The evolving landscape of complement therapeutics in rheumatology

Area of Science:

• Immunology
• Rheumatology
• Pathogenesis of Human Diseases

Background:

• The complement system's role in human diseases is increasingly recognized.
• Therapeutics targeting complement pathways are under development for various conditions.
• This review focuses on insights relevant to rheumatologists.

Purpose of the Study:

• To review lessons learned from complement pathway studies and clinical trials.
• To emphasize diseases of interest to rheumatologists, including AAV and RA.
• To discuss the therapeutic potential of targeting complement components.

Main Methods:

• Summarized publications on complement pathogenesis and clinical trials.
• Focused on antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and rheumatoid arthritis (RA).
• Included studies relevant to other rheumatological diseases.

Main Results:

• Complement alternative pathway generation of C5a is a key driver of organ damage in AAV and RA.
• A C5a receptor (C5aR1) antagonist demonstrated corticosteroid-sparing effects and clinical benefit in AAV.
• C5 and C5aR1 inhibitors showed modest benefit in RA, necessitating further investigation into targets and timing.
• Complement activation is implicated in numerous other rheumatological conditions.

Conclusions:

• Inappropriate complement pathway activation contributes to tissue inflammation and damage in many diseases.
• Understanding complement's role is crucial for developing targeted therapies in rheumatology.