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Editorial |
Division of Molecular Medicine, Harbor-University of California, Los Angeles (UCLA) Medical Center, David Geffen School of Medicine at UCLA, Torrance, California 90502
Address all correspondence and reprint requests to: Terry J. Smith, M.D., Division of Molecular Medicine, Building C-2, Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, California 90502. E-mail: tjsmith{at}ucla.edu.
Human immunity requires participation of many cell types and the myriad of small molecule mediators (e.g. cytokines) they produce. This elaborate network focuses on defending the body against foreign invaders and countering any misbehavior on the part of the host. B cells are insinuated in the heart of normal immune responses and represent relatively recent evolutionary additions. They can further develop into Ig-secreting plasma cells. Besides their function as precursors to antibody-secreting cells, B cells present antigens to T cells and synthesize cytokines such as IL-6, lymphotoxin, TNF-
, and IL-10 (1). B cells are dependent on the "help" of other cells such as T lymphocytes, and conversely they contribute richly to the organization of lymphoid tissue and govern how other immune cells such as dendritic cells function. Fetal liver produces B cells, but they emanate from the bone marrow after birth. They mature as a consequence of numerous converging influences. These include the B cell antigen receptor, assorted coreceptors, and an array of signaling pathways (2). Antigen-provoked signaling pushes B cells to escape the primary lymphoid tissues and to differentiate. After maturation, they can gain access to follicles and generate new germinal centers. They can also reside in bone marrow as plasma cells where they become dedicated to secreting Igs. B cells are firmly implicated in the pathogenesis of many neoplastic and chronic inflammatory diseases. Major advances have been made recently in our understanding of so-called "autoreactive" B cells and their putative roles in the pathogenesis of autoimmune diseases. They are not simply precursors of self-antibody-generating cells. The central pathogenic role of autoantibodies in human disease remains controversial, and fitting multifaceted B cells into a single, neat model of autoimmunity remains very difficult (3).
Given their broad array of functions and importance to immunity, the therapeutic use of B cell depletion emerged more than 10 yr ago as a promising strategy for treating non-Hodgkin’s lymphoma (4). After its introduction to the market, rituximab [aka IDEC-C2B8 (RTX)] was found to exhibit a relatively favorable side-effect profile as a well-used treatment for B cell malignancies. More recently, it has also become useful in the management of chronic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, giant cell arteritis, and dermatomyositis (5, 6). RTX is a monoclonal antibody that binds CD20, a phosphorylated surface protein expressed by immature and mature B cells but absent on plasma cells (7). This receptor, the natural ligand for which remains unidentified, appears to regulate lymphocyte cell cycle progression. When ligated with RTX, B cell proliferation is blocked. RTX now occupies an important position in our armamentarium for treating diseases in which B cells play important roles. The worldwide experience with RTX currently numbers in the hundreds of thousands of patients treated. Clearly B cell depletion represents a therapeutic direction in search of additional applications.
The pathogenesis of Graves’ disease (GD) remains largely enigmatic despite substantial effort to understand it by many active investigators (8). Insight into the synthesis of thyroid hormone has led to effective strategies for treating hyperthyroidism, but the underlying immunological processes are only partially identified. At its core, this hyperthyroidism associated with GD results from the generation of autoantibodies directed against the TSH receptor and among these, the predominance of a receptor-activating type (9). The connective tissue manifestations of GD, namely thyroid-associated ophthalmopathy (TAO) and dermopathy, remain poorly characterized, misunderstood, and ineffectively treated (10). No convincing evidence has thus far been generated to directly implicate anti-TSH receptor antibodies in the pathogenesis of either TAO or dermopathy. But antibodies activating the IGF-I receptor have been detected in most patients with GD (11), and these may play a role in the pathogenesis of GD by stimulating fibroblasts (12) and thyrocytes (13) and expanding memory T cells (14). Thus, B cells appear to play multiple critical roles in the pathogenesis of GD and TAO by providing support for the function of both professional (T cells) and nonprofessional immune cells such as fibroblasts, as well as through their production of autoantibodies.
It is not surprising that RTX might be examined for its ability to alter the course of GD, a process widely considered a good example of an autoantibody-driven disease. Indeed, recent papers have appeared attempting to assess the efficacy of B cell depletion as therapy for hyperthyroidism and TAO. Salvi et al. (15) reported a single case of GD with TAO where the clinical activity score decreased within 3 months of RTX therapy, whereas the hyperthyroidism remained unchanged despite a documented B cell depletion. Subsequently, the same group studied nine patients with GD, of whom seven manifested clinically active TAO. These subjects were compared with 20 consecutive patients receiving iv steroids (16). The study was limited by nonrandomization, was not controlled, and included a relatively small number of subjects. Loss of peripheral B cells was documented in all patients receiving RTX after the first round of treatment. As with the initial patient, hyperthyroidism failed to respond to RTX therapy, but the study design precludes drawing firm conclusions. However, the clinical activity score of the TAO dropped significantly. Importantly, orbital disease in the group receiving RTX improved to a greater degree than that observed in subjects treated with steroids. This apparent response to RTX therapy occurred despite no reduction in the levels of TSH receptor antibody (TRAb), suggesting that relative levels of anti-TSH receptor antibodies and the clinical activity of TAO may be unrelated.
