methimazole and Eye-Diseases

Topics: Eye Diseases; Graves Disease; Humans; Iodine Isotopes; Long-Acting Thyroid Stimulator; Methimazole; Propylthiouracil; Thyroid Function Tests; Thyroxine

It is commonly recognized that a few patients with Graves' disease (GD) develop an overt ophthalmopathy, although most of them show subclinical extraocular muscle enlargement by appropriate imaging techniques. At present, it is not possible to identify the subgroup of GD patients with subclinical retroorbital connective involvement. Recently, it has been shown that increase of soluble intercellular adhesion molecule-1 (sICAM-1) serum levels is correlated to clinical activity score in active Graves' ophthalmopathy (GO) patients with or without hyperthyroidism, suggesting that sICAM-1 serum values could reflect the degree of ocular inflammatory activity. The aim of this longitudinal study was to evaluate sICAM-1 serum levels in GD patients without clinical ophthalmopathy and to assess their possible relationship with occurrence of GO. We measured sICAM-1 serum levels in 103 initially hyperthyroid GD patients without clinical ophthalmopathy and in 100 healthy subjects. All patients were treated with methimazole for 2 yr. Sera were collected from all patients before treatment and then monthly for the first 6 months of therapy, every 2 months in the following 6 months, and finally at the end of the follow-up study. Patients developing GO were excluded from the follow-up at the onset of ophthalmopathy. During the follow-up 17 GD patients (16.5%, group 1) developed overt eye involvement (14 as active inflammatory ophthalmopathy and 3 as ophthalmopathy without clinical retroorbital connective inflammation) and 86 (83.5%, group 2) did not. At start of the study, the mean of sICAM-1 serum concentrations did not differ significantly between the 2 groups, but it was significantly higher than in controls in both groups. No significant correlation between serum sICAM-1 concentrations and free thyroid hormone levels was found in the 2 groups of patients. During the follow-up study, a further increase of sICAM-1 serum levels was observed in 12 of the 14 patients (85.7%) of group 1 who developed active inflammatory ophthalmopathy not only at the onset but also before clinical GO appearance. On the contrary, the 3 patients of group 1 that developed ophthalmopathy without clinical retroorbital inflammation did not show any further increase of sICAM-1 levels at every time of follow-up in comparison with the starting values, even if their sICAM-1 levels were always higher than in normal controls. Finally, group 2 patients showed significantly decreased sICAM-1 levels througho

Topics: Adult; Antithyroid Agents; Eye Diseases; Female; Follow-Up Studies; Graves Disease; Humans; Intercellular Adhesion Molecule-1; Male; Methimazole; Middle Aged; Solubility

Radioactive iodine-131 (RAI) has been reported to be associated with a high incidence of development or exacerbation of Graves' ophthalmopathy (GO). This is thought to be associated with a surge of autoantibodies after RAI therapy. The role of methimazole (MMI), which possesses immunomodulatory action, in the prevention of GO was explored by studying 114 patients with Graves' disease. They were assigned randomly to receive either RAI alone or adjunctive antithyroid drugs, which consisted of MMI and L-T4 as a block-replacement therapy for 12 months and were followed for 2 yr. Thirty-five patients (30.7%) had GO at presentation. Twenty-one (18%) patients developed new GO, and six had worsening of preexisting GO. The development of hypothyroidism (P < 0.01) and an elevation of TSH (P < 0.05) were associated with increased risk of development or exacerbation of GO. The chance of development or exacerbation of GO is higher in those with no ophthalmopathy than in those with preexisting GO at presentation (P = 0.002). The incidence of development or exacerbation of GO was similar in the two treatment groups (RAI, 22.8%; adjunctive antithyroid drugs, 23.7%; P = NS). MMI was able to suppress the surge of TSH receptor antibody (TRAB) after RAI, but a surge in TRAB was not of prognostic significance for the development of GO after RAI. Patients who developed or had exacerbation of GO actually had lower TRAB at presentation (P = 0.02). We conclude that hypothyroidism with elevated TSH is an important adverse factor for the development or exacerbation of GO, and MMI was unable to prevent the development or exacerbation of GO after RAI.

