Although cyclophosphamide and corticosteroids have effects on B-cells, the advent of B-cell directed therapies using specific antibodies against CD20, CD22, and against B-cell survival factors and cytokines (anti-BAFF, anti-BR3, TACI-Ig, anti-IL10, anti-IL6), or agents modulating B-cell receptor strength (LJP394, Epratide) provide different mechanisms of action, potential different efficacies and different adverse events

Although cyclophosphamide and corticosteroids have effects on B-cells, the advent of B-cell directed therapies using specific antibodies against CD20, CD22, and against B-cell survival factors and cytokines (anti-BAFF, anti-BR3, TACI-Ig, anti-IL10, anti-IL6), or agents modulating B-cell receptor strength (LJP394, Epratide) provide different mechanisms of action, potential different efficacies and different adverse events. therapeutic effects and may Brivanib alaninate (BMS-582664) be complementary to the known effects and role of CD20 antibodies. Keywords: Brivanib alaninate (BMS-582664) autoimmune diseases, CD22, B-cells, epratuzumab Autoimmune diseases Autoimmune diseases comprise more than 80 chronic diseases that affect about 5%C8% of the general populace (Jacobson et al 1997), with the prevalence being, in decreasing order, rheumatoid arthritis (RA), primary Sj?grens syndrome (pSS), and systemic lupus erythematosus (SLE). There has been considerable progress made in understanding the immune system during recent decades, resulting in a better appreciation of the role of B-cells in the conversation of innate and adaptive immunity, lymphocyte activation and antigen processing, the principles of immune tolerance, B- and T-cell crosstalk, cytokine signaling, and new approaches of treating autoimmune diseases by depleting or modulating B-cells, including blockade of co-stimulation. This resulted in a plethora of articles and reviews on the importance of B-cells in autoimmunity (Mitchison and Wedderburn 2000; Edwards and Cambridge 2001; Lipsky 2001; De Vita et al 2002; Leandro et al 2002a; D?rner and Burmester 2003; Oligino and Dalrymple 2003; Uchida et al 2004; Park et al 2005; Tedder et al 2005a; Keystone 2005; Viau and Zouali 2005; D?rner 2006; D?rner and Lipsky 2006; Martin and Chan 2006). These diseases, particularly RA, SLE, and pSS, are complex, usually multi-organ manifestations with a wide heterogeneity in clinical presentations and disease course. Whereas many were traditionally considered to implicate T-cells in their pathogenesis, as referenced above, B-cell disturbances and hyperactivity are now considered to be a hallmark of many of these diseases, as indicated by the development of autoantibodies, and an increased risk of developing B-cell lymphoma, such as in pSS and RA (Voulgarelis et al 1999). Although B-cells were attributed previously only to cause autoantibody production, they have now gained a central role in the pathogenesis of several autoimmune diseases. A breakdown of tolerance mechanisms that normally regulate B-cell development leads to the development of autoimmune diseases (William et al 2006), including induction and maintenance of self-reactive B-cell antigen receptor (BCR) complexes (Voulgarelis Dafni et al 1999; D?rner 2006; D?rner and Lipsky 2006; Martin and Chan 2006; Brivanib alaninate (BMS-582664) Radbruch et al 2006). Because B-cells are considered as being of central importance in the immunopathogenicity, they represent current targets of immunotherapy. To date, there are a number of therapeutic antibodies targeting B-cell-specific antigens in order to deplete or modulate B-cells, rituximab (anti-CD20 chimeric antibody), ocrelizumab (humanized anti-CD20 antibody), belimumab (anti-BlyS or BAFF human antibody), and epratuzumab (anti-CD22 humanized antibody) that are in advanced clinical trials in several autoimmune diseases (D?rner 2006; D?rner and Lipsky 2006; Edwards and Cambridge 2006; Martin and Chan 2006). A number of other anti-CD20 antibodies (HuMax, hA20 or veltuzumab, ofatumumab) are also in clinical development but no clinical data have been reported so far other than in abstract form. Rituximab was the first monoclonal antibody approved by the US Food and Drug Administration for the treatment of B-cell non-Hodgkins lymphoma (NHL) in 1997, followed by licensing for Brivanib alaninate (BMS-582664) RA after anti-TNF failure in 2006. The success and the very good safety profile of rituximab therapy in lymphoma, as well as incidental case observations, motivated many investigators to consider its use in autoimmune diseases. In the last 4-years, clinical trials have shown promising efficacy in various autoimmune diseases (Edwards and Cambridge 2006), such as RA (Edwards et al 2004b; Leandro et al 2002a), Sj?grens syndrome (Pijpe et al 2005), SLE (Leandro et al 2002b), and chronic immune thrombocytopenic purpura (Stasi et al 2001). Dynorphin A (1-13) Acetate These studies indicated that circulating B-cells are undetectable after a brief dosing regimen of rituximab. Whether complete depletion of peripheral B-cells and remaining CD20- plasmablasts may be used as a biomarker of clinical response requires further careful analysis in RA. Long-term efficacy and safety was reported in RA (Edwards et al.