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Department of Internal Medicine (M.N.S., M.D.B., R.S.B.), Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Ophthalmology (J.A.G., E.A.B., J.J.W.), Department of Radiology (M.M.B.), Division of Neuroradiology, and Department of Health Sciences Research (S.C.B., S.J.A.), Division of Biostatistics, Mayo Clinic, Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Rebecca S Bahn, M.D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: bahn.rebecca{at}mayo.edu.
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Abstract |
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Objective: The objective of the study was to determine whether octreotide long-acting release (LAR) is effective treatment for active GO.
Design: This was a prospective, randomized, double-blind, placebo-controlled study.
Setting: The setting was a single tertiary referral center.
Patients: Twenty-nine consecutive euthyroid patients with active GO [clinical activity score (CAS) 
3] were enrolled; 25 completed the study.
Intervention: Patients received four monthly doses of either octreotide LAR (20 mg) or saline by im injections.
Main Outcome Measures: Primary measure was a change in CAS; the secondary measure was changes in retrobulbar tissue volume, proptosis, lid fissure width, range of motion, and diplopia fields.
Results: Median (range) CAS change was 2.5 (1, 5) in the treatment and 1.0 (0, 7) in the placebo group (P = 0.02). Median lid fissure width improved in the treatment group, (decreased 1 mm on the right and 0.5 mm on the left), compared with the placebo group (no change on the right, P < 0.01; increased 1 mm on the left, P < 0.01). No other significant differences between groups were identified.
Conclusions: CAS improved to a greater extent in octreotide-LAR-treated patients than the control group. However, this finding may not represent clinical benefit because patients with higher baseline CAS were overrepresented in the treatment group, and the control group was small. In contrast, treatment-related improvement in eyelid fissure width was noted, suggesting that octreotide LAR may be useful in the treatment of a subgroup of active GO patients with significant lid retraction.
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Introduction |
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Somatostatin analogs have immunomodulatory effects that make them, in theory, an attractive option for treatment of this condition. Somatostatin inhibits lymphocyte proliferation and production of colony-stimulating factor (2), inflammatory cytokines (3), and immunoglobulins (4), factors thought to play a role in the orbital autoimmune process (1). Also, somatostatin receptors have been identified on orbital fibroblasts (5, 6) and activated lymphocytes (7), and GO disease activity has been shown to correlate with the uptake of somatostatin analogs in orbital scintigrams (8, 9).
Several uncontrolled studies have suggested benefit from somatostatin analogs (10, 11, 12, 13, 14, 15). In contrast, two recent large randomized trials showed limited benefit (16, 17) from long-acting release (LAR) octreotide preparations. We undertook this double-blind, randomized trial to test the efficacy of an LAR analog, Sandostatin LAR Depot, in the management of moderate to severe GO in a North American population.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Twenty-nine consecutive euthyroid patients (with or without T4 therapy), previously treated for Graves’ hyperthyroidism (except for one patient having euthyroid GO) with active GO with a clinical activity score (CAS) of 3 or greater and not requiring immediate surgical ophthalmological intervention, were enrolled in the study between 2000 and 2005. CAS was measured on a seven-point scale that included spontaneous retrobulbar pain, pain on eye movement, eyelid erythema, conjunctival injection, chemosis, swelling of the caruncle, and eyelid edema or fullness (18). Exclusion criteria included the presence of optic neuropathy, corneal ulcers, treatment with systemic steroids, or other immunosuppressive agents within the previous 4 wk, previous eye surgery or orbital irradiation, history of biliary disease, pregnancy, nursing, diabetes, or other serious illness.
Intervention
All patients participating in this study were recruited and evaluated at Mayo Clinic Rochester. The natural history of the disease led us to choose a 4-month treatment window because the response would be expected during that time frame. Patients were randomized to receive either Sandostatin LAR Depot (20 mg) or saline by four monthly injections. The initial evaluation after randomization included a history and physical examination performed by an endocrinologist (M.D.B. or R.S.B.), a detailed quantitative ophthalmological exam performed by an ophthalmologist (J.A.G., E.A.B., or J.J.W.), an orbital computerized tomography (CT) scan, and the administration of the first injection. Three more doses of therapy were administered at monthly intervals. At each interim visit, we performed an abbreviated history, symptom inventory, and eye exam (including proptosis measurements with Krahn exophthalmometer and visual field testing by confrontation). One month after the final injection, all baseline examinations and measurements were repeated. All injections were administered in the Mayo Clinic Endocrine Testing Unit.
