B cell and aquaporin-4 antibody relationships with neuromyelitis optica spectrum disorder activity

Abstract

This post hoc analysis of the randomized, placebo-controlled N-MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B-cell subsets and aquaporin-4 immunoglobulin G (AQP4-lgG) titers and attacks. Among participants receiving placebo, CD20⁺ and CD27⁺ B-cell counts were modestly increased from the pre-attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre-attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B-cell subset counts decreased and did not increase with attacks. No difference in change of AQP4-IgG titers from baseline to time of attack was observed.

Figure 1

CD20⁺ B‐cell counts, CD27⁺ memory B‐cell counts, and PB/PC signature among participants receiving placebo during the N‐MOmentum study. BL, baseline; PB, plasmablast; PC, plasma cell. Results expressed as fold change from BL for (A) CD20⁺ B cells, (B) CD27⁺ memory B cells, and (C) PB/PC signature. Data presented at BL, before attack (pre), and during attack, or for participants not experiencing an attack (no). Lines between points indicate individual patient profiles. Dashed red line indicates a 2‐fold change from baseline. The n values correspond to individual samples; each patient may have >1 sample and/or may be included in multiple groups. ^aSamples from participants with no attacks are included for reference. ^bPaired fold change from baseline cell counts or PB/PC signature measurements at each timepoint (BL, pre, attack) were analyzed using a Wilcoxon signed rank test. *p < 0.05. **p < 0.01.

Figure 2

AQP4‐IgG titers during the N‐MOmentum study. AQP4‐IgG, aquaporin‐4 immunoglobulin G; IQR, interquartile range; RCP, randomized controlled period; SEM, standard error of the mean; T, tertile. (A) Histogram of baseline AQP4‐IgG titers by tertile among participants with baseline titers >1:20. (B) The percentage of participants experiencing a ≥2‐fold, ≥4‐fold, and ≥8‐fold decrease in AQP4‐IgG titers at the end of the RCP in the placebo and inebilizumab groups. P values generated from Fisher's exact test for the proportion of participants with decreases in titers surpassing each cutoff. (C) The percentage of participants with baseline titers >1:20 who experienced a ≥2‐fold decrease in AQP4‐IgG titers at the end of the RCP stratified by baseline AQP4‐IgG tertile in the placebo and inebilizumab groups. p values generated from Fisher's exact test for the proportion of participants with decreases in titers surpassing each cutoff. (D) Box plots of AQP4‐IgG titers for participants receiving placebo or inebilizumab at baseline and time of attack. p values for within‐group differences vs baseline were calculated using Wilcoxon signed rank test, while p values for differences between the placebo vs inebilizumab groups were calculated using Mann–Whitney U test. (E) Annualized attack rate over time by AQP4‐IgG tertiles at Day 1 of the RCP. Data presented as mean (SEM) estimated by Poisson regression. *p < 0.05. **p < 0.01.

Figure 3

Longitudinal analysis of AQP4‐IgG titers. AQP4‐IgG, aquaporin 4 immunoglobin G; LOD, level of detection. Titers were measured over time among participants who were AQP4‐IgG seropositive at baseline and had undetectable levels of AQP4‐IgG while receiving inebilizumab during the N‐MOmentum study. One participant (in orange) experienced an attack at D85 post treatment. This participant converted to seronegative via the titer assay by Day 57.