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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 11 3790-3794
Copyright © 1998 by The Endocrine Society

Original Studies

Orbital Scintigraphy with [111In-Diethylenetriamine Pentaacetic Acid-D-Phe1]-Octreotide Predicts the Clinical Response to Corticosteroid Therapy in Patients with Graves’ Ophthalmopathy

Annamaria Colao, Secondo Lastoria, Diego Ferone, Rosario Pivonello, Paolo E. Macchia, Patrizia Vassallo, Giulio BonavolontÁ, Pietro Muto, Gaetano Lombardi and Gianfranco Fenzi

Departments of Molecular and Clinical Endocrinology and Oncology (A.C., D.F., R.P., P.E.M., G.L., G.F.) and Ophthalmology (P.V., G.B.), Federico II University, and Nuclear Medicine, INT G. Pascale (S.L., P.M.), Naples, Italy

Address correspondence and requests for reprints to: Annamaria Colao, Department of Molecular and Clinical, Endocrinology and Oncology, "Federico II", University, Via Sergio Pansini, 5 80131, Naples, Italy.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Corticosteroid treatment is successfully used in Graves’ ophthalmopathy, and its effect varies according to the phase of the disease. The infiltration of the orbit by activated lymphocytes may explain the effectiveness of corticosteroid therapy. Scintigraphy with [111In-DTPA-D-Phe1]-octreotide was recently used to reveal the presence of activated lymphocytes in foci of autoimmune diseases, because elevated amounts of somatostatin receptors are expressed in the surface of these cells. The aim of the current study was to evaluate whether the degree of orbital [111In-DTPA-D-Phe1]-octreotide uptake is able to predict the response to corticosteroid therapy in patients with Graves’ ophthalmopathy.

Ten patients with Graves’ ophthalmopathy entered the study. In all patients scintigraphy was performed, and subsequently, corticosteroid therapy (methylprednisolone, 1 g iv for 2 consecutive days a week for 6 weeks) was given. Clinical activity of Graves’ ophthalmopathy was evaluated before and after treatment by calculating the ophthalmopathy index (OI). Planar and single photon emission computed tomography (SPECT) images of the head were obtained 24 h after the iv injection of 120–190 MBq of [111In-DTPA-D-Phe1]-octreotide. Radioligand uptake within each orbit (O) and brain (B) was measured using the region of interests (ROI) method and the O-to-B ratio was determined. According to the O-to-B ratio, the images were classified using the following three points score: 0 = O-to-B ratio <=1; 1 = O-to-B ratio between 1 and 2.5; 2 = O-to-B ratio >=2.5. The value of OI, measured before and after corticosteroid treatment, was correlated to the scintigraphic score.

A significant change of OI was observed between posttreatment and pretreatment evaluation both in orbits with score 2 (OI: 15.4 ± 1.5 vs. 9.6 ± 0.5, P < 0.005) and in those with score 1 or 0 (OI: 12.9 ± 1.5 vs. 11.5 ± 1.4, P < 0.05) at the scintigraphy. However, when the OI was calculated excluding the changes in the soft tissue, which generally occur in all patients independently from the phase of the disease, a significant change of OI was observed only in the orbits with score 2 (OI: 12.9 ± 1.3 vs. 8.3 ± 0.5, P < 0.01) but not in those with score 0 or 1 (OI: 11.2 ± 1.3 vs. 10.4 ± 1.3). In particular, 6 weeks after corticosteroid treatment, the patients with orbital score 2 at the scintigraphy had a significant improvement of soft tissue changes, proptosis, lagophthalmos, extraocular muscle movements impairment, and diplopia, whereas patients with score 0 or 1 had only a significant improvement of the soft tissue inflammation.

