Eculizumab for Treating Aquaporin-4 Antibody-Positive NMOSD

By Jai S. Perumal, MD

Synopsis: In this retrospective study of a cohort of aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (NMOSD) patients treated with eculizumab, the authors reported efficacy with decreasing relapse rate, magnetic resonance imaging changes, and disability outcomes, but cautioned about the risk of serious infections.

Source: Ringelstein M, Asseyer S, Lindenblatt G, et al. Eculizumab use in neuromyelitis optica spectrum disorders: Routine clinical care data from a European cohort. Neurology. 2024;103(9):e209888.

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system that preferentially affects the optic nerves and spinal cord. Classic NMO, or Devic’s disease, is characterized by concurrent episodes of optic neuritis (ON) and transverse myelitis (TM). NMO spectrum disorder (NMOSD) is diagnosed in patients with isolated ON or TM who have the NMO immunoglobulin G (IgG) aquaporin-4 antibody, which is potentially pathogenic and has high specificity for this group of diseases.

Eculizumab, a humanized monoclonal antibody, is a complement inhibitor. It binds to complement protein C5, inhibiting cleavage to C5a and C5b, which cause inflammatory injury. Data suggest that aquaporin-4 antibody triggers a complement-mediated attack on astrocytes, resulting in injury and neuronal loss. Eculizumab is a U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved treatment for aquaporin-4 antibody-positive NMOSD patients.

This was a retrospective study of 52 patients from a European registry of NMOSD patients, the Neuromyelitis Optica Study Group (NEMOS). The primary efficacy outcomes assessed were annualized relapse rate (ARR), magnetic resonance imaging (MRI) changes (including new or enlarging T2 lesions or gadolinium-enhancing lesions), and disability score.

The authors also evaluated safety based on adverse events, mortality, and meningococcal vaccinations, which are required prior to starting this treatment. Seventy-five percent of patients had been undergoing prior treatments before starting eculizumab, the most frequent being rituximab in 60%, followed by azathioprine in 25% and intravenous immunoglobulin (IVIG) in 17%.

Twenty-five percent of patients were treatment-naïve. Following treatment initiation, 39/52 (75%) patients were taking eculizumab alone and 13/52 (25%) were treated with add-on prednisolone, azathioprine (n = 3), or mycophenolate mofetil (n = 2).

Fifty-two patients who received eculizumab were followed for a period of 16.2 months (interquartile range [IQR], 9.6 to 21.7). Eighty-seven percent were women, and the mean age was 55.0 ± 16.3 years. The median average relapse rate decreased from 1 (range, 0 to 4) in the preceding two years to 0 (range, 0 to 8; P < 0.001). The median Expanded Disability Status Scale (EDSS) score remained at 6.0 throughout the period of the study. Prior to starting eculizumab, the baseline brain and spinal cord imaging was available in 47 and 41 of the 52 patients, respectively. Post-treatment, follow-up brain and spinal cord imaging was available in 27 and 28 patients, respectively, at 10.0 months (median IQR, 7.2 to 21.2) and 11.6 months (median IQR, 6.3 to 20.5). The proportion of new or enlarging T2 lesions or gadolinium-enhancing lesions decreased significantly, 44% vs. 7% for brain MRI and 64% vs. 16% for spine MRI.

Forty-five patients (87%) received at least one meningococcal vaccination. Of these, 25 (48%) patients were first vaccinated while undergoing eculizumab treatment (n = 5) or were re-vaccinated while taking it (n = 20). Seven relapses of NMOSD occurred in temporal association with the vaccination, after a median of nine days (IQR, 6 to10). All of these were in patients who were vaccinated before the start of treatment. None of the patients who received the vaccination during treatment or who were taking concurrent prednisolone had relapses.

Seven patients (13%) experienced serious infections. Of these, two were taking eculizumab alone and five had add-on therapy with steroids, azathioprine, or mycophenolate mofetil. There were five fatalities, one from myocardial infarction, one from meningococcal sepsis, and the others from sepsis or systemic infections.

Commentary

In a disease that is characterized by severe relapses and where the accrual of disability mainly is through residual deficits from relapses rather than the progressive disease course, medications that decrease the risk of a relapse are vital in preventing disability. In keeping with the results from its clinical trials, this study also demonstrated that eculizumab was effective in decreasing the risk of a relapse, decreasing MRI activity, and potentially having a benefit on preventing disability in aquaporin-4 antibody-positive NMOSD patients.

However, in addition to the general infection risk with immune suppression, an important specific issue is the risk of Neisseria meningitides infection with eculizumab. Vaccination is required prior to treatment.

But there appears to be a risk of triggering a relapse immediately following meningococcal vaccination in this study. The risk was found to be lower in patients who were vaccinated while undergoing steroid treatment or taking eculizumab. One has to consider the possibility that patients undergoing these treatments may not mount an adequate response to vaccines and, hence, may not be fully protected against the infection.

In summary, eculizumab appears to be an effective treatment for aquaporin-4 antibody-positive NMOSD, but one must be vigilant about infections and exercise special caution regarding meningococcal infections and vaccination.

Jai S. Perumal, MD, is Assistant Professor of Neurology, Weill Cornell Medical College.