Topics: Adult; Aged; Autoantibodies; Eye Diseases; Female; Graves Disease; Humans; Hypothyroidism; Immunoglobulins, Thyroid-Stimulating; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Prognosis; Smoking; Thyrotropin; Thyroxine

We have carried out a prospective study to investigate whether orbital radiotherapy combined with high dose systemic glucocorticoids is more effective than orbital radiotherapy alone for Graves' ophthalmopathy. Thirty consecutive patients with relevant and active Graves' ophthalmopathy were randomly assigned to treatment either with orbital radiotherapy combined with systemic glucocorticoids (Group 1, n = 15) or with orbital radiotherapy alone (Group 2, n = 15). The final evaluation was made 6-9 months after beginning treatment. Two patients in each group were lost to follow-up. Ocular involvement and response to treatment were evaluated by the ophthalmopathy index and by clinical assessment. Mean ophthalmopathy index values were 5.85 in Group 1 and 5.46 in Group 2 (p = NS) before treatment, and 2.46 in Group 1 and 3.61 in Group 2 after treatment (p = 0.0001 and p = 0.003 vs initial value, respectively). The mean ophthalmopathy index decrease in Group 1 (-3.39) was significantly greater (p = 0.043) than that in Group 2 (-1.85). Favorable responses on clinical ground occurred in 9 patients (69%) in Group 1 and in 5 patients (38%) in Group 2. The difference was particularly evident on soft tissue changes and extraocular muscle involvement. Severe eye muscle restriction was substantially unaffected by either treatment. In conclusion, the association of orbital irradiation and high dose systemic glucocorticoids in the treatment of severe Graves' ophthalmopathy provides more favorable responses than orbital radiotherapy alone.

Topics: Adult; Combined Modality Therapy; Eye; Eye Diseases; Female; Glucocorticoids; Graves Disease; Humans; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Orbit; Prospective Studies; Radiography; Thyroxine

In the present study we have measured the concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1Ra) in the serum of patients with Graves' disease (GD). By multivariate analysis, we have evaluated the effect of antithyroid treatment, thyroid function, the presence or absence of active thyroid-associated ophthalmopathy (TAO), the patient's smoking habits and the relation to circulating anti-thyrotropin (TSH) receptor (TRAb) and anti-thyroperoxidase antibodies (TPOAb).. We studied 84 GD patients, 51 untreated and 33 receiving methimazole (MMI) therapy. Twenty-three (45%) untreated patients and 18 (54%) patients on MMI had active TAO. We also studied 67 normal subjects as controls. Thirty-one GD patients (43%) and 16 controls (36%) were smokers.. Serum IL-6 concentrations were significantly higher in both untreated patients (P<0.001) and treated patients (P<0.006), when compared with controls. Serum sIL-6R concentrations were significantly affected by treatment (P=0.001). Serum IL-1Ra concentrations were not different in GD patients, whether treated or untreated, compared with controls. Serum IL-6 concentrations were not influenced by thyroid function and there was a significant interaction between treatment and the presence of active TAO (P=0.003). In hyperthyroid patients with active TAO serum, sIL-6R concentrations were significantly higher than in those with inactive TAO (P=0.003). In untreated GD patients there was no significant effect of thyroid function and TAO activity on the serum concentrations of TNF-alpha and IL-1 beta. Serum IL-1Ra concentrations were not affected by the presence of TAO. Smoking had no effect on serum IL-6, sIL-6R, TNF-alpha, IL-1 beta and IL-1Ra concentrations, even in the presence of an active TAO. Serum concentrations of IL-6, sIL-6R, TNF-alpha and IL-1 beta and IL-1Ra were not different in patients with and without TRAb or TPOAb, in relation to either thyroid function, TAO activity or smoking.. Our work shows that: (i) the proinflammatory cytokine pattern in GD is greatly influenced by antithyroid drug treatment; (ii) the increased circulating IL-6/sIL-6R concentrations observed in patients with active TAO may derive from the activation of humoral reactions in sites other than the thyroid; and, (iii) cigarette smoking has no effect on serum IL-1/IL-1Ra concentrations in TAO.

Topics: Adolescent; Adult; Aged; Antithyroid Agents; Autoantibodies; Cytokines; Eye Diseases; Female; Graves Disease; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-6; Iodide Peroxidase; Male; Methimazole; Middle Aged; Receptors, Interleukin-1; Receptors, Interleukin-6; Receptors, Thyrotropin; Sialoglycoproteins; Smoking; Solubility; Thyroid Gland; Tumor Necrosis Factor-alpha

Visualization of malignant lymphomas and granulomatous disease is possible by [111In-DTPA-D-Phe1]octreotide scintigraphy through binding of the radioligand to somatostatin receptors on activated leukocytes. Because thyroidal and orbital tissues are infiltrated by activated leukocytes in Graves' disease, a cross-sectional study to visualize disease activity with [111In-DTPA-D-Phe1]octreotide scintigraphy was performed. A correlation between thyroidal [111In-DTPA-D-Phe1]octreotide accumulation and free T4 (disease expression) and thyroid binding-inhibiting immunoglobulins (disease activity) is present in untreated hyperthyroid Graves' disease. There is also a correlation between orbital [111In-DTPA-D-Phe1]octreotide uptake and the clinical activity score (disease activity) and total eye score (disease expression), respectively, in Graves' orbitopathy. Visualization of thyroidal and orbital Graves' disease is feasible, but further investigation is necessary to establish the role of [111In-DTPA-D-Phe1]octreotide scintigraphy in representing disease activity and expression and in predicting therapeutical outcome.

