Neuromyelitis optica (NMO), initially described by Devic, was clinically characterized by a severe episode of optic neuritis and transverse myelitis (1, 2). The discovery of autoantibodies directed against the aquaporin-4 (AQP4) astrocyte water channels led to the concept of Neuromyelitis Optica Spectrum Disorders (NMOSD) for seropositive patients, in whom typical NMO, isolated optic neuritis (ON), or inaugural longitudinally extensive transverse myelitis (LETM) could coexist with or even be preceded by other clinical presentations (3). Approximately 73% of NMOSD patients are AQP4-seropositive. Subsequently, it has been acknowledged that some patients were seronegative for AQP4 antibodies, while anti-myelin oligodendrocyte glycoprotein (MOG) antibodies could be detected or not (double seronegative cases) (1). Among patients with AQP4-IgG-negative disease, 42% were positive for anti-MOG antibodies (4). The current definition of NMOSD was established in 2015 by an international panel of experts that was convened to develop revised diagnostic criteria and clarify the nomenclature of the disease (3). The core clinical characteristics requirements for patients with AQP4-IgG-positive NMOSD include syndromes related to the optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for the diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable (3). AQP4-antibody seropositive disease is considered primarily an autoimmune astrocytopathic disease with lytic and non-lytic clinical consequences for astrocytes, while MOG-antibody seropositive disease is an inflammatory demyelinating disease associated with a better prognosis (1, 5). The worldwide prevalence of NMOSD is estimated at around 1–3 per 100,000 people. NMOSD is more frequent in women, with a female-to-male ratio up to 9:1 and an age at onset of 40 years on average (6). In France, 669 NMOSD patients with AQP4-IgG+ were included in the NOMADMUS cohort by April 2022. The age at onset was 41 years on average, and a similar female-to-male ratio was observed in this cohort.

In NMOSD, relapses are more frequent (90%) (7) and more severe (8), and prognosis is generally poorer with potentially higher Expanded Disability Status Scale (EDSS) scores (2) compared to multiple sclerosis. NMOSD is a severe and debilitating disease, the evolution of which is mainly driven by the occurrence of relapses. Relapses may lead to vision loss and paralysis, often only partially reversible, and this is also in contrast to MS, where relapses generally involve full recovery (9). The proportion of patients with complete remission inversely correlates with the number of attacks (10), and neurological deficits accumulate over time. Patients with relapses exhibit diminished visual acuity, clinically meaningful worsening of neurological disability, and greater use of analgesics use than non-relapsing patients (11). Quality of life is significantly reduced in patients with NMOSD, and most patients report impairment in several domains (12). Thus, the burden of disease is particularly high, and every effort must be made to reduce the incidence of relapses since they are closely associated with disease progression.

Treatment of NMOSD comprises three components: acute treatment of relapses, preventive therapy, and symptomatic therapies. The mainstay of acute treatment consists of corticosteroids and plasma exchange (PLEX). A recent retrospective study using data from NOMADMUS suggested that aggressive anti-inflammatory treatment requiring an early combination of PLEX with corticosteroids for the first attack is associated with better recovery and treatment outcomes (13). Preventive therapy is aggressively pursued through immunosuppressants (14). It relies on off-label use of immunosuppressive drugs, commonly azathioprine, mycophenolate mofetil, and rituximab or immunoglobulins in patients with contraindications to immunosuppressants (14, 15). Nevertheless, new approved therapies are emerging in the NMOSD treatment strategies, such as satralizumab, inebilizumab, eculizumab, and ravulizumab. In France, specific guidelines for the management of NMOSD were published in 2021 (16).

