GENETIC FACTORS IN GRAVES'' OPHTHALMOPATHY

We investigated the distribution of HLA and immunoglobulin G heavy chain markers (Gm) in 117 patients with Graves' disease, 62 with ophthalmopathy and 55 without. With Graves' disease per se, there is a closer association with HLA-DR3 than with B8. The opposite was true for Graves' patients with ophthalmopathy (odds ratio for ophthalmopathy associated with B8 was 12.4 and with DR3 was 7.7, both with P less than 0.0005). HLA-DR7 interacts with B8 in modifying the risk for eye disease; using the phenotype B8- DR7- as reference, the odds ratios were 16.7 for B8+ DR7+, 8.7 for B8+ DR7- and 0.26 for B8- DR7+. Thus, DR7 enhanced the risk for ophthalmopathy in the presence of B8+ but had a protective influence in its absence. Although Gm showed no association with eye disease, it modified the risk for ophthalmopathy associated with HLA-B8; the odds ratios were 20.9 for B8+ Gmfb homozygozity (fb+), 15.3 for B8+ fb- and 1.7 for B8- fb+ (B8- fb- = 1.00). We conclude that the genetic factors contributing to Graves' ophthalmopathy are different from those related to liability for Graves' hyperthyroidism.     

Correlation of HLA types and clinical findings in Japanese patients with hyperthyroid Graves'' disease: evidence indicating the existence of four subpopulations

OBJECTIVES: To re-evaluate the associations of HLA types with Japanese patients having hyperthyroid Graves' disease, HLA types and clinical findings were correlated. DESIGN: Four independent clinical findings (ophthalmopathy, family history, age at onset and size of goitre) and two autoantibody titres, thyrotrophin binding inhibitor immunoglobulin (TBII) and anti-thyroid microsmall antibody (anti-M), were analysed. PATIENTS: Eighty-eight Japanese patients with hyperthyroid Graves' disease and 186 control subjects were assessed. MEASUREMENT: Serological HLA typing was performed on 73 antigens in HLA-A, -B, -C, -DR and -DQ loci. HLA-D and -DP (29 antigens) were determined by the restricted fragment length polymorphism (RFLP) methods. TBII and anti-M were measured by commercially available kits. RESULTS: Patients with potent antibody titres had HLA antigens commonly seen among all the patients with Graves' disease. Interestingly, however, HLA-B35 and -Cw11 were found to relate with negative and/or weak TBII, and HLA-B7 and absence of HLA-Aw19 with negative anti-M. Significant associations were observed between HLA-DRw8 and large goitre and absence of ophthalmopathy, and between HLA-DQw4 and a negative family history of diffuse goitre (corrected P less than 0.05). Several other antigens were also found to be significant. Among these antigens, four pairs of MHC classes I and II were found to relate to the clinical findings independently. HLA-DQw4 and negative -A31 pair was closely related to ophthalmopathy, negative family history and late onset of disease. The HLA-B5 and -Dw12 pair was associated with ophthalmopathy, positive family history and early onset of disease. The HLA-A11 and negative -DPw2 pair was associated with ophthalmopathy, negative family history and early onset of disease. The HLA-Bw46 and -DRw8 pair did not increase in frequency above that seen with HLA-DRw8 alone. These four antigen groups (HLA-DRw8, HLA-DQw4 and negative-A31, HLA-B5 and -Dw12, and HLA-A11 and negative -DPw2) were observed in the majority (68%) of patients with Graves' disease and at a significantly higher incidence than in the control group (P less than 0.05). CONCLUSION: There are four subpopulations of Japanese patients with hyperthyroid Graves' disease. This is one of the reasons why the association of HLA types in Japanese patients is rather weak when they are studied as one group.     

Association between HLA-DR antigens and rheumatoid arthritis in Arabs.

