B-Cell-Targeted Therapy for Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a complex disease characterised by numerous autoantibodies and clinical involvement in multiple organ systems. The immunological events triggering the onset of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis of this disease has more recently gained prominence as a result of research in both mice and humans. Both antibody-dependent and -independent mechanisms of B cells are important in SLE. Autoantibodies contribute to autoimmunity by multiple mechanisms, including immune complex-mediated type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines such as interferon-alpha, tumour necrosis factor and interleukin-1. Suggested autoantibody-independent B-cell functions include antigen presentation, T-cell activation and polarisation, and dendritic-cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines, chemokines and lymphangiogenic growth factors, and by their critical contribution to lymphoid tissue development and organisation, including the development of ectopic tertiary lymphoid tissue. Given the large body of evidence implicating abnormalities in the B-cell compartment in SLE, a recent therapeutic focus has been to develop interventions that target the B-cell compartment by multiple mechanisms.Rituximab, a mouse-human chimeric monoclonal antibody against CD20 that specifically depletes B cells, has been studied the most extensively. Although promising open-label data await confirmation in ongoing multicentre placebo-controlled trials, a number of preliminary conclusions can be drawn. The adequacy of peripheral B-cell depletion depends on achieving high and sustained serum rituximab concentrations, pharmacokinetics that can be varied with treatment dose and factors that may affect drug clearance, such as human anti-chimeric antibodies. In SLE patients with effective B-cell depletion, the clinical response can be significant, with favourable responses observed in a diverse array of disease manifestations. Moreover, rituximab appears to have the potential to induce clinical remission in severe, refractory disease. B-cell depletion has the potential to induce disease amelioration by inhibiting autoantibody production and/or by interfering with other B-cell pathogenic functions. The fact that clinical improvement correlates with B-cell depletion and precedes by several months any decline in serum levels of relevant autoantibodies suggests a predominant effect of autoantibody-independent functions of B cells, although the subset of patients with disease remission ultimately also experience autoantibody normalisation. Significant questions remain about rituximab therapy in SLE, including the immunological determinants of treatment response and remission, the role of combination therapy, and the safety of repeated courses of rituximab. In addition, the efficacy and role...

Rituximab in relapsing Graves' disease, a phase II study

“…Apparently, no clear relation exists between the degree of depletion of MS4A1 positive cells from peripheral blood and the therapeutic effect. The relation between circulating levels of MS4A1 positive lymphocytes, serological markers of autoimmune disease and effectiveness of rituximab in autoimmune disease is complex, but a number of studies suggest an inverse relationship between proportions of B-cells, autoantibody titres and therapeutic effect in rheumatoid arthritis and lupus (10,17,26,27). In our study, the proportion of CD-20 positive lymphocytes was not associated with TBII levels.…”

“…Median FT 3 at 26 weeks was 4.8 (3.5-5.9) pmol/l for responders (PZ0.011 versus baseline), whereas median FT 3 for non-responders when they were withdrawn from the study was 13.21 (9.6-18.7) pmol/l (PZ0.457 versus baseline). The median relapse free survival in these patients is now 18 months (range [14][15][16][17][18][19][20], with normal FT 4 levels (P!0.001 versus baseline) and normal TSH levels (PZ0.008 versus baseline) in all patients. According to the criteria for success as defined in the Patients and methods section, the criterion of more than three patients being euthyroid was reached.…”

“…rituximab was the first therapeutic monoclonal antibody used for the treatment of non-Hodgkin lymphoma (13,14). It has subsequently been successfully applied in various autoimmune diseases (15), including idiopathic thrombocytic purpura (16), systemic lupus erythematosus (17,18), haemolytic anaemia (19) and rheumatoid arthritis (10,20,21).…”

Chapter 4 B Cells and Autoantibodies in the Pathogenesis of Multiple Sclerosis and Related Inflammatory Demyelinating Diseases

“…On the basis of these results, Rituximab was approved in 2006 for use in RA patients who do not respond to TNF-antagonists (Sabahi and Anolik, 2006). Rituximab has also shown benefit in several other autoimmune diseases, including autoantibody-associated neuropathies, immune thrombocytopenia and systemic lupus erythematosus (Edwards and Cambridge, 2006;Renaud et al, 2003Renaud et al, , 2006Sabahi and Anolik, 2006;Tanaka et al, 2007).…”

Regulatory B Cells - Implications in Autoimmune and Allergic Disorders

“…It is mainly characterised by the presence of autoantibodies to a variety of self antigens, particularly against nuclear components (Mills 1994). Because of the high production of pathogenic auto-antibodies, B cells are considered a major contributor to SLE pathogenesis and several therapies targeting B cells in SLE patients have been introduced (Sabahi and Anolik 2006). In addition however, there is evidence for the existence of a subset of B cells with regulatory capacity in lupus (Amano, Amano et al 2003).…”