Eculizumab is a recombinant humanized monoclonal IgG2/4k antibody that binds to the human C5 complement protein and inhibits the activation of terminal complement. Eculizumab was the first drug to be approved for the treatment of AQP4+ NMOSD, based on the results of the phase III PREVENT study (ClinicalTrials.gov; PREVENT: NCT01892345; open-label extension: NCT02003144) that demonstrated a statistically significant reduction in the risk of adjudicated relapse by 94% compared with placebo (p < 0.0001) in patients with AQP4-IgG+ NMOSD. Eculizumab safety data were also consistent with its well-characterized safety profile, with the specific risk of meningococcal infections in its other approved indications, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and generalized myasthenia gravis (gMG), based on clinical trial data and more than 10 years of post-marketing experience (17–22). Eculizumab was granted in 2019 a marketing authorization for the treatment of adult patients with NMOSD who are AQP4 antibody-positive with a relapsing course of the disease by the European Medicines Agency (EMA). In France, the Health Authority, Haute Autorité de Santé (HAS), Transparency Commission issued a favorable opinion on reimbursement of eculizumab in adults with NMOSD AQP4+ and with a relapsing course of the disease (two relapses in the past year or 3 relapses in the past 2 years, including one in the past year) and not responding to background immunosuppressant therapy (rituximab, azathioprine, mycophenolate mofetil) (23). To further assess the benefits of eculizumab in post-marketing surveillance, the French authorities required an observational study to evaluate the long-term effectiveness, safety, and patient-reported outcomes of eculizumab in patients with NMOSD in a real-world setting.

ECUP4 is a real-world study that will investigate the long-term benefits of eculizumab in NMOSD patients in France. The main purpose of the study is to evaluate the long-term effectiveness and safety of eculizumab in real-world use and to capture patients' perspective toward treatment outcomes. The study was planned in the context of a post-marketing surveillance request by the French authorities. The ECUP4 study is nested in the national registry NOMADMUS, which will ensure the quality and reliability of the collected data and will provide evidence for medical decision-making in treating NMOSD patients.

The rationale for the use of eculizumab in NMOSD was based on the evidence that complement activation with extensive vasculocentric immune complex deposition has been identified as one of the pathophysiological features of the disease (29). AQP4 antibodies trigger the complement system and lead to the formation of a membrane attack complex via the complement-dependent cytotoxicity pathway, which results in astrocyte damage and secondary neuronal injury (29). Eculizumab inhibits terminal C5 complement protein cleavage into the C5a and C5b fragments. It demonstrated its efficacy in the phase III PREVENT study, where 143 patients were randomized in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1,200 mg every 2 weeks starting at week 4) or matched placebo (28). Adjudicated relapses occurred in 3 and 43% of patients in the eculizumab and placebo arms, respectively, resulting in adjudicated annualized relapse rates of 0.02 and 0.35, respectively (rate ratio: 0.04; 95% CI: 0.01–0.15; p < 0.001). More recently, an interim analysis of combined data from PREVENT and its open-label extension, performed at 192 weeks (3.7 years), showed that 94.4% of patients treated by eculizumab remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI: 0.013–0.048) in all eculizumab-treated patients vs. 0.350 (95% CI: 0.199–0.616) in the placebo group (30). Importantly, during the open-label extension phase, 37% of patients could stop or decrease their background immunosuppressive therapy use.

An indirect comparison of newly approved drugs using a Bayesian network meta-analysis suggested that eculizumab was more efficient than satralizumab or inebilizumab to reduce the risk of relapse, which was decreased by 90% compared to satralizumab and by 89% compared to inebilizumab, all drugs being used in monotherapy (31). Whether used as a single agent or combined with immunosuppressive drugs, eculizumab was associated with the highest probability (>80%) of being the best option to prevent relapses.

Eculizumab has also been approved in other indications: PNH, aHUS, and gMG. In these patient populations, it demonstrated a favorable safety profile. Socié et al. (21) published the largest safety data representing more than 10 years of post-marketing pharmacovigilance surveillance of eculizumab for the treatment of PNH and aHUS and confirmed that the overall safety profile of eculizumab is consistent with that reported from clinical trials. The major risk of eculizumab treatment remains the risk of neisserial infections, and there is a need for appropriate monitoring to effectively mitigate the risk of meningococcal infection (21).

