Severity Of Ophthalmopathy Research Articles

English

BACKGROUND Thyroid eye disease is a relatively rare condition, with an incidence of 2.9 to 16.0 cases per 100 000 population per year. Approximately 50 % of patients with Graves’ disease (GD) develop clinically apparent thyroid eye disease. It may cause severe damage to vision and orbital architecture. It is the most frequent cause of unilateral or bilateral proptosis in adults. METHODS A cross sectional study of 80 patients with GD was carried out in association with thyroid clinic of Government Medical college Thiruvananthapuram for a period of 1 year from April 2017 to March 2018. Subjects who have a prior diagnosis of Graves’ disease including those who are on antithyroid drugs were included in the study. Patients who are sick due to other systemic diseases like cardiac failure and end stage renal disease were excluded. RESULTS Eighty patients with mean age of 45.31 years were studied. Out of them, 66% were females and 34% were males. Ophthalmopathy was present in 38.8%.Majority had mild and bilateral disease (61.2 %). Only a small percentage had sight threatening disease (6.4 %).The mean age of patients with ophthalmopathy was 47.93. Major population with ophthalmopathy was females. Majority of patients with ophthalmopathy (64.5 %) retained a good visual acuity better than 6 / 9. Lid retraction was the most common manifestation among patients with Graves’ ophthalmopathy that is 74.2% followed by exophthalmos (64.5 %) and eye movement restriction and soft tissue involvement (58.1 %). Diplopia, optic nerve dysfunction were rare (3.2 %). Only 19.3 % patients had active disease according to clinical activity score. Major clinical sign of activity was redness of conjunctiva. Maximum no. of patients with active disease had a clinical activity score of 4. Smoking showed a significant association with the severity of ophthalmopathy. (p value 0.001) There was a significant association between age and activity of disease. (p value 0.021). No association was found between duration of disease with presence or severity of ophthalmopathy. There was no association between co- morbidities with presence or severity of ophthalmopathy. No association was found between hormone status and presence or severity of ophthalmopathy. CONCLUSIONS Our results indicated that the prevalence of ophthalmopathy in our population with GD evaluated at our tertiary care centre was similar to that reported in the Caucasians of European origin. Clinically active and sight threatening ophthalmopathy was uncommon. KEYWORDS Graves’ Disease, Ophthalmopathy

Efficacy and safety of radioiodine therapy for mild Graves ophthalmopathy depending on cigarette consumption: a 6‑month follow‑up.

INTRODUCTION Graves ophthalmopathy (GO) is an autoimmune disease associated with Graves disease. Its treatment is largely dependent on the severity and activity of ocular lesions. Particular attention should be given to radioiodine (RAI) therapy. Although its use is a valuable therapeutic option for hyperthyroidism, it may be followed by worsening of GO. OBJECTIVES The aim of the present study was to analyze how the severity of nicotine addiction affects the response to RAI treatment in patients with GO. PATIENTS AND METHODS A total of 106 patients (58 smokers and 48 nonsmokers) with mild GO treated with 800 MBq of RAI were included to the study. We assessed the serum levels of thyroid‑stimulating hormone (TSH), thyroid hormones, autoantibodies against thyroperoxidase, thyroglobulin, and TSH receptor (TSHR‑Abs), as well as urinary cotinine levels and severity of ophthalmopathy. Analyses were conducted at baseline (before RAI treatment) and 2 and 6 months after the therapy. RESULTS Significant differences in serum levels of TSHR‑Abs were found between nonsmokers and smokers at 2 and 6 months after RAI therapy, whereas there were no differences at baseline. In smokers, there were significant differences in the severity of ophthalmopathy and the concentration of serum TSHR‑Abs assessed at baseline and at 6 months of follow‑up. Six months after RAI therapy, 46.2% of smokers and 4.3% of nonsmokers (P <0.001) progressed from mild to moderate GO. CONCLUSIONS High urinary cotinine levels in smokers were associated with the deterioration of ocular lesions after RAI treatment. A high dose of RAI did not induce an exacerbation of GO in nonsmokers who were administered oral steroid prophylaxis.