Eighty five Arab patients with classical and definite rheumatoid arthritis were typed to determine the prevalence of HLA A, B, C, and DR antigens. A significant increase in the prevalence of HLA-A10, B8, B21, and DR3 was found in comparison with a control population matched for age and sex. HLA-DR5 was significantly decreased in the patient group. The classical association of HLA-DR4 with rheumatoid arthritis could not be confirmed in the Arab patients resident in Kuwait, supporting reported observations in different ethnic groups of associations with HLA antigens other than HLA-DR4 and indicating a heterogeneous genetic susceptibility to rheumatoid arthritis.     

GRAVES' DISEASE AND HLA: CLINICAL AND EPIDEMIOLOGIC ASSOCIATIONS

Correlation between clinical and epidemiological features of Graves' disease and HLA were sought in 175 patients, eighty-three of whom were typed for HLA DR antigens. The relative risks (x) conferred by HLA-B8 and DR3 were 3.1 and 5–7 respectively ( P <0.0005 uncorrected). The disease occurred at an earlier age in HLA-DR3 positive patients compared to negative patients ( P <0.005 in females> and <30-years-old). Eighty-four out of ninety-two patients could specify the season of onset of hyperthyroidism; an excess of HLA-B8 positive patients in the summer and a lack of these in the spring and autumn was found. No associations between B8 and exophthalmos and/or soft tissue eye changes were observed. However, significant associations between exophthalmos and either exophthalmos and/or soft tissue changes were found with DR3 (x=3.6 and 3.8 respectively). HLA-DR3 positive patients were found to be more resistant to radioiodine therapy than patients negative for these antigens. No heterogeneity in the distribution of HLA antigens was found when the following indices were examined: sex, goitre size, severity of disease, pretibial myxoedema, antecedent psychological disorder, consumption of oral contraceptives, family history of Graves' disease or thyroid antibody titre. HLA does not appear to distinguish subvariants of Graves' disease, rather it influences the susceptibility to disease and its persistence once it becomes clinically manifest.     

TSH BINDING-INHIBITING ANTIBODIES IN HYPERTHYROIDISM: RELATIONSHIP TO CLINICAL SIGNS AND HORMONE LEVELS

TSH binding-inhibiting antibody (TBIAb) activity was measured in 809 European patients with different forms of hyperthyroidism. Distribution of these TBIAb was skewed, with a peak in the range of normal controls, and an ill defined, not clearly separated peak at higher levels of TSH displacement. There was no unequivocal separation of two possible subgroups of hyperthyroidism (immunogenic and non-immunogenic). TBIAb distributions of patients with and without endocrine ophthalmopathy (EO) overlapped considerably. Although patients with Graves' disease, arbitrarily defined by the presence of endocrine ophthalmopathy or diffuse nuclide uptake by thyroid scanning, had mostly elevated TBIAb activity, 24.3% had values within the range of normal controls (mean + 2SD). Patients with diffuse thyroid uptake had significantly higher TBIAb levels than patients with nodular scan findings. In Graves' disease, TBIAb activity was positively correlated with the severity of endocrine ophthalmopathy, the size of the thyroid, and the serum levels of total and free triiodothyronine. There was no influence of age, sex, pretreatment, or regional iodine supply. These results suggest (1) that the clinical manifestations of Graves' disease are statistically related to TBIAb activity and (2) that separation of immunogenic and non-immunogenic forms of hyperthyroidism by means of TBIAb determination is unsatisfactory. The almost continuous distribution of TBIAb points to insufficient sensitivity of the present technique and raises doubts as to whether TBIAb values can be reliably classified as 'positive' or 'negative'.     

