From the Guidelines
In lupus, the complement system plays a crucial role in both protecting against and contributing to disease pathology, with low complement levels, particularly C3 and C4, being a hallmark of active lupus, especially during flares of lupus nephritis, as noted in a recent study 1. The complement system's dual role in lupus is complex, involving the clearance of immune complexes and the fight against infections, but also becoming depleted as it is consumed during the clearance of numerous immune complexes formed when autoantibodies bind to self-antigens. Key points about the complement system in lupus include:
- Low complement levels are associated with active lupus, especially lupus nephritis, and are used to monitor disease activity, with decreasing levels often indicating an impending flare 1.
- Deficiencies in early complement components, such as C1q, C2, and C4, are risk factors for developing lupus, as they impair the body's ability to clear apoptotic cells and immune complexes, leading to increased autoantigen exposure and autoantibody production.
- The measurement of complement levels, particularly C3 and C4, is a critical component of lupus management, as emphasized in recent recommendations for the management of systemic lupus erythematosus 1.
- Treatment of lupus focuses on controlling the underlying autoimmune process through immunosuppressive medications, rather than directly targeting the complement system, with recent studies highlighting the efficacy of combination treatments, including belimumab and voclosporin, in patients with lupus nephritis 1. Therefore, monitoring and managing complement levels is essential in the care of patients with lupus, as it can help predict and prevent flares, and improve patient outcomes, as supported by the most recent evidence 1.
From the Research
Role of Complement in Lupus
- The complement system plays a complex role in systemic lupus erythematosus (SLE), contributing to both protective and damaging effects 2, 3, 4, 5, 6.
- Complement activation can lead to the generation of inflammatory mediators, promoting tissue injury, while also playing a role in maintaining tolerance to self-antigens 3.
- Defects in early complement components, such as C1q, C1s, C1r, C2, or C4, can predispose individuals to lupus, highlighting the importance of complement in clearing immune complexes and apoptotic debris 4, 5.
Dual Role of Complement in SLE
- Complement has a dual role in the pathogenesis of SLE, with deficiency of complement components predisposing to lupus, while excess complement activation contributes to organ damage 4, 6.
- The classical pathway of complement activation is involved in the clearance of immune complexes, and defects in this pathway can lead to the development of lupus nephritis 2, 6.
- Complement inhibitors, such as complement factor H (CFH) or decay-accelerating factor (DAF), play a crucial role in regulating complement activation and preventing tissue damage 6.
Complement-Targeted Therapies
- Complement-targeted therapies, including soluble complement receptor 1 (TP10), C1 esterase inhibitor, and a monoclonal anti-C5 antibody (eculizumab), have shown promise in inhibiting complement activation and ameliorating disease development in experimental lupus models and clinical trials 6.
- Further research is needed to fully understand the role of complement in SLE and to develop effective complement-targeted therapies for the treatment of this complex autoimmune disease 2, 3, 4, 5, 6.