長内一,大塚賢二,中村靖,橋本雅人ら：甲状腺眼症242例における臨床的血液学的検討. あたらしい眼科 15:1043-1047, 1998.
Ohtsuka K, Hashimoto M.
H-magnetic resonance spectroscopy of retrobulbar tissue in Graves ophthalmopathy.
Am J Ophthalmol. 1999 Dec;128(6):715-9. doi: 10.1016/s0002-9394(99)00229-9.
Abstract/Text
PURPOSE: Accumulation of glycosaminoglycans in the orbit may play an important role in the development of Graves ophthalmopathy. Therefore, it might be clinically useful to evaluate the concentration of glycosaminoglycans in the orbit in patients with Graves disease. We investigated the concentration of glycosaminoglycans in retrobulbar tissue using in vivo 1H-magnetic resonance spectroscopy.
METHODS: A model solution of 1% chondroitin sulfate (one of the components of the glycosaminoglycans complex) was initially examined using 1H-magnetic resonance spectroscopy, and the resonance of chondroitin sulfate was identified. 1H-magnetic resonance-spectroscopy spectra of retrobulbar tissue were obtained in 16 normal volunteers (28 eyes) and 23 patients with Graves ophthalmopathy (36 eyes). The 1H-magnetic resonance spectroscopy spectrum of chondroitin sulphate in the retrobulbar in vivo tissue was identified by assignments through lineshape comparisons of spectra of the model solutions in vitro and the retrobulbar tissue in vivo. Chondroitin sulphate-peak/H2O-peak ratios were calculated. To verify the results of in vivo 1H-magnetic resonance spectroscopy, retrobulbar tissue samples from five patients, who underwent orbital decompression surgery, were tested for reactivity to chondroitin sulfate proteoglycan by enzyme-linked immunosorbent assay (ELISA).
RESULTS: Multiple peaks, with a large peak at 5.24 ppm, were observed in 1H-magnetic resonance spectroscopy spectra of the model solution. A peak at 5.24 ppm was also observed in spectra of the retrobulbar tissue in all of the normal subjects and the patients. The mean value of the 5.24 ppm-peak/H2O-peak ratio was 0.1781 (SD = 0.0498, range, 0.0775 to 0.2282) in the normal subjects and 0.2874 (SD = 0.1357, range, 0.1405 to 0.7377) in the patients. The 5.24 ppm-peak/H2O-peak ratios were significantly increased in the patients with Graves ophthalmopathy (P < .01). The 5.24 ppm-peak/ H2O-peak ratio was correlated with the chondroitin sulphate concentration in retrobulbar tissue samples as evaluated by ELISA (r = .69).
CONCLUSIONS: This study suggests that 1H-magnetic resonance spectroscopy of the retrobulbar tissue allows us to estimate the concentration of chondroitin sulphate proteoglycan in the retrobulbar tissue. 1H-magnetic resonance spectroscopy of the retrobulbar tissue may be a new clinical tool for the evaluation of Graves ophthalmopathy.
三浦道子,大塚賢二,橋本雅人ら：CTを用いたバセドウ病患者での外眼筋計測. 臨床眼科 50巻1号 (1996年1月)、50:35-39,1996.
Mourits MP, Prummel MF, Wiersinga WM, Koornneef L.
Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy.
Clin Endocrinol (Oxf). 1997 Jul;47(1):9-14. doi: 10.1046/j.1365-2265.1997.2331047.x.
Abstract/Text
OBJECTIVE: Approximately 35% of patients with Graves' ophthalmopathy do not respond to immunosuppressive treatment. A possible explanation for this finding is that only patients with active ophthalmopathy respond to immunosuppressive treatment, whereas patients with fibrotic end stage disease do not. To distinguish between these two groups and to predict the outcome of immunosuppressive treatment, we developed a clinical activity score (CAS) based on four of the five classical signs of inflammation and tested its efficacy in a double-blind, prospective study.
DESIGN, PATIENTS AND MEASUREMENTS: The CAS was determined by an opthalmologist before, on the day of, and after the start of either oral prednisone or retrobulbar irradiation in 43 patients with moderate to severe Graves' ophthalmopathy. The therapeutic outcome was determined by a second ophthalmologist unaware of the CAS stores given. Success of treatment was defined as an improvement in NOSPECS class or grade.
RESULTS: Responders (22) and non-responders (21) did not differ in age, sex, duration or severity of their Graves' ophthalmopathy. The pretreatment CAS, however, was significantly higher in responders than in non-responders. Twelve of 22 responders and three of 21 non-responders had a CAS > or = 4 (55% vs 14%; P < 0.01) [corrected]. Using this CAS cut-off point, the accuracy of CAS in predicting the therapeutic outcome was: specificity 86%, sensitivity 55%, positive predictive value 80%, negative predictive value 64%. Patients with a CAS > or = 4 had a similar duration of Graves' ophthalmopathy as patients with a CAS < 4.
CONCLUSIONS: The clinical activity score has a high predictive value for the outcome of immunosuppressive treatment in Graves' ophthalmopathy. Disease activity, and not disease duration, is the prime determinant of therapeutic outcome.
