Complement-Targeted Therapies in Lupus

Abstract

Systemic lupus erythematosus is a complex disease affecting most organs in the body. Deficiency of early components of the classical complement pathway is a key predisposing genetic factor for lupus in both mice and humans. Activation of the complement cascade downstream of C3 is a key factor in tissue inflammation and damage in lupus. Thus, lupus provides an interesting puzzle for how and when to block complement activation as a therapy. Interventions blocking C5, the alternative pathway, the lectin pathway, and the terminal membrane attack complex are all effective in treating murine models of lupus. Over 20 complement-directed therapies are in clinical trials for various diseases. Despite the promising results regarding efficacy of complement inhibition in murine lupus, the overall lack of effective therapies in lupus, and the availability of a number of complement inhibitors for human trials, there have been and currently are no trials of complement inhibitors for treating lupus. The complexity of lupus and the failure of many recent clinical trials in lupus have perhaps discouraged industry sponsors from testing their complement therapies in lupus. There may also be concern that blocking complement alone may not be effective in treating lupus as other inflammatory mediators are also involved in disease pathogenesis. Despite these possible confounders, it is clear that complement is a key mediator of tissue inflammation and damage in lupus. Complement inhibitors may not be effective at long-term chronic management of lupus, but would appear to be very attractive as an acute intervention during disease flares, especially in lupus nephritis. Ongoing efforts by the NIH and by the lupus organizations to bring new lupus drugs to patients will hopefully lead to clinical trials of complement inhibitors in lupus in the near future.