Department of Clinical Medicine (L.B.), University of Insubria at Varese, Varese 21100, Italy; and Department of Endocrinology and Metabolism (C.M., A.P.), University of Pisa, Pisa 56124, Italy
Address all correspondence and requests for reprints to: Professor Luigi Bartalena, Department of Clinical Medicine, University of Insubria, Division of Endocrinology, Ospedale di Circolo, Viale Borri, 57, 21100 Varese, Italy. E-mail: l.bartalena{at}libero.it or luigi.bartalena{at}uninsubria.it.
Management of Graves ophthalmopathy (GO) is difficult, and the outcome of treatment is frequently unsatisfactory to the patient (and the physician) (1). Physicians may report favorable results of treatment, based on objective and subjective criteria, but residual eye manifestations, such as proptosis and even mild diplopia, from the patients point of view are recognized as treatment failure. In this regard, it is worth recalling that GO, even in its mild expression, profoundly impairs the quality of life of affected individuals (2). The ideal would be to prevent GO development, but this is in most instances impossible, even though smoking withdrawal and prompt correction of thyroid dysfunction are certainly relevant for a more favorable course of eye disease (3). Once GO is established and florid, "jurassic" treatments, such as high-dose glucocorticoids and orbital radiotherapy, that have been used for more than 50 yr are often effective in reducing the increased orbital content, especially in patients with active GO, by their nonspecific antiinflammatory actions and, possibly, by immunosupressive effects. On the contrary, orbital decompression does not intervene on disease mechanisms but increases the space available in the orbit for the increased volume of orbital tissues (extraocular muscles, fibro-adipose tissue). Beneficial effects (at least from the physicians point of view) can be achieved by medical treatments in about two thirds of cases (1). Neither medical treatments nor orbital surgery are devoid of risks and complications, and nobody has carried out a precise and accurate cost/benefit analysis of different treatments for GO. However, these are the weapons we have, and we must do anything we can to alleviate GO-related disturbances and to avoid possible progression of eye disease to more severe forms that threaten patients sight.
Given these premises, it is easy to understand that in recent years efforts have been made to identify novel treatments for this disfiguring disease. Intravenous high-dose Igs, cyclosporine, antioxidants, and cytokine antagonists are among proposed treatments, but well-designed, randomized, and controlled studies are lacking, hampering clear-cut demonstration of the efficacy (or lack of efficacy) of these drugs. Interest in somatostatin (SST) analogs as a potential therapeutic tool for GO stemmed from the observation that infiltrating cells in the orbit of GO patients express SST receptors (see Ref.4 for review). This was first demonstrated in vivo with the use of radiolabeled octreotide scintigraphy (octreoscan). Graves patients with ophthalmopathy have been reported to have a higher octreoscan positivity than Graves patients without eye disease; octreoscan positivity was correlated with GO activity and appeared to predict subsequent response to immunosuppressive treatment (see Ref.5 for review). Subsequent in vitro studies have confirmed the presence of different SST receptor subtypes (SST15) in the orbital tissue of GO patients. In primary cultures of orbital fibroblasts, Pasquali et al. (6) found SST1 expression in five of 10 GO samples and in zero of 10 control samples, SST2 in nine of 10 GO samples and in six of six controls, SST3 in five of 10 GO samples and in three of six controls, SST4 in one of 10 GO samples and in zero of 10 controls, and SST5 in eight of 10 GO samples and in zero of six controls (Table 1). Addition of octreotide to culture medium arrested cell growth and induced apoptosis (6). In a subsequent study, the same group demonstrated that all SST receptor transcripts were present in lymphocytes from both GO orbital tissue and blood samples: the level of expression of SST1, SST2, and SST4 was higher than that of SST3 and SST5 (7); however, lymphocytes from control subjects barely expressed SST receptor subtypes.
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The study by Dickinson et al. (8) published in this issue greatly contributes to mitigate the initial enthusiasm for SST analogs and to support a more cautious interpretation of their role in GO management. This is the first double-blind, placebo-controlled trial of octreotide long-acting release (LAR) in a large series (n = 50) of patients with active GO. Treatment with octreotide LAR was associated with a significant decrease in soft tissue inflammation, but the same effect was observed in control patients receiving placebo (8). Only marginally more pronounced changes in proptosis (<1 mm) were found in patients treated with octreotide LAR for a longer period of time. Accordingly, the observed changes in octreotide LAR-treated patients seem most likely related to the natural history of GO. It should be noted that approximately half of the patients described by Dickinson et al. smoked, whereas smokers had been excluded in some previous studies reporting favorable effects of SST analogs (see Refs.4 and 5 for review). This might have, to some extent, affected the substantially negative results reported by Dickinson et al. (8), in view of the notion that smoking reduces the effectiveness of medical treatment for GO (9). Another randomized, placebo-controlled, double-blind trial of octreotide LAR in 51 patients with mild to moderately severe GO, published at this time only in abstract form (10), showed only a marginal decrease in proptosis, whereas other major eye manifestations, namely soft tissue involvement and extraocular muscle dysfunction, were not affected. Thus, the latter study seems to militate against a relevant role of SST analogs in GO management.
On the basis of the above-described randomized, controlled trials, should we consider SST analogs as a rubber bullet, at least for GO, and forget about them? This may very well be the case, but the role of SST analogs might be revitalized by the use of analogs with higher affinity for all SST receptor subtypes. Both octreotide and lanreotide act predominantly on SST-2 and, to a lesser extent, SST-5 (11). As mentioned earlier, both orbital fibroblasts and lymphocytes from GO patients express not only SST-2 and SST-5, but also SST-1 and SST-3 (6, 7). Recently, a novel SST analog, named SOM230, has been developed, showing a much higher affinity for SST-1, SST-3, and SST-5 and a slightly lower affinity for SST-2 than octreotide and lanreotide (12). Ongoing trials are evaluating its effectiveness in disorders, such as acromegaly, for which SST analogs represent a well-established and effective treatment. Presently we cannot exclude the possibility that SOM230 may prove more effective than octreotide and lanreotide on GO, but this can only be demonstrated by properly designed, randomized, controlled studies with carefully selected inclusion criteria, because patients who smoke and have longstanding and inactive (or fairly active) ophthalmopathy are candidates to be poor responders to SST analogs, as well as to well-established methods of GO treatment, such as high-dose glucocorticoids and orbital radiotherapy. While waiting for future studies that might make us change our minds, we do not include SST analogs among our therapeutic weapons for GO and stick to "jurassic" treatments of proven, although incomplete, efficacy.
Footnotes
This work was supported in part by grants from the University of Insubria (Fondi di Ateneo per la Ricerca) and the Ministry of Education, University and Research (Rome; Project "Studies on the relationship between fetal microchimerism and thyroid autoimmune diseases") to L.B.
Abbreviations: GO, Graves ophthalmopathy; LAR, long-acting release; SST, somatostatin.
Received October 7, 2004.
Accepted October 11, 2004.
References