Study Reveals Membrane Attack Complex Formation Significantly Lower in MOGAD Than in NMOSD

In a new study, findings showed that the complement pathway was activated in both myelin oligodendrocyte glycoprotein IgG-associated disease (MOGAD) and aquaporin-4 IgG+ neuromyelitis optica spectrum disorder (AQP4+NMOSD) but membrane attack complex (MAC) formation was lower in MOGAD, particularly in those with mild attacks, compared with AQP4+NMOSD. Published in Neurology Neuroimmunology & Neuroinflammation, investigators noted that these results may have pathogenetic and therapeutic implications in MOGAD.¹

Findings revealed that cerebrospinal fluid (CSF)-C3a and CSF-C5a levels were significantly higher in MOGAD (mean, 5629 pg/mL [SD, 1079]; 2930 pg/mL [SD, 435.8], respectively) and AQP4+NMOSD (6,017 pg/mL [SD, 3937]; 2544 pg/mL [SD, 1,231], respectively) in comparison with multiple sclerosis (MS, 1507 pg/mL [SD, 1,286]; 193.8 pg/mL [SD, 0.53]). CSF-C3a, CSF-C4a, and CSF-C5a did not differ between MOGAD and AQP4+NMOSD; however, CSF-C5b-9 (MAC) levels were significantly lower in MOGAD (17.4 ng/mL [SD, 27.9]) than in AQP4+NMOSD (62.5 ng/mL [SD, 45.1], P = .0019).

“We have already published in Brain,² which could explain the good evidence of less activated complement cascade in MOGAD compared with NMOSD. In NMOSD, complement-activated tissue damage is related to astrocyte loss and tissue necrosis, but in MOGAD the tissue damage might be relatively mild with pure demyelination with good response to treatment,” coauthor Tatsuro Misu, MD, specially appointed professor and the director in the department of clinical trial implementation at Clinical Research Innovation and Education Center (CRIETO) Tohoku University Hospital, told NeurologyLive^® when asked about his interpretation of the differences in CSF-C5b-9 levels between MOGAD and AQP4+NMOSD, and what this might imply about the pathophysiology of these diseases.

In the study, conducted by senior author Masashi Aoki, MD, PhD, a professor in the department of neurology at Tohoku University Graduate School of Medicine in Japan, and colleagues, CSF samples were obtained from adult patients with MOGAD, AQP4+NMOSD, MS, and noninflammatory neurologic disease between 2018 and 2023. Researchers also collected clinical and laboratory data from these groups of patients. Authors then measured CSF-C3a, CSF-C4a, CSF-C5a, and CSF-C5b-9 levels during the acute phase prior to treatment in MOGAD (n = 12), AQP4+NMOSD (n = 11), multiple sclerosis (n = 5), and noninflammatory neurologic disease (n = 2).

Top Clinical Takeaways

Complement pathway activation occured in both MOGAD and AQP4+NMOSD, but with lower MAC formation in MOGAD, particularly during mild attacks.
Higher levels of CSF-C5b-9 were associated with more severe disability in MOGAD, potentially serving as a marker for prognosis.
The study's. findings highlighted the need for larger, more inclusive studies, particularly involving pediatric-onset MOGAD and patients with optic neuritis, to better understand the immunopathology of MOGAD.

“The majority of MOGAD attacks are relatively mild, which could be cured well with intravenous steroid therapy, however, there are several refractory severe cases, suggesting heterogeneity of pathophysiology in MOGAD. This may be a point for coming up therapeutic strategy and be a good candidate for trying anti-complement C5 treatment in MOGAD, but we think the sample size is too small and needs further studies for confirmation,” Misu, who also serves as the deputy director of CRIETO, added when questioned about the ways these findings on complement activation in MOGAD could influence future therapeutic approaches or treatment strategies for this condition.

All told, patients who had higher EDSS scores (Expanded Disability Status Scale [EDSS] ≥ 3.5) also reported significantly higher CSF-C5b-9 than those who had low EDSS scores (EDSS ≤ 3.0; P =.030). Additionally, patients with high EDSS scores at the last follow-up (≥ 3.5, n = 3) tended to have higher CSF-C5b-9 (34.0 ng/mL [SD, 38.4]) than those with low EDSS scores (≤ 3.0, n = 8; 0.90 ng/mL [SD, 0.72]; P = .064). Authors highlighted that CSF-C5b-9/C5a was significantly lower in MOGAD (mean, 17.4 [SD, 27.9]) compared with AQP4+NMOSD (62.5 [SD, 45.1]; P = .0019).

“As mentioned above, it is unexpected to find a severe case in MOGAD with upregulation of C5b-9, in contrast, C5a is equally high both in NMOSD and MOGAD, so we thought this dissociation might be partially due to targeted cells in tissue condition for complement activation. These facts could explain the mechanisms of refractory courses in one part of MOGAD cases, but the sample size is too small and we could not confirm them all and would like to study in more detail in the near future,” Misu said in reply when being asked about unexpected results in the study, particularly concerning the relationship between CSF complement levels and disease severity in MOGAD.