HLA antigens and toxicity to gold and penicillamine in rheumatoid arthritis

One hundred sixty-eight patients with rheumatoid arthritis treated with chloroquine (n = 87), gold salts (n = 133) and/or penicillamine (n = 77) were investigated for possible associations between HLA antigens and toxic reactions. Patients with 2 or more side effects to gold and/or penicillamine had a significantly increased frequency of antigens HLA-B8 and DR3 compared to patients with one or without adverse reactions. Proteinuria to gold or penicillamine was significantly associated with HLA-B8 (relative risk [RR] 4.2) and DR3 (RR 14.0) whereas nonnephrologic side effects to gold or penicillamine were associated with B7 and DR2 (RR 3.5 and 2.8). Patients with skin reactions to gold had a significantly greater frequency of HLA-B7. We found no correlation between chloroquine side effects and any HLA antigen. The results suggest a genetic predisposition to toxic reactions to gold or penicillamine based on an immunologic dysregulation.     

More on smoking habits and Graves' ophthalmopathy

Since a relationship between cigarette smoking and the occurrence of Graves' ophthalmopathy has been recently postulated, we reviewed the smoking habits of 1730 women, including subjects without thyroid disease, with nontoxic goiter (NTG), toxic nodular goiter or toxic adenoma (TNG), Hashimoto's thyroiditis (HT), Graves' disease without ophthalmopathy (GD) or with ophthalmopathy (GO). The prevalence of smokers in NTG, TNG and HT was about 30%, not different from that of controls. Smokers were 47.9% in GD and 64.2% in GO groups. The latter figures were highly different from those of the other groups and also from each other. The percentage of heavy smokers was higher in patients with more severe ophthalmopathy. No clear explanation for this phenomenon can be offered. The absence of a high prevalence of smokers among patients with non-toxic goiter, nonautoimmune hyperthyroidism and Hashimoto's thyroiditis, limits the impact that smoking might have had in the pathogenesis of goiter, hyperthyroidism and autoimmune phenomena of GD and GO.     

Linkage of HLA-DR beta specific restriction fragment length polymorphisms with Graves' disease

HLA-DR3 positive patients with Graves' disease (6 homozygotes, 7 heterozygotes, i.e. yielding 19 haplotypes) were studied by restriction fragment length polymorphism analysis using TaqI as restriction enzyme in order to look for polymorphisms in the HLA-DR3 allele of the human major histocompatibility complex. Polymorphic TaqI fragments of 11.6, 9.8 and 5.8 kb, each corresponding to HLA-DR beta sequences, were shown to differ in their prevalence in patients with Graves' disease and controls. The prevalence of DR3 polymorphisms in a total of 35 HLA-DR3-containing haplotypes was markedly different within patients with Graves' disease and Caucasian controls. Whereas a 11.6 kb fragment was rare in Graves' disease (2/19 haplotypes vs 8/16 in controls), the inverse ratio was found for a 9.8 kb fragment, with a prevalence of 17/19 and 8/16 haplotypes, respectively. A polymorphic fragment of 5.8 kb was exclusively seen in two DR3-containing haplotypes of patients with Graves' disease. Our data provide evidence that a DNA polymorphism of the HLA-DR beta genes, which is also reflected at the product level, is linked to Graves' disease.     

IDENTIFICATION OF SUBSETS OF PATIENTS WITH GRAVES''DISEASE BY CLUSTER ANALYSIS

We have applied cluster analysis methods to forty-nine laboratory and clinical characteristics (including 26 HLA-A, B antigens) observed in 196 Graves' disease patients. Three subgroups could be identified: group I (seventy-nine patients) had small goitres, low indices of autoimmunity and a tendency to remission with medical treatment; group IIa (twenty-nine patients) had clinical and laboratory features of 'Hashitoxicosis'; Group IIb (eighty-four patients) had a high incidence of ophthalmopathy, familial aggregation, marked evidence of autoaggression and a tendency to relapsing hyperthyroidism. The prevalence of HLA-B8 was 8.9% in group I, 20.7% in group IIa and 86.9% in group IIb. This study demonstrates that Graves' disease can be subdivided using cluster analysis into clinically relevant subgroups which are further distinguished by their correlation with HLA-B8. Possible immunological bases for these observed patterns are discussed.     

