Elsevier

Survey of Ophthalmology

Volume 58, Issue 3, May–June 2013, Pages 252-265
Survey of Ophthalmology

Therapeutic Reviews
B-Cell Targeted Therapy With Rituximab for Thyroid Eye Disease: Closer to the Clinic

https://doi.org/10.1016/j.survophthal.2012.10.006Get rights and content

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.

Introduction

Thyroid eye disease (TED) is an autoimmune inflammation of the orbital tissues that develops in about 20–50% of patients with Graves disease.1 The current established therapies of oral or intravenous glucocorticoids, orbital irradiation, and surgical decompression have many limitations. They are non-specific and offer symptomatic control in only one-third of patients.3

The long-term use of glucocorticoids, especially in high doses, is associated with many systemic side effects that include hypertension, hyperglycemia, diabetes, osteoporosis, Cushingoid features, proximal myopathy, peptic ulceration, increased susceptibility to infection, and psychiatric reactions. External beam radiotherapy may cause transient exacerbation of ocular symptoms and cataract in 10–14% of patients.38, 42 Moreover, it is prohibited in patients with concomitant diabetes or hypertension because of the rare but sight-threatening complication of radiation retinopathy.6, 64 Radiotherapy is also contraindicated in patients under the age of 35 for the theoretical concern of carcinogenesis. Surgical decompression is performed as an emergency procedure for optic neuropathy during the active phase of TED or as part of the cosmetic and functional rehabilitation of the patient when the disease is stable and inactive.

Rituximab (RTX) is an anti-CD (cluster of differentiation) 20 monoclonal antibody, administration of which results in transient depletion of CD20+ B-cells.46, 56 Based on its successful use in other autoimmune diseases, including rheumatoid arthritis, immune thrombocytopenic purpura, and systemic lupus erythematosus, RTX has recently been proposed as a novel therapeutic option for Graves disease and TED.13, 17, 24, 39, 51, 65 Although the early reports of RTX in TED have been encouraging, there have been no large-scale, randomized controlled trials or meta-analyses. We review the available literature as of June 2012 on the clinical application of RTX in TED and examine the theories on the role of B-cells in this condition.

Section snippets

Case Report

A 26-year-old woman, non-smoker, with a known history of Graves disease, biochemically euthyroid, was referred to us for the management of inactive TED and exophthalmos. After a year of monitoring, she underwent a successful bilateral three-wall and fat orbital decompression (Hertel exophthalmometry measurements: 28 mm before vs 21 mm after surgery). Three months post operation, when the patient was still euthyroid, she developed a reactivation of TED with inflammatory signs and strabismus,

Rituximab

Rituximab is a genetically engineered, high affinity, monoclonal antibody. It is chimeric with a variable (antigen-binding) region of murine origin and a constant region of human immunoglobulin G1. The antigen-binding region of RTX targets CD20, a specific transmembrane phosphoprotein that is expressed on the late pre-B-cells, early B-cells, mature B-cells (CD20+ B-cells) and a subset of T-cells of the immune system (Table 1). The constant region of RTX depletes circulating CD20+ B-cells within

The Clinical Experience

The success of RTX in rheumatoid arthritis has led to its application in other autoantibody-related autoimmune diseases such as Graves disease.17, 24, 43 The fact that Graves hyperthyroidism is a classic autoantibody-dependent autoimmune disease against the thyroid gland’s receptor for thyroid stimulating hormone (and the possible immunological cross-reactivity between thyroid and orbital tissue antigens) has prompted the empirical use of RTX in TED.1, 51

Rituximab as an alternative treatment

Conclusion

The management of TED remains a therapeutic challenge, largely because our understanding of its pathogenesis is still incomplete. Started as an experimental treatment for Graves disease, these early experiences with RTX have broadened our understanding of the TED immunopathogenesis by highlighting the possible roles of B-cells in this condition.

As we await the results of large-scale, randomized controlled trials (at least two trials are upcoming from Bahn et alD and Salvi et alE) RTX should be

Method of Literature Search

The primary search was performed on all accessible literature as of 31 May 2012. The MeSH database was used to target the search of Medline/PubMed and similar terms were used in EMBASE. In this review, the term rituximab and various synonyms and eponyms of thyroid eye disease were used. Full-text manuscripts of relevant English-language literature were reviewed. Additional references were identified by examining the bibliographies of retrieved articles.

Disclosure

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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