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Complement therapeutics are coming of age in rheumatology

Nature Reviews Rheumatology volume 19, pages 470–485 (2023)Cite this article

Subjects

Abstract

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.

Key points

  • Analyses of both tissue and circulating biomarkers indicate that the complement pathway is activated in the majority of rheumatological and autoimmune diseases.

  • A complement inhibitor targeting interaction of the anaphylatoxin C5a with its receptor is effective and approved for the treatment of ANCA-associated vasculitis.

  • A separate inhibitor of C5 activation is also effective and approved for use in atypical haemolytic uraemic syndrome (aHUS), a thrombotic microangiopathy disorder, as well as neuromyelitis optica spectrum disorder.

  • Complement system biomarkers assessed using multiple formats can provide diagnostic as well as prognostic information in diseases for which there are approved complement therapeutics, as well as in certain other clinical settings.

  • Murine models of human rheumatic and autoimmune diseases, including ANCA-associated vasculitis, aHUS, thrombotic microangiopathy and lupus nephritis, demonstrate that complement activation is upstream of tissue injury and the generation of other effector mechanisms.

  • Polymorphic variation and mutations in complement genes are associated with the risks of development of several rheumatic and autoimmune diseases.

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Fig. 1: Complement pathway overview: pathways, activators and effector mechanisms.
Fig. 2: Activation and regulatory steps in the amplification loop of the complement pathways.
Fig. 3: Complement receptors, cell distributions and primary roles.
Fig. 4: Roles of complement in the pathogenesis of ANCA-associated vasculitis.

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Acknowledgements

The author thanks his many colleagues with whom he has worked to understand the biological and clinical roles of the complement system in human disease. These individuals include J. Thurman, N. Banda, L. Kulik, F. Zhang, S. Tomlinson, R. Quigg, C. Atkinson, A. Lynch, J. Atkinson, B. Dixon and A. Frazer-Abel. The author also thanks colleagues from Taligen Therapeutics and Q32 Bio, who have worked to develop therapeutics designed to translate to patient care the discoveries made in academic research laboratories.

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    V. Michael Holers

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The author declares that he is a co-founder of Q32 Bio, a complement therapeutics company, and through those efforts has received sponsored research funding, consulting income and stock.

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Holers, V.M. Complement therapeutics are coming of age in rheumatology. Nat Rev Rheumatol 19, 470–485 (2023). https://doi.org/10.1038/s41584-023-00981-x

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