patients had MuSK antibodies. Patients in the refractory group more frequently had an earlier disease onset, thymic pathology, and thymectomy (P ≤. 03 for all). In this study, patients with refractory MG were more likely than those with nonrefractory MG to be DSN; and refractory DSNMG patients had worse MGFA classes in their recent visit compared with anti-AChR positive refractory patients. Refractory DSNMG patients may represent a distinct group that requires more individualized and targeted treatment approaches.

P-PN015. Rituximab therapy in post thymectomy refractory myasthenia gravis: A case report

Introduction . Myasthenia gravis (MG) is one of the autoimmune diseases caused by disruption of synaptic transmission at the neuromuscular junction. An estimated 10–20% patients with MG will still experience frequent relapses even after receiving the standard MG treatment with pyridostigmine and immunosuppressants. Rituximab can be considered as a therapeutic option in MG patients that show unsatisfactory response to standard therapy. Case report: A female patient, 31 years old, was diagnosed with myasthenia gravis in 2017, and tested positive for acetylcholine receptor antibody (AChR antibody). Upon diagnosis, her Myasthenia Gravis Composite (MGC) score was 22. She was administered with pyridostigmine 4x60 mg per oral (PO) and methylprednisolone 3x16 mg PO. She was hospitalized three times in two months due to MG relapses. In addition, the patient suffered an episode of myasthenic crisis with mechanical ventilator support one year after diagnosis, after which she had thymectomy. Post thymectomy, MGC score was 13, with medication pyridostigmine 4x60 mg PO, methylprednisolone 1x8 mg PO, and azathioprine 1x200 mg PO. The patient was still experiencing MG relapses and was admitted to hospital five times in two months. She was then administered rituximab. After rituximab therapy, her MGC score was 4, she only had relapse once within a year. Pyridostigmine 2x60 mg and methylprednisolone 1x8 mg PO were still continued. Results . A recent systematic review shows that rituximab administration gives satisfactory results in 72% of MuSK patient, 30% of AChR antibody patients, and 44% in combined both groups. In this patient, it was found that initial treatment with thymectomy surgery had unsatisfactory improvement, and relapses were remained relatively frequent. However, with additional treatment with rituximab, clinical improvement was significant. Conclusion . Rituximab is an effective therapeutic choice for refractory MG patients who fail to attain good disease control even after thymectomy.

Rituximab in Refractory Myasthenia Gravis: Experience in a Single Healthcare Center in Mexico.

Background: Ten to fifteen percent of patients with myasthenia gravis (MG) have treatment-refractory disease. In short series and case reports, rituximab has proven to be effective in refractory MG.Methods: A retrospective, longitudinal study was conducted. Recruitment was performed in an MG cohort from a single third-level healthcare center in Mexico. The selection included refractory MG patients that were treated with rituximab. Response after rituximab therapy was assessed with MG composite score (MGCS) and prednisone dose reduction at 6, 12, and 18 months after initiation. Wilcoxon signed-rank test was used to evaluate differences between related groups for non-continual variables. P<0.05 was considered statistically significant.Results: Ten patients (7%) fulfilled criteria for refractory MG, and eight of them were treated with rituximab. The mean age at MG diagnosis was 25.5 (±2) years, with a female predominance (75%). All our patients (100%) had positive acetylcholine receptor (AchR) antibodies. The median MG duration was six years (interquartile range [IQR] 4.2-6) before rituximab initiation. All patients were previously treated with azathioprine and 50% additionally with cyclophosphamide. The median prednisone doses before rituximab treatment and 18-month follow-up were 50 mg (IQR 30-50 mg) and 10 mg (IQR 0-20 mg), respectively (p=0.011). The median baseline MGCS and at 18-month follow-up were 19.5 (IQR 11-31) and 6 (IQR0-16), respectively (p = 0.012).Conclusion: Rituximab appears to be associated with clinical improvement and prednisone dose reduction in Latin-American patients diagnosed with anti-AchR MG. Our findings need to be interpreted in light of the limitations mentioned.

Efficacy and safety of different dosages of rituximab for refractory generalized AChR myasthenia gravis: A meta-analysis

BackgroundRituximab (RTX) is a mouse-human chimeric anti-CD20 monoclonal antibody and has been increasingly used for preventing relapses in myasthenia gravis (MG). However, the appropriate dose for maximizing the beneficial effects in refractory MG with acetylcholine receptor (AChR) autoantibody is a long-standing and critical debating question. MethodsWe performed a meta-analysis to evaluate the efficacy and safety of the different doses of RTX in 260 refractory AChR-MG patients. ResultsThe AChR-MG patients were divided into low or routine RTX dose groups. An overall proportion of 77% (p = 0.000) AChR-MG patients demonstrated improved clinical status as indicated by the Myasthenia Gravis Foundation of America post-intervention scale (MGFA-PIS). There were 77.1% patients showed improved clinical status in lower dose of RTX group (p = 0.000) and 76.8% in routine protocol group (p = 0.000). Although we found there was no significant difference in the proportion of AChR-MG patients with improved clinical status or adverse reactions between the two groups, adverse reactions might be lower in the lower dose RTX group. ConclusionMost of refractory MG patients with anti-AChR autoantibody were well responsive and tolerated to RTX treatment. Repeated application of lower dose of RTX was effective and might be more appropriate for refractory AChR-MG patients with potential lower side effects.

