Complement therapeutics are coming of age in rheumatology

The complement system was described over 100 years ago, and it is well established that activation of this pathway accompanies the great majority of autoimmune and inflammatory diseases. In addition, over three decades of work in murine models of human disease have nearly universally demonstrated that complement activation is upstream of tissue injury and the engagement of pro-inflammatory mechanisms such as the elaboration of cytokines and chemokines, as well as myeloid cell recruitment and activation. With that background, and taking advantage of advances in the development of biologic and small-molecule therapeutics, the creation and clinical evaluation of complement therapeutics is now rapidly expanding. This article reviews the current state of the complement therapeutics field, with a focus on their use in diseases cared for or consulted upon by rheumatologists. Included is an overview of the activation mechanisms and components of the system, in addition to the mechanisms by which the complement system interacts with other immune system constituents. The various therapeutic approaches to modulating the system in rheumatic and autoimmune diseases are reviewed. To understand how best to clinically assess the complement system, methods of its evaluation are described. Finally, next-generation therapeutic and diagnostic advances that can be envisioned for the future are discussed.