Targeting the complement system in systemic lupus erythematosus and other diseases.

The importance of the complement system in the pathogenesis of systemic lupus erythematosus (SLE) has long been recognized. However, despite an unprecedented amount of SLE clinical trial activities ongoing at this time, complement inhibitors have been omitted from the therapeutic assault on this disease. We review data generated from murine lupus that provide scientific support for the study of human SLE. Also reviewed is the sole study of a complement inhibitor, eculizumab, performed in patients with SLE. We conclude with a review of other inflammatory diseases where ongoing programs might provide the groundwork for the development of complement inhibitors in SLE.

Lessons Learned From the Clinical Trials of Novel Biologics and Small Molecules in Lupus Nephritis.

Systemic lupus erythematosus (SLE) is a ripe area for drug development. There are great unmet needs, especially for those with lupus nephritis, in which good responses occur only in the minority of treated patients. An expanded understanding of immunopathogenesis of SLE coupled with the availability of sophisticated bioengineering technologies has resulted in the ability to supply the lupus community with the reagents needed to perform clinical trials. However, drug development in SLE has proven to be particularly challenging. Only one drug, belimumab, has been approved for patients with SLE through the traditional route of randomized controlled trials. The basis for our failures is unknown, but most assuredly relates to trial design issues, confounding by background medicines, and the multiplicity of active biologic pathways in this disease. Off-label use of failed trial drugs such as mycophenolate mofetil and rituximab paradoxically has become routine in many parts of the world. Despite the obstacles, there currently is unprecedented clinical trial activity in lupus nephritis, which most likely will lead to at least one drug approval in years to come.