Systemic lupus erythematosus (SLE) is an autoimmune disease with a polymorphic 
presentation. The variability in the clinical expression and severity of SLE 
makes new treatments both essential and challenging to develop. Several 
biotherapies targeting different pathophysiological pathways have been developed 
over the past 15 years. The results of Phase II trials were encouraging but 
rarely borne out by Phase III trials. Recent data, which are discussed in detail 
in this review, allowed belimumab - a monoclonal antibody against BLyS 
(B-lymphocyte stimulator) - to become the first biotherapy approved for use in 
SLE. Other molecules targeting B cells include the two anti-BLyS antibodies 
tabalumab and blisibimod; atacicept, which targets both BLyS and APRIL (a 
proliferation-inducing ligand); and the monoclonal antibody to CD22 epratuzumab. 
The rekindling of interest in the B-cell pathway has also driven new clinical 
research into rituximab, a monoclonal antibody targeting CD20 with evaluations 
of new strategies. A new and promising approach is the use of inhibitors of the 
type 1 interferon (IFN) pathway, of which the most promising is anifrolumab, a 
monoclonal antibody targeting the type 1 IFN receptor. In this review, we 
discuss study findings and their clinical relevance, present the most promising 
targets, and analyze possible explanations to negative results, such as 
inappropriate patient selection and treatment response criteria or the erratic 
use of high-dose glucocorticoid therapy.