Complement Activation Profiles Predict Clinical Outcomes in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease

Abstract

Background and objectives: The role of the complement system in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is not completely understood, and studies exploring its potential utility for diagnosis and prognosis are lacking. We aimed to investigate the value of complement factors (CFs) as diagnostic and prognostic biomarkers in patients with MOGAD.

Methods: Multicentric retrospective cohort study including patients with MOGAD, multiple sclerosis (MS) and aquaporin-4 seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD) with available paired serum and CSF samples. A panel of CFs were measured by multiplex ELISA, and the levels were compared between the 3 conditions. Univariable and multivariable analyses were performed to evaluate the association between levels of CFs and relapse and disability outcomes in MOGAD patients.

Results: Ninety-four patients (MOGAD, n = 60; MS, n = 18; AQP4-NMOSD, n = 16) were included. Mean (SD) age at sampling was 39.4 (16.7), 40.7 (7.0), and 43.3 (21.0), respectively. Female were predominant, especially in AQP4-NMOSD (88%). Combination of the serum levels of C3a, C4a, and C3a/C3 ratio showed excellent potential to discriminate MOGAD from patients with MS (area under the curve [AUC] [95% CI] 0.95 [0.90-0.99]) and from AQP4-NMOSD (AUC 0.88 [0.76-1.00]). In patients with MOGAD, CSF levels of CFs of the classical/lectin pathway influenced relapse-related outcomes, and lower C4 levels were associated with higher number of relapses during follow-up (incidence rate ratio [95% CI] 0.88 [0.78-0.99]; p = 0.04 in multivariable analysis), and a high C4a/C4 ratio was associated with increased risk of second relapse during the first year (hazard ratio [95% CI] 3.68 [1.26-10.78]; p = 0.02 in multivariable analysis). Time to second relapse was shorter in patients with MOGAD with a high CSF C4a/C4 ratio (log-rank p = 0.01). CSF levels of the membrane attack complex SC5b9 influenced disability-related outcomes, and baseline CSF SC5b9 levels were higher in patients who reached the final Expanded Disability Status Scale (EDSS) ≥ 3.0 (p = 0.002), and elevated SC5b9 levels were associated with increased risk of reaching EDSS ≥ 3.0 (odds ratio [95% CI] 1.79 [1.16-3.67]; p = 0.04 in multivariable analyses).

Discussion: Our results suggest that serum and CSF levels of CFs have diagnostic and prognostic value respectively in patients with MOGAD. These findings support the use of complement inhibitors as a therapeutic approach in these patients.

Figure 1. Comparison of Serum Levels of Complement Factors Between Patient With MOGAD, MS, and AQP4-NMOSD

Boxplots depict the distribution of serum levels of complement factors showing statistically significant differences between the three different cohorts of patients. Median values are represented by the horizontal bar, IQR by hinges, and 1.5 × IQR by whiskers. Group comparisons were computed with the Kruskal-Wallis test and post hoc pairwise analysis. * <0.05, ** <0.01, *** <0.001. IQR = interquartile range; MOGAD = MOG-IgG antibody-associated disease; MS = multiple sclerosis.

Figure 2. Potential of Complement Factors as Prognostic Biomarkers in Patients With MOGAD

(A) Kaplan-Meier curves evaluating the time to second relapse in patients with high (>10.8) and low (<10.8) CSF values of the C4a/C4 ratio, revealing a higher risk of second relapse in patients with MOGAD with higher CSF values (log-rank test p value: 0.01). (B) Boxplots depicting the distribution of CSF SC5b9 levels in patients reaching and not reaching an EDSS of 3.0. Median values are represented by the horizontal bar, IQR by hinges, and 1.5 × IQR by whiskers. The comparison analysis (Mann-Whitney test) demonstrated higher CSF SC5b9 levels in patients reaching an EDSS of 3.0 (p = 0.002). (C) Performance of CSF SC5b9 levels (in ng/mL) to discriminate between patients with MOGAD who will and will not reach an EDSS of 3.0. AUC = area under the curve; EDSS = Expanded Disability Status Scale; IQR = interquartile range; MOGAD = MOG-IgG antibody-associated disease; SE = sensitivity; SP = specificity.