The evolving landscape of complement therapeutics in rheumatology.

Abstract

The pathogenic roles of the complement system in many human diseases have become increasingly understood, in large part through the results of informative clinical trials. In addition, based on biomarker studies in patients and results of murine models, there are an increasing number of indications under consideration for the use of therapeutics targeting different components of the pathway. Here, lessons learned from several of these studies are reviewed, with an emphasis on diseases of clinical and research interest to rheumatologists. Publications focused on the complement-related pathogenesis and clinical trials of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and rheumatoid arthritis (RA), in addition to studies relevant to other diseases, are summarised. Following translational studies demonstrating activation in affected tissues and blood from patients, the potential pathogenic roles of complement in AAV and RA were studied in murine models. These studies suggested in both diseases that complement alternative pathway generation of C5a is a primary driver of target organ damage. In AAV, clinical trials using a novel small molecular oral C5a anaphylatoxin receptor (C5aR1) antagonist revealed a substantial corticosteroid-sparing effect and initial evidence of clinical benefit. With regard to RA, although there is strong support through biomarker and murine model studies, intervention with C5 and C5aR1 inhibitors revealed only modest benefit, and additional work is necessary to determine if different targets or timing of intervention is necessary. Beyond AAV and RA, a substantial number of additional diseases cared for by rheumatologists exhibit evidence of complement activation in a potentially pathogenic manner. Inappropriate activation of the complement pathway mediates tissue inflammation and damage in many human diseases, including key ones cared for by rheumatologists.