Absence of HLA-B8 and HLA-DR3 in Japanese patients with Sj?gren's syndrome positive for anti-SSA(Ro).

Forty Japanese anti-SSA(Ro) positive patients with Sj?gren's syndrome were typed for HLA-A, B, C, DR and DQ antigens. No patient had either HLA-B8 or HLA-DR3 which has been reportedly associated with the immune response to SSA(Ro) antigens in white and black patients. Our patients had higher frequencies of HLA-DRw8 and HLA-DRw52 than the control population.     

DIFFERENTIATION OF AUTOIMMUNE OPHTHALMOPATHY FROM GRAVES''HYPERTHYROIDISM BY ANALYSIS OF GENETIC MARKERS

Graves' hyperthyroidism and dysthyroid eye disease are closely related autoimmune conditions. Whether the eye disease is an integral part of Graves' disease or a separate entity is controversial. To investigate this we have examined the genetic associations of ophthalmopathy and hyperthyroidism, and compared their phenotype and gene frequencies with a control normal population. HLA-A, B, and DR antigens were typed in 67 patients with dysthyroid eye disease (GO), 60 hyperthyroid patients without significant eye disease (HT) and 500 normal subjects. Patients were also typed for a variety of other genetic markers: blood group systems (10), serum proteins (6) and red cell enzyme systems (10). Increased frequency of B8 and DR3 in Graves' disease was confirmed; B17 occurred less frequently and appears to be protective. HLA antigen frequencies for GO did not differ from HT. The MNS blood group showed a significant association with Graves' disease, the HT patients having a deficit of the s gene compared with controls. The most interesting finding was an increased frequency of blood group P in GO patients compared with either HT or controls. Significant differences were not seen with any of the other HLA antigens, blood groups, protein or enzyme markers considered individually. Multivariate analysis applied first to the HLA and then to the non-HLA systems indicated clear separation of the two patient groups. Although Graves' eye disease shares the same HLA associations as hyperthyroidism, it differs in the increased frequency of P blood group, suggesting that additional genetic factors may determine which patients with Graves' disease develop ophthalmopathy.     

Graves' disease with ophthalmopathy following radiotherapy for Hodgkin's disease

The number of patients achieving long-term survival following neck irradiation for Hodgkin's disease and other malignancies is increasing. Paralleling this increase in survivors is the development of late complications of the therapy itself. Eleven patients have previously been reported who developed Graves' ophthalmopathy 18 months to seven years after receiving neck radiotherapy for nonthyroidal malignancies. The seven patients who had HLA typing were all HLA-B8 negative, despite the reported association of the HLA-B8 antigen with Graves' disease. A patient who is HLA-B8 positive who developed Graves' ophthalmopathy and hyperthyroidism nine years after receiving mantle radiotherapy for Hodgkin's disease is reported. It is recommended that Graves' disease be included among the thyroid diseases that receive consideration during follow-up of patients who have received mantle radiotherapy.     

Hyperthyroidism due to Graves' disease and due to autonomous goiter

An attempt was made to classify 326 patients with hyperthyroidism due to Graves' disease and due to autonomous goiter in an area of endemic iodine deficient goiter using the following two sets of criteria: Primary criteria: the presence of endocrine ophthalmopathy (Graves' disease) and the absence of endocrine ophthalmopathy and the absence of microsomal antibodies greater than or equal to 1:1600 (autonomous goiter). Sixty-nine percent of the patients could be divided in the two groups with the aid of these criteria. Secondary criteria: age greater than 50 years, presence of a goiter, presence of thyroid nodules, activity distribution in the scan, iodine intake determined by iodine excretion in the urine. These criteria had to be applied in the 31% of the patients who could not be divided into one of the two groups using the primary criteria. The secondary criteria were accumulative. Using these criteria 55% of the 326 patients were classified as having Graves' disease and 45% as having autonomous goiter. The probability of correct grouping when both primary and secondary criteria were applied was estimated to be 90% compared to 54% when we used only the classical terms, i.e. endocrine ophthalmopathy and diffuse goiter on the one hand and multinodular goiter without endocrine ophthalmopathy on the other hand. In a second group of 120 hyperthyroid patients classified in this way, thyrotropin displacing activity was determined independently. Its prevalence was 79% in patients classified as having Graves' disease but only 3% in those classified as having autonomous goiter. The prevalence of TDA observed in patients who presumably had autonomous goiter was in the same range as in the following groups: 45 normal individuals; 126 patients with euthyroid goiter; and in 112 patients with euthyroid and hyperthyroid autonomous adenoma.(ABSTRACT TRUNCATED AT 250 WORDS)     

