Publication of the supplement was supported by Medimmune. == Recommendations ==. improve the design of therapeutic tests in SLE. A better understanding of what went wrong in these tests is essential to elucidate the underlying reasons for the disparate observations mentioned in open studies and controlled tests. With this review, we focus on numerous factors that may impact the ability to accurately and confidently set up the level of treatment effect of the investigational agent, in this case rituximab, in the two studies and explore hurdles confronted in the randomised controlled trials investigating the effectiveness of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based on the lessons learned from the medical tests, we make suggestions that may be implemented in future clinical trial design to overcome the hurdles faced. == Background == B cells have been targeted in the treatment of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) owing to the central role they play in the BTZ043 (BTZ038, BTZ044) Racemate pathogenesis of these disorders. These cells play a critical role in host defence through their maturation into antibody-secreting plasma cells, secretion of proinflammatory cytokines, antigen BTZ043 (BTZ038, BTZ044) Racemate presentation and co-stimulatory support for T cells. However, dysfunctional recognition of self-antigens as nonself-antigens results in autoantibody production, sustained by plasma cells derived from the B-cell lineage that survive for prolonged periods in the lymphoid tissues. BTZ043 (BTZ038, BTZ044) Racemate B cells also participate in inflammatory reactions through antibody-independent mechanisms by acting as antigen-presenting cells and co-stimulation of T cells and other inflammatory cell types, although as yet there are no validated biomarkers that distinguish pathogenic from protective B-cell subsets. Reagents that specifically target pathogenic B-cell subsets are therefore not likely to be available in the near future. This reality provides the rationale for targeting B cells in patients with SLE, RA and other autoimmune diseases [1-5]. B-cell-targeted immunotherapy was initially developed for the treatment of B-cell-related malignancies, which are associated with poor prognosis despite aggressive cytotoxic therapies. Of the many surface-expressed antigens on B cells studied as possible targets, CD20 – a transmembrane phosphoprotein expressed in normal B BTZ043 (BTZ038, BTZ044) Racemate cells as well as 90% of lymphomas – is not shed or modulated, making Rabbit Polyclonal to SIX2 it an attractive target. In 1994, Reff and colleagues reported a major (95%) and sustained (up to 90 days) B-cell depletion using a murine mAb (2B8) that targeted CD20 on B cells in nonhuman primates [6]. In 1997, a landmark study reported on both the safety and efficacy of rituximab, a chimeric (mouse-human) mAb directed against CD20, for the treatment of relapsed, refractory low-grade or follicular lymphoma [7]. In November 1997, rituximab was licensed for this indication. Rituximab is now a part of the standard therapeutic regimen in the management of B-cell malignancies and remains among the most successful therapeutic mAbs. Interestingly, the response rate is variable amongst individuals with the same histological type of lymphoma as well as the overall response rate between different histological types [8]. This suggests that B-cell depletion is not uniform across patients or indeed diseases for reasons yet to be fully comprehended, but Fc receptor function appears important with enhanced Fc receptor IIb expression being associated with reduced rituximab efficacy in lymphoma [9]. Intriguingly, polymorphisms of this receptor are associated with SLE, although their precise role in the disease and potential for targeted therapeutic intervention is not comprehended. In 1999, Professor Edwards’ group at University College London treated a small number of patients with refractory RA using rituximab, having been encouraged by the safety and efficacy profile of induced transient depletion of B cells in haematological malignancies. This study and subsequent studies of rituximab in.