Anti-muscle antibodies in Graves' ophthalmopathy

The nature of the humoral immune response in patients with Graves' ophthalmopathy has been investigated using a solid phase 125I Protein A binding assay. Retro-orbital muscle (R.O.M.), skeletal muscle (Sk.M.), R.O.M.-membranes, thyroid, kidney, liver, harderian gland, acetylcholine receptors (AchR), actin and myosin were used as target antigens. No significant difference in antibody binding profile to R.O.M. and Sk.M. was found indicating that the ophthalmic immunoglobulins (OIgs) were not recognising a R.O.M. specific antigen(s). Comparison between R.O.M. and R.O.M.-membranes, however, revealed that these antigens were detecting very different antibody populations. Using the former, it appeared that the predominant antibody population being measured was anti-myosin whereas the latter appeared to be detecting primarily anti-AchR antibodies. Anti-actin antibodies were also present in some of the sera. Thus a spectrum of anti-R.O.M. antibodies appears to be present in Graves' ophthalmopathy but the cross-reactivity of these with non-R.O.M. skeletal muscle and their similarity to those found in myasthenia gravis prevent them as yet being used to explain the specific immunopathology observed in this disease.     

Ophthalmic surgery on Graves' ophthalmopathy

We evaluated various ophthalmic surgeries for patients with Graves' ophthalmopathy. In 2005, surgical procedures were employed on 178 patients with Graves' ophthalmopathy (male 69, female 109). Eyelid surgery was indicated for treatment of various anterior eye changes. Eyelid surgery was employed on 121 eyes of 84 cases. Extraocular muscle surgery was performed on 138 eyes of 105 cases, simple type 86 cases and complex type 19 cases. The cicatrical adhesion to the surface of the affected muscle was always observed. Orbital decompression was performed on 57 eyes of 33 cases. Better results and few complications were considered attributable to the stabilization of orbitopathy before surgery.     

Radiation therapy for Graves' ophthalmopathy

External irradiation for thyroid eye disease has been employed for more than three decades. Destruction of infiltrating lymphocytes in the retroorbital tissue may account for its beneficial effects. Using high voltage X-ray generated from linear accelerator, usually a total dose of 20 Gy is delivered to both orbits in 2 Gy daily fractions. This therapy is devoid of grave side effects and can be done on outpatient bases, alone or in combination with glucocorticoid regimen. Its reported effectiveness lies between 50-70%. However, results of recent randomized controlled trials on its effects were controversial. As monotherapy, while in some studies the authors observed improvement in eye movement and/or diplopia, in another one there was no significant difference in changes of objective indices between irradiated and sham-irradiated eyes. Moreover, another controlled trial on combined therapy has failed to detect additional benefit of orbital radiation on high-dose intravenous steroid pulse treatment. To ascertain its true effectiveness and indication, multicenter trials with large number of subjects seems necessary.     

Steroid therapy for Graves' ophthalmopathy

Glucocorticoids are usually given for management of Graves' ophthalmopathy (GO) for their anti-inflammatory and immunosuppressive effects. The overall rate of favorable response for moderately severe and active GO is 77% in patients treated with methylprednisolone iv pulse therapy. When radioiodine therapy is indicated for hyperthyroidism in Graves' patients with high risk factors, the use of glucocorticoid with small doses and short periods is recommended to prevent the development or progression of GO. Cushingoid features, glucose intolerance, gastritis, hypertension, hepatitis, and depression are major adverse effects of glucocorticoids. Fatal liver failure after high dose of pulse therapy (9-12g) was observed in 0.8%. Limiting the cumulative dose to 4.5-6g, assessment of liver virus markers and monitoring liver function before, during and after i.v. treatment are warranted.     

Graves' disease (clinical aspects of Graves' disease)]

Graves' disease (GD) is an autoimmune thyroid disease. In addition to the etiology of hyperthyroidism, TSH receptor antibodies play an important role in the pathogenesis of pretibial myxedema, ophthalmopathy, and neonatal GD. The previous epidemiological surveys have revealed that 0.08-0.6% of the population were affected by GD in Japan. Clinical signs and symptoms as well as laboratory abnormalities are described with emphasis on elevated serum VEGF and G-CSF levels in untreated GD patients. It should be noted that elderly patients may not have typical symptoms of hyperthyroidism, but cardiac symptoms and weight loss usually predominate. Abnormal laboratory findings may help to make a diagnosis in asymptomatic patients. Patients with ophthalmopathy may have antibodies to 64 kD/55 kD external orbital muscle proteins.     