The clinical and immunomorphological characteristics of diffuse toxic goiter

The presence of HLA antigens B8 and DR3 in an individual is associated with his predisposition to developing Basedow's disease. A comparative study of a clinical course and immunological characterization of this disease in 208 patients, divided with relation to the presence or absence of the above antigens, showed that the disease developed in patients with HLA B8 and DR3 at a younger age and was accompanied twice as more frequently by ophthalmopathy. Thyrotoxicosis relapsed among these patients in conservative therapy much more frequently. A relapse after surgical intervention in the study group was noted thrice as more frequently compared to the control group. Focal infiltration of thyroid tissue with lymphoid cells was determined twice as less frequently in patients with HLA B8 and DR3. Any statistically significant difference was unnoticed in the severity of thyrotoxicosis and the frequency of detection of antibodies to thyroglobulin.     

HLA-DR4 associated response to corticosteroids in Graves' ophthalmopathy patients

Fifty-seven patients with severe Graves' ophthalmopathy were treated with corticosteroids. Therapeutic outcome was assessed according to predetermined criteria as response (n = 37) or non-response (n = 20) to therapy. Patients were typed for HLA-A, -B, -C, -DR and -DQ. HLA-DR4 was completely absent in the 20 non-responder patients (corrected p value = 0.042). In the responder group 14 of the 37 patients were HLA-DR4 positive. This study shows that in Graves' ophthalmopathy patients the presence of HLA-DR4 is associated with a good response to corticosteroid therapy. The frequency of HLA-DR4 in the Graves' ophthalmopathy population as a whole, however, was not different from normal (25% versus 26%). But as reported previously, the frequency of HLA-DR3 was significantly increased in the Graves' ophthalmopathy patients when compared to healthy blood donors (47% versus 24%, corrected p value = 0.02). No significant deviations were found in the HLA-A, -B, or -C loci.     

Effect of therapy on the serum thyroglobulin concentration in patients with toxic diffuse goiter, toxic nodular goiter and toxic adenoma

Serum thyroglobulin (S-Tg) was measured in 104 patients with thyrotoxicosis, 59 of whom had toxic diffuse goiter (Graves' disease), in 30 with toxic nodular goiter and in 15 with toxic adenoma. Before treatment, most patients had increased S-Tg concentrations, regardless of what type of thyrotoxicosis they had. After therapy the course of the S-Tg varied, two major patterns being observed: the S-Tg concentration increased in some patients but decreased in others, although no relationship could be found between these patterns and the outcome of therapy, the presence or absence of thyroglobulin antibodies (Tg-ab) or changes in the Tg-ab titer. However, the median pretreatment concentrations of S-Tg were significantly higher in patients with toxic nodular goiter and toxic adenoma than in those with toxic diffuse goiter (p less than 0.001 and p less than 0.05, respectively), but did not differ significantly between patients with toxic nodular goiter and toxic adenoma. The lowest posttreatment S-Tg concentrations were found after surgery, irrespective of type of thyrotoxicosis. The median pretreatment and posttreatment S-Tg concentrations in patients with toxic diffuse goiter who relapsed, did not differ from those patients in remission. This was also true of patients with toxic nodular goiter. In both groups, however, there was a tendency towards higher pretreatment S-Tg values in patients who subsequently relapsed. Serial determinations of S-Tg, on the other hand, are of limited value in predicting the risk of recurrence, independent of which type of thyrotoxicosis is involved.     

