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Rituximab Displays Superiority to Azathioprine, Mycophenolate Mofetil as Initial NMOSD Treatment

Disease Spotlight | <b>Disease Spotlight: NMOSD</b>

Among a cohort of more than 300 patients in China, those with APQ4 positive NMOSD reported a significantly lower risk of relapse among those treated with rituximab compared with the other groups.

New data from a study published in the European Journal of Neurology add to the available evidence supporting rituximab in the treatment of neuromyelitis optica spectrum disorder (NMOSD), with the findings of the retrospective study suggesting reduced-dose rituximab is superior to azathioprine and mycophenolate mofetil.1

Ultimately, the risk of NMOSD relapse was significantly reduced in patients treated with rituximab compared with those who were on azathioprine (HR, 4.40; 95% CI, 1.41-13.80; P = .011) or mycophenolate mofetil (HR, 5.20; 95% CI, 1.60-16.86; P = .006).

Consisting of more than 300 patients with aquaporin-4 (APQ4) antibody positive NMOSD in China who were treated initially with azathioprine (n = 167), mycophenolate mofetil (n = 131), or rituximab (n = 55), the study was conducted by Chao Quan, MD, of the Department of Neurology and Huashan Rare Disease Center, Huashan Hospital and Shanghai Medical College, Fudan University; and National Center for Neurological Disorders, and colleagues in the Pan-Yangtze River Delta Alliance for Demyelinating Disease.

“Data regarding the efficacy and safety of currently widely available preventive therapies in [NMOSD] are needed,” Quan et al wrote. The group concluded that, “We provide class III evidence that reduced dose of [rituximab] is superior to [azathioprine] and [mycophenolate mofetil] as initial treatment to reduce the risk of relapse and is better tolerated than [azathioprine]in Chinese patients with AQP4 antibody-positive NMOSD.”

Notably, drug discontinuations were also less likely for those in the rituximab group compared with the azathioprine group (HR, 2.22; 95% CI, 1.34-3.66; P = .002). As for safety, the rituximab group displayed a lower incidence of AEs (32.7%) than the azathioprine group (62.3%; P <.001).

The study’s primary outcome was the occurrence of relapse after the initiation of immunotherapy, while the secondary outcomes were annual relapse rate (ARR), disability accumulation, drug persistence, and adverse events (AEs). The median patient follow-up time for the 353-patient cohort was 30.3 months. Patients in the rituximab group were treated with 100 mg on day 1, followed by 500 mg on day 2, continuing at that dose every 6 months. Among those in the rituximab group, 76.4% were on concomitant steroid treatment. Of those in the azathioprine and mycophenolate mofetil groups, those percentages were 96.4% and 95.4%, respectively.

These data add to an ever-growing foundation of findings suggestive of rituximab’s efficacy in the treatment of NMOSD.2-5 Previously, systematic reviews have suggested that therapy with the agent reduces the frequency of NMOSD relapse rates and neurological disability in patients with NMOSDs.2,5 This efficacy may be driven by the treatment’s effect on germinal center activity, according to recent findings from Sarosh R. Irani, DPhil, FRCP, FEAN, Head, Oxford Autoimmune Neurology Group, University of Oxford, and colleagues.6

“Our findings implicate ongoing [germinal center] activity as a rituximab-sensitive driver of AQP4 antibody production. They may explain rituximab’s clinical efficacy in several autoantibody-mediated diseases and highlight the potential value of direct [germinal center] measurements across autoimmune conditions,” Irani et al wrote, adding that the therapy’s efficacy occurs “despite no accompanying reduction in serum autoantibody levels.”

Irani et al observed clinical relapses associated with features of germinal center activity such as aquaporin-4 antibody immunoglobulin (AQP4-IgG) generation or shifts in AQP4-IgG subclasses (odds ratio [OR], 6.0; range, 3.3-10.8; P <.0001). Additionally, once rituximab was administered, the investigators reported fewer clinical relapses (annual relapse rate, 0.79 to 0; P <.001) accompanied by significant reductions equaling 4-fold changes in AQP4-IgG (P = 0.004) and 430-fold changes in intranodal B cells (P < 0.0001) from 11 dCLNs.6

REFERENCES
1. Huang W, Wang L, Xia J, et al. Efficacy and safety of azathioprine, mycophenolate mofetil, and reduced dose of rituximab in neuromyelitis optica spectrum disorder. Eur J Neurol. 2022;29(8):2343-2354. doi:10.1111/ene.15355
2. Damato V, Evoli A, Iorio R. Efficacy and Safety of Rituximab Therapy in Neuromyelitis Optica Spectrum Disorders: A Systematic Review and Meta-analysis. JAMA Neurol. 2016;73(11):1342-1348. doi:10.1001/jamaneurol.2016.1637
3. Uzunköprü C, Tütüncü M, Gündüz T, et al. The efficacy of rituximab in patients with neuromyelitis optica spectrum disorder: A real-world study from Turkey. Int J Clin Pract. 2021;75(7):e14158. doi:10.1111/ijcp.14158
4. Tahara M, Oeda T, Okada K, et al. Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2020;19(4):298-306. doi:10.1016/S1474-4422(20)30066-1
5. Wang Y, Chang H, Zhang X, Yin L. Efficacy of rituximab in the treatment of neuromyelitis optica spectrum disorders: An update systematic review and meta -analysis. Mult Scler Relat Disord. 2021;50:102843. doi:10.1016/j.msard.2021.102843
6. Damato V, Theorell J, Al-Diwani A, et al. Rituximab abrogates aquaporin-4–specific germinal center activity in patients with neuromyelitis optica spectrum disorders. PNAS. 2022;119(24):e2121804119. doi:10.1073/pnas.2121804119