Childhood Graves' disease

Because of the low frequency of childhood Graves' disease, detailed evidence-based clinical studies have not been reported. Practical clinical work has been performed on the basis of adult clinical references. Therapeutic management includes antithyroid drugs, surgical thyroidectomy and radiologic therapy. Recently in the U.S.A. radiotherapy has become the recommended course of action, even for childhood Graves' disease, whereas in Japan, antithyroid drug therapy is the primary course of action for childhood Graves' disease. In some cases, thyroidectomy is performed following drug therapy. Methimazole (MMI) and propylthiouracil (PTU) have been used, however, MMI is the preferred drug treatment. Compared to PTU, MMI is administered once a day and the frequency of side effects is lower than that of PTU. Evaluation of the TSH receptor antibody value before administration of antithyroid drugs is very useful in estimating the duration of the treatment. No appropriate index has been established guiding when to quit antithyroid drug therapy.     

Oxidative stress peripheral parameters in Graves' disease: the effect of methimazole treatment in patients with and without infiltrative ophthalmopathy

OBJECTIVES: The study was designed to estimate the influence of hyperthyroidism and antithyroid treatment on oxidative stress peripheral parameters in Graves' disease patients with and without infiltrative ophthalmopathy. DESIGN AND METHODS: Free radical generation and scavenging plasma indices were determined in 47 patients with hyperthyroidism due to Graves' disease (22 with and 25 without infiltrative ophthalmopathy), as well as in 24 healthy volunteers after euthyroidism achievement with methimazole. RESULTS: In the hyperthyroid patients, hydrogen peroxide, lipid hydroperoxides, thiobarbituric acid-reacting substances, ceruloplasmin, superoxide dismutase, and catalase were increased. Glutathione peroxidase and glutathione reductase, however, were reduced. Methimazole treatment resulted in all markers being normalized in the patients without infiltrative ophthalmopathy, yet oxidative stress was still present in the ophthalmopathy group. CONCLUSION: We suggest that apart from the thyroid metabolic status influence, it is orbital inflammation that triggers changes in blood extracellular indices of reactive oxygen species metabolism.     

Autoimmunity and Graves' disease

Current treatment options for Graves' hyperthyroidism and the related ophthalmopathy (GO) are not uniformly effective and carry with them potentially serious side effects. As a result, efforts have been focused on the development of novel therapies. Progress has been made, particularly in the production of thyroid-stimulating hormone receptor (TSHR) antagonists, as either monoclonal blocking antibodies or small-molecule ligands. In addition, rituximab (RTX) is the first targeted biological therapy to be studied as treatment for these conditions.     

Graves' ophthalmopathy: comparison of the Doppler sonography parameters with the clinical activity score

PURPOSE: Our aim was to compare the Doppler ultrasonography (US) parameters with clinical activity score (CAS) in patients with Graves' ophthalmopathy. METHODS: Blood flow parameters in the ophthalmic artery (OA), superior ophthalmic vein (SOV), central retinal artery (CRA) and central retinal vein (CRV) were measured by Doppler US in 118 patients with Graves' disease in 3 groups (A, B, and C) and 20 control subjects. Group A included 25 patients with CAS value "0"; group B 55 patients with CAS value "1 or 2"; group C 38 patients with CAS value "3 or above." RESULTS: Peak systolic velocities (PSV) and end-diastolic velocities (EDV) in the OA, PSV, and in the CRA calculated for group C were significantly higher than for group A, group B, and the control group. Resistance index in the OA and maximal velocity (MV) in the SOV calculated for group C were significantly lower than those calculated for group A, group B, and the control group. CONCLUSION: Doppler parameters of MV in SOV, PSV and EDV in OA, and PSV in CRA seem to be helpful in the differentiation of active and inactive phases of Graves' ophthalmopathy.     

Extrathyroidal complications of Graves' disease

Ophthalmopathy, pretibial myxoedema and acropachy are progressivelyless common features of Graves' disease with unknown but probablyrelated aetiologies (Table 1). Treatment for affected eyes andskin is unsatisfactory and will only improve when we understandthe pathogenesis of these complications and their arcane relationshipwith thyroid autoimmunity. This brief review will highlightrecent research which suggests that fibroblast activation iscritical to the appearance of ophthalmopathy and dermopathy;more general overviews can be found elsewhere.^1,2