The complement system plays an important role in the etiology of many autoimmune diseases, including cold agglutinin disease (CAD), a subset of autoimmune hemolytic anemia. In CAD, auto-antibodies start to react at low temperatures, causing hemolysis and giving rise to clinical symptoms such as fever, dark urine, and flank pain.
Scientists are taking a closer look at the complement system: how it works, how it can go wrong, and what we can do about it.
“The complement system has been essentially ignored and/or unknown in the clinic, and treatment of diseases with dysfunction of complement has been limited,” Garred and colleagues wrote in Pharmacological Reviews.
There are several reasons for this. One of the reasons that much of the complement system remains shrouded in mystery is a lack of willingness to contemplate its role in disease initiation and progression. This is perhaps understandable, given the gap that exists between physicians working in clinical settings and researchers working in laboratories. The task of unraveling the role of the complement system in the pathophysiology of various diseases is sometimes viewed by physicians as an academic pursuit best reserved for clinical researchers.
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Another reason is that the relevance of the complement system in human diseases is still unclear. We understand enough to conclude that the complement system plays an active role in autoimmune diseases; we are less certain of its role in other diseases. In addition, there is a relative lack of clinical trials and drug development efforts directed toward the complement system.
An Increased Understanding
However, things are moving in the right direction. We are beginning to understand that the complement system plays an elegant and vital role in maintaining homeostasis.
“One of the most important reasons for tissue insults and end organ damage in autoimmune diseases is the excessive activation of the complement pathway,” Vignesh and colleagues wrote in Clinica Chimica Acta. The flip side of the coin is that deficiencies in any part of the complement pathway can also give rise to autoimmune diseases, such as systemic lupus erythematosus (SLE).
Scientists have identified 3 separate mechanisms in which the complement system may be activated. Briefly, the first mechanism (classical pathway) involves the activation of immune complex deposits, namely IgG or IgM. The second (alternate pathway) is a pathway independent of antibodies, involving proteins such as factor B and factor D. The third (lectin pathway) is activated by mannose-binding lectin or ficolin recognizing specific carbohydrate moieties in microbes.
The key point is that all 3 pathways converge at the activation of C3 and C5. This then causes the membrane attack complex (MAC) to form. The MAC disrupts cell membranes by forming pores and causes osmotic cell lysis.
The Link With Cold Agglutinin Disease
How does the complement system go wrong in CAD? At lower-than-core body temperatures, erythrocyte agglutination can occur. This then activates the classical pathway (the first pathway described above) of the complement system, causing the opsonization of erythrocytes, which are then phagocytosed by the liver.
“This extravascular hemolysis is considered to be the predominant mechanism of erythrocyte destruction in patients with cold agglutinin disease,” Jäger and colleagues wrote in Blood.
The upstream inhibition of the complement system would prevent C3 from being deposited on erythrocytes, while the downstream inhibition of the activation of C5 would limit the effects of extravascular hemolysis. Hence, in Hematology, Gertz concluded, “The theory behind the use of complement inhibition in CAD is sound.”
Jäger and colleagues conducted a study to investigate how patients with CAD (N=10) responded to sutimlimab, a drug that inhibits the complement system. They recruited patients who had a diagnosis of CAD and a direct antiglobulin test that was strongly positive for C3d. Participants were prescribed sutimlimab and observed for more than a month.
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The results demonstrated that sutimlimab successfully increased hemoglobin levels and quickly inhibited extravascular hemolysis.
“In 7 of 10 patients, the hemoglobin level increased by >2 g/dL,” the research team wrote. “Furthermore, hemoglobin levels increased by ≥4 g/dL in 5 patients and completely normalized (≥12 g/dL) in 4 patients.” In addition, the drug was reported to be well-tolerated.
This study confirms that the inhibition of the complement system in CAD can yield significant clinical benefits. Sutimlimab managed to halt the pathological processes underpinning CAD; in addition, it precludes the need for transfusions in patients with CAD. Considering that anemia can be life-threatening, the effects of sutimlimab in resolving this condition are impressive. It was hence designated as a breakthrough therapy by the US Food and Drug Administration.
The results from this clinical study, combined with our existing knowledge of the complement system, should prompt further investigation into the aspects of the complement system that we still have not fully grasped. If the clinical condition of patients with autoimmune diseases such as CAD can be reprieved by accurately targeting a component of the immune system, there is every reason to investigate if this strategy works in other autoimmune diseases that currently have no cure.
Gertz MA. Updates on the diagnosis and management of cold autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 2022;36(2):341-352. doi:10.1016/j.hoc.2021.11.001
Garred P, Tenner AJ, Mollnes TE. Therapeutic targeting of the complement system: from rare diseases to pandemics. Pharmacol Rev. 2021;73(2):792-827. doi:10.1124/pharmrev.120.000072
Jäger U, D’Sa S, Schörgenhofer C, et al. Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial. Blood. 2019;133(9):893-901. doi:10.1182/blood-2018-06-856930
Vignesh P, Rawat A, Sharma M, Singh S. Complement in autoimmune diseases. Clin Chim Acta. 2017;465:123-130. doi:10.1016/j.cca.2016.12.017