Real-world data are increasingly used to obtain additional information, complementary to that provided by randomized controlled trials (RCTs) (32). One of the key advantages of real-world studies is that they enlarge the patient population compared to RCTs that require homogenous cohorts and exhibit, therefore, low external validity and generalizability to other settings (33). Follow-up is usually limited to relatively short periods in RCTs, external parameters are thoroughly controlled, and patients' monitoring is very stringent, which yields results that are reliable but poorly applicable in the overall population (32–34). Real-world data are therefore a very useful tool for decision-making, not only at the physician level but also at the regulatory level (34). The European Medicine Agency (EMA) and the Food and Drug Administration (FDA) issued recommendations to encourage pharmaceutical companies to perform real-world studies and provide real-world data as complementary information in their marketing authorization application files, or after drug approval, to allow reevaluation of the benefit-risk ratio (35, 36). In France, the HAS published guidelines on the methods to be used in post-marketing studies (37). The results of this study will add evidence to supplement results from clinical trials PREVENT on the effects of the complement inhibitor eculizumab and its safety profile. This might also help to inform the discussion of benefit and risk in the shared decision-making process for relapse prevention between healthcare providers and individual NMOSD patients. Currently, a post-marketing surveillance study is being conducted in Japan, including 179 NMOSD patients treated with eculizumab, which may last up to 7 years (38).

The main aspect of the study lies in the expected nationwide coverage of patient recruitment. To reduce any bias in patients' selection, inclusions must be as large and exhaustive as possible. In France, patients with rare diseases are usually managed in reference centers as part of a reference network. In this study, all possible sites identified as treating patients with NMOSD are involved in the MIRCEM network and CRC-SEP, which allow an almost comprehensive inventory of eligible patients. Nevertheless, some patients treated outside of these sites might be missed. In this study, the utilization of a well-defined NMOSD cohort with high diagnostic certainty needs to be acknowledged. All included patients have been positively tested for AQP4-IgG, and their diagnosis has been confirmed by expert neurologists. The attacks are commonly confirmed by MRI, enabling a precise measure of relapse. However, it is possible that some attacks are missed or not confirmed by MRI in the real world. The planned follow-up period will be potentially sufficient to provide long-term data on safety and effectiveness in this indication, extended for 5.5 years.

Some other aspects of the study deserve consideration. Since patients who started eculizumab <6 months prior to inclusion are eligible for the study, some historic data at baseline will be recorded retrospectively in case report forms, a situation considered a possible source of bias. However, follow-up data in the NOMADMUS cohort will be collected in a prospective manner using high-quality procedures, with few missing data points. Moreover, the classification of relapses will reflect real-world practice; thus, a classification bias cannot be fully ruled out. Yet, only highly specialized sites will participate, where physicians have long-lasting experience in patients' assessments.

Finally, new drugs are emerging in NMOSD. Ravulizumab is a second-generation humanized monoclonal antibody that binds to C5 and was developed to reduce the treatment burden associated with eculizumab through an improved dosing regimen. It provides the same benefits as eculizumab but has a substantially longer half-life (50 vs. 11 days), thereby permitting a longer intravenous dosing interval (every 8 vs. every 2 weeks). The efficacy and safety of ravulizumab were evaluated in a phase 3, open-label, externally controlled interventional study, CHAMPION-NMOSD (NCT04201262) (39). The PREVENT placebo group was used as an external comparator. Results showed that ravulizumab significantly reduced relapse risk in patients with AQP4+ NMOSD. Ravulizumab was recently approved by the EMA, as well as by the Brazilian and Japanese regulatory authorities. Once ravulizumab is available in France, it is expected that patients treated with eculizumab will switch to ravulizumab to reduce the treatment burden. Therefore, the number of patients to be enrolled in ECUP4 might be limited by the approval of ravulizumab in France.

The study was approved by Commission Nationale de l'Informatique et des Libertés. The study was conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants' legal guardians/next of kin in accordance with the national legislation and institutional requirements.

RM: Conceptualization, Investigation, Methodology, Supervision, Validation, Writing – review & editing, Project administration. DL: Writing – review & editing, Conceptualization, Investigation, Methodology, Supervision, Validation. HZ: Conceptualization, Investigation, Methodology, Supervision, Validation, Writing – review & editing. CP: Conceptualization, Investigation, Methodology, Supervision, Validation, Writing – review & editing. EL: Investigation, Methodology, Software, Supervision, Validation, Writing – review & editing. EA: Writing – review & editing, Writing – original draft, Methodology, Supervision, Conceptualization, Project administration, Validation, Resources, Visualization. MP: Conceptualization, Methodology, Supervision, Validation, Project administration, Resources, Visualization, Writing – original draft, Writing – review & editing. JS: Conceptualization, Investigation, Methodology, Supervision, Validation, Writing – review & editing.