B Cell Depletion With the Anti-CD20 Monoclonal Antibody Rituximab in the Treatment of Graves' Disease

Background

Rituximab is a chimeric murine/human anti-CD20 monoclonal antibody which was originally introduced in the clinic years ago for the treatment of malignant lymphomas. The antibody is an IgG1 kappa immunoglobulin containing murine light-and heavy chain variable region sequences and human constant region sequences. The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes. Possible mechanisms of cell lysis include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis.

The mechanism(s) behind the favourable response of rituximab in autoimmune cytopenias are unsettled. A depletion of peripheral blood B cells occurs after just one antibody infusion. Accordingly, it has been proposed that opsonized CD20+ B cells inhibit and saturate macrophage Fc-receptor function and thereby clearance of IgG-coated blood cells by reticuloendothelial cells. Suppression of auto reactive B-cell clones may be another potential mechanism.

Most recently several studies have shown that rituximab- also is very effective in the treatment of various autoimmune cytopenias and autoimmune diseases - idiopathic thrombocytopenic purpura (ITP), warm and cold autoimmune haemolytic anemias, autoimmune neutropenia, pure red cell aplasia, Wegener's granulomatosis, systemic lupus erythematosus, membranous glomerulonephritis, and rheumatoid arthritis - , including disorders which have been considered to be primarily diseases elicited by aberrant T-cell responses, e.g., rheumatoid arthritis. However, recently the importance of the B-cell in the pathogenesis of these autoimmune disorders have been debated and emphasized.

Graves' disease is an autoimmune disease in which both B- and T-cells are activated and participate in its pathogenesis. However, B-cell activation with the production of IgG - thyroid-stimulating antibodies, binding to and activating the thyrotropin receptor on thyroid cells is a prerequisite for the development of Graves' hyperthyroidism. The thyroid-stimulating antibodies cause thyroid hypersecretion, hypertrophy and hyperplasia of the thyroid follicles and ultimately diffuse goiter together with clinical hyperthyroidism. In addition to thyroid-stimulating antibodies against thyroglobulin and thyroid peroxidase are also produced in Graves' disease. The pathogenesis of the other clinical features of disease - the ophthalmopathy and the localized dermopathy or myxedema - is far less elucidated. It has been proposed that the ophthalmopathy develops consequent to an autoimmune response to the thyrotropin receptor, which is also expressed by a preadipocyte subpopulation of orbital fibroblasts. The treatment of Graves' disease includes antithyroid drugs, radioactive iodine and surgery. All three treatment modalities are associated with adverse effects or side-effects.