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MF Prummel and WM Wiersinga

To ascertain the strength of the association between thyroid autoimmunity and miscarriage, we performed a meta-analysis of both case-control and longitudinal studies performed since 1990 when this association was first described. A clear association between the presence of thyroid antibodies and miscarriage was found with an odds ratio (OR) of 2.73 (95 % confidence interval (CI), 2.20-3.40) in eight case-control and ten longitudinal (OR, 2.30; 95 % CI, 1.80-2.95) studies. This association may be explained by a heightened autoimmune state affecting the fetal allograft, of which thyroid antibodies are just a marker. Alternatively, the association can be partly explained by the slightly higher age of women with antibodies compared with those without (mean+/-S.D. age difference, 0.7+/-1.0 years; P<0.001). A third possibility is mild thyroid failure, as thyroid-stimulating hormone (TSH) levels in antibody-positive but euthyroid women are higher than in antibody-negative women: difference 0.81+/-0.58 mU/l (P=0.005). Randomized clinical trials with l-thyroxine (aiming at TSH values between 0.4 and 2.0 mU/l) and with selenium (to decrease antibodies against thyroid peroxidase) are clearly needed to elucidate further the nature of this association.

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MF Prummel, T Strieder, and WM Wiersinga

Genetic factors play an important role in the pathogenesis of autoimmune thyroid disease (AITD) and it has been calculated that 80% of the susceptibility to develop Graves' disease is attributable to genes. The concordance rate for AITD among monozygotic twins is, however, well below 1 and environmental factors thus must play an important role. We have attempted to carry out a comprehensive review of all the environmental and hormonal risk factors thought to bring about AITD in genetically predisposed individuals. Low birth weight, iodine excess and deficiency, selenium deficiency, parity, oral contraceptive use, reproductive span, fetal microchimerism, stress, seasonal variation, allergy, smoking, radiation damage to the thyroid gland, viral and bacterial infections all play a role in the development of autoimmune thyroid disorders. The use of certain drugs (lithium, interferon-alpha, Campath-1H) also increases the risk of the development of autoimmunity against the thyroid gland. Further research is warranted into the importance of fetal microchimerism and of viral infections capable of mounting an endogenous interferon-alpha response.

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C Terwee, I Wakelkamp, S Tan, F Dekker, MF Prummel, and W Wiersinga

OBJECTIVE: Little is known about the long-term effects of Graves' ophthalmopathy (GO) on health-related quality of life (HRQL) after the eye treatment is considered to be finished. The aim of this study was to quantify these effects using validated HRQL questionnaires. DESIGN: A cross-sectional follow-up study was carried out in GO patients who had started radiotherapy and/or prednisone treatment between 1982 and 1992. METHODS: Between 1998 and 2000 these patients received an HRQL questionnaire containing the SF-36, EuroQol and GO-QOL questionnaires. All patients were invited for a follow-up ophthalmological examination. HRQL scores of the respondents were compared with those of two reference populations of 'healthy' persons and to scores of several other GO populations. RESULTS: One hundred and sixty-eight patients were included; 163 completed the HRQL questionnaire and 154 visited the outpatient clinic. The median follow-up was 11.7 years. A considerable number of symptoms related to GO were found. More than half of the patients had diplopia and 28% had a low visual acuity. Sixty per cent had a proptosis of at least 20 mm. The HRQL scores were considerably better than those of newly diagnosed GO patients (untreated) and GO patients who completed the questionnaire during treatment, but worse than those of 'healthy' persons. Although we did not perform a longitudinal study, we included a selected group of patients who had been treated with radiotherapy and/or prednisone in the Academic Medical Centre of the University of Amsterdam, and though we could not assess HRQL at comparable times after receiving treatment, this is the first study that presents any data on the long-term effects of GO on HRQL. CONCLUSION: GO has a marked negative effect on HRQL, even many years after treatment. These findings suggest that GO should be considered a chronic disease. Aftercare is needed for these patients after their immunosuppressive and surgical treatments.

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MF Prummel, A Bakker, WM Wiersinga, L Baldeschi, MP Mourits, P Kendall-Taylor, P Perros, C Neoh, AJ Dickinson, JH Lazarus, CM Lane, AE Heufelder, GJ Kahaly, S Pitz, J Orgiazzi, A Hullo, A Pinchera, C Marcocci, MS Sartini, R Rocchi, M Nardi, GE Krassas, and A Halkias

To improve management of patients with Graves' orbitopathy, a multi-center collaborative approach is necessary in order to have large enough sample sizes for meaningful randomized clinical trials. This is hampered by a lack of consensus on how to investigate the eye condition. The European Group on Graves' Orbitopathy aims to overcome this and has designed a preliminary case record form (CRF) to assess Graves' orbitopathy patients. This form was used in this first multi-center study. AIM: To investigate patient characteristics and treatment strategies in 152 new consecutively referred patients with thyroid eye disease seen in nine large European referral centers. METHODS: Newly referred patients with Graves' orbitopathy were included who were seen between September and December 2000. Demographic data and a complete ophthalmological assessment were recorded. RESULTS: One-hundred and fifty-two patients (77% females) were included. Diabetes was present in 9%, and glaucoma or cataract in 14% of patients. Forty percent were current smokers, 9% also had dermopathy, and only 33% reported a positive family history of thyroid disease. Mild eye disease was seen in 40%, moderately severe eye disease was seen in 33% and severe eye disease was seen in 28% of patients. Soft tissue involvement was the most frequent abnormality (seen in 75%), proptosis > or =21 mm was found in 63%, eye motility dysfunction in 49%, keratopathy in 16% and optic nerve involvement was found in 21% of patients. According to the clinical impression, 60% had active eye disease. Immunosuppressive treatment was planned more frequently in active patients (57/86; 66%) than in inactive patients (5/57, 9%; Chi-square 46.16; P<0.02). There were no important differences among the eight centers regarding the severity and the activity of their patients. CONCLUSIONS: In view of the large number of patients recruited in only 4 months, multi-center studies in the eight EUGOGO centers appear to be feasible.