Current Medications for the Treatment of NMOSD Brenda 1Donald
Background
1 Neuman ,
Dr. Asaff Harel
1,2 MD
and Barbara Zucker School of Medicine at Hofstra/Northwell 2Lenox Hill Hospital
Results and Discussion
Neuromyelitis Optica is an autoimmune disease against astrocytes that leads to symptoms of transverse myelitis and optic neuritis. Transverse myelitis is acutely appearing spinal cord dysfunction due to demyelination and inflammation. Optic neuritis is destruction and inflammation of the optic nerve leading to different impairments like vision loss. Aquaporin-4 (AQP4) antibodies play an integral role in the pathogenesis of this disease. The pathophysiology of NMOSD includes reoccurring attacks that lead to the accumulation of further deterioration and disability. For this reason, medications that prevent relapses are integral for the treatment of NMOSD. We aimed to discuss and compare the different treatment options for NMOSD with a specific focus on the efficacy and adverse effects of each medication.
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• • Figure 2. Mechanism of action of medications for NMOSD *AZA and MMF suppress the proliferation of rapidly dividing cells. AZA and MMF suppress the proliferation of B cells and T cells because they are rapidly dividing.
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AZA has been shown to reduce ARR and stabilize EDSS in multiple studies. Adverse effects of AZA included in different studies are GI symptoms including nausea and vomiting, leukopenia, elevated liver enzymes, and increased risk for infection. One comparison study on AZA, RTX, and MMF demonstrated that patients on AZA experienced significantly more side effects than patients on MMF, and patients on AZA experienced more hepatotoxicity than patients on RTX. Rituximab has been shown to reduce ARR and EDSS in multiple studies. Relapses have occurred shorty after treatment in some studies as well as relapses have occurred later possibly due to nonadherence to the medicine regimen. Multiple studies have found that RTX is a superior treatment than AZA in the aspect of efficacy. However, other studies did not find any significant differences in the reduction of ARR and EDSS between AZA, MMF, and RTX. A systemic review that compared the side effects of AZA, MMF, and RTX found that RTX caused the most allergic reactions. Multiple studies have shown that MMF reduces ARR and EDSS. Eculizumab has been shown to reduce ARR in multiple studies. In one study patients treated with eculizumab had a decreased median EDSS after treatment. However a double blinded clinical trial performed a few years later found no significant difference in change in EDSS score between the eculizumab treated group and the placebo group. In a randomized controlled clinical trial patients on satralizumab, an IL-6 inhibitor, had fewer relapses than patients on a placebo. In multiple studies tocilizumab, an IL-6 inhibitor, has been shown to decrease ARR and EDSS in NMOSD patients. A randomized control clinical trial on inebilizumab found that NMOSD patients treated with inebilizumab had fewer relapses when compared to the placebo group.
Future Direction Figure 1a. Image taken from Pekcevik, Y., Mitchell, C. H., Mealy, M. A., Orman, G., Lee, I. H., Newsome, S. D., Thompson, C. B., Pardo, C. A., Calabresi, P. A., Levy, M., & Izbudak, I. (2016). Differentiating neuromyelitis optica from other causes of longitudinally extensive transverse myelitis on spinal magnetic resonance imaging. Multiple sclerosis (Houndmills, Basingstoke, England), 22(3), 302–311. https://doi.org/10.1177/1352458515591069MRI showing transverse myelitis in NMOSD.
Future studies could focus on comparing Eculizumab, IL-6 inhibitors, Inebilizumab to each other as well as to azathioprine, rituximab, Mycophenolate mofetil.
Figure 1b. Image taken from Kim, H. J., Paul, F., Lana-Peixoto, M. A., Tenembaum, S., Asgari, N., Palace, J., Klawiter, E. C., Sato, D. K., de Seze, J., Wuerfel, J., Banwell, B. L., Villoslada, P., Saiz, A., Fujihara, K., Kim, S. H., & Guthy-Jackson Charitable Foundation NMO International Clinical Consortium & Biorepository (2015). MRI characteristics of neuromyelitis optica spectrum disorder: an international update. Neurology, 84(11), 1165–1173. https://doi.org/10.1212/WNL.0000000000001367MRI showing transverse myelitis in NMOSD.
Resources
Methods We reviewed research papers that discussed azathioprine (AZA), rituximab (RTX), Mycophenolate mofetil (MMF), Eculizumab, IL-6 inhibitors, Inebilizumab as treatments for NMOSD. Some of the measures of efficacy evaluated were ARR (annual relapse rate), and EDSS (expanded disability status scale score). We researched and discussed MOA, FDA approval status, and adverse effect of each medication. We also reviewed any studies that compared the efficacy and side effect of different medications for NMOSD.
Bichuetti, D. B., de Oliveira, E. M. L., Oliveira, D. M., de Souza, N. A., & Gabbai, A. A. (2010). Neuromyelitis Optica Treatment. In Archives of Neurology (Vol. 67, Issue 9). https://doi.org/10.1001/archneurol.2010.203
Figure 7: Independent CRISPR knockout of CDK4 or CDK6 does not cause dropout in most breast cancer cell lines studied. Figure 3. FDA approval and adverse
effects of medications for NMOSD
Cree, B. A. C., Bennett, J. L., Kim, H. J., Weinshenker, B. G., Pittock, S. J., Wingerchuk, D. M., Fujihara, K., Paul, F., Cutter, G. R., Marignier, R., Green, A. J., Aktas, O., Hartung, H.-P., Lublin, F. D., Drappa, J., Barron, G., Madani, S., Ratchford, J. N., She, D., … NMOmentum study investigators. (2019). Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. The Lancet, 394(10206), 1352–1363. Espiritu, A. I., & Pasco, P. M. D. (2019). Efficacy and tolerability of azathioprine for neuromyelitis optica spectrum disorder: A systematic review and meta-analysis. In Multiple Sclerosis and Related Disorders (Vol. 33, pp. 22–32). https://doi.org/10.1016/j.msard.2019.05.011 Jade, J. D., Bansi, S., & Singhal, B. (2017). Rituximab in Neuromyelitis Optica Spectrum Disorders: Our Experience. Annals of Indian Academy of Neurology, 20(3), 229–232. Pittock, S. J., Berthele, A., Fujihara, K., Kim, H. J., Levy, M., Palace, J., Nakashima, I., Terzi, M., Totolyan, N., Viswanathan, S., Wang, K.C., Pace, A., Fujita, K. P., Armstrong, R., & Wingerchuk, D. M. (2019). Eculizumab in Aquaporin-4–Positive Neuromyelitis Optica Spectrum Disorder. The New England Journal of Medicine, 381(7), 614–625.