Advances in the Treatment of Graves’ Disease – A Focus on Rituximab

Advances in the Treatment of Graves’ Disease – A Focus on Rituximab

Johannes WA Smit, Karen A Heemstra
European Endocrinology - Volume 4 - Issue II
Published: February 2009
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Graves’ disease is the most common cause of hyperthyroidism. The incidence is 5/1,000 per year, with a female-to-male ratio of 7:1.1,2 Graves’ disease is caused by autoantibodies that bind to and stimulate the thyrotropin (TSH) receptor on thyroid follicular cells, thereby stimulating thyroid hormone synthesis and secretion as well as thyroid growth. The pathogenesis of Graves’ disease is multifactoral, including genetic, environmental and endogenous factors.3-6

Current therapies of Graves’ disease are aimed at reducing thyroid hormone synthesis and consist of thionamides, radioiodine and surgery.6 Thionamides block the thyroid hormone synthesis by inhibition of thyroid peroxidase, and are usually prescribed for at least one year. The major disadvantage of thionamides is the low remission rate of only 30-40% of patients after 10 years.7,8 In addition, rare but serious side effects of thionamides, such as agranulocytosis and hepatotoxicity,8 limit prolonged use of these drugs. Radioiodine therapy is indicated for relapsing Graves’ disease in Europe and Japan, whereas this is the treatment of choice in first episodes of Graves’ disease in the US. Hypothyroidism is the major complication of radioiodine therapy with an estimated incidence of 30% in the first two years after therapy and thereafter a yearly incidence of 5%.9,10 Surgery is not used often as a treatment for Graves’ disease and is mainly restricted to patients with obstructive goitre, opthalmopathy and uncertain histology of nodes and patients refusing radioiodine therapy. Obvious complications of surgery are lesions of the n recurrens and hypothyroidism. Obviously, current therapies are not aimed at the underlying pathogenetic mechanisms in Graves’ disease. The imperfections of current therapies for Graves’ disease substantiate the need for new treatment options aimed at the pathology of Graves’ disease.

Rituximab
Auto-antibodies directed against the TSH receptor are crucial in the pathogenesis of Graves’ disease. These antibodies are synthesised by infiltrating B cells into the thyroid. Plasma cells from the bone marrow and cervical lymph nodes are also involved in the synthesis of autoantibodies.11–13 Therefore, a promising strategy for treating Graves’ disease would be the elimination of activated B-lymphocytes. Pre-B-lymphocytes as well as activated mature B-lymphocytes express CD20 on the surface,14 but this expression is lost following differentiation into plasma cells. CD20 is also expressed on some pro-B-cells, the precursors of pre-B-cells, although in low numbers.15,12 This makes the CD20 antigen an attractive target for treating Graves’ disease. Moreover, anti-CD20 therapy could also interfere with the B-cell antigen-presenting role to T cells and thereby interfere with T-cell activities.16

Rituximab is a chimeric monoclonal antibody specific for human CD20.14,17,18

Rituximab was originally used for the treatment of non-Hodgkins lymphoma.19,20 It has subsequently been successfully used in the treatment of various autoimmune diseases,21 including idiopathic thrombocytic purpura,22 systemic lupus erythomatosus,23,24 haemolytic anaemia25 and rheumatoid arthritis.16,26,27 Rituximab causes an immediate depletion of circulating B cells. This depletion lasts for four to six months, but may last for more than 24 months.12,28,29 Pre-treatment levels of B cells will be reached after nine to 12 months. Rituximab kills B cells by induction of apoptosis by altering calcium influx,30 antibody-dependent cellular toxicity and complement-dependent cellular cytotoxicity.12

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