Complement targeting in autoimmune diseases

Complement is a central effector of cell and tissue injury in hematological and autoimmune diseases, and recent intensive research brought new inhibitors to the clinic. This review summarizes complement-mediated mechanisms across hematological, systemic, and kidney-specific autoimmune diseases, appraises emerging biomarker strategies, and evaluates these therapies.

For years, clinical complement inhibition was possible only at C5, first in paroxysmal nocturnal hemoglobinuria. The arsenal has now expanded to the initiation pathways: sutimlimab (anti-C1s) is effective in the hematological autoimmune condition cold agglutinin disease, pegcetacoplan (C3-inhibitor) in C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis, and oral iptacopan (Factor B-inhibitor) reduces proteinuria in immunoglobulin A nephropathy and C3 glomerulopathy. Nevertheless, challenges remain. Avacopan (C5aR1-inhibitor) faces proposed withdrawal after trial manipulation and hepatotoxicity, and although complement is central to systemic lupus erythematosus and contributes to membranous nephropathy, no effective strategy has yet emerged.

Recognizing complement's role in the pathophysiology of hematological and autoimmune diseases has driven effective new therapies. Comprehensive profiling complement biomarkers, now feasible through complementomics in fluids and tissues, may reveal responsive endotypes and optimal cascade steps to target in diseases where complement is implicated but trials have not yet matched the right drug to the right patients.