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.
K Ohtsuka, M Hashimoto
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.
M P Mourits, M F Prummel, W M Wiersinga, L Koornneef
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.
Peter Vestergaard
Smoking and thyroid disorders--a meta-analysis.
Eur J Endocrinol. 2002 Feb;146(2):153-61.
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.
Luigi Bartalena, Lelio Baldeschi, Kostas Boboridis, Anja Eckstein, George J Kahaly, Claudio Marcocci, Petros Perros, Mario Salvi, Wilmar M Wiersinga, 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.
Kenji Ohtsuka, Akihiko Sato, Satoshi Kawaguchi, Masato Hashimoto, Yasuo Suzuki
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.
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.
Luigi Bartalena, Lelio Baldeschi, Alison Dickinson, Anja Eckstein, Pat Kendall-Taylor, Claudio Marcocci, Maarten Mourits, Petros Perros, Kostas Boboridis, Antonella Boschi, Nicola Currò, Chantal Daumerie, George J Kahaly, Gerasimos E Krassas, Carol M Lane, John H Lazarus, Michele Marinò, Marco Nardi, Christopher Neoh, Jacques Orgiazzi, Simon Pearce, Aldo Pinchera, Susanne Pitz, Mario Salvi, Paolo Sivelli, Matthias Stahl, Georg von Arx, Wilmar M Wiersinga, 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
Ai Kozaki, Hiroshi Nakamura, Toshu Inoue
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.
Terry J Smith, George J Kahaly, Daniel G Ezra, James C Fleming, Roger A Dailey, Rosa A Tang, Gerald J Harris, Alessandro Antonelli, Mario Salvi, Robert A Goldberg, James W Gigantelli, Steven M Couch, Erin M Shriver, Brent R Hayek, Eric M Hink, Richard M Woodward, Kathleen Gabriel, Guido Magni, Raymond S Douglas
Teprotumumab for Thyroid-Associated Ophthalmopathy.
N Engl J Med. 2017 May 4;376(18):1748-1761. doi: 10.1056/NEJMoa1614949.
Abstract/Text
BACKGROUND: Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy.
METHODS: We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves' ophthalmopathy-specific quality-of-life questionnaire. Adverse events were assessed.
RESULTS: In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes.
CONCLUSIONS: In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997 .).