Objectives and outcomes
The primary outcome measure was change in CAS. Secondary outcome measures were changes in quantitative ocular parameters relevant to disease activity: retrobulbar muscle and connective tissue volume, proptosis, lid fissure width, range of motion on perimeter, and diplopia fields (19). Patient perception of disease was determined through a self-assessment questionnaire.
Randomization and blinding
Enrolled patients were given a sc test dose of octreotide (100 µg). If tolerated 24 h later, patients were randomized to receive either octreotide LAR or saline by im injection. Randomization of sequential patients, stratified according to smoking history, was determined using a random number generation program; nonsmokers were defined as not having smoked ever or for more than 1 yr. All investigators and patients were unaware of the treatment assignment during the study. Only the registered nurse whose role in the study was to prepare and administer medications had access to this information. Twenty-nine patients were enrolled; one patient was intolerant to the test dose of octreotide, two patients were withdrawn due to protocol violations, and one patient withdrew for personal reasons; 25 patients completed the study.
Quantitative ocular parameters
Data were collected at study enrollment and 4 months later at study completion. Ophthalmological data included visual acuity by 4-m test chart (Early Treatment of Diabetic Retinopathy Study), slit lamp (corneal) examination, color vision evaluation (D15 test), measurement of eyelid retraction (lid fissure width at central eyelid, limbus to upper lid and limbus to lower lid margin, central marginal reflex distance-1), lagophthalmos, proptosis measurement (Krahn exophthalmometer), extraocular muscle function evaluation (Lancaster red/green testing, monocular range of motion, and Goldman perimetry for diplopia fields), dilated fundus examination, and intraocular pressure measurement.
Clinical assessments
In general, to eliminate interobserver variability, clinical assessments were performed by the same ophthalmologist throughout the study. Each patient was assigned a CAS at entry and at the end of the study. In addition, patients were questioned regarding diplopia, gritty or sandy ocular sensation, deep orbital pressure, lacrimation, blurring, photophobia, and overall progression of symptoms over the previous several months. Upper facial photographs were obtained. These were graded in a blinded fashion by a panel of three ophthalmologists (J.A.G., E.A.B., J.J.W.) (20). The features scored included periorbital swelling and conjunctival injection (scale normal, mild, moderate, severe) and eyelid erythema (scale absent, present). We also assessed the global trend of the disease, defined as the overall estimate of disease progression/regression between the baseline and 4-month photograph (scale worse, same, better).
Volumetric orbital CT scanning
Volumetric orbital CT scans were performed using a GE 9800 scanner (GE Medical Systems, Milwaukee, WI). The 1.5-mm sections with threshold settings of –200 Hounsfield units (HU) to 0 HU for fat and 0 HU to +200 HU for muscle were analyzed. The orbit was defined by its bony margins. The anterior orbit was defined by a line connecting the medial and lateral orbital rim. If the medial orbital rim was not visible, the anterior orbit was defined by a line angled 20° anterior to the line connecting the lateral orbital rims bilaterally.
Measurements of orbital volumes were computed with the GE three-dimensional analysis package. The software calculated the intraorbital volume designated as fat or muscle on each 1.5-mm section and computed total muscle and fat volume; the term fat encompasses all the adipose/connective tissues behind the anterior orbital boundary that are not globe, muscle, or optic nerve.
The axial CT slice that bisected the crystalline lens was selected to measure the degree of proptosis. A line was drawn between the lateral orbital rims, and then a perpendicular line was drawn forward to the most anterior point of the inner surface of each cornea, and this length represented the proptosis measurement.