Soluble CTLA-4 receptor an immunological marker of Graves' disease and severity of ophthalmopathy is associated with CTLA-4 Jo31 and CT60 gene polymorphisms

Graves' disease (GD) is an autoimmune disorder with genetic and environmental background. CTLA-4 is a candidate gene for thyroid autoimmunity. Increased serum levels of soluble CTLA-4 (sCTLA-4) were found in some autoimmune diseases. The aim of the study was to evaluate the relation between sCTLA-4 level and clinical manifestation of Graves' ophthalmopathy (GO), thyroid status, and CTLA-4 gene polymorphisms. Serum sCTLA-4 concentrations were determined in 93 GO patients and 93 healthy controls. In the GO group, CTLA-4 gene was genotyped in five polymorphic sites: g.319C>T, c.49A>G, CT60 by means of PRC-RFLP, Jo31, and g.*642AT(8_33) by means of minisequencing assay. Serum sCTLA-4 level was significantly higher in the GO group than in controls (median: 7.94 vs 0.00 ng/ml, P=0.000001). This level was higher in severe than in nonsevere GO (median: 10.3 vs 5.6 ng/ml, P=0.01). sCTLA-4 concentration was related neither to the activity of GO nor to thyroid function. Elevated sCTLA-4 levels were observed in carriers Jo31[G] allele (genotype GG+GT) as compared with subjects with an absence of the [G] allele (TT genotype; median: 9.18 vs 4.0 ng/ml, P=0.02). Also patients possessing CT60[G] allele (genotype GG+GA) had higher serum sCTLA-4 levels than subjects who lack the [G] allele (AA genotype; median: 8.73 vs 2.28 ng/ml, P=0.03). It was shown for the first time that increased serum concentration of sCTLA-4 correlate with the severity of GO. Genetic variation in the CTLA-4 gene region in GD patients at least partially determines the level of sCTLA-4.

Age Influences the Severity of Graves' Ophthalmopathy

This study compared the ocular manifestations of Graves' disease in different age groups and between genders. This was a retrospective study with a chart review of 210 patients seen in the Kaohsiung Veterans General Hospital Ophthalmology Department from 1990 to 2006. Clinical manifestations were recorded, scored, and compared between different age groups and between genders. A total of 77 male and 133 female patients were included. The mean age of the patients was 48.71 years (53.80 for male and 45.77 for female patients). The average ophthalmopathy score was 3.72 (4.51 for male and 3.26 for female patients). Age was positively correlated with ophthalmopathy score (p < 0.01). The male patients scored higher than the female patients, generally and in different age groups, but the difference did not reach a statistically significant level. One hundred and six patients underwent tests for thyroid-stimulating hormone receptor antibody (TRAb); 92 (86.80%) were positive, but the titers did not correlate with the severity of ophthalmopathy. In conclusion, the severity of Graves' ophthalmopathy is correlated with age (r = 0.286). Thus, older patients should be more closely followed up and more aggressively treated.

A polymorphism of the 5' flanking region of tumour necrosis factor α gene is associated with thyroid-associated ophthalmopathy in Japanese.

We have studied the polymorphism of the 5' flanking region of the tumour necrosis factor (TNF)-α gene in order to better understand the genetic background of autoimmune thyroid disorders and thyroid-associated ophthalmopathy. We studied the polymorphism of the 5' flanking region of the TNF-α gene at positions - 1031 (T to C change, termed as - 1031C), - 863 (C to A, - 863 A), - 857 (C to T, - 857T), - 308 (G to A, - 308 A) and - 238 (G to A, - 238 A) in Japanese patients with Graves' disease [n = 173, 62 of whom had associated ophthalmopathy (American Thyroid Association (ATA) class III or greater)] and healthy control subjects (n = 575), using a polymerase chain reaction sequence-specific oligonucleotide probe method. The allele frequency of - 857T in the Graves' disease patients (22.5% vs. 17.7%, OR = 1.35, P = 0.045, corrected P = 0.23) was slightly greater than in the Japanese healthy subjects, respectively. However, the difference was not statistically significant. In Graves' disease patients with evident ophthalmopathy (ATA class III or greater), the allele frequencies of - 1031C and - 863 A were significantly greater than those with no or mild ophthalmopathy (ATA class 0-II) (31.5% vs. 13.5%, OR =2.94, P < 0.0001, corrected P < 0.0005; 23.4% vs. 11.7%, OR =2.30, P = 0.0044, corrected P = 0.022, respectively) and in control subjects. The strength of the association of the polymorphism - 1031C increased with the severity of ophthalmopathy, with odds ratios of 2.36 for ATA class III, and 5.43 for ATA class IV-VI, respectively, compared with Graves' disease with no or mild ophthalmopathy (ATA class 0-II). Although the phenotype frequency of DRB1*0901 was not different among Graves' disease patients with or without ophthalmopathy and control subjects, the phenotype frequency of DRB1*0901(-)/-1031C(+) was significantly increased in Graves' disease patients with ophthalmopathy compared to those with no or mild ophthalmopathy (OR = 4.91, P = 0.0005) or control subjects (OR = 4.59, P < 0.0001). These results suggest that the - 1031C or - 863 A alleles, or a gene in linkage disequilibrium with the TNF-α gene, predispose to the development of ophthalmopathy in Japanese patients with Graves' disease.

