Rituximab in the Treatment of Graves' Disease
Rituximab in the Treatment of Graves' Disease
Aim:

 In a phase II pilot study encompassing 20 patients with Graves' disease to evaluate the
 effect of rituximab:

 1. Biochemically as assessed by markers of disease activity ( free T4, free T3, TSH,
 TSH-receptor antibodies, anti-TPO)
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.

 The most serious complication of antithyroid drugs is agranulocytosis and less frequently
 acute hepatic necrosis, cholestatic hepatitis and vasculitis. As to treatment with
 radioactive iodine this therapy may worsen ophthalmopathy. In addition, the treatment is
 followed by hypothyroidism in a large proportion of the patients.

 Based upon the above mentioned observations of a very effective response in many patients
 with otherwise refractory autoimmune disorders and the pathogenetic concept of Graves'
 disease as a disorder elicited by auto antibodies stimulating the thyrotropin receptor on
 thyroid cells ( hyperthyroidism and goiter) and similar antigens in the orbit (
 ophthalmopathy ) the hypothesis is that B-cell depletion with rituximab may be a very
 efficacious therapy reducing or abolishing the production of the auto antibodies which are
 responsible for Graves' disease.

 Aim of the study:

 In a phase II pilot study encompassing 20 patients with Graves' disease to evaluate the
 effect of rituximab:

 1. Biochemically as assessed by markers of disease activity ( free T4, free T3, TSH,
 TSH-receptor antibodies, anti-TPO)

 Study design

 Material and methods 20 patients with recent onset untreated Graves' disease start
 antithyroid treatment (methimazole). When euthyroidism is reached - defined by normal thyroid
 parameters (free T4, free T3, and TSH) - the patients are randomised to +/- rituximab
 treatment.

 Afterwards, the 2 patient groups are followed for 1 year:

 -  10 euthyroid patients treated 4 weeks with rituximab, when antithyroid treatment is
 discontinued.

 -  10 euthyroid patients who do not receive rituximab antithyroid treatment being
 discontinued after 4 weeks.

 Effect parameters

 Differences in relapse, remission rate at 3, 6, 9 and 12 months follow up/ time to relapse as
 assessed by:

 • Biochemistry ( free T4, free T3, TSH, TSH-receptor antibodies, anti-TPO)

 Treatment

 Rituximab in a dose of 375 mg/m², administered by iv. Infusion once a week for 4 weeks.

 Premedication with paracetamol 1g p.o. or tavestin 2 mg i.v. is given 30-60 min. before each
 infusion.
Inclusion Criteria:

 -  Graves´ disease

 -  Adequate anticonception in women.

 Exclusion Criteria:

 -  Performance status >2

 -  Previous rituximab treatment

 -  Immunosuppressive treatment

 -  Serious concomitant disease

 -  Active infections

 -  Pregnancy / breast feeding.