Rituximab for Myasthenia
Rituximab for Myasthenia
Abstract & Commentary
By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports that he receives grant/research support from Pfizer and is on the speaker's bureau of Athena Diagnostics.
Synopsis: The monoclonal antibody, rituximab, appears to benefit patients with myasthenia gravis that is refractory to other modalities.
Source: Lebrun C, Bourg V, Tieulie N, et al. Successful treatment of refractory generalized myasthenia gravis with rituximab. Eur J Neurol 2009;16;246-250.
What can you offer a patient with refractory generalized myasthenia gravis (MG) after he or she has failed plasma exchange, intravenous immunoglobulin (IVIG), and immunosuppressive therapy? Rituximab may be an option. Six MG patients who responded poorly to thymectomy followed by subsequent immunosuppression with at least two different drugs (corticosteroids, azathioprine, intravenous cyclophosphamide, cyclosporine, or mycophenolate mofetil) received rituximab intravenously. Refractory MG was defined as no symptomatic improvement within six months, with patients requiring over 360 mg of cholinesterase inhibitors daily, and IVIG infusion resulting in no additional improvement. Four were male, all were bedridden, ages ranged from 27 to 78 years, and only one was anti-acetylcholine receptor antibody positive. Anti-MuSK (muscle-specific receptor tyrosine kinase) antibodies were present in three others. Diagnosis in the seronegative patients was made by clinical presentation, decremental response on repetitive nerve stimulation, and positive prostigmine test. Rituximab infusion was given at lymphoma doses, 375 mg/m2 weekly for the first month, followed by a single dose every two months thereafter, subject to clinical response.
Improvement was evident by the end of the first month of treatment, with all patients requiring reduced dosage of anti-cholinesterase medication and demonstrating clinical improvement as indicated by their Osserman score. Subsequent infusion frequency was determined by clinical course and was administered when patients felt a need for increased anti-cholinesterase medication. Two patients each required infusion for one and two years. By one year following treatment induction, five patients were no longer receiving steroid medication, the single exception being a patient who also suffered from Crohn's disease. Maximum anti-cholinesterase dosage was 180 mg/day. Adverse events, including significant infection and hematologic or metabolic toxicity, were not seen, and rituximab was well tolerated. Acute gout was precipitated in one patient with hyperuricemia, and transient worsening of diabetes and hypertension was seen in another. Rituximab appears to be beneficial and safe for refractory generalized MG.
Monoclonal antibodies, as a therapeutic modality, are the new frontier in medicine. Rituximab, developed by recombinant DNA technology using human and murine genes, is a chimeric IgG1 monoclonal antibody against the B-lymphocyte antigen CD20, beneficial in the treatment of autoimmune disorders, including myasthenia gravis (MG), and neoplastic diseases, including B-cell non-Hodgkin's lymphoma and B-cell leukemia. T cells play a role in the development of MG and antibodies (basiliximab) directed against CD25, expressed on activated T and B cells, may also be beneficial in MG.1 Administered intravenously and intermittently over nine months in a patient with severe MG, moderate improvement was achieved, allowing withdrawal of steroid medication. However, repeated bacterial infections including sinusitis, tonsillitis, and pneumonia necessitated close monitoring. Studies in the rat model now indicate that experimental autoimmune MG can also be modulated by interfering with signaling between IFN-g inducible protein 10 and its receptor CXCR3, suggesting this as a further potential treatment for MG.2 Where all of this will lead remains to be determined but monoclonal antibodies appear to be a promising treatment worth future study.
1. Kakoulidou M, Pirskanen-Matell R, Lefvert AK. Treatment of a patient with myasthenia gravis using antibodies against CD25. Acta Neurol Scand 2008:117: 211-216.
2. Feferman T, Aricha R, Mizrachi K, et al. Suppression of experimental autoimmune myasthenia gravis by inhibiting the signaling between IFN-g inducible protein 10 (IP-10) and its receptor CXCR3. J Neuroimmunol 2009;doi:10.1016/j.jneuroim.2009.01.021.The monoclonal antibody, rituximab, appears to benefit patients with myasthenia gravis that is refractory to other modalities.
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