In conclusion, the current preliminary data suggested that [111In-DTPA-D-Phe1]-octreotide scintigraphy is able to predict the clinical response to corticosteroid treatment in patients with Graves’ ophthalmopathy, and may be considered an useful approach to select the patients for the proper treatment.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
OPHTHALMOPATHY is one the most frequent complication of Graves’ disease (1). Graves’ ophthalmopathy is characterized by eye proptosis caused by enlargement of the extraocular muscles and augmentation of retrobulbar fat and orbital soft tissues inflammation. Involvement of cornea and optic nerve may also occur during the natural history of the disease (2). Orbital infiltration primarily sustained by activated lymphocytes, local release of cytokines, and interactions of lymphocytes with retrobulbar fibroblasts, suggest an organ-specific autoimmune nature of Graves’ ophthalmopathy (3, 4). In the early stage of the disease, the retrobulbar infiltration is characterized by lymphocytes and interstitial edema, whereas in later stages fatty infiltration and fibrosis occur (5). The clinical examination often fails in defining the stage of the disease and particularly the presence or not of fibrosis (6). Thus, the active inflammatory early-stage disease cannot be distinguished from the stable fibrotic end-stage disease on the basis of clinical examination. Nevertheless, at the clinical presentation, the definition of the phase of ophthalmopathy plays a pivotal role in selecting the proper therapeutical regimen. In fact, the treatment of Graves’ ophthalmopathy varies from immunosuppressive to surgical therapy (1, 7). Immunosuppressive therapy is beneficial only in the early active stage, whereas surgery is effective in the stable end stage of the disease.

Somatostatin (SS) receptors have been ubiquitously identified, mostly on cells of neuroendocrine origin (8, 9), but also on cells not originated from neuroendocrine precursors, such as lymphocytes (10). The scintigraphy with [111In-DTPA-D-phe1]-octreotide (SRS), a radionuclide-coupled SS-analog, is commonly used to visualize SS receptor-expressing cells (11, 12). SRS has been recently shown able to reveal the presence of activated lymphocytes in inflammatory foci of several autoimmune diseases (13). In patients with active Graves’ ophthalmopathy, SRS showed markedly increased orbital uptake of [111In-DTPA-D-Phe1]-octreotide compared with healthy subjects, as well as with patients with stable disease (14, 15, 16, 17). Furthermore, SRS correctly predicted the response to treatment with SS-analogs in patients with Graves’ ophthalmopathy (18, 19, 20).

Because the presence of activated lymphocytes in the orbits represents the main target of corticosteroid therapy, and these cells can be revealed by SRS, the aim of the current study was to evaluate the potential role of orbital [111In-DTPA-D-Phe1]-octreotide uptake in predicting the response to corticosteroid therapy in patients with Graves’ ophthalmopathy.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Ten patients (5 males, 5 females, age range 25–50 yr) with clinical history of Graves’ disease and clinically active ophthalmopathy entered the study after their informed consent had been obtained. Clinically, the diagnosis of active Graves’ ophthalmopathy was made on the basis of the presence of one or more of typical clinical features: esophthalmos, lagophthalmos, soft tissue inflammation, diplopia, and impairment of extraocular muscle movements associated to the evidence of enlargement of extraocular muscles by computed tomography. The diagnosis of Graves’ disease was made on the basis of the following criteria: 1) diffuse goiter; 2) hyperthyroid symptoms and signs; 3) increased serum thyroid hormone levels; 4) suppressed serum TSH levels; 5) increased 99mTc thyroid uptake; and 6) measurable circulating levels of antithyroid antibodies. At study entry patients were in euthyroid status after medical and/or radioiodine treatment. However, they had been not receiving corticosteroid treatment for at least 1 yr and had never received therapy with SS analogs. Among the 10 patients, 2 still received antithyroid therapy and 2 had developed hypothyroidism after radioiodine therapy and were on replacement treatment with levothyroxine. The remaining six patients were not taking any drug. The patients’ profile at study entry is summarized in Table 1Go.


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  		Table 1. Patients profile at study entry

 
SRS

[111In-DTPA-D-Phe1]-octreotide (spec. act. range: 120–190 MBq) was purchased from Byk Gulden (Milan, Italy). The labeling was performed as previously described by Bakker et al. (21). Quality controls were performed on labeled peptide before the injection. More than 95% of the radioactivity was peptide bound in injectable preparations. Planar and SPECT images were obtained 24 h after the iv injection of the radioligand. The studies were performed using a large field of view gamma camera equipped with a medium-energy collimator. Tomographic acquisition was performed in a step-and-shoot mode. Sixty-four frames of 40 sec each were collected during the 180° rotation. Reconstruction was performed using a Hamming filter on back-projected images. No attenuation correction was applied.

Analysis of images and score of [111In-DTPA-D-Phe1]-octreotide uptake

Irregular regions of interest (ROI) were manually drawn on planar images as well as in SPECT reconstruction by the same observer (S.L.). The ROIs delineated either the orbits (O) or the brain (B). The O-to-B ratio was calculating by dividing the counts of the orbit and the counts of the brain ROIs. According to the O-to-B ratio the studies were classified within three points score: 0 = O-to-B ratio <=1; 1 = O-to-B ratio between 1 and 2.5; 2 = O-to-B ratio >=2.5.