Patient self-assessment
The Patient Self-Assessment Questionnaire (PSAQ) was completed by patients at enrollment into the study and at the final visit to assess their subjective experience of the disease (Table 1
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This study was approved by the Mayo Clinic Institutional Review Board, and all patients signed an informed consent form. Adverse events were recorded at each visit.
Statistical analysis
This study was planned to recruit 15 patients per group. With this sample size, a change of 1.2 in CAS would be able to be detected, assuming an average CAS measure of 5.2, SD of 1.1, and correlation between baseline CAS and 4-month CAS of at least 0.5. Patients were randomized to octreotide LAR treatment or placebo with stratification on smoking status. Continuous variables were compared between the two treatment groups using the Wilcoxon rank sum test, whereas categorical variables were analyzed using the Fisher exact test. Nonparametric methods were used throughout because normality and 
2 assumptions were frequently violated. Change in CAS and lid fissures were compared between treatment and control groups after adjusting for a previous history of systemic steroid use, smoking, or both using nonparametric regression using ranks. In this regression, the dependent variable was a rank of either the CAS score or the lid fissure. The independent variable was treatment group. The covariates of history of systemic steroid use, smoking, and their interaction were assessed using backward elimination. P < 0.05 was considered significant. All statistical analyses were performed using SAS (Cary, NC).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The two groups were well matched in respect to age, sex, history of hyperthyroidism, duration from diagnosis of hyperthyroidism or GO, history of antithyroid drug, corticosteroid treatment, smoking history, thyroid stimulating immunoglobulin (TSI), and sensitive TSH levels (Table 2). TSH was suppressed on levothyroxine in five cases, all with normal free T4 (range 0.4–1.3 ng/dl, normal range 0.8–1.8 ng/dl). Corticosteroid therapy was the only immunosuppressive treatment received by study patients (six in the treatment group, three in the control group). Patients received tapering doses with duration between 2 wk and 12 months. No patient was on corticosteroids during the 4 wk before enrollment.
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). In addition, the range of baseline CAS scores was smaller in the treatment group (range 5, 6) than the control group (range 3, 7; except for one, all patients had CAS 4). The statistical significance of the baseline comparisons between groups in all other parameters was unchanged, regardless of whether all 26 enrolled patients or the 25 who completed the trial were included. Clinical eye symptoms, overall recent progression of symptoms, and scoring of baseline photographs were not different between the groups. Regarding quantitative ocular parameters, the only difference between groups at baseline was the left eyelid fissure width, which was greater in the treatment group than the control group (P = 0.03). However, neither the right eyelid fissure width nor the average of the left and right lid fissures differed between the groups at baseline. None of the volumes or proptosis measurements determined by orbital CT scanning differed between the groups at baseline.
The PSAQ identified no differences between the groups at baseline with regard to self-reported symptoms or history of disease progression in the 4 months preceding enrollment in the trial.
Baseline to 4-month comparisons
CAS. All 14 patients in the octreotide LAR treatment group and seven of 11 patients in the placebo group improved in CAS by at least one point over the course of the study; no patient in either group showed worsening in CAS (Fig. 1, A and B). Remarkably, the single patient experiencing the greatest drop (seven points) in CAS was in the placebo group (Fig. 1B). However, a CAS improvement of two or more points [thought to be clinically significant (21)] was found in 12 of 14 treated patients (86%) and four of 11 control patients (36%) (P = 0.02). A drop in CAS of three or more points was apparent in seven of 14 (50%) in the treatment group and two of 11 (18%) in the control group (P = 0.21; Fig. 1C).
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), we adjusted for this difference by comparing percent change in CAS from baseline between the groups. This analysis did not alter the results (octreotide LAR median 45% change, placebo median 25% change; P = 0.03). Findings were not influenced by previous history of systemic steroid use, smoking, or both (P for treatment = 0.04, 0.03, and 0.04, respectively). There was a moderately positive correlation in all patients (regardless of study group) between baseline CAS and the change in the CAS over the course of the study (Spearman r = 0.54). Clinical symptoms and laboratory data
No differences between groups were identified during the study regarding clinical symptoms, TSH (P = 0.22), and TSI (P = 0.50). Also TSH and TSI were relatively stable throughout the study (octreotide LAR group median TSH decreased by 0.1 mIU/liter and median TSI increased by 0.15; placebo group median TSH increased by 0.20 mIU/liter and median TSI increased by 0.10).