In this issue of JCEM, El Fassi et al. (17) report their findings from an open pilot study involving 16 newly diagnosed patients with GD and four additional subjects with recently relapsing disease. All participants had been treated with methimazole for approximately 3.5 months and had been rendered euthyroid before entry into the study. Two of the subjects exhibited active TAO, and the apparent response of their orbital disease to RTX was described earlier (18). All were continued on methimazole, while half received RTX (375 mg/m2) weekly for four doses. Methimazole was stopped in all subjects on the occasion of the final infusion of RTX. One year after treatment had been withdrawn, four patients who had received RTX remained euthyroid, whereas none of those not having been treated with B cell depletion remained so. TRAb levels appear to have been lower before RTX therapy in the group of four who remained euthyroid than in those receiving RTX but in whom hyperthyroidism had recurred. Those receiving RTX exhibited a similar decline in TRAb levels as those who did not. Half of the 10 patients receiving RTX experienced significant but not serious side effects from the drug. The study suggests that RTX may induce remission in a subset of hyperthyroid patients. But it suffers from many of the same limitations plaguing the study of Salvi et al. (16). Moreover, the group receiving RTX therapy included four individuals with recurrent disease and two with active TAO, whereas the control group included subjects with neither. No documentation of B cell depletion was provided. Most importantly, the study by El Fassi et al. (17) asks the wrong question. It was designed to examine the impact of RTX on the recurrence of hyperthyroidism, a facet of GD we currently manage very effectively. It does not attempt to examine the efficacy of the drug on severe TAO. The costs, inconvenience, and side effects of RTX therapy make its use in uncomplicated GD hyperthyroidism unattractive. Should it be shown effective in controlled studies, this drug might prove an important therapy in patients with aggressive and sight-threatening forms of TAO.
Despite their shortcomings, the reports by Salvi et al. (16) and El Fassi et al. (17) represent the first steps in assessing the potential benefit that B cell depletion might offer patients with GD. They underscore the serious deficiencies remaining in our understanding of GD, such as the mechanistic relationship between hyperthyroidism and TAO. But their preliminary nature makes additional, well-controlled, and prospective studies essential. What form should these take? Seemingly endless debate has arisen from earlier clinical trials examining the efficacy of steroids and radiotherapy in TAO (19, 20). The issues surrounding individuals with TAO and their responses to therapy remain particularly complex. Lack of consensus regarding nomenclature, objective parameters for grading clinical response to therapy, and the highly idiosyncratic natural course of the disease have confounded attempts to judge the beneficial impact of therapy. Use of the clinical activity score has been met with substantial criticism, and we need a better method of quantifying disease activity and severity. Absence of specific therapies for TAO remains arguably the greatest unmet challenge in our approach to patients with autoimmune thyroid disease.
Last fall, a meeting of investigators was convened at the Jules Stein Eye Institute at the University of California, Los Angeles. Our goal was to bring together ophthalmologists, endocrinologists, and basic scientists who are interested in the pathogenesis of TAO. Individuals were invited who might help create the platform upon which collaborations between research groups could be facilitated. The participants were asked to prioritize the proximate needs of the field. Worthwhile goals identified included building an infrastructure for large, multicenter clinical trials; creation of objective guidelines for judging clinical response to therapy; standardization of clinical assessment; developing mechanisms for disseminating clinical samples; and increased involvement of scientists currently focusing on allied autoimmune diseases. Access to tissue early in the disease process constitutes a major hurdle to our progress in refining our insights into TAO, as does the absence of a complete and robust experimental model for GD. In addition, expanded funding from governmental agencies and private/commercial sources for research into the molecular and cellular underpinnings of the disease was identified as essential. Subsequent meetings are being planned, and participation of additional investigators is welcome. A working group has been charged with systematically advancing the objectives articulated at the meeting. This effort is launched in the context of the efforts made by the European Group on Graves’ Orbitopathy, with which meaningful interactions are important. Over the next few months and years, their invigorated efforts should provide traction to what now remain laudable goals.
Acknowledgments
The author thanks Drs. Andrew Gianoukakis, Raymond Douglas, and Richard Phipps for their critical review of the manuscript.
Footnotes
This work was funded in part by National Institutes of Health Grants EY008976, EY011708, and DK063121 and by support from the Bell Charitable Foundation.
Abbreviations: GD, Graves’ disease; RTX, rituximab; TAO, thyroid-associated ophthalmopathy; TRAb, TSH receptor antibody.
Received February 27, 2007.
Accepted March 14, 2007.
References
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