Topics: Eye; Eye Diseases; Graves Disease; Humans; Indium Radioisotopes; Methimazole; Octreotide; Pentetic Acid; Radionuclide Imaging; Thyroid Gland; Thyroxine

We analyzed the evolution of the ophthalmopathy associated with Graves' hyperthyroidism in 45 patients treated with two different antithyroid drug regimens. Group A patients (n = 31) received either methimazole (40-100 mg daily) or propylthiouracil (400-900 mg daily) combined with T3 daily throughout treatment. Group B patients (n = 14) were treated with conventional regimen with lower doses of either methimazole (5-25 mg daily) or propylthiouracil (50-300 mg daily) and no T3 addition. Eye signs and proptosis measurement were evaluated just before the beginning of the treatment and compared with the results after antithyroid drug withdrawal. Improvement of the eye signs considered on grounds of the NOSPECS classification was greater in group A than group B (p less than 0.01). Also, the decrease in proptosis measurement was greater (p less than 0.01) in patients treated with combined regimen (21.5 +/- 2.4 mm to 20.4 +/- 2.3 mm) than in patients receiving conventional therapy (20.4 +/- 1.6 mm to 20.0 +/- 1.7 mm). Serum thyroglobulin concentrations did not correlate with either the severity or the evolution of the ophthalmopathy. Negative serum antithyroglobulin antibody (TgAb) was associated with the improvement of the ophthalmopathy that was noted in 24 out of 27 patients (Chi-Square = 5.84; p less than 0.001). Thus, serum TgAb levels might have some connection with progression of eye signs but serum Tg concentration does not. Our study suggests that in most patients the transition from hyperthyroidism to euthyroidism induced by antithyroid drug therapy is associated with the improvement of the Graves' ophthalmopathy. However, no marked difference can be drawn between the two treatment regimens.

Topics: Adolescent; Adult; Autoantibodies; Drug Therapy, Combination; Eye Diseases; Female; Graves Disease; Humans; Male; Methimazole; Middle Aged; Propylthiouracil; Thyroglobulin; Triiodothyronine

Soluble interleukin-2 receptor was studied in 20 patients with Graves' disease before and after methimazole treatment. Soluble interleukin-2 receptor level was significantly increased in newly diagnosed Graves' disease compared to controls (667 +/- 270 vs 205 +/- 45 U/ml) (P less than 0.001). In untreated patients' sera the soluble interleukin-2 receptor levels were higher in patients with active ophthalmopathy than in those without eye symptoms. Soluble interleukin-2 receptor levels were normalized in remission induced by methimazole treatment in the majority of patients except those with infiltrative ophthalmopathy. Furthermore, a correlation was found at the hyperthyroid stage of the disease between soluble interleukin-2 receptor level and titre of anti-TSH-receptor antibodies. However, the association with other parameters including anti-eye muscle, anti-thyroid peroxidase, anti-thyroglobulin antibodies was not significant.

Topics: Adult; Antibodies; Eye Diseases; Female; Graves Disease; Humans; Male; Methimazole; Middle Aged; Receptors, Interleukin-2; Receptors, Thyrotropin; Remission Induction

Activation of T lymphocytes has been found to be associated with an increase in soluble interleukin-2 receptor (sIL-2R) levels. The aim of this study was to investigate serum levels of sIL-2R in 20 untreated patients with Graves' disease and to relate these levels to disease activity and to TSH-receptor, anti-thyroglobulin, anti-microsomal and anti-eye muscle antibodies. sIL-2R levels were significantly increased in newly diagnosed Graves' patients compared with controls (667 +/- 270 vs 205 +/- 45 U/ml) (P less than 0.001). The sIL-2R levels were higher in patients with active infiltrative ophthalmology than in those without eye symptoms (810 +/- 313 vs 525 +/- 180 U/ml). All patients were treated with methimazole for at least 12 months. sIL-2R levels were normalized by methimazole treatment in the majority of patients without ophthalmopathy but not in those with ophthalmopathy. In five patients sIL-2R serum levels were studied after interruption of thyrostatic therapy. An increase was observed in three patients and hyperthyroidism subsequently relapsed in two of these. Furthermore, a correlation was found between soluble interleukin-2 receptor levels and TSH-receptor antibodies but not with other immune parameters examined. Serum sIL-2R represents a useful marker of immunological activity in Graves' disease.