Natural killer cell activity in patients with Graves' disease and Hashimoto's thyroiditis.

Natural killer (NK) cell activity of peripheral blood lymphocytes (PBL) against k562 human tumor cell targets was studied in patients with Graves' disease and Hashimoto's thyroiditis. NK activity was measured in a standard 4-hour 51chromium (Cr) release assay. Cytotoxicity was expressed as lytic units (LU)/10(6) PBL. Significantly decreased NK cell activity was demonstrated in both groups of patients, with mean (+/- SE) lytic units of 10.3 (+/- 9.1) and 13.3 (+/- 10.3) for patients with Graves' disease and Hashimoto's thyroiditis, respectively, compared with 36.0 (+/- 26.3) for age- and sex-matched normal subjects. When patients with Graves' disease were analyzed according to their thyroid status; NK activity was significantly depressed in (1) hyperthyroid patients before treatment; (2) hyperthyroid patients receiving antithyroid therapy; and (3) euthyroid patients receiving antithyroid therapy, compared with normal subjects. Graves' disease patients who were hypothyroid after radioactive iodine therapy or thyroidectomy had normal NK activity. No significant differences between hyperthyroid and euthyroid patients or between hypothyroid patients and normal subjects were demonstrated. NK activity in patients with Graves' disease did not correlate with serum levels of thyroxine, the presence or severity of ophthalmopathy, or titers of serum thyroid antibodies. In patients with Hashimoto's thyroiditis there was no correlation between NK activity and goiter size, titers of antithyroid antibodies, or thyroid status. These findings suggest that depression of NK activity in both disorders is secondary to abnormalities of thyroid hormone secretion, although an effect of the underlying autoimmune reactions has not been excluded.

Localization and clinical significance of thyrotropin receptor mRNA expression in orbital fat and eye muscle tissues from patients with thyroid-associated ophthalmopathy.

We have studied the cellular localization of thyrotropin receptor (TSH-R) mRNA in orbital fat and extraocular muscle tissues from patients with thyroid-associated ophthalmopathy (TAO) using Northern blot, reverse transcriptase polymerase chain reaction (RT-PCR), and in situ hybridization, and we correlated the findings with clinical estimates of ophthalmopathy. Although we failed to detect TSH-R mRNA in orbital tissues by Northern blot, TSH-R cDNA was amplified in orbital fat tissue from 13 of 25 patients with TAO and from 2 of 4 control subjects, in eye muscle tissue from 2 out of 7 patients with TAO, and in cultured orbital fibroblasts and subcutaneous fibroblasts from TAO patients. In situ hybridization showed that TSH-R mRNA was detected in cultured orbital fibroblasts as well as skin fibroblasts obtained from the patient. Furthermore, the expression of TSH-R mRNA in orbital fat tissue from patients with TAO significantly correlated with the orbital fat volume and the severity of ophthalmopathy, especially the extent of eye muscle dysfunction. These results suggest that the expression of TSH-R in the orbit, especially fibroblasts, may play a role in the pathogenesis and clinical manifestations of the ophthalmopathy in patients with TAO, although a secondary effect, involving fibroblasts in TAO is also possible.

Significance of anti-eye muscle antibody in patients with thyroid-associated ophthalmopathy by quantitative western blot.

