Balancing efficacy and safety of complement inhibitors

• Published in: Journal of autoimmunity Vol. 145; p. 103216
• Main Authors: Watanabe-Kusunoki, Kanako, Anders, Hans-Joachim
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2024
• Subjects: ANCA; Animals; Complement Activation - drug effects; Complement Inactivating Agents - adverse effects; Complement Inactivating Agents - therapeutic use; Complement System Proteins - immunology; Complement System Proteins - metabolism; Glomerulonephritis; Glomerulonephritis - drug therapy; Glomerulonephritis - immunology; Glucocorticosteroids; Humans; Immunothrombosis; Inflammation; Treatment Outcome; Vasculitis; Glomerulonephritis; Glucocorticosteroids; Inflammation; Immunothrombosis; Vasculitis; ANCA
• ISSN: 0896-8411; 1095-9157; 1095-9157
• DOI: 10.1016/j.jaut.2024.103216

Complement inhibitors have been approved for several immune-mediated diseases and they are considered the next paradigm-shifting approach in the treatment of glomerulonephritis. The hierarchical organization of the complement system offers numerous molecular targets for therapeutic intervention. However, complement is an integral element of host defense and therefore complement inhibition can be associated with serious infectious complications. Here we give a closer look to the hierarchical complement system and how interfering with proximal versus distal or selective versus unselective molecular targets could determine efficacy and safety. Furthermore, we propose to consider the type of disease, immunological activity, and patient immunocompetence when stratifying patients, e.g., proximal/unselective targets for highly active and potentially fatal diseases while distal and selective targets may suit more chronic disease conditions with low or moderate disease activity requiring persistent complement blockade in patients with concomitant immunodeficiency. Certainly, there exists substantial promise for anti-complement therapeutics. However, balancing efficacy and safety will be key to establish powerful treatment effects with minimal adverse events, especially when complement blockade is continued over longer periods of time in chronic disorders. •We need to optimize the benefits and infectious risks of complement inhibitors.•Proximal or unselective targets are suited for highly active and fatal diseases.•Distal or selective targets may be appropriate for chronic disease conditions.•Patient immunocompetencies are a pivotal determinant in the risk assessment.•Biomarkers are needed for patient stratification and personalized therapeutics.