Lid fissure width
Median lid fissure width improved significantly over the course of the study in the octreotide-LAR-treated group (decreased 1 mm on the right; 0.5 mm on the left), compared with placebo (0-mm change on the right; increased 1 mm on the left). These changes were independently significant for each eye (right, P = 0.01; left, P = 0.008; Fig. 2). Eight of 14 octreotide-LAR-treated patients (57%) improved by at least 1 mm in average lid fissure width (left plus right), whereas only one of 11 (9%) in the placebo group showed any improvement (P = 0.03). In addition, four of 14 patients (28%) in the treatment group, and no patients in the control group, improved by 2 mm or more in this parameter (P = 0.10). In fact, improvement of 4–5 mm was apparent in one octreotide-LAR-treated patient. Two or more millimeters of improvement were found only in eyes having a baseline lid fissure ranging from 10 to 16 mm. Of the 23 octreotide-treated eyes in this range, nine (39%) improved by 2 mm or more, whereas none of 16 placebo-treated eyes in this range improved to this degree (P = 0.005). Overall, 16 of 28 eyes in the octreotide LAR group improved (i.e. any reduction from baseline), compared with only one of 22 eyes in the placebo group [P < 0.001, odds ratio (OR) [95% confidence interval (CI)] = 28 (3.3,1228); Fig. 3].
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]. When average lid fissure width was assessed, we found that three of 14 patients in the octreotide LAR group worsened, as did eight of 11 in the placebo group [P = 0.02, OR (95% CI) = 0.10 (0.01–0.84)]. Two patients, both in the octreotide LAR group, had discordant lid fissure changes between the eyes (both improved by 1 mm on the right and worsened by 1 mm on the left). Results were not influenced by previous steroid use, smoking history, or the combination of these parameters (P < 0.01 for left, right, and average fissures for all). The margin reflex distance (MRD)-1 (the distance between the center of the pupillary light reflex and the upper eyelid margin with the eye in primary gaze) is a measure similar to the lid fissure width. Median MRD-1 on the right worsened by 0.5 mm in the placebo group and improved by 0.75 mm in the octreotide LAR group (P = 0.29); on the left the median value was unchanged in the placebo group and improved by 1 mm in the octreotide LAR group (P = 0.28). Other ocular parameters
There were no differences measured over the course of the study in any of the other ocular parameters, including visual acuity, color vision, extraocular muscle function, corneal evaluation, dilated fundus examinations, limbus to lower lid margin, limbus to upper lid margin, presence of cataract, intraocular pressure measurement, etc. (Table 3).
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There was a small but statistically significant decrease (P = 0.027) in median total orbital volume in the octreotide LAR group on the right (0.38 cc), and a small increase in total orbital volume on the right (0.7 cc) in the placebo group (P = 0.03). Similar changes, not reaching statistical significance, were noted on the left (0.08-cc median decrease in the octreotide LAR treated patients; 0.53-cc median increase in the placebo-treated patients; P = 0.43). Changes in all other orbital volumes and proptosis measurements did not differ between the groups (Table 4).
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Analysis of PSAQ data identified a marginally significant difference between groups in regard to sharpness of vision after therapy: five of 13 patients reported this parameter to be better at the end of the trial in the octreotide LAR group, whereas no patients in the placebo group reported improvement in this parameter (P = 0.046). Whereas it is possible that patients having gastrointestinal side effects may have suspected that they were receiving octreotide LAR instead of placebo, none of the other parameters was found on PSAQ to be different between study groups. A blinded scored analysis of the clinical photographs conducted by a panel of three ophthalmologists failed to show any differences between the clinical appearances of the patients in the two groups.
