Ординатура / Офтальмология / Английские материалы / Graves' Orbitopathy A Multidisciplinary Approach_Wiersinga, Kahaly_2007

25Bartalena L, Marcocci C, Tanda ML, Manetti L, Dell’Unto E, Bartolomei MP, Nardi M, Martino E, Pinchera A: Cigarette smoking and treatment outcomes in Graves’ ophthalmopathy. Ann Intern Med 1998;129:632–635.

26Eckstein A, Quadbeck B, Mueller G, Rettenmeier AW, Hoermann R, Mann K, Steuhl P, Esser J: Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br J Ophthalmol 2003;87:773–776.

Prof. Luigi Bartalena

Division of Endocrinology, Department of Clinical Medicine University of Insubria, Ospedale di Circolo

Viale Borri, 57 IT–21100 Varese (Italy)

Tel. 39 0332 278561, Fax 39 0332 278358, E-Mail l.bartalena@libero.it

the TSH receptor-mediated pathogenic mechanisms of GO [5]. A short course of oral steroids has been successfully administered to prevent GO in patients at high risk, after thyroid ablation with I-131 for recurrent hyperthyroidism [6]. In that study, steroids helped preventing both the initiation of GO or the worsening of pre-existing disease, suggesting their potential immunosuppressive effect on either pathogenic mechanism.

What Are the Reasons for Exploring the Potential

Efficacy of New Immunosuppressive Medications?

Established treating agents in GO such as steroids (which have acceptable efficacy at the cost of relevant side effects [2, 7–9]), and radiotherapy (which is effective mainly in combination with steroids [10, 11] but has a safer long-term side effect profile [12]) have been used for years with different administering modalities and probably limited true immunosuppressive effects. Since we do not yet understand the specific immune mechanisms involved in the pathogenesis of GO, we are only using agents that act as general immunosuppressants, similarly employed in other autoimmune diseases. The need for new immunosuppressive medication is opportune. Lately, a large panel of newly synthesized monoclonal antibodies directed to various molecules expressed on immune cells and involved at different levels in the autoimmune reactions has become available. Some of these have been used in pilot studies and preliminary clinical trials in various autoimmune diseases with promising results.

Is There Evidence for the Efficacy of New

Immunotherapy Agents in Graves’Orbitopathy?

Immunotherapeutic agents in GO have been proposed and employed with only partially satisfying results over the last 20 years but only recently drugs interacting with the action of both Th1 and Th2 cytokines have been made available and tried in GO, although not in controlled studies. Etanercept, a TNF receptor antagonist [13], has been successfully used to treat a patient with severe GO [14] and by Paridaens et al. [15] in a group of 10 GO patients who showed improvement of clinical activity but not of proptosis. The lack of effect on orbital tissue hypertrophy may be due to absent TNFreceptor expression on orbital fat in active GO [16]. There have been recent reports of significant amelioration of the signs of GO in single patients treated with rituximab, an anti-CD20 monoclonal antibody [17, 18]. Subsequently, Salvi et al. [19] have completed a phase 2 clinical study with rituximab on 10 patients with active GO and different degree of severity and have observed improvement of the CAS, proptosis and motility and stabilization

of GO without evidence of recurrence after 12–24 months, when compared to the response to i.v. steroids in a similar group of patients with active GO.

Which Anticytokine Treatment Would Be the Most

Effective in Your Opinion?

