Treatment Of Refractory Myasthenia Gravis Research Articles

Immune checkpoint inhibitor treatment of advanced age metastatic melanoma (MM) patients.

e14603 Background: Immune checkpoint inhibitor (ICI) treatment has become effective method of treating mm including in those over 65 years of age. Increasing number of advanced age mm patients (pts.) are eligible for ICI treatment but not much is known about its efficacy and safety in relation to senescent immune system. We are reporting our updated experience of ICI treatment of advanced age mm pts. from a single Institute. Methods: Between 2011 and 2016, 32 eligible pts. diagnosed with mm were treated at the University of Connecticut with ICI including anti CTLA-4 antibody Ipilimumab, anti PD-1 antibody Pembrolizumab or combination of Ipilimumab and Nivolumab at their FDA approved doses on a standard protocol. Pts. were monitored for immune related adverse events (irAE) that were graded and managed with standard immune suppressive regimens Results: 12 out of 32 mm pts. were over 70 years of age (median 82.5 years, range 73-88 years). Nine pts. were treatment naïve, two had previously failed Ipilimumab treatment and one anti-BRAF and anti- MEK targeted therapy. Clinical benefit occurred in 5 out of 12 pts. (Complete response (CR) 3, partial response 1 and stable disease 1). Nine out of 12 pts. developed irAE that included three grade II (fatigue, diarrhea, hypopituitarism each) and 6 grade IV events (skin rash-1, colitis-1, encephalopathy-1, myasthenia gravis-1, and pneumonitis in 2 pts. each respectively). Of note, an 87-year-old male developed polymyalgia rheumatica after second dose of anti PD-1 treatment that responded to steroids, but developed autoimmune diabetes mellitus and pneumonitis following third dose. Two pts. died from irAE that included an 87-year-old woman from treatment refractory myasthenia gravis and 77-year-old male who suffered sudden death during steroid treatment of pneumonitis. Six pts. died of progressive disease including sudden death in a 77-year old woman and a 87-year-old male following five and two anti PD-1 treatments respectively. One pt. died from pulmonary embolism and four pts. are alive, 2 in CR and two with disease. Conclusions: Our experience indicate advanced age mm pts. respond to ICI treatment but have heightened risk of developing serious irAEs.

A possible role of low regulatory T cells in anti-acetylcholine receptor antibody positive myasthenia gravis after bone marrow transplantation

BackgroundChronic graft-versus-host disease (GVHD) appears several months following allogenic hematopoietic stem cell transplantation (HSCT) and is clinically analogous to autoimmune disorder. Polymyositis is a common neuromuscular disorder in chronic GVHD, but myasthenia gravis (MG) is extremely rare. Hence, its pathophysiology and treatment have not been elucidated.Case presentationA 63-year-old man with a history of chronic GVHD presented with ptosis, dropped head, and dyspnea on exertion, which had worsened over the previous several months. He showed progressive decrement of compound muscle action potential in the deltoid muscle evoked by 3-Hz repetitive nerve stimulation, a positive edrophonium test, and elevated levels of serum anti-acetylcholine receptor antibodies, which suggested a diagnosis of generalized MG. No thymoma was found. Flow cytometric analysis revealed a remarkable depletion of peripheral Tregs (CD4+CD25highFOXP3+ cells, 0.24% of the total lymphocytes). Administration of prednisolone and tacrolimus was insufficient to alleviate his symptoms; however, the use of rituximab successfully improved his condition.ConclusionsMyasthenic symptoms appeared in the process of tapering prednisolone for the treatment of chronic GVHD, supporting the diagnosis of MG associated with chronic GVHD. The present case proposes a possibility that reduction of Tregs might contribute to the pathogenesis of MG underlying chronic GVHD. Immunotherapy with rituximab is beneficial for treatment of refractory MG and GVHD.

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.

Rituximab in refractory myasthenia gravis: a prospective, open-label study with long-term follow-up.

We examined the clinical effectiveness of rituximab in fourteen patients with refractory myasthenia gravis (MG). Manual muscle testing (MMT) score was recorded at baseline and followed during the course of the study. Steroid dose, frequency of intravenous immunoglobulin (IVIG) infusions, and plasma exchange (PLEX) were also monitored throughout the duration of the study. All patients responded dramatically to rituximab, as measured by a change in MMT score, prednisone dose, or the frequency of IVIG infusions or PLEX. Rituximab appears safe and effective for the treatment of refractory MG. It should be considered as a therapeutic option in refractory patients.

Treatment-refractory myasthenia gravis.

