Rebound Relapse Effect Identified in NMOSD Following Eculizumab Discontinuation
In this small-scale Turkish-based substudy, stopping eciluzumab appeared to be associated with a “rebound” effect with a high risk of relapse in patients with NMOSD.
Aksel Siva, MD
Findings from a subpopulation of Turkish patients with a long-term stable course of neuromyelitis optica spectrum disorder (NMOSD) enrolled in the PREVENT trial (NCT01892345) showed that several patients experienced early relapse months after discontinuing treatment with eculizumab (Soliris; Alexion). Because of the small sample size, investigators were not able to reach a definite conclusion; however, they noted that these findings raise practical implications on the use of eculizumab in patients with NMOSD.1
Eculizumab, a humanized monoclonal antibody that targets human complement component 5 and inhibits activation of the terminal complement pathway, was approved as a treatment for NMOSD in 2019 based on data from PREVENT. In the newly published analysis consisting of 10 patients who participated in PREVENT and its open-label extension (OLE), 4 of the 6 who could not continue eculizumab treatment experienced an early relapse within 3 months after stopping the drug.
Senior author Aksel Siva, MD, Cerrahpasa School of Medicine, Istanbul University, and colleagues concluded that these findings have several ramifications, "one of them being whether eculizumab in a treatment-responsive AQP4-IgG+ NMOSD patients causes early disease reactivation and if so, what precautions should we consider taking in such instances. One of the other outcomes of this observation is the reinforcement of the concept that in eculizumab-treatment responsive NMOSD patients treatment should not be stopped even after many years of disease inactivity."
Among the cohort, the disease duration ranged from 7.75 to 23.53 years, with all patients enrolled due to recurrent relapses. At the time of enrollment, the mean Expanded Disability Status Scale scores was 2.6, with a number of annual attacks varying between 0.22 to 4. One patient entered the study treatment-naïve whereas all other received different immunosuppressive treatments (azathioprine, rituximab, mycophenolate mofetil, cyclophosphamide, and oral steroid).
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During the OLE study, 7 patients were relapse-free, whereas 3 experienced relapses and 2 of these 3 patients dropped out because of moderate-to-severe relapses. These 2 patients received rituximab treatment after cessation of eculizumab. After 3.7 years, patient 3 could not continue eculizumab as she had recurrent urinary tract infections.
A total of 7 patients completed the OLE, with eculizumab usage for a mean of 5.51 (±1.51) years. Six of them could not continue the drug because of reimbursement conditions of the health system, and 4 of these experienced early relapses after cessation of eculizumab. All patients were hospitalized, 2 patients received only intravenous corticosteroids while the rest 2 received additionally intravenous immunoglobulin or plasmapheresis. Of those who relapses following discontinuation, 3 developed new spinal cord lesions mainly in cervical spinal cord.
According to the study authors knowledge, no early and severe disease reactivation after cessation of any of the NMOSD-approved treatments (eculizumab, inebilizumab, and satralizumab) have been reported. In the treatment of multiple sclerosis, disease reactivation after cessation has been documented in different immunomodulatory drugs. In a 2022 study published in Neurology, specialty treatment modalities, notably fingolimod and natalizumab, were shown to have additional risk for disease reactivation.2
That trial, which featured 14,213 patients, showed that after discontinuing fingolimod, rates of relapse increased overall (month 1-2 annualized relapse rate [ARR], 0.15; 95% CI, 0.08-0.22) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference, 0.14; 95% CI, –0.01 to 0.29). ARRs started to increase 2 months after natalizumab cessation (month 2-4 ARR, 0.47; 95% CI, 0.43-0.51), and commencement of a subsequent therapy reduced both the risk of relapse (HR, 0.76; 95% CI, 0.72-0.81) and disability accumulation (HR, 0.73; 95% CI, 0.65-0.80).
