Systemic lupus erythematosus as the paradigm for understanding the complex immune relationships and therapeutic opportunities for targeting complement in autoimmune diseases

Complement therapeutics have been increasingly tested and approved for human diseases, often in orphan diseases with strong and apparently causal genetic linkage or mutation-associated features. However, the complement system has been demonstrated to be activated in essentially all human inflammatory, ischemic and autoimmune diseases, suggesting the possibility of even wider therapeutic applications. The goal of this manuscript is to review some of the evidence supporting a wide role for complement in the specific treatment of autoimmune diseases, especially as recent approvals in autoantibody-driven diseases are opening the door to others of these indications. However, in part because of a dearth of complement biomarker data obtained during clinical trials, it is not known what findings would help to predict therapeutic success in other autoimmune diseases. To frame the discussion, it is relevant to point out that the disease systemic lupus erythematosus (SLE) has been among the most extensively studied autoimmune disease with regards to the varied roles of the complement system, and there are available both human phenotypic studies and murine model data. Because of that history, SLE will be focused upon herein, the many roles of complement in SLE will be reviewed, and informative comparisons to other autoimmune diseases will be made. In aggregate, experimental and phenotypic data suggest that each human autoimmune disease deserves careful attention to the possibility that a specific complement inhibitor targeting the most relevant complement convertase or component will be of benefit, and thus therapeutic approaches should be tested using informative biomarker-driven clinical trial strategies.