Antithyroid drug therapy for Graves' disease during pregnancy. Optimal regimen for fetal thyroid status

We compared fetal and maternal serum indexes of thyroid status at delivery in 70 patients with Graves' disease who required therapy with thionamides (such as propylthiouracil) during pregnancy. Forty-three mothers required thionamides until delivery (Group 1), whereas the drugs were discontinued during pregnancy after remission in 27 mothers (Group 2). Maternal free thyroxine levels were closely correlated with cord levels in both groups, being essentially identical in Group 2 but slightly lower in fetuses than in mothers in Group 1. Normal maternal free thyroxine levels did not preclude fetal hypothyroidism. The mothers and fetuses in Group 1 had a significantly higher incidence of antibodies that inhibit thyrotropin binding than did those of Group 2. However, a significant correlation between maternal levels of these antibodies and cord levels of free thyroxine or triiodothyronine was found only in Group 2, in which some maternal and cord thyroxine levels were in the thyrotoxic range at delivery, presumably because therapy was discontinued. These findings indicate that high free thyroxine levels and the presence of antibodies that inhibit binding of thyrotropin are useful indexes of the fetal need for antithyroid treatment, and that the thionamide dosage that maintains maternal free thyroxine levels in a mildly thyrotoxic range seems appropriate for maintaining euthyroid status in the fetus.     

Immunogenetic markers in patients with Graves' disease

Summary 110 carefully characterized Caucasoid patients with Graves' disease were tested for HLA class I and class II antigens. Compared with Caucasian controls (n=193), the frequencies of HLA B8, Cw7 and DR3 were significantly increased (p_c<0.05). In the subgroups with and without exophthalmos, HLA A3 exhibited a negative but insignificant association with the eye involvement, while A19 and Cw2 showed positive, however even weaker correlations with eye disease. HLA DR5 was associated with relapsing thyrotoxicosis, whereas HLA DR7 and B12 were negatively correlated with relapse. These results confirm the positive correlation of HLA B8 and DR3 with Graves' disease and reveal a not yet observed association with Cw7. Reported correlations of antigen frequencies with eye disease and relapsing thyrotoxicosis could not be confirmed. Other previously unknown, however subtle differences in disease subgroups were observed.Abbreviations EF etiologic fraction - HLA Human leukocyte antigens - RR relative risk - TRAb TSH receptor antibodies - TSH Thyroid stimulating hormone     

Secretor status and infection in patients with Graves' disease

We have demonstrated that the inability to secrete the water soluble glycoprotein form of the ABO blood group antigens into saliva is significantly more common in patients with Graves' disease than control subjects (40% vs 27%: P less than 0.025) but not among those with Hashimoto's thyroiditis or spontaneous primary atrophic hypothyroidism. Non-secretion is associated with increased susceptibility to infection and to asymptomatic carriage of some microorganisms. Although Yersinia enterocolitica has been found to express antigen cross reactive with the TSH receptor, we did not find an increased prevalence of Yersinia species in the faeces of 107 patients with Graves' disease. The isolation rate (less than 1%) was similar to that observed in the local population with diarrhoeal illness. Salivary IgA levels determined by whole cell ELISA with Y. enterocolitica 03 were not elevated in the majority of specimens examined. The results suggest that in contrast to reports from Scandinavia, there is no strong evidence that yersiniae play a role in the pathogenesis of Graves' disease among patients in South east Scotland. Non-secretors are significantly over represented among patients with several other autoimmune diseases; however, with the exception of antitubulin antibodies, non-secretors with Graves' disease did not have more antibodies to other human antigens than secretor patients.     

Soluble endothelium-associated adhesion molecules in patients with Graves' disease.

