The Complement System in Systemic Lupus Erythematosus: Overview and Outlook

The Complement system is a participant in many diseases such as paroxysmal nocturnal hemoglobinuria (PNH), hemolytic uremic syndrome (HUS), hereditary angioedema (HAE), etc. Among these rheumatic diseases, systemic lupus erythematosus (SLE) is proved to have the closest relationship with the complement system.

In 1896, Jules Bordet discovered the complement system, and related research earned him the Nobel Prize in Physiology in 1919. At that time, it happened that World War I caused the Nobel Prize to cease for four consecutive years. Jules Bordet became the first recipient of the Physiology Award after the re-award.

After this, complement-related research has experienced many developments and even subversions. Compared to Jules Bordet’s study back then, today's understanding of complement system is beyond recognition. This article will discuss the relationship between complement and SLE.

Defects in the Complement System Lead to SLE

Congenital defects in the complement system make people more vulnerable to bacterial viruses. This is a major category of congenital immunodeficiency. Interestingly, this not only leads to a decline in resistance to pathogens, but also brings autoimmune diseases.

About 93% of C1q-deficient people will suffer from SLE. Similarly, 75% of those with C4 deficiency and over 30% of those with C2 defects also lead to SLE. Most of the C1r and C1s defecting will also result in SLE. However, due to their low prevalence, it is not appropriate to accurately determine the strength of their association. No stronger innate factors related to SLE have been found. Fortunately, the incidence of such birth defects is low.

Secondary Complement Deficiency and SLE

Bacterial infections, SLE, etc. will cause the level of complement to drop. SLE brings a lot of immune complexes, which combine with complement to cause damage to the body. This is particularly evident in lupus nephritis.

Except that the combination of immune complex and complement leads to the decrease of complement, there are also antibodies against complement. The most widely used is anti-C1q antibody. About 30% of patients with SLE have anti-C1q antibodies, and it is 68% of patients with lupus nephritis. Therefore, a positive anti-C1q antibody indicates a high possibility of lupus nephritis.

Complement-related Drugs and SLE Treatment

The complement system plays an important role in the pathogenesis of many diseases. The pharmaceutical industry has also developed many drugs in a targeted manner.

1. Eculizumab

Eculizumab is a humanized monoclonal antibody. The antibody binds to complement component 5 and prevents it from cleaving into C5a and C5b, and C5b is necessary to form a membrane attack complex (MAC), which is an important link for complement to participate in body damage, so eculizumab can be used to treat PNH and HUS. However, it is a pity that the clinical practical significance has not been seen in the clinical drug experiments for the treatment of SLE.

2. Avacopan

The latest major breakthrough in the rheumatology research is Avacopan, a small molecule compound that targets the complement C5a receptor.

Recent clinical randomized double-blind controlled trials have confirmed that Avacopan can successfully replace hormones in combination with other drugs. The biggest problem of this experiment is that the number of cases participating in the experiment is not enough, and the observation time is not long enough. Can Avacopan replace hormones during SLE treatment? There is no reliable clinical controlled trial to verify.

Clinical experience tells us that compared with SLE, ANCA-associated vasculitis tends to rely more on hormones. Since ANCA-associated vasculitis can get out of hormones during treatment, it is possible to look forward to hormone replacement during SLE treatment. The complement therapeutics might the hope of the hormonal-free era of lupus treatment.

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