To investigate the prevalence of antibody against rat eye muscle membrane antigen, as determined from SDS-polyacrylamide gel electrophoresis and western blotting, in sera from patients with thyroid-associated ophthalmopathy (TAO), we quantitatively analyzed the binding activity with a rat eye muscle membrane 64 kDa protein using chromato-scanner. Eye muscle antibody activity was expressed as ratio of density of the 64 kDa band to that at 66 kDa found with all normal sera and phosphate buffered saline. The mean (+/- SD) eye muscle antibody activity was 2.7 +/- 2.7 in TAO (P < 0.01 v.s. normal), 1.5 +/- 1.7 in Graves' disease without evident eye disease, 1.6 +/- 2.5 in Hashimoto's thyroiditis and 0.45 +/- 0.26 in normal subjects. A positive band at 64 kDa was found in 71% of patients with TAO, 36% of those of Graves' disease without evident eye disease and in 35% of patients with Hashimoto's thyroiditis without eye disease. The prevalence of this antibody activity tended to correlate to the severity of ophthalmopathy. Furthermore, the level of eye muscle antibody activity decreased in parallel with the improvement of eye signs in two patients. Sera reactive with rat eye muscle membrane 64 kDa protein reacted also with a human eye muscle membrane 64 kDa protein but not with human thyroid, liver, spleen or pancreas membrane preparations. In conclusion, antibody to rat eye muscle membrane 64 kDa protein is present in TAO and may be a useful clinical marker of ophthalmopathy.

Role of magnetic resonance imaging in thyroid-associated ophthalmopathy: its predictive value for therapeutic outcome of immunosuppressive therapy.

To investigate the efficacy of magnetic resonance imaging (MRI) in the assessment of thyroid-associated ophthalmopathy (TAO), 51 patients with TAO were evaluated by ophthalmologic examinations and MRI at 0.5 T. Thickness of extraocular muscles (EM) was measured by T1-weighted image. Signal intensities of EM and orbital connective tissue (OCT) were measured by short inversion time inversion recovery (STIR) image and expressed as a ratio by comparison to the signal intensity of cerebral substantia alba (SI, signal intensity ratio). Significant enlargement of one or more EM was observed in 86% of patients with TAO, and SI of EM (2.15 +/- 0.63, mean +/- SD) was significantly increased compared with control values (n = 16; 1.35 +/- 0.33; t test, p < 0.01). SI of OCT tended to be greater than that in the control group, although the difference was not significant. There was a significant positive correlation between thickness of EM and severity of ophthalmopathy, assessed as an ophthalmopathy index (p < 0.05). SI of neither EM nor OCT correlated with the severity of the eye disease. To investigate whether MRI findings could predict the outcome of methylprednisolone pulse therapy, we studied 23 patients with TAO who received this treatment. SI of EM and OCT in the 12 patients giving favorable responses were significantly greater than those in the 11 patients without good response (t test, p < 0.01). On the other hand, the thickness of eye muscles did not correlate with the outcome of treatment except for that of medial rectus muscle. There was a significant correlation between SI of EM and that of OCT (r = 0.78, p < 0.01), suggesting possible similar pathologic processes in these tissues in TAO.(ABSTRACT TRUNCATED AT 250 WORDS)

Ophthalmopathy in Early Thyrotoxicosis — Relationship to Thyroid Receptor Antibodies and Effects of Treatment

A prospective study of 25 newly diagnosed thyrotoxic patients was undertaken to determine the incidence and severity of ophthalmopathy in the early stages of the disease. A quantitative analysis of the ocular muscle changes was made using B scan ultrasonography, and the effects of treatment for the thyroid disease on the course of the eye changes was assessed. Although the majority (75%) of patients showed only mild clinical signs of ophthalmopathy (Werner Class 3 or less), 92% had ultrasonographic evidence of ocular muscle enlargement. Clinical involvement of the extraocular muscles was seen in 12% of the cases. There was an inverse correlation between the serum level of thyroid stimulating hormone receptor antibody (TR Ab) and the size of the extraocular muscles. Recovery of the euthyroid state with treatment was accompanied by a decrease in orbital infiltration in some cases, both clinically (reduced amplitude of intraocular pressure rise on elevation of the globe) and by ultrasonography, but the improvement was not statistically significant.