Low-dose rituximab lowers serum Exosomal miR-150-5p in AChR-positive refractory myasthenia gravis patients

Two potentially related microRNAs (miRNAs; miR-150-5p and miR-146a-5p) were examined after low-dose rituximab (RTX) treatment in patients with acetylcholine receptor antibody (AChR)-positive refractory myasthenia gravis (MG). In this prospective, open-label, and self-controlled pilot trial, 12 AChR-positive refractory MG patients were administrated a single, low dose of RTX and followed up at six months. Results showed that RTX decreased the serum exosomal miR-150-5p, scores on three clinical indices (MGFA, MMT, ADL), and patients' prednisolone requirement. Additionally, CD19+ and CD27+ B cells decreased, showing a strong correlation with miR-150-5p. In conclusion, low-dose RTX is effective for AChR-positive refractory MG treatment. Furthermore, our data support the role of miR-150-5p as a potential biomarker for MG.

Intravenous cyclophosphamide monthly pulses in refractory myasthenia gravis.

Refractory myasthenia gravis (MG) is defined as a failure to respond adequately to conventional therapies, the inability to reduce immunosuppressive therapy without clinical relapse or the need for ongoing rescue therapy, severe adverse effects from immunosuppressive therapy (treatment intolerant) or frequent myasthenic crisis even on therapy. Cyclophosphamide (CYC) is a DNA alkylating agent that causes important interference in transcription processes and DNA replication, it has been used in refractory MG with controversial results. We aim to determine the efficacy of CYC in refractory MG in the Mexican population. In an observational, longitudinal retrospective study, we identified eight refractory MG patients treated with 30-50mg/kg monthly CYC for at least 6months. The efficacy was assessed by Osserman scale considering significant improvement a ≥ 1 point reduction and Myasthenia Gravis Composite Scale. The relapse-free and remission-free period were also calculated using the Kaplan-Meier statistic. Clinical improvement was achieved in 75% of the patients. According to the Kaplan-Meier analysis, the median progression-free survival (PFS) was 9 (6.2-11.5) months and the median time to progression (TTP) was 4 (1-8) months. Response was independent of patient's characteristics, except for the MG age of onset (p = 0.0025). CYC was effective in all patients with refractory MG for a mean of 9months, with worsening thereafter, which could be associated with low cumulative dose. The symptomatic improvement with CYC was noted within the 1st month. We conclude that CYC is effective as an induction to remission therapy, although our data suggest it is not effective as a long-term therapy.

Refractory myasthenia gravis: Characteristics of a portuguese cohort.

Some myasthenia gravis (MG) patients are refractory to conventional treatments. To describe the clinical features of refractory MG (RMG) and explore the association with human leukocyte antigen HLA-DRB1 alleles, a cohort study of 114 consecutive MG patients was performed. Patients were classified as RMG based on predefined criteria. Twenty-two patients were found to have RMG (19.3%). There were no differences between non-RMG and RMG patients with respect to sex, age of onset, abnormal 3-Hz repetitive nerve stimulation, anti-acetylcholine receptor antibody positivity, thymectomy, thymoma or thymic hyperplasia, and polyautoimmunity. HLA-DRB1*03 was more frequent in the non-RMG vs. control population (P = 3 × 10-6 ). The HLA-DRB1*13 allele was less frequent in non-RMG patients compared with controls (P = 0.002), and less frequent in the non-RMG group compared with the RMG group (P = 0.003). HLA-DRB1*03 was more common in non-RMG, and the HLA-DRB1*13 allele appeared to have a protective role, as reported previously in other autoimmune disorders. Muscle Nerve 60: 188-191, 2019.

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

We aimed to explore the effects of low-dose rituximab (RTX) on circulating T- and B-cell lymphocytes and the improvement of clinical symptoms in refractory myasthenia gravis (MG) patients. Fifteen patients with refractory MG were treated with a low dose of 600 mg RTX and were evaluated by serial-clinical scales, flow cytometry of peripheral blood T and B cells, and antibody titer before and after six months of RTX treatment. The quantitative MG score (QMGS), manual muscle testing (MMT), MG-related activities of daily living (MG-ADL) and MG-specific quality-of-life (QOL) were significantly improved and the average steroid-dosage reduction was 40% (p = .001) in refractory MG patients at six months after RTX infusion. Compared to eighteen non-refractory MG patients and eighteen Healthy controls, our study showed that the frequencies of circulating regulatory B cells (Bregs) and regulatory T cells (Tregs) were significantly lower and the expression of B-cell activating factor receptors (BAFF-Rs) was greater in refractory MG patients without RTX treatment. Importantly, 600-mg RTX was sufficient to deplete B cells and maintain low B-cell counts for up to six months after infusion. Additionally, a low dose of RTX further increased the frequencies of Tregs. Hence, there is an immune imbalance in circulating T- and B-cell lymphocytes in refractory MG patients compared to non-refractory MG patients. We conclude that remarkable T- and B-cell lymphocyte imbalance exists in refractory MG. Low-dose RTX can improve myasthenic symptom and deplete B cells and increase Tregs%.

