Small dose of rituximab for graves orbitopathy: new insights into the mechanism of action.

Endocrine Unit, Department of Medical Sciences, University of Milan, Italy.
Archives of ophthalmology (Impact Factor: 4.4). 01/2012; 130(1):122-4. DOI: 10.1001/archopthalmol.2011.1215
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    ABSTRACT: The management of thyroid eye disease (TED) remains a therapeutic challenge. The current established therapies are unsatisfactory in one-third of the patients and have many limitations. Rituximab (RTX) is a CD20+ B-cell-depleting monoclonal antibody approved for the treatment of non-Hodgkin lymphomas, chronic lymphocytic leukemia, and rheumatoid arthritis. The early experience with RTX suggests that it is a promising alternative therapy for TED. Rituximab may compare favorably to the conventional glucocorticoid therapy and causes less collateral damage than retrobulbar orbital radiation and decompression surgery. In addition, the preliminary studies on RTX's proposed mechanism of action have revealed new insights into the pathogenic role of B-cells in TED. We summarize the current literature on the clinical application of RTX in TED and discuss its putative mechanisms of action.
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    ABSTRACT: This case series documents the response of nine individuals with glucocorticoid-refractory Graves' orbitopathy (GO) to B cell depletion therapy with rituximab (RTX). Graves' disease (GD) is one of the commonest autoimmune conditions and is frequently associated with inflammatory changes around the eyes (GO). GO frequently results in significant functional visual impairment, and in the most severe cases, it can result in permanent loss of sight. RTX is a therapeutic monoclonal antibody, which targets cell-surface CD-20, resulting in depletion of circulating B lymphocytes. It has been found to be useful for the treatment of a number of autoimmune conditions including, in preliminary studies, GO. We have treated nine individuals (1 male, 8 female, age range 37–87 years) with glucocorticoid-resistant GO with RTX since 2008. RTX was administered in divided doses at fortnightly intervals, following 500 mg IV methylprednisolone pretreatment. Each patient underwent thorough assessment before and after RTX therapy, including thyroid function tests, B cell counts, thyroid autoantibody levels and detailed clinical assessment according to EUGOGO standard protocols. All patients have now been followed up for 16 months or more. There was a significant reduction in thyrotropin receptor binding inhibitory immunoglobulin (TBII) levels in all patients following RTX treatment and a reduction in the clinical activity score (CAS) was seen in all cases. We also report striking improvement in pretibial thyroid dermopathy in one patient following RTX. This case series adds to the growing literature demonstrating that RTX, administered in our patients with concomitant methylprednisolone, is safe and clinically effective in the treatment of active, moderate to severe and sight-threatening GO. Randomized controlled trials are now needed to confirm the efficacy of RTX for GO.
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    ABSTRACT: Rituximab is an emerging treatment for thyroid eye disease. Rituximab effectively depletes circulating CD20+ B-lymphocytes; however, its effect on target tissues has not been well-studied. Failures of rituximab have been infrequently reported. The authors describe a patient treated with rituximab for thyroid eye disease who failed to respond to treatment, and underwent orbital decompression. Orbital fat samples and peripheral blood samples were evaluated for the presence of CD20+ B-lymphocytes. Complete depletion of CD20+ B-lymphocytes was demonstrated in both the orbit and the blood. This case demonstrates that rituximab effectively depletes orbital CD20+ B-lymphocytes, and this depletion was maintained for 2 months despite a clinical deterioration.
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