Evaluation of clinical activity of Graves’ ophthalmopathy

A careful clinical evaluation of Graves’ ophthalmopathy was performed in all patients before and after corticosteroid treatment. In agreement with Bartalena et al. (22), the severity of the disease was evaluated on the basis of seven different parameters: 1) soft tissue changes (periorbital edema, conjunctival injection, chemosis); 2) proptosis; 3) lagophthalmos; 4) impairment of extraocular muscle movements; 5) diplopia; 6) corneal involvement; and 7) optic neuropathy.

Treatment protocol

A pulse therapy with iv high doses of methylprednisolone was used similarly to a schedule previously reported (23, 24, 25). All patients were treated on day hospital basis with methylprednisolone (Solumedrol, Upjohn, Milan, Italy) at the dose of 1 g diluted in 500 mL saline solution (NaCl 0.9%), administered in slow infusion in 2 consecutive days a week over 6 weeks. Before entering the study, diabetes mellitus was excluded by a standard oral glucose tolerance test (75 g p.o.) and gastric lesions were excluded by hemoccult analysis. General clinical conditions and blood glucose were carefully monitored throughout the treatment in all patients.

Study design

In all patients SRS was performed, and subsequently corticosteroid therapy was started. The evaluation of clinical activity of the Graves’ ophthalmopathy was performed in all patients before and 6 weeks after corticosteroid treatment. Radioligand uptake was correlated to clinical activity of Graves’ ophthalmopathy evaluated before and after corticosteroid treatment.

Statistical analysis

The comparison between pre- and posttreatment ophthalmopathy index (OI) was performed by Student’s t test for paired data. Linear regression coefficient was calculated between scintigraphic score and OI changes after treatment. Data were expressed as mean ± SEM.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Table 2Go summarizes the results of SRS and the response to corticosteroid therapy in the 10 patients enrolled in the study. As far as SRS results were concerned, among the 20 orbits evaluated, 7 had scores of 2 (O-to-B ratio >=2.5), 1 had a score of 1 (O-to-B ratio between 1 and 2.5), and the remaining 12 had scores of 0 (O-to-B ratio <=1). Examples of SRS score are shown in the Fig. 1Go. A blunt thyroid uptake of [111In-DTPA-D-Phe1]-octreotide was observed in 5 patients, a moderate uptake was observed in 4 patients, and an intense uptake was observed in 1 patient (Fig. 1Go), which was probably caused by a thyroiditic process. As far as ophthalmic examination was concerned, variable baseline OI values were observed, suggesting the presence of different degrees of ophthalmic impairment in the 10 patients. No significant correlation was observed between SRS score and baseline OI value [r = 0.3, P = not significant (NS)]. A significant change between pre- and posttreatment OI values was observed in all the orbits independently from the SRS score, as summarized in Table 3Go. The OI changes were more significant in the orbits with scores of 2 than in those with scores of 0 or 1. When the analysis of the changes in the ocular signs and symptoms included in the OI was performed separately, it appeared that soft tissue changes improved both in the orbits with scores of 2 and 0–1, whereas proptosis, lagophthalmos, impairment of extraocular muscle movements, and diplopia improved only in the orbits with scores of 2 but not in those with scores of 0 or 1 (Table 3Go). Thus, when the OI was calculated excluding the score for the soft tissue changes, a significant change of OI was observed in those orbits classified with scores of 2 by SRS being unmodified in those classified score 0 or 1 (Table 3Go). No significant side effects, except cutaneous flushes in four patients and gastric burn in three patients, were observed during corticosteroid therapy.


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  		Table 2. Results of [111In-DTPA-D-Phe1]-octreotide scintigraphy and response to corticosteroid therapy in patients with Graves’ ophthalmopathy

 


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  		Figure 1. Examples of score 0, score 1, and score 2 of orbital scintigraphy with [111In-DTPA-D-Phe1]-octreotide in patients with Graves’ ophthalmopathy.