The targeting and recruitment of inflammatory cells to vascular endothelium in Graves' disease (GD) is mediated by intercellular adhesion molecule-1 (ICAM-1), endothelial leucocyte adhesion molecule-1 (ELAM-1), and vascular cell adhesion molecule-1 (VCAM-1). We have studied serum levels of soluble ICAM-1 (sICAM-1), soluble ELAM-1 (sELAM-1), and soluble VCAM-1 (sVCAM-1) in patients with GD (n = 21) and in patients with iodine-deficient goitre (IDG) (n = 23). The serum levels of sICAM-1 were markedly elevated in patients with GD before treatment with thiamazole (median 560 ng/ml versus 185 ng/ml in patients with IDG). In addition, elevated serum concentrations of sELAM-1 (median 85 ng/ml versus 33 ng/ml, respectively) and sVCAM-1 (median 42 ng/ml versus 15 ng/ml, respectively) were observed in patients with GD (P < 0.01 for all). The serum levels of sELAM-1 and sVCAM-1 dropped significantly after initiation of therapy and were within the normal range after 4, and 8 weeks of therapy, respectively. Serum levels of sICAM-1 were elevated even after 8 weeks of therapy. Serum levels of sVACM-1 and sICAM-1 correlated with the serum concentrations of anti-thyroid-stimulating hormone (TSH)-receptor antibodies (TSHR-R) (n = 21; r = 0.929 and r = 0.810, respectively) and anti-thyroid peroxidase antibodies (TPO-Ab) (n = 21; r = 0.673 and r = 0.750, respectively). However, no correlation between sELAM-1 and TPO-Ab, TSHR-R, and anti-thyroglobulin antibodies (Tg-Ab), respectively, could be found. In addition to thyroid hormones and autoantibodies, serum concentrations of sELAM-1 and sVCAM-1, but not sICAM-1, could be useful as clinical markers for disease activity.     

HLA-DRB3 gene alleles in Caucasian patients with Graves' disease

Summary Graves' disease (GD) is a human leukocyte antigen (HLA) linked organ-specific autoimmune disease. In German GD patients the disease is associated with HLA specificities of the HLA-DRw52 family (HLA-DR3, -DR5, and DR6; HLA-DRB3 positive HLA haplotypes). Recently, a strong association with a HLA-DRB3 restriction fragment length polymorphism gene has been described. To study HLA-DRB3 alleles and their association with the disease, a large cohort of controls (n = 3724) and GD patients (n = 304) was analyzed. HLA-DR allelic combinations revealed an increase in HLA-DR3/DR5 heterozygous patients (relative risk 2.9; P<0.001). HLA-DRB3 alleles, as defined by DNA typing in HLA-DR matched groups revealed a significant increase in DRB3^*0101 homozygosity (relative risk 17.5; P< 0.001) in HLA-DR3 homozygous patients. In GD patients with ophthalmopathy (grade II or higher, according to Werner) DRB3^*0101/^*0202 heterozygosity revealed an increased relative risk of 5.5 (P<0.001). Non-HLA-DR3 homozygous, DRB3^*0101/^*0202 heterozygous patients were at the highest risk for endocrine ophthalmopathy (relative risk 10; P<0.001). Our data, based on DNA typing methods of HLA-D genes, provide evidence that the susceptibility is strongly associated with HLA-DRB3 genes.Abbreviations EF etiological fraction - GD Graves' disease - HLA human leukocyte antigen - RR relative risk     

Endothelial dysfunction in Graves' disease

PurposeGraves' disease (GD) is an organ-specific autoimmune thyroid disease, characterized by hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. In this study, we determined serum levels of the soluble forms of ICAM-1, VCAM-1, vWF, IL-6, IL-12, IL-18, fibrinogen and CRP in patients with subclinical (SH) and overt hyperthyroidism (OH) caused by GD to elucidate a possible role of those parameters as markers of endothelium dysfunction (ED).Material/MethodsThe study included 96 patients: 52 with GD and 44 euthyroid controls, divided into 3 groups according to their thyroid function tests: SH, OH and controls (CG).ResultsThe values of IL-6, IL-12 and IL-18 were significantly higher in GD than in CG patients (p < 0.0001, p < 0.0001; p < 0.00001, respectively). Significant difference of sVCAM-1 values were found in the patients with GD compared to CG (p < 0.0001). Patients with GD had significantly higher levels of PAI-1 (p < 0.00001), vWF (p < 0.0001), fibrinogen (p < 0.0001) in comparison to CG. In patients with OH, we observed statistically higher values of fibrinogen compared to SH group (p < 0.05). There were no significant differences in serum concentration of other study parameters in patients with SH compared to the OH.ConclusionsED occurs during subclinical and overt hyperthyroidism causing decreased fibrinolytic activity, hypercoagulability and increased levels of IL-6, Il-12 and IL-18. These results support the notion that serum cytokines could be used as a marker of GD activity. Results of this study support the opinion that GD might require treatment as early as in the phase of SH.     