Eye Muscle Membrane Reactive Antibodies are not Detected in the Serum or Immunoglobulin Fraction of Patients with Thyroid-Associated Ophthalmopathy Using an Elisa and Crude Membranes

We tested sera and purified immunoglobulin (Ig) fractions from patients with autoimmune thyroid disorders (AITD), with and without ophthalmopathy, and normal subjects, for the presence of antibodies reactive with eye muscle membrane antigens in an optimized enzyme-linked immunosorbent assay (ELISA). We found no correlation between ELISA results and the presence or severity of ophthalmopathy in patients with AITD for either serum or Ig, and there were no significant differences between the mean values (+/- SE) for the three groups (AITD with ophthalmopathy, AITD without ophthalmopathy and normals) for either serum or Ig. In contrast Ig from 8 of 19 (45%) patients with thyroid-associated ophthalmopathy reacted with a 64 kDa eye muscle membrane antigen in SDS-polyacrylamide gel electrophoresis and Western blotting, while tests were positive in only one of the 8 patients with AITD without eye disease and in none of the 8 normal subjects. The presence of antibodies to a 64 kDa antigen in immunoblotting did not correlate with the levels of antibodies measured in ELISA. We conclude that the ELISA, incorporating a crude membrane fractions as antigen, is not useful as a clinical test for eye muscle autoantibodies.

Prednisone and Cyclosporine in the Treatment of Severe Graves' Ophthalmopathy

It is uncertain what is the most appropriate medical therapy for patients with severe Graves' ophthalmopathy. Therefore, we carried out a single-blind, randomized clinical trial to compare the efficacy of prednisone with that of cyclosporine in 36 patients who had been euthyroid for at least two months. The two groups, each consisting of 18 patients, were similar in age, sex, and the duration and severity of ophthalmopathy. The initial dose of cyclosporine was 7.5 mg per kilogram of body weight per day, and that of prednisone was 60 mg per day, which was subsequently tapered to 20 mg per day. During the 12-week treatment period, 11 prednisone-treated and 4 cyclosporine-treated patients responded to therapy (61 percent vs. 22 percent; P = 0.018); response was manifested by decreases in eye-muscle enlargement and proptosis and improved visual acuity and total and subjective eye scores. There were no differences at base line between the patients who later responded and those who did not. Prednisone was tolerated less well than cyclosporine. After 12 weeks, patients who did not respond were treated for another 12 weeks with a combination of cyclosporine and a low dose of prednisone. Among the 9 patients who initially received prednisone, the addition of cyclosporine resulted in improvement in 5 (56 percent); among the 13 patients who received cyclosporine initially, 8 (62 percent) improved after the addition of prednisone. Combination therapy was better tolerated than prednisone treatment alone. We conclude that single-drug therapy with prednisone is more effective than cyclosporine in patients with severe Graves' ophthalmopathy. The combination can be effective in patients who do not respond to either drug alone.

A study of the binding of Graves' immunoglobulins to orbital antigens.

The binding of Graves' immunoglobulins to membranes of human eye muscle (HEM) and guinea pig Harderian gland (HG) were studied. The membrane fraction of 100,000 X g sediment was used for ELISA. Serum samples from 55 patients with Graves' ophthalmopathy were evaluated for binding to the membrane preparation. There was a higher binding to HG with the sera from the patients with Graves' ophthalmopathy than in the control group (p less than 0.01), but there was no difference in binding to HEM. Purification of IgG from sera improved binding to HG in both patients' (p less than 0.001) and control group (p less than 0.005). There was also an increase in percentage of positive responses obtained with IgG 48% vs serum samples 37%. In 23 out of 24 patients we found the thickening of extraocular muscles by A-scan ultrasonography. In these groups of patients and 3 others with malignant ophthalmopathy the binding of IgG preparation to HG was similar to control group. In all assays there was an overlap between patients with Graves' ophthalmopathy and control subjects, and a lack of relationship between the responses in ELISA and clinical or severity of ophthalmopathy.

Observations against a causal relationship between the long-acting thyroid stimulator and ophthalmopathy in Graves' disease.

ABSTRACT An analysis was made of observations carried out in 65 patients with ophthalmopathy of Graves' disease, in an attempt to identify any statistical correlation between the level of long-acting thyroid stimulator in the blood of the patients, the severity of opthalmopathy and the incidence of preceding radioiodine therapy. Thirty-five of the sera did not give a positive response in the bioassay for the thyroid stimulator; with 17 a positive response up to 300% at 9 hr with 0.5 ml/mouse was found; and with the remaining 13 the value was greater than 300%. There was no correlation between these values and the severity of ophthalmopathy or the assessment of whether or not the eye condition was progressing at the time that serum was obtained. There was no correlation between the incidence of preceding radioiodine therapy and the severity of ophthalmopathy or the value obtained on assay of serum for the long-acting thyroid stimulator. With one additional patient, observations over a period of 15 months s...