Tolerability
The therapy was well tolerated; no patient discontinued the study due to adverse effects of medication. Occasional diarrhea or abdominal cramping was noted in four of 14 octreotide-LAR-treated patients, especially during the first 2 wk after an injection. Saline-treated patients reported no similar symptoms. Only one patient reported a more significant adverse event (transient mild to moderate abdominal pain) after the first injection; the event was short lived, lasting only several hours, and did not recur with subsequent injections. Although biliary ultrasonography was not performed, no cholelithiasis was clinically identified in any patient during the trial.
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Discussion |
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The natural history of GO is one of gradual improvement over several months (22, 23); it is thus important that treatment studies include a well-matched placebo control group. Our CAS changes appear to be in agreement with other studies in which octreotide-treated patients improved significantly over a several-month period (10, 11, 12, 13, 14, 15, 24). However, some of those early studies are flawed due to the lack of a control group (10, 11, 13, 24). In those studies including a control group (12, 14, 15), only treated patients improved during the study period. In contrast, two recent trials found that both treated and untreated patients improved in CAS and did so to a similar extent, suggesting that LAR has no significant effect on disease activity (16, 17). Dickinson et al. used a CAS scoring system of 0–10, a soft tissue inflammation score derived from a comparative atlas of GO patients (20) and ophthalmopathy index to assess treatment effect (17). They found that LAR- and placebo-treated patients showed similar decreases in CAS and soft tissue inflammation over the initial 4 months of the study; the borderline significant improvement in ophthalmopathy index noted in the treatment group was not considered to represent a significant therapeutic effect. Similarly, Wemeau et al. (16) observed no treatment effect for their primary end point, a composite parameter involving changes in both class/grade of the severity index of NOSPECS (No signs or symptoms; Only signs, no symptoms; Signs only; Proptosis; Eye muscle involvement; Corneal involvement; Sight visual acuity reduction) and the CAS. A decrease in CAS of similar magnitude was observed in both the treatment and control groups over the 4-month study period. They additionally assessed several quantitative ocular parameters as secondary end points and noted a significant reduction in proptosis in the treatment group, as measured using the Hertel exophthalmometer. Similarly, Dickinson and colleagues measured a statistically significant, but not clinically beneficial, reduction in proptosis. Whereas our CT measurements of proptosis did not reveal a significant difference between the groups, there was a trend toward a treatment-related reduction in this parameter in each eye (P = 0.62 on the right; P = 0.09 on the left).
Differences between our results and those of Dickinson et al. (17) and Wemeau et al. (16) may relate to differences in the mode of treatment for hyperthyroidism or in doses of octreotide LAR used (20 mg, compared with 30 mg). The majority of the patients in our study had been treated for Graves’ hyperthyroidism with radioactive iodine, whereas only a minority (24%) had taken antithyroid drugs. The opposite was true in the study by Wemeau et al. (16) in which approximately 65% of patients received these medications. Because octreotide accumulates to only a small extent in iodine-ablated thyroid glands (25), it is possible that this allows a greater proportion of the administered octreotide LAR dose to access the intraorbital tissues.
Our study differed from the studies of Dickinson et al. (17) and Wemeau et al. (16) with regard to baseline CAS and the number of patients studied (i.e. a total of 29, compared with 50 and 51, respectively). In our study, the mean CAS of the treatment and control groups were 5.7 and 4.9, respectively, whereas in the Dickinson study, they were 5.4 and 5.8, respectively. Wemeau et al. (16) documented baseline CAS of 4.2 and 4.5, respectively. We used a CAS scale of 0–7 (18), whereas the other two studies used a scale of 0–10 (21). The additional three points on the 10-point scale refer to the measured stability of the disease over the previous 4-month period (changes in proptosis, decrease in visual acuity, and decrease in eye movements). Unfortunately, we were not able to collect this information at the time of study enrollment due to the referral nature of our practice. However, our patients clearly had a higher baseline CAS than those in the study by Wemeau et al. (16) and may have had more active disease than patients in the Dickinson study. Thus, it is possible that the beneficial effects that we found relate to our studying a population with particularly active disease. In addition, had our control group been larger than 11 patients, we may have seen a greater drop in CAS in this group.