Vestergaard P.
Smoking and thyroid disorders--a meta-analysis.
Eur J Endocrinol. 2002 Feb;146(2):153-61. doi: 10.1530/eje.0.1460153.
Abstract/Text
BACKGROUND: Smoking has been associated with Graves' disease, but it remains unclear if the association is present in other thyroid disorders.
OUTCOME VARIABLES: Graves' disease, Graves' ophthalmopathy, toxic nodular goitre, non-toxic goitre, post-partum thyroid disease, Hashimoto's thyroiditis, or hypothyroidism.
MATERIAL AND METHODS: A search of MEDLINE identified 25 studies on the association between smoking and thyroid diseases.
RESULTS: In Graves' disease eight studies were available showing an odds ratio (OR) of 3.30 (95% confidence interval (CI): 2.09-5.22) in current smokers compared with never smokers. In ex-smokers there was no significant excess risk of Graves' disease (OR=1.41, 95% CI: 0.77-2.58). The OR associated with ever smoking in Graves' ophthalmopathy (4.40, 95% CI: 2.88-6.73, six studies) was significantly higher than in Graves' disease (1.90, 95% CI: 1.42-2.55, two-sided P-value <0.01). Ever smoking was not associated with toxic nodular goitre (OR=1.27, 95% CI: 0.69-2.33, three studies), while there was an increased risk of non-toxic goitre in smokers if men were excluded (OR=1.29, 95% CI: 1.01-1.65, eight studies). The risk associated with smoking was significantly lower in men than in women for both Graves' disease and non-toxic goitre. Hashimoto's thyroiditis and post-partum thyroid dysfunction were also associated with smoking while the association with hypothyroidism did not reach statistical significance.
CONCLUSIONS: Cessation of smoking seems associated with a lower risk of Graves' disease than current smoking. Smoking increases the risk of Graves' ophthalmopathy beyond the risk associated with Graves' disease alone. Smoking cessation may lead to a decrease in morbidity from Graves' disease, especially in women.
Douglas RS, Kahaly GJ, Patel A, Sile S, Thompson EHZ, Perdok R, Fleming JC, Fowler BT, Marcocci C, Marinò M, Antonelli A, Dailey R, Harris GJ, Eckstein A, Schiffman J, Tang R, Nelson C, Salvi M, Wester S, Sherman JW, Vescio T, Holt RJ, Smith TJ.
Teprotumumab for the Treatment of Active Thyroid Eye Disease.
N Engl J Med. 2020 Jan 23;382(4):341-352. doi: 10.1056/NEJMoa1910434.
Abstract/Text
BACKGROUND: Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease.
METHODS: In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful).
RESULTS: A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation.
CONCLUSIONS: Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).
Copyright © 2020 Massachusetts Medical Society.
Ugradar S, Kang J, Kossler AL, Zimmerman E, Braun J, Harrison AR, Bose S, Cockerham K, Douglas RS.
Teprotumumab for the treatment of chronic thyroid eye disease.
Eye (Lond). 2022 Aug;36(8):1553-1559. doi: 10.1038/s41433-021-01593-z. Epub 2021 Jul 9.
Abstract/Text
BACKGROUND: Teprotumumab, a novel IGF-1R antibody was recently shown to significantly reduce the signs of active Thyroid eye disease (TED). The current study reviews its efficacy in chronic TED.
METHODS: In this retrospective review, consecutive patients with chronic stable TED (>2 years), who had received ≥3 infusions of teprotumumab were included. All patients had measurements of proptosis, and calculation of the CAS and diplopia scores before and after therapy. Five-point strabismus scores were also calculated. Patients who had imaging within 4 months prior to therapy and 6 weeks post therapy underwent orbital 3D volumetric analysis.
RESULTS: Thirty-one patients met the inclusion criteria. The mean (SD) duration of TED was 81 months (56) and the mean (SD) number of infusions received by each patient was 7 (2). Mean (SD) reduction in proptosis for each study orbit was 3.5 mm (0.4) and 3 mm (0.3) for the fellow orbit. The CAS response was 90% for the study orbit and 87% for the fellow orbit. Of the 15 patients who had diplopia at baseline, 67% had a clinically significant response, while 47% had complete resolution following treatment. Following teprotumumab, mean (SD) reduction of muscle tissue was 2011 mm3 (1847) in the study orbit and 1620 mm3 (1759) in the fellow orbit. The mean (SD) reduction of fat volume was 2101 mm3 (1681) in the study orbit and 1370 mm3 (1181) in the fellow orbit.
CONCLUSION: Teprotumumab significantly reduces proptosis, inflammation, diplopia, strabismus and orbital soft tissue volume in patients with chronic TED.
© 2021. The Author(s).
Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, Perros P, Salvi M, Wiersinga WM; European Group on Graves' Orbitopathy (EUGOGO).
The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy.
Eur Thyroid J. 2016 Mar;5(1):9-26. doi: 10.1159/000443828. Epub 2016 Mar 2.