 

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  		Table 3. Correlation between response to [111In-DTPA-D-Phe1]-octreotide scintigraphy and changes of individual clinical parameters considered in calculation of OI in patients with Graves’ ophthalmopathy

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The clinical phase of Graves’ ophthalmopathy in each individual patient is important to select the most proper treatment, because immunosuppressive therapy is successful in the active early phase, whereas rehabilitative surgery, such as orbital decompression and eye muscle and lid correction, is indicated in the stable end phase disease (1, 7). Clinical score (26), laboratory tests (27), and imaging techniques (17) are less than accurate because of poor sensitivity. The evidence that [111In-DTPA-D-Phe1]-octreotide is highly concentrated in the orbits of patients with Graves’ ophthalmopathy indicated new frontiers in the diagnostic work-up of the disease (14, 15, 16, 17). In fact, Kahaly et al. (15, 16) reported that orbital [111In-DTPA-D-Phe1]-octreotide uptake, measured 4 and 24 h after the injection of [111In-DTPA-D-Phe1]-octreotide, was significantly higher in patients with clinically active Graves’ ophthalmopathy than in patients with inactive disease and controls. Postema et al. (14) reported in patients with Graves’ ophthalmopathy a positive correlation between clinical activity score and [111In-DTPA-D-Phe1]-octreotide uptake measured 5 h after the injection of the radioligand, using a semiquantitative scoring system. Moncayo et al. (17) found a similar positive correlation between clinical activity score and [111In-DTPA-D-Phe1]-octreotide uptake measuring it 2 h after the injection of the radioligand and using a positive-negative scoring system. These studies demonstrated that orbital SRS is able to determine the pathological phase of Graves’ disease, giving a high positive scan in the active early phase and a low positive or negative scan in the stable end phase of the disease. These findings are likely caused by the presence or absence of activated lymphocytes respectively in the early and end phase of the disease. Although a specific binding of [111In-DTPA-D-Phe1]-octreotide to SS receptors on eye myocytes, fibroblasts, or endothelial cells cannot be ruled out (28), it should not be relevant, because it is negligible in control subjects. Krassas et al. (19) demonstrated that SRS correctly predicted the response to treatment with SS-analogs in patients with Graves’ ophthalmopathy, as demonstrated for neuroendocrine tumors (29), and suggested for GH-secreting pituitary tumors (30, 31, 32). To date, there is no evidence that SRS results predict the therapeutical outcome in patients with Graves’ ophthalmopathy treated with corticosteroids. In the present open, prospective study, although performed in a small number of patients, we demonstrated that the O-to-B ratio is a valuable semiquantitative method to predict the therapeutical outcome in these patients. In fact, a significant improvement was observed in the orbits scored 2 at the scintigraphy but not in those scored 0 or 1. The orbital [111In-DTPA-D-Phe1]-octreotide uptake seems to mirror the expression of the density of SS-receptors and more likely the number of activated lymphocytes. Therefore, the lymphocytolitic activity of corticosteroids may be predicted by SRS. The efficacy of corticosteroid treatment was evaluated, calculating the changes measured in OI. The measurement of OI was chosen because it provides reliable information on the severity of ophthalmopathy and can be used in the assessment of the effects of treatment (22). A significant change of OI was observed in a great majority of patients independently from the SRS score because OI was greatly influenced by the changes in soft tissues. However, when this parameter was excluded and proptosis, lagophthalmos, diplopia, and impairment of extraocular muscle movements were evaluated, a significant change of OI was observed only in the orbits scored 2 by SRS. The significant changes of soft tissue involvement in all patients may be caused by the nonspecific antiinflammatory action of corticosteroids, which is independent from the clinical phase of the ophthalmopathy. The improvement of extraocular muscle movements after corticosteroid treatment in these patients seems to suggest that it was mainly caused by retro- and periorbital edema rather than fibrosis. The lack of a significant change of corneal involvement and optic neuropathy were probably caused by the scarce or absent impairment of these parameters in the patients enrolled in this study, before corticosteroid treatment.

The results of the current study demonstrated that SRS is able to recognize the early active phase from the late stable phase of the disease and to predict the response to corticosteroid treatment in Graves’ ophthalmopathy. The OI alone was unable to predict the response to corticosteroid treatment in these patients. In fact, both patients with high or low OI scores may have a positive or negative response to corticosteroid treatment. In addition, no significant correlation was found between scintigraphic score and baseline OI score in the patients enrolled in this study.

Received February 10, 1998.

Revised June 22, 1998.

Accepted July 21, 1998.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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