Data from the above studies suggest that B cells are key regulators of the immune response in the orbit, perhaps by acting as antigen presenting cells [20] and that rituximab is at the moment the most promising immunomodulating drug in GO. GO pathogenesis is yet unclear, but evidence would support more Th1 cytokine-driven mechanisms, at least in the early stages [21–23]. Specifically, one could hypothesize the use of anti-TNF- and anti-IL-1 antibodies to be effective in controlling the development of active GO. In vitro evidence that the TNFreceptor may not be expressed by orbital tissue in the active GO phase [16] and that IL-1 stimulates glycosaminoglycans production and adipogenesis by fibroblasts in tissues derived from either GO patients or controls [24] poses the question of their efficacy until clinical trials are carried out. Other therapeutic targets could be the T cell co-stimulation pathway CTLA4-B7 (abatacept, an immunoglobulin directed against CTLA4, which has shown to be promising in rheumatoid arthritis [25]), and the antigen-presenting capacity of monocytes and inhibition of T cell clones proliferaton by IL-10 [26]. Very recently, Douglas et al. [27] have reported that memory T cells of Graves’ disease patients largely express the IGF- 1 receptor that could be the target of autoantibodies in GO which stimulate fibroblasts growth and prolong T cell survival, thereby perpetuating the autoimmune process. These data raise the possibility of developing an effective drug to block the IGF-1 receptor. The serum-soluble IL-6 receptor (sIL-6R) has been reported to be elevated in active GO, independently of thyroid autoimmune reactions [28]. Tocilizumab, an anti-IL-6R humanized monoclonal antibody, has been shown to be a promising agent in rheumatic diseases because of its effect on the blockade of the pro-inflammatory cytokine milieu [29].

What About Rituximab?

Rituximab binds to the CD20 antigen expressed on B cells and blocks the formation of new plasmacells and immunoglobulins [30, 31]. The results of an open trial on rituximab in GO [19] suggest that the drug is effective in modifying the disease course and its clinical impact. A plausible explanation for its effect on GO is that it may affect B cell antigen presentation at the orbital level [20]. On the other hand, evidence for the involvement of autoantibodies directed against the IGF-1 receptor in the initiation of GO [32] suggests that blocking CD20 might

Fig. 1. Immunohistochemistry of orbital fat tissue from patients with Graves’ ophthalmopathy. Upper panel: Tissue from a patient treated with rituximab that shows the absence of any significant lymphoid infiltrate. Lower panel: Tissue from a patient treated with steroids, with evident lymphocytes. HE.

interrupt the cascade of autoimmune reactions in the orbit. Salvi et al. [17] have indeed reported absence of both B and T cells in orbital tissue specimens after rituximab therapy in 1 patient (fig. 1). In addition, a significant reduction of proptosis measurements was observed after rituximab in 2 patients with Graves’ disease and only eye lid inflammation [19]. It is possible that TSH receptormediated fibroblast and adipocyte stimulation is also inhibited [22, 33] and this results in the observed decrease of the eye protrusion.

What About Interfering with the TSH Receptor Pathways?

The pathogenesis of Graves’ hyperthyroidism is B cell mediated through TSH receptor binding autoantibodies and there is evidence to support a role of this interaction in fibroblasts and adipose tissue proliferation in the orbit. It is also of interest that TSH receptor mRNA levels in orbital adipose tissue have been shown to be increased in patients with active GO [16]. In addition, early adipogenesis is activated by PPARligation [33]. Effective immunotherapy should therefore interfere with TSH receptor expression and binding or with blocking of PPARligation [23]. CD20 blocking would be expected to induce a decrease of TRAb in the serum of patients with Graves’ disease [34] and perhaps consequent orbital fibroblast stimulation. Interestingly, in the study of Salvi et al. [19] rituximab, while effective on orbital disease, had no effect on serum TRAb and hyperthyroidism (fig. 2), despite the attainment of total peripheral B cell depletion. The lack of effect of rituximab on serum TRAb suggests that this autoantibody, and in general thyroid autoimmune reactions, might be involved in the cross-reactive mechanisms between the thyroid and the orbit but not in the subsequent development of clinical disease.

Are Technical Developments in Surgical

Approaches to Be Expected?

Orbital bone decompression is currently accomplished by piecemeal fracturing with bone nibbing rongeurs and by grinding with high-speed drill equipped with a cutting-burr or a diamond-burr tip. The use of rotary instrumentation in tight spaces, as those available in orbital surgery, carries the not negligible risk of catching soft orbital tissues or damaging the dura. Ultrasonic bone removal recently proposed for orbital surgery represents a promising field of technical development [35]. Hand pieces which transmit 25–29 kHz vibration can easily selectively carve/cut only mineralized tissues. The reliability of ultrasonic bone curettes in orbital surgery, however, still needs to be tested against large numbers, and issues of concern about possible damages to soft tissues when using such devices have been recently aroused in neurosurgery [36].