Abstract/Text
Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease, though severe forms are rare. Management of GO is often suboptimal, largely because available treatments do not target pathogenic mechanisms of the disease. Treatment should rely on a thorough assessment of the activity and severity of GO and its impact on the patient's quality of life. Local measures (artificial tears, ointments and dark glasses) and control of risk factors for progression (smoking and thyroid dysfunction) are recommended for all patients. In mild GO, a watchful strategy is usually sufficient, but a 6-month course of selenium supplementation is effective in improving mild manifestations and preventing progression to more severe forms. High-dose glucocorticoids (GCs), preferably via the intravenous route, are the first line of treatment for moderate-to-severe and active GO. The optimal cumulative dose appears to be 4.5-5 g of methylprednisolone, but higher doses (up to 8 g) can be used for more severe forms. Shared decision-making is recommended for selecting second-line treatments, including a second course of intravenous GCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab or watchful waiting. Rehabilitative treatment (orbital decompression surgery, squint surgery or eyelid surgery) is needed in the majority of patients when GO has been conservatively managed and inactivated by immunosuppressive treatment.
Ohtsuka K, Sato A, Kawaguchi S, Hashimoto M, Suzuki Y.
Effect of high-dose intravenous steroid pulse therapy followed by 3-month oral steroid therapy for Graves' ophthalmopathy.
Jpn J Ophthalmol. 2002 Sep-Oct;46(5):563-7. doi: 10.1016/s0021-5155(02)00544-0.
Abstract/Text
PURPOSE: To evaluate the effect of high-dose intravenous steroid pulse therapy followed by 3-month oral steroid therapy for Graves' ophthalmopathy.
METHODS: We selected 41 Japanese patients (age range, 21-76 years; mean = 49 years) who had active Graves' ophthalmopathy among 205 consecutive patients examined at Sapporo Medical University Hospital between 1997 and 1999. In a prospective study, we investigated the effect on the 41 patients of high-dose intravenous methylprednisolone pulse therapy (1 g/day x 3 days x 3 times) followed by 3-month oral prednisone therapy. Coronal computed tomography (CT) of the orbit, exophthalmometry and monocular fixation field measured by Goldmann perimetry were carried out before the steroid pulse therapy, and 1 and 6 months after the steroid pulse therapy. The maximum coronal section area of the rectus muscle in each eye was measured using an orbital CT image.
RESULTS: Extraocular muscle hypertrophy was significantly reduced 1 and 6 months after the pulse therapy (paired t-test, P <.01), and was not significantly different between 1 and 6 months after the pulse therapy. Proptosis was not significantly reduced by the pulse therapy. Monocular fixation fields were measured in 34 patients with diplopia, and limitation of eye movements was improved in 15 patients (44%) by the pulse therapy. In the other patients, improvement of the limitation was not detectable by the test of the monocular fixation field.
CONCLUSIONS: The treatment in this study is effective for extraocular muscle hypertrophy, and relapse was minimum within 6 months. However, this treatment has limited effect on limitation of eye movements and less effect on proptosis.
Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM; European Group on Graves' Orbitopathy (EUGOGO).
Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO.
Eur J Endocrinol. 2008 Mar;158(3):273-85. doi: 10.1530/EJE-07-0666.
Abstract/Text
Kozaki A, Nakamura H, Inoue T.
Clinical efficacy of transcutaneous triamcinolone acetonide injection for upper eyelid retraction and swelling in patients with thyroid eye disease.
Int Med Case Rep J. 2018;11:325-331. doi: 10.2147/IMCRJ.S177671. Epub 2018 Nov 9.
Abstract/Text
AIM: To evaluate the efficacy of transcutaneous triamcinolone acetonide (TA) injection for the treatment of upper eyelid retraction and swelling in thyroid eye disease (TED) patients.
PATIENTS AND METHODS: This is a case series. Three euthyroid TED patients with features of both upper eyelid retraction and swelling were recruited. TED signs appeared within 6 months prior to treatment. Next, 0.5 mL of TA (40 mg/mL) was transcutaneously injected targeting the orbital fat around the levator palpebrae superioris (LPS) muscle. At each visit, eyelid retraction was evaluated by palpebral fissure height and the presence of scleral show above the superior corneoscleral limbus. Eyelid swelling was judged by the appearance of upper eyelid bulging and the lack of an eyelid sulcus. In addition, the LPS muscle, orbital and retro-orbicularis oculi fat were observed using MRI before and after treatment.
RESULTS: Two patients had resolution of their upper lid retraction and swelling within 12 months. In the other patient who had proptosis, eyelid retraction resolved, while eyelid swelling remained mild. In all cases, MRI revealed that treatment resulted in thinner LPS muscle and reduced fat swelling. In addition, both high-intensity signals on T2 images and prolonged T2 relaxation time were normalized. No adverse signs were observed.
CONCLUSION: Transcutaneous TA injection was effective as a treatment for upper eyelid retraction and swelling in euthyroid TED patients who had signs within 6 months prior to treatment. Transcutaneous TA injection induced reduction of LPS muscle enlargement and fat tissue swelling. These reductions by transcutaneous TA injection were verified using MRI.