Association of HLA-DR7 with rheumatic fever in the Brazilian population

OBJECTIVE: Rheumatic fever (RF) is a multisystem inflammatory disease that develops as a sequel of untreated throat infection by the group A beta-hemolytic streptococcus. As HLA antigens are known to be important in controlling immunological responsiveness, studies have investigated HLA antigen association with RF. Studies with Caucasians, Black Americans, and Indians showed associations with HLA-DR4, DR2, and DR3, respectively. One study on a Brazilian population suggested an association with HLA-DR7 and HLA-DR53. We investigated the association between RF and antigens HLA-DR7 and DR53 in the white Brazilian population. METHODS: Thirty-five patients and 209 healthy individuals living in the northern region of the state of Parana, Brazil, were used as test and control groups, respectively. Classical statistical methods were used to compare HLA frequencies between these groups. Results. Data confirmed positive association with HLA-DR7 (46.7 vs. 25.7%; p = 0.015), but not with HLA-DR53 (54.3 vs. 44.5%; p = 0.28). The relative risk and etiologic fractions were 2.4 and 0.27%, respectively. CONCLUSION: Positive association between HLA-DR7 specificity and RF was observed in the white Brazilian population by 2 independent studies, supporting the hypothesis of the involvement of genetic factors in susceptibility of rheumatic fever.     

Thyrotrophin-binding Inhibitory Immunoglobulin and HLA-DRW3—Two Prognostic Factors in Graves' Disease*

Abstract: Thyrotrophin-binding inhibitory immuno-globulin (TBII) activity and HLA typing were performed in 38 Chinese patients with Graves' disease to find out the relationship among TBII activity, HLA antigen and relapse. Twelve out of 13 patients who were TBII-positive at anti-thyroid drug withdrawal relapsed. All seven patients with HLA-DR3 antigen relapsed, whereas all ten patients in remission did not have DR3. Therefore, both TBII activity at drug withdrawal and DR3 antigen could predict subsequent relapse. However, a larger patient sample is required to determine the precise relationship between TBII activity and HLA-DR3 antigen.     

Toxic multinodular goiter: a variant of autoimmune hyperthyroidism

The aim of this study was to examine whether at least a subgroup of patients with toxic multinodular goiter may have autoimmune thyroid disease. Thyroid-stimulating immunoglobulin (TSI) activity, measured by a sensitive bioassay employing cultured human thyroid cells, was determined in patients with toxic multinodular goiter and other thyroid disorders. All patients with active Graves' disease (n = 47) had detectable serum TSI activity, whereas TSI was undetectable in patients with thyroid disease not believed to be of autoimmune origin: toxic adenoma (n = 13), cold nodule (n = 5), and nontoxic goiter (n = 19), with a single exception in the latter group. Toxic multinodular goiter (n = 26) was diagnosed based on clinical and laboratory evidence of hyperthyroidism associated with a multinodular goiter on palpation and scintiscan. The toxic multinodular goiter group was then subclassified according to scintiscan pattern (type A, diffuse but uneven distribution of technetium uptake; type B, multiple discrete nodules of varying size and function). All but 1 of the 11 TSI-positive toxic multinodular goiter patients had a type A scintiscan pattern. The patients with the type A scintiscan pattern were younger and more often had elevated antithyroid antibody titers, ophthalmopathy, and concurrent development of goiter and hyperthyroidism (rather than long-standing goiter preceding hyperthyroidism) compared to the type B patients. Thus, a subgroup of patients with clinically defined toxic multinodular goiter (type A) probably have autoimmune hyperthyroidism (a variant of Graves' disease), while in another subgroup (type B) hyperthyroidism is not related to an autoimmune etiology (a variant of toxic adenoma).