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  • Review Article
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The complement system as a potential therapeutic target in rheumatic disease

Nature Reviews Rheumatology volume 13, pages 538–547 (2017)Cite this article

Subjects

Key Points

  • The complement system provides essential protection against infections but also contributes to the severity of autoimmune diseases

  • The complement system is activated in many rheumatic diseases, as evident from deposition of activation fragments in affected tissue, decreased residual complement function and increased levels of circulating activated complement fragments

  • Although complement is activated in rheumatic diseases, this finding does not mean that complement has a major role in the clinical presentation

  • Systemic complement inhibition is feasible and reasonably safe when the right precautions are taken

  • Complement inhibition has not yet become a common therapeutic strategy for rheumatic disease

Abstract

Complement activation is associated with common rheumatic diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic vasculitis. Evidence linking complement activation to these diseases includes the presence of complement deposition in affected tissues, decreased levels of complement proteins and high levels of complement activation fragments in the blood and/or synovial fluid of patients with these diseases, as well as data from experimental models. Eculizumab, a monoclonal antibody that inhibits the complement component C5, is now approved for the treatment of rare conditions involving complement hyperactivation, and the success of this therapy has renewed interest in understanding the utility of complement inhibition in rheumatological practice, particularly for SLE. For example, inhibiting C5 is a potential means of reducing glomerular inflammation in lupus nephritis or treating thrombotic microangiopathy in SLE. The complement system is one of multiple mediators of tissue injury in complex diseases such as SLE, and identifying the disease context in which complement activation has a predominant role is a challenge. An added difficulty in RA is identifying a role for therapeutic complement inhibition within the diverse treatment modalities already available. In this Review, evidence for the therapeutic potential of complement manipulation in rheumatology practice is evaluated.

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Figure 1: The complement system.
Figure 2: Complement activation in rheumatic disease.

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Authors and Affiliations

  1. Department of Rheumatology, Leiden University Medical Center,

    Leendert A. Trouw

  2. Department of Immunohematology and blood transfusion, Leiden University Medical Center, P.O. Box 9600, Leiden, 2300 RC, Netherlands

    Leendert A. Trouw

  3. Centre for Complement and Inflammation Research, Imperial College London, Hammersmith Campus, London, W12 0NN, UK

    Matthew C. Pickering

  4. Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Malmö, 205 02, Sweden

    Anna M. Blom

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  3. Anna M. Blom
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All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

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Correspondence to Leendert A. Trouw.

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Competing interests

M.C.P. declares that he is a scientific adviser for Alexion Pharmaceuticals, Achillion and Ra Pharmaceuticals. A.M.B. declares that she is listed as an inventor on the patent application “Antibodies specific for complement component C4d and uses thereof”. L.A.T. declares no competing interests.

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Trouw, L., Pickering, M. & Blom, A. The complement system as a potential therapeutic target in rheumatic disease. Nat Rev Rheumatol 13, 538–547 (2017). https://doi.org/10.1038/nrrheum.2017.125

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