Graves' disease in HTLV-I carriers

Three carriers of human T-lymphotropic virus type I (HTLV-I) with Graves' disease are reported. All three cases were complicated with uveitis, and one also showed chronic arthropathy. Anti-HLTV-I antibody was found in the serum by the particle agglutination method and western blotting, and HTLV-I proviral DNA was detected in peripheral lymphocytes by the polymerase chain reaction and Southern blotting. HTLV-I is a causal agent of adult T-cell leukemia and HTLV-I associated myelopathy/tropical spastic paraparesis, and is believed to be related to the pathogenesis of diseases such as chronic arthropathy, uveitis, chronic bronchoalveolitis, and Sjögren's syndrome. On the other hand, retrovirus infection is considered to cause autoimmune diseases. Thus, the pathogenesis of Graves' disease in the present patients might be associated with HTLV-I infection.Abbreviations HTLV-I Human T-lymphotropic virus type I - ATL adult T-cell leukemia - HAM HTLV-I associated myelopathy - TSP Tropical spastic paraparesis     

Graves病患者杀伤细胞免疫球蛋白样受体基因型分析

目的: 探讨杀伤细胞免疫球蛋白样受体(KIR)基因型在Graves病(GD)患者中的分布规律.方法: 采用序列特异性引物聚合酶链反应(PCR-SSP) 的方法,分析96例Graves病患者和96 例正常对照人群的KIR基因型.结果: GD患者中2DS2-,2DL2-,2DL3+,2DL1+,3DL1+,3DS1-,2DL5-,2DS3-,2DS5-,2DS1-,2DS4-基因型频率高于对照组(6.25% vs 0,P<0.05);对照组中,基因频率最高的基因型为2DS2-,2DL2-,2DL3+,2DL1+,3DL1+,3DS1-,2DL5-,2DS3-,2DS5-,2DS1-,2DS4+,该基因型的基因型频率较GD患者组高,且有显著性差异(28.13% vs 10.42%,P<0.01);GD患者组不携带活化性KIR基因的基因型频率较对照组明显升高(10.42% vs 0%,P=0.001).结论: KIR基因型在GD患者与正常人群分布的差异可能与GD的发病有关.     

The influence of Epstein-Barr virus reactivation in patients with Graves' disease

In Graves' disease, the IgG class autoantibody against thyrotropin receptor (TRAb) is produced excessively and induces hyperthyroidism. Epstein-Barr virus (EBV) is one of the human herpesviruses that persists for life, mainly in B lymphocytes, and is occasionally reactivated. Therefore, EBV may affect the antibody production of B lymphocytes that would normally produce TRAb. The purpose of the present study was to evaluate the association of EBV reactivation with the etiology of Graves' disease. Serum levels of EBV antibodies and IgE were determined by ELISA. TRAb levels were determined by radioreceptor assay. We performed in-situ hybridization (ISH) of EBV-encoded small RNA (EBER)1 on the thyroid tissue of one of our patients. In Graves' disease patients with TRAb levels ≥ 10%, EA antibody levels, which indicate EBV reactivation, were moderately but significantly correlated with the levels of TRAb, and weakly but significantly correlated with IgE. EBER1-ISH revealed that one of our patients had EBV-infected lymphocytes infiltrating the thyroid gland. EBV reactivation may stimulate antibody-producing B lymphocytes predisposed to make TRAb, and this may contribute to or exacerbate the disease.     