Rituximab as induction therapy in refractory myasthenia gravis: 18month follow-up study.

Myasthenia gravis is an immune-mediated disorder characterized by easy fatigability and diurnal variation in skeletal muscle weakness. Aim of therapy is to prevent crisis and maintain remission. However, despite standard therapy, some remain refractory to treatment. To look for efficacy of rituximab in treating refractory myasthenia gravis (MG) in the form of MGFA-PIS score, number of crisis, and dose reduction in immunotherapies. A retrospective study was performed in patients with myasthenia gravis (MG) referred to the All India Institute of Medical Sciences (AIIMS) from January 2012 to December 2017 with follow-up of at least 6 months. Eight refractory MG patients (six AchR positive and two Musk-positive) were identified on oral corticosteroids and azathioprine. After four cycles of rituximab, all patients showed a dose reduction of whom seven were completely tapered off prednisone and there was a 53.8% dose reduction in azathioprine. All patients were continued on AZA after RTX infusion unless contraindicated. Seven achieved minimal manifestation (MM)-2 status as per the MGFA-PIS scale. None of the patients had infusion associated reactions or cytopenia post-RTX infusion. In this small retrospective study, we used RTX as induction therapy and results suggest that repeated RTX infusions may not be necessary as it adds to cost of therapy, especially in LMIC like India.

Burden of illness in patients with treatment refractory myasthenia gravis.

This study assessed the clinical burden of refractory myasthenia gravis (MG), relative to nonrefractory MG. Rates of myasthenic crises, exacerbations, inpatient hospitalizations, and emergency room (ER) visits over a 1-year period were measured for 403 refractory, 3,811 nonrefractory, and 403 non-MG control patients from two administrative health plan databases. Compared with nonrefractory patients, a significantly greater percentage of refractory patients had at least one myasthenic crisis (21.3% vs. 6.1%; P < 0.001) and at least one exacerbation (71.2% vs. 32.4%; P < 0.001) over a 1-year period. Refractory patients were also significantly more likely to be hospitalized and/or have an ER visit than nonrefractory patients and non-MG controls (P < 0.001 for all). Refractory MG patients have significantly greater clinical burden and are more likely to utilize intensive healthcare resources than nonrefractory patients. Furthermore, refractory patients may be at greater risk of crises throughout the disease course than previous studies have suggested. Muscle Nerve, 2018.

Escalation Strategies in the Treatment of Refractory Myasthenia Gravis

AbstractAmong all patients with myasthenia gravis (MG), 10 to 15% are considered to be refractory to (expanded) standard treatments. Current international consensus guidelines for the management of myasthenia gravis recommend referral of refractory MG patients to centers with expertise in the treatment of MG and chronic intravenous immunoglobulin therapy or plasmapheresis. Here we briefly summarize current approaches to overcome refractory myasthenia gravis.

Refractory myasthenia gravis - clinical profile, comorbidities and response to rituximab.

Introduction: Myasthenia gravis (MG) is an antibody mediated autoimmune neuromuscular disorder characterized by fatigable muscle weakness. A proportion of myasthenia gravis patients are classified as refractory due to non responsiveness to conventional treatment. This retrospective study was done to evaluate clinical profile, epidemiological, laboratory, and features of patients with MG and mode of management using rituximab and complications.Methods: Data of myasthenia gravis patients admitted or presented to outpatient department (previous medical records) with MG between January 2008 and January 2016 were included. A total of 512 patients fulfilled the clinical and diagnostic criteria of myasthenia gravis of which 76 patients met the diagnostic certainty for refractory myasthenia gravis and were evaluated. Results: Out of 76 refractory MG patients, 53 (69.73%) patients fulfilled all the three defined criteria. The median age of onset of the refractory MG group was 36 years with a range of 27–53 years. In our study 25 patients (32.89%) belonged to the age group of 21–30 years. Anti-MuSK antibodies were positive in 8 non-refractory MG patients (2.06%) and 36 refractory MG patients (47.36%). Mean HbA1C was found to be 8.6±2.33. The dose of administered prednisone decreased by a mean of 59.7% (p=3.3x10–8) to 94.6% (p=2.2x10–14) after the third cycle of rituximab treatment.Conclusion: The refractory MG patients are most commonly female with an early age of onset, anti-MuSK antibodies, and thymomas. Refractory MG patients have higher prevalence and poor control (HbA1C >8%) of diabetes mellitus and dyslipidemia probably due to increased steroid usage. Rituximab is very efficient in treatment of refractory MG with adverse effects being low.