Myasthenia gravis (MG) is the most common disorder of neuromuscular transmission and is a prototypical autoimmune disorder. Most patients with MG are successfully treated with acetylcholinesterase inhibitors, corticosteroids, and/or steroid sparing agents such as azathioprine and mycophenolate mofetil. There is a small subset of patients, however, with treatment-refractory disease. In these cases, medications such as rituximab, high-dose cyclophosphamide, and eculizumab may be used. Thymectomy (in some cases repeat thymectomy) is another option in selected patients. Studies evaluating these and other forms of therapy in treatment-refractory MG are reviewed.

Rituximab for the Treatment of Thymoma-Associated and De Novo Myasthenia Gravis: 3 Cases and Review

Myasthenia gravis (MG) is an immune-mediated disorder associated with autoantibodies against postsynaptic nicotinic acetylcholine receptors at neuromuscular junctions. Rituximab, a monoclonal antibody specific for CD20, is used primarily to treat B-cell non-Hodgkin lymphoma. Although it has been used for treatment of a number of autoimmune diseases, there is limited experience in MG. Three patients with refractory MG (2 with concurrent thymoma) were given rituximab. Symptoms stabilized and reductions in immunosuppressive medications were tolerated for extended periods, without adverse effects or infectious complications. These observations support the concept that rituximab may be helpful for the treatment of MG. Remissions in patients with or without thymoma are achievable with rituximab given in combination with commonly used modalities. Furthermore, rituximab is not necessarily contraindicated for the treatment of MG in patients being treated for thymoma. Controlled studies are called for to define its role in the treatment of refractory MG.

Rebooting the Immune System with High‐Dose Cyclophosphamide for Treatment of Refractory Myasthenia Gravis

A small but important proportion of patients with myasthenia gravis (MG) are refractory to conventional immunotherapy. We have treated 12 such patients by "rebooting" the immune system with high-dose cyclophosphamide (Hi Cy, 200 mg/kg), which largely eliminates the mature immune system, while leaving hematopoietic precursors intact. The objective of this report is to describe the clinical and immunologic results of Hi Cy treatment of refractory MG. We have followed 12 patients clinically for 1-9 years, and have analyzed their humoral and cellular immunologic parameters. Hi Cy is safe and effective. All but one of the patients experienced dramatic clinical improvement for variable periods from 5 months to 7.5 years, lasting for more than 1 year in seven of the patients. Two patients are still in treatment-free remission at 5.5 and 7.5 years, and five have achieved responsiveness to immunosuppressive agents that were previously ineffective. Hi Cy typically reduced, but did not completely eliminate, antibodies to the autoantigen AChR or to tetanus or diphtheria toxin; re-immunization with tetanus or diphtheria toxoid increased the antibody levels. Despite prior thymectomy, T cell receptor excision circles, generally considered to reflect thymic emigrant T cells, were produced by all patients. Hi Cy treatment results in effective, but often not permanent, remission in most refractory myasthenic patients, suggesting that the immune system is in fact "rebooted," but not "reformatted." We therefore recommend that treatment of refractory MG with Hi Cy be followed with maintenance immunotherapy.

Extended rethymectomy in the treatment of refractory myasthenia gravis: original video-assisted technique of resternotomy and results of the treatment in 21 patients

The aim of the study was to analyze the impact of extended rethymectomy in patients with myasthenia gravis. Additionally, an original technique of resternotomy is described. Extended rethymectomy was performed on 21 patients with refractory myastenic symptoms after a previous transsternal thymectomy. In 8 patients the original video-assisted technique of complete longitudinal resternotomy with the aid of a special sternal retractor elevating the sternum from above and below was used. Severe intraoperative haemorrhage from the lacerated left innominate vein occurred in 3/13 patients operated on before the video-assisted technique of resternotomy had been introduced. In none of the 8 patients operated on with video-assisted resternotomy such a complication was noted. retained thymic lobe (4/21 patients), ectopic foci of thymic tissue (13/21 patients) no thymic tissue (4/21 patients). Results of follow-up: complete remission (11.8%), improvement (64.7%); no improvement (35.3%) during the follow-up period (mean 3.4 years). There was neither deterioration of myasthenia nor mortality during follow-up in this group. We conclude that described technique of video-assisted resternotomy reliably prevents the laceration of the heart and great vessels, and that complete remission and improvement rates in patients operated on with the extended rethymectomy are relatively low but deterioration of myasthenia is prevented.

Successful treatment of refractory myasthenia gravis using rituximab: a pediatric case report

We report the successful use of anti-CD20 therapy in a child with refractory myasthenia gravis (MG), an antibody-mediated autoimmune disease, who did not respond to conventional therapy. After initiation of anti-CD20 therapy, clinical improvement (muscular strength, pulmonary function) was observed.