Pituitary-cell autoantibody diversity in sera from patients with untreated Graves' disease

Sera from 22 untreated patients with recently diagnosed Graves' disease (GD) were screened in an immunocytochemical tissue assay for presumptive pituitary IgG autoantibodies, as defined by the presence of immunoreaction with rat and swine pituitary cell types. Forty four patients with Hashimoto's thyroiditis (HT) and 97 healthy subjects were also studied. Anti-pituitary antibodies were found in 14 of the 22 GD sera (64%). Of these, 6 sera reacted with cytoplasmic components of growth hormone (GH) cells, 3 with prolactin (PRL) cells, and 5 with both GH and PRL cells. Yet, none of the immunoreactive sera reacted with human GH, bovine PRL or TSH in dot-blot assays and absorption studies. Anti-pituitary antibodies also occurred in 4 of the 44 HT patients (9.1%) and in 9 of the 97 healthy subjects (9.2%). The frequency of sera revealing anti-pituitary antibodies was significantly higher in patients with GD compared to the groups of HT patients (P less than 0.00005), and healthy subjects (P less than 0.00005). Healthy subjects and patients with HT had a similar frequency of anti-pituitary antibodies (P = 1.0000). These data demonstrate that in thyroid autoimmune conditions antibodies reactive with cytoplasmic components of pituitary GH/PRL cells, may be present in sera from patients with GD. The pathological importance of this observation is at present unknown.     

Lung involvement and drug-induced lung disease in patients with rheumatoid arthritis

Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA) and a significant cause of morbidity and mortality. Usual interstitial pneumonia and nonspecific interstitial pneumonia seem to be the most frequent patterns in RA patients with ILD, although the proportion of patients with usual interstitial pneumonia is higher than among patients with other systemic rheumatic autoimmune diseases. RA patients with ILD most frequently present with chronic symptoms of cough and dyspnea when climbing stairs or walking uphill. A physical examination may reveal inhalatory crackles and a pulmonary function test demonstrates restrictive physiology, often with reduced diffusing capacity. High-resolution computed tomography is generally sufficient to confirm a diagnosis of ILD, although a minority of cases may require a surgical lung biopsy. Conventional disease-modifying antirheumatic drugs such as methotrexate (MTX) or leflunomide (LEF) and biological agents such as TNF-blocking agents or rituximab may trigger or aggravate ILD in RA patients, and infections may contribute to increased mortality in such patients. LEF should not be used in patients with a history of MTX pneumonitis. The prevalence of interstitial pneumonia among RA patients treated with anti-TNF agents ranges from 0.5 to 3%; however, as the evidence that anti-TNF increases or decreases the risk of ILD is controversial, it is not clear whether this indicates more severe RA requiring biological therapy or the effect of exposure to potentially toxic drugs such as MTX or LEF. The development of treatment-related ILD is a paradoxical adverse event, and patients should be warned about this rare but serious complication of biological or disease-modifying antirheumatic drug therapy.     

Soluble interleukin-2 receptor in sera of patients with Graves' disease.

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.     

CTLA-4 promoter variants in patients with Graves' disease and Hashimoto's thyroiditis

Abstract: Graves' disease (GD) and Hashimoto's thyroiditis (HT) are T-cell mediated organ-specific autoimmune disorders with a genetic predisposition. The cytotoxic T-lymphocyte antigen 4 (CTLA-4) molecule is the predominant receptor for B7 on activated T cells and represents a negative regulator for T-cell function. Since the CTLA-4-guanine at position 49 of exon 1 is associated with susceptibility to GD as well as to HT and IDDM, we investigated a recently detected cytosine/thymine substitution at position -318 within the CTLA-4 promoter region in patients with GD and HT. 125 patients with GD were significantly more often homozygous for cytosine (86% vs. 73% in controls, P=0.006) and less frequently heterozygous for cytosine and thymine (14% vs. 27%, P=0.008). In 64 patients with HT, the distribution was similar but not significant (81% homozygous for cytosine and 16% heterozygous). When correlating the promoter and the exon 1 polymorphism we found the strongest linkage between thymine (promoter) and adenine (exon 1). In conclusion, a promoter variant of the CTLA-4 gene represents an additional risk marker for GD and HT, but their predisposition is linked to the exon 1 alleles.     

