Sustained Terminal Complement Inhibition on the Endothelium with Ravulizumab in Patients with Atypical Haemolytic Uraemic Syndrome.

INTRODUCTION: Atypical haemolytic uraemic syndrome (aHUS) is a rare and severe form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway, leading to sustained complement activation at the endothelial level and microvascular thrombosis, predominantly affecting the kidney. Anti-C5 therapy with eculizumab has markedly improved patient outcomes, with ex vivo studies showing suppression of endothelial C5b-9 deposition by sera from treated patients, in contrast to the marked C5b-9 formation induced by acute-phase sera. Ravulizumab, a long-acting anti-C5 antibody derived from eculizumab, has recently been approved for aHUS, offering extended dosing intervals and maintaining (in patients switched from eculizumab) or inducing (in de novo treated patients) disease remission. Its ability to inhibit terminal complement activation at the endothelial level has not yet been evaluated.

METHODS: In this retrospective study, six patients with primary aHUS were assessed, including 4 switched from eculizumab and 2 treated de novo with ravulizumab. Serum-induced C5b-9 formation on human microvascular endothelial cells (HMEC-1) was measured ex vivo at multiple time points during treatment.

RESULTS: C5b-9 formation was in normal range on HMEC-1 exposed to sera collected from all aHUS patients treated with ravulizumab, regardless of prior eculizumab exposure, and all patients remained in or achieved clinical remission.

CONCLUSION: These findings provide mechanistic evidence supporting ravulizumab as an effective inhibitor of terminal complement activation and highlight ex vivo C5b-9 assessment as a potential tool for monitoring treatment efficacy in aHUS.