Technical innovations for decompression surgery are limited as compared with those that are already available and constantly undergo implementation for blepharoand eyebrowplasty. The reason of this difference is that rehabilitative blepharoplasty and browplasty can benefit from the technical solutions that the most commercial, dynamic world of cosmetic periorbital surgery is offering. These include different types of technologically advanced, incisional, or photo ablative lasers; radiofrequency or laser powered devices aimed at subcutaneous

Fig. 2. Changes of serum thyroid autoantibodies levels in relation to peripheral depletion of CD20 lymphocytes after treatment with rituximab in 9 patients with active thyroidassociated ophthalmopathy. Six patients were treated with methimazole, 1 with L-thyroxine replacement and 2 were euthyroid without therapy. TRAb TSH receptor antibodies; TPOAb thyroperoxidase antibodies; TgAb thyroglobulin antibodies. Values are indicated as mean SE.

collagen contraction and/or neocollagen genesis; diamond laser scalpels; fillers; endoscopic instrumentation and fixation systems/devices for brow lift.

At present, hard palate mucosa, providing structural and epithelial elements, represents the graft of choice for posterior lamella augmentation in lower lid lengthening, although presenting the disadvantage of not negligible donor site morbidity and surgical time for graft harvesting. Homologous acellular dermal matrix is a processed donor tissue not available in Europe with appropriate consistency for posterior lamella augmentation; one surface is sectioned through the dermis and the other has an intact basement membrane, which provides a structural template that guides conjunctival epithelium migration and repopulation. It is not excluded that in the close future bioengineering (already capable of offering cultured hyaluronan-based dermal autografts) will

be able to provide effortless autografts with characteristics similar to homologous acellular dermal matrix with the result of speeding up surgery and eliminating the problem of donor site morbidity.

Are Conceptual Developments in Surgical

Approaches to Be Expected?

Waiting for a specific medical therapy to cure GO, orbital fat and every bone in the orbit have been removed, either alone or in combination, to achieve orbital decompression. Through the years, indications, osteotomies, and incisions for decompression surgery have changed in order to decrease the occurrence of unwanted side effects and possible complications in a simultaneous attempt to maximalize satisfaction for an increasingly demanding patient population. At the basis of this type of surgery, however, remains the same conceptual principle of decreasing mechanically, the mechanical contribution to the pathogenesis of GO, or the mechanical sequels of the stable disease, no matter which technique is used [37]. At present, no conceptual departure from this approach has been proposed or explored.

The principles that regulate timing and techniques for surgical correction of restrictive strabismus, primarily due to the orbitopathy itself, are well established, while the pathogenesis of the strabismus consecutive to orbital decompression is not fully understood. A better understanding of the latter may result in conceptual advancements beneficial for its treatment and eventual prevention [38]. Recently, injections of hyaluronic acid gel have been proposed for the treatment of lower lid retraction of various aetiologies. Although its effectiveness still needs to be proven, the layered expansion/reinforcement offered by the hyaluronic acid gel eventually associated to weakening of the retractors may represent a possible conceptual alternative to the traditional autologous, homologous, xenogenic and synthetic spacer grafts which are currently used to provide stiffness and support against gravity [39].

In light of the current literature, no substantial conceptual changes are to be expected regarding blepharoplasty and eyebrowplasty for the near future.

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Dr. Lelio Baldeschi

Room A2–119, Orbital Center, Department of Ophthalmology Academic Medical Center, University of Amsterdam Meibergdreef 9

NL–1105 AZ Amsterdam (The Netherlands)

Tel. 31 20 566 3580, Fax 31 20 556 9053, E-Mail l.baldeschi@amc.uva.nl