The importance of terminal complement inhibition in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic hematologic disorder associated with inappropriate terminal complement activity on blood cells that can result in intravascular hemolysis (IVH), thromboembolic events (TEs), and organ damage. Untreated individuals with PNH have an increased risk of morbidity and mortality. Patients with PNH experiencing IVH often present with an elevated lactate dehydrogenase (LDH; ⩾ 1.5 × the upper limit of normal) level which is associated with a significantly higher risk of TEs, one of the leading causes of death in PNH. LDH is therefore used as a biomarker for IVH in PNH. The main objective of PNH treatment should therefore be prevention of morbidity and mortality due to terminal complement activation, with the aim of improving patient outcomes. Approval of the first terminal complement inhibitor, eculizumab, greatly changed the treatment landscape of PNH by giving patients an effective therapy and demonstrated the critical role of terminal complement and the possibility of modulating it therapeutically. The current mainstays of treatment for PNH are the terminal complement component 5 (C5) inhibitors, eculizumab and ravulizumab, which have shown efficacy in controlling terminal complement-mediated IVH, reducing TEs and organ damage, and improving health-related quality of life in patients with PNH since their approval by the United States Food and Drug Administration in 2007 and 2018, respectively. Moreover, the use of eculizumab has been shown to reduce mortality due to PNH. More recently, interest has arisen in developing additional complement inhibitors with different modes of administration and therapeutics targeting other components of the complement cascade. This review focuses on the pathophysiology of clinical complications in PNH and explores why sustained inhibition of terminal complement activity through the use of complement inhibitors is essential for the management of patients with this chronic and debilitating disease.

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© The Author(s), 2022.

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Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AK received consulting fees from Alexion, Celgene/BMS, Novartis, Ra Pharma, BioCryst, Amgen, Apellis, and Roche, and honoraria from Alexion, Celgene/BMS, Novartis, Ra Pharma, BioCryst, Amgen, Apellis, Roche, Takeda, and Jansen. AK received support for attending meetings and/or travel from Alexion, Ra Pharma, and Takeda, and has participated on a data safety monitoring board or advisory board for Alexion, Celgene/BMS, Novartis, Ra Pharma, BioCryst, Amgen, Apellis, and Roche. CJP has received honoraria and consulting fees from Alexion, Apellis/Sobi, Regeneron, and BioCryst Pharmaceuticals. CJP has participated on an outcomes adjudication committee for Amgen. HS received travel support, honoraria, and research support (all to University of Ulm) from Alexion, AstraZeneca Rare Disease, and honoraria (to University of Ulm) from Novartis, Roche, Apellis, and Sanofi. JN received honoraria from Alexion and Chugai, and served as an advisor to Apellis Pharmaceuticals, Alexion, Novartis, Chugai, F. Hoffmann-La Roche, and BioCryst Pharmaceuticals. RB received research funding and consultancy fees from Alexion and received honoraria from UpToDate, Indy Hematology Review, Alexion, ISTH Congress and American Society of Hematology.