Several well-defined quantitative parameters were used as secondary end points against which to assess the effects of octreotide LAR. We found one of these parameters, lid fissure width, to be positively impacted by octreotide LAR treatment. This parameter is one of five clinically relevant measures proposed to assess the efficacy of treatments for GO (19) and has been shown to be a significant predictor of ocular surface damage (26). In our study, it was significantly improved by therapy both when each eye was assessed independently and when a combined (right plus left) average measurement was used (P = 0.004). In addition, changes in MRD-1 closely tracked the improvement in eyelid fissures but did not reach statistical significance. These changes suggest that the measured improvement in eyelid fissure width might be primarily due to changes in upper eyelid position. Dickinson et al. (17) found a trend toward improvement in palpebral aperture in the octreotide LAR group after 4 months of treatment, whereas Wemeau et al. (16) found nonsignificant improvement (0.3 mm) in upper eyelid opening in the octreotide-LAR-treated group, with worsening (0.1 mm) in the control group.
A recent study of full-thickness eyelid transsection (blepharotomy) performed to improve lid retraction in patients with GO found a mean reduction in palpebral aperture of 3 mm (range 0–6 mm) after this procedure (27). Improvement in lid fissure width in our study in response to octreotide LAR therapy was of a similar magnitude (i.e. 28% of patients in the treatment group improved by at least 2 mm, overall range 1 to 5 mm), suggesting that the beneficial effect of treatment in our study was clinically relevant. In a post hoc analysis of our study patients, we found that no patient in the treatment group underwent a surgical eyelid procedure after the trial, whereas three patients in the placebo group had lid surgery to treat retraction. In contrast, no gross differences were noted regarding noneyelid ophthalmological interventions. Therefore, although patients did not perceive improvement in lid fissure appearance on PSAQ, it is possible that this medication could obviate the eventual need for eyelid surgery in some patients with active GO and significant lid retraction. However, further studies using lid fissure measurement as the primary outcome are needed to clarify this potential benefit. In addition, use of a more robust and regionally validated questionnaire, as are now available [Graves’ Ophthalmopathy Quality of Life Questionnaire (GOQOL)] or under development, might have revealed significant differences in response to therapy.
In conclusion, we found that CAS improved to a greater extent in octreotide-LAR-treated patients than patients receiving the placebo. However, this finding may not represent clinical benefit because patients with higher baseline CAS were overrepresented in the treatment group, and the control group was small. In contrast, we found a clinically significant improvement in eyelid fissure width in the treatment group, especially in patients having a width of 10 mm or greater. This finding suggests that the medication may be useful in the treatment of a small subgroup of active GO patients with significant lid retraction.
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Footnotes |
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First Published Online September 19, 2006
Abbreviations: CAS, Clinical activity score; CI, confidence interval; CT, computerized tomography; GO, Graves’ ophthalmopathy; HU, Hounsfield unit; LAR, long-acting release; MRD, margin reflex distance; OR, odds ratio; PSAQ, Patient Self-Assessment Questionnaire; TSI, thyroid stimulating immunoglobulin.
Received May 22, 2006.
Accepted September 7, 2006.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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secretion. J Immunol 149:3621–3626[Abstract]This article has been cited by other articles:
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  H. Stiebel-Kalish, E. Robenshtok, M. Hasanreisoglu, D. Ezrachi, I. Shimon, and L. Leibovici Treatment Modalities for Graves' Ophthalmopathy: Systematic Review and Metaanalysis J. Clin. Endocrinol. Metab., August 1, 2009; 94(8): 2708 - 2716. [Abstract] [Full Text] [PDF]
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 L. Bartalena, L. Baldeschi, A. Dickinson, A. Eckstein, P. Kendall-Taylor, C. Marcocci, M. Mourits, P. Perros, K. Boboridis, A. Boschi, et al. Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO Eur. J. Endocrinol., March 1, 2008; 158(3): 273 - 285. [Full Text] [PDF]
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