Levels of cytokines and thyroid autoantibodies in Omani patients with Graves' disease

An altered balance of pro- and anti-inflammatory cytokines is thought to play an important role in the pathogenesis of autoimmune thyroiditis. The aim of the present study is to assess the cytokine and autoantibody profiles in Omani patients with Graves' disease (GD). Cytokines and autoantibodies including interleukin (IL)-2, IL-4, tumour necrosis factor (TNF)alpha, interferon (IFN)gamma, thyroid stimulating hormone receptor antibody (TRA) and thyroid peroxidase antibody (TPO) are measured in GD patients (n=59) before treatment (n=23) and after treatment (n=36) with 131I-labelled iodine, and compared with normal controls (n=20). Patients with GD showed comparable serum levels of IL-2 but significantly higher levels of IL-4, TNFalpha, IFNgamma, TRA and TPO, compared with the normal controls. There was also a significant increase in serum levels of IL-4 and TNFalpha, and a decrease in TRA in the treated group, compared to the untreated group. IL-4, TNFalpha, IFNgamma, TRA and TPO showed a high prevalence in Omani patients with GD. Thus, cytokines and autoantibodies may prove useful in the diagnosis of GD and in assessing prognosis.     

Human foamy virus antigens in thyroid tissue of Graves' disease patients.

Human foamy virus (HFV) is a recently characterized member of the retrovirus subfamily Spumaretrovirinae. HFV has a complex structure: it encodes the classical three retroviral structural genes gag, pol and env, but also possesses additional regulatory, so-called bel sequences. Foamy viruses have been discussed occasionally as being possibly involved in the pathogenesis of autoimmune thyroiditis. By indirect immunofluorescence we were able to demonstrate the expression of HFV gag proteins on the epithelial cells of 7/7 thyroid glands of patients with Graves' disease, but not in those of 9 patients with struma parenchymatosa, 3 with follicular carcinoma and 2 normal thyroids. The thyroids of 5 patients with Hashimoto's disease were also negative with the exception of a single small focus in 1 case. These observations may have importance for our understanding of the development of Graves' disease.     

Soluble interleukin-2 receptor in sera of patients with Graves' disease.

Recently, in vitro production of interleukin-2 receptor induced by mitogens have been shown to be impaired in autoimmune disorders including organo-specific autoimmune diseases. The aim of this study was to investigate serum levels of soluble interleukin-2 receptor in 20 untreated patients with Graves' disease and to follow up their changes in relation to clinical picture and TSH-receptor-, anti-thyroglobulin-, anti-microsomal as well as anti-eye muscle antibodies. Soluble interleukin-2 receptor level was significantly increased in newly-diagnosed Graves' patients compared to controls (667 +/- 270 vs. 205 +/- 45 U/ml) (P less than 0.001). Among the patients sera those with active infiltrative ophthalmopathy had higher soluble interleukin-2 receptor levels than those without eye symptoms (810 +/- 313 vs. 525 +/- 180 U/ml). Soluble interleukin-2 receptor level was normalized in Methimazole-treatment-induced remission in the majority of patients except those with ophthalopathy. In five patients the soluble interleukin-2 receptor levels were studied after interruption of thyrostatic therapy; an increase was observed in three patients; thereafter hyperthyrosis relapsed in two cases. Furthermore, a correlation was found between soluble interleukin-2 receptor levels and TSH-receptor antibodies, however, the association with other immune parameters examined was not significant. In conclusion, an enhanced level of soluble interleukin-2 receptor was detected in patients with untreated Graves' disease. This finding might play a significant role in regulation of impaired cell-mediated immune mechanism and has a prognostic value for relapse of autoreactive processes.