Background There are many possible explanations for the high percentage of failed clinical trials in systemic lupus erythematosus (SLE). Our preferred explanation relates to the heterogeneity of immune phenotypes in SLE patients. We have, therefore, put considerable effort into dissecting immune phenotypes among patients.

Methods First, we hypothesize that in each SLE patient, either myeloid cells or B cells drive the disease. This hypothesis is supported by the transcriptional profiles of SLE patients and both serologic analyses and transcriptional profiles of unaffected sisters of SLE patients. This paradigm, if confirmed, will influence the appropriate therapy for maintenance of remission. Second, we believe we can identify patients in whom IgG autoantibodies are made by plasma cells maturing through an extrafollicular pathway and patients in whom IgG autoantibodies are made by germinal center derived plasma cells.

Results Patients might be stratified by plasma cell differentiation pathway so that therapies could be designed to target only one subset of plasma cells and therefore might be less immunosuppressive.

Conclusions These approaches to patient stratification need further exploration in clinical trials for distinct therapeutic interventions.