Topics: Autoantibodies; Eye Diseases; Female; Graves Disease; Humans; Male; Methimazole; Prednisolone; Receptors, Interleukin-2; Receptors, Thyrotropin; Thyrotoxicosis

This study was undertaken to determine the effect of methimazole on the pharmacokinetics of iv prednisolone in patients with Graves' disease. Twenty women were studied, including eight with severe infiltrative ophthalmopathy who had taken methimazole and T4 for at least 4 months, six with severe infiltrative ophthalmopathy who had undergone subtotal thyroidectomy and, therefore, required no antithyroid treatment, and six age-matched normal women. All were euthyroid. Each women received 0.54 mg/kg prednisolone as an iv bolus dose. Plasma total and unbound prednisolone concentrations were measured at multiple times during a 10-h study period by high pressure liquid chromatography and equilibrium dialysis. The clearance of both total and unbound prednisolone was increased significantly in the women receiving methimazole therapy compared to values in both control groups. The volume of distribution at steady state was similar in all groups. These results suggest that patients receiving methimazole have enhanced prednisolone metabolism and, therefore, they may require higher prednisolone doses.

Topics: Adult; Eye Diseases; Female; Graves Disease; Humans; Metabolic Clearance Rate; Methimazole; Middle Aged; Prednisolone

Two patients with hyperthyroidism and Graves' ophthalmopathy were treated with cyclosporin A (CyA), in addition to methimazole, after failure of steroid therapy. Eye disease showed favorable responses and TSH receptor antibody concentration showed precipitous decline in concentrations compared to a gradual linear decline in antibody concentrations observed in 10 patients not treated with CyA. These results prompted us to investigate the in vitro influence of CyA on the synthesis of TSH receptor antibody by a patient's lymphocytes (with highest antibody concentration) in response to thyroid membrane antigen. CyA caused a dose-dependent reduction of TSH receptor antibody synthesis compared to control cultures. The effect of CyA was more marked when added to lymphocyte culture at the same time rather than 24 h after addition of antigen, consistent with CyA's interference of early T cell triggering by antigen. This study emphasizes the importance of helper T cells in synthesis of TSH-receptor antibody by cells and suggests that the drug may be therapeutically beneficial in severe Graves' ophthalmopathy and/or Graves' hyperthyroidism resistant to conventional treatment.

Topics: Adult; Antibody Formation; Cyclosporins; Eye Diseases; Female; Graves Disease; Humans; Methimazole; Middle Aged; Receptors, Thyrotropin; Time Factors

In a patient with active Graves' disease an infiltrative ophthalmopathy developed during antithyroid drug therapy. Her eye symptoms were effectively treated with a large dose of prednisolone (PD), plasma exchanges (PE), cyclophosphamide, orbital irradiation, antithyroid drug and a supplemental dose of triiodothyronine. Before, during and after these treatments thyrotropin binding inhibitor immunoglobulin (TBII) activities in a unit serum immunoglobulin (IgG) were measured after adjusting the IgG concentration by adding normal IgG. Relative TBII concentrations were calculated by extrapolating individual data on a standard curve constructed from serial dilutions of the most potent IgG. Approximately a 5 fold increase in the TBII concentration was observed during the 2 months of progression of the ophthalmopathy, while TBII activity revealed only a 13.3% increase. After treatment TBII concentrations decreased gradually showing a close relation with the severity of the eye symptoms. Every PE was found to remove 48.5 +/- 7.9 (s.e.m.) % of TBII. After PE TBII returned to the preexchange level very rapidly and then overshot it in 2 to 3 weeks. Sixty mg of PD failed to prevent the overshoot but a 100 mg initial dose of PD after 5 PEs inhibited it to some extent. The effectiveness of combined therapy with PE, PD and cyclophosphamide appeared to confirm a role of humoral factors in the pathogenesis of Graves' ophthalmopathy. Serial determinations of TBII in a relative concentration were considered quite useful in analyzing the effectiveness of treatment in Graves' ophthalmopathy.

Topics: Eye Diseases; Female; Graves Disease; Humans; Immunoglobulin G; Immunoglobulins, Thyroid-Stimulating; Methimazole; Middle Aged; Plasmapheresis; Propylthiouracil; Radiography; Skull

Topics: Adult; Blepharoptosis; Dexamethasone; Diagnosis, Differential; Eye Diseases; Female; Functional Laterality; Graves Disease; Humans; Iodine Radioisotopes; Methimazole; Orbit; Prednisone; Thyroiditis, Autoimmune; Thyroxine; Triamcinolone