Targeted Biologic Therapy for Systemic Lupus Erythematosus: Emerging Pathways and Drug Pipeline.

Following the approval of belimumab, the first drug to be approved for systemic lupus erythematosus (SLE) in over 50 years, advances in our understanding of the pathogenesis of the disease have led to a remarkable number of clinical trials for investigational drugs, each with a unique mechanism of action. These include, but are not limited to, antibodies targeting B or T cells or their interaction, dendritic cells, interferon, and other cytokines. Frustratingly, this boost of studies has not been accompanied by a corresponding success and subsequent approval of novel agents, for reasons only partly attributed to the efficacy of the drugs per se. Successful phase II trials are often followed by failed phase III studies, which typically require many more patients. Nevertheless, recent successes, such as the ustekinumab and baricitinib trials and the positive results from the phase III TULIP-2 study of anifrolumab, provide room for cautious optimism. In this review, we attempt to draw the current landscape of the drug pipeline in SLE, focusing on the rationale behind each drug development, its mechanism of action, and the available preclinical and clinical data. We also highlight lessons learned from failed attempts that have helped to optimize clinical trial design for this challenging disease. We conclude with a look into the future, commenting on the surge of studies in the field of biomarkers and the use of omics technologies in lupus, which aim to pinpoint different disease phenotypes and, ideally, identify subsets of patients with disease that will respond to different biologic drugs.