To assess the impact of Graves' ophthalmopathy (GO) on quality of life using a general questionnaire, we performed a descriptive study on consecutive ophthalmopathy patients. We included 70 consecutive, euthyroid patients (age >18 years, 50 females, 20 males, mean +/- SD age 53 +/- 13 years) with varying degrees of severity of GO. General quality of life was assessed with the brief survey (24 questions) from the Medical Outcomes Study (MOS-24), and three subscales of the Sickness Impact Profile (SIP). In comparison with a large published reference group, low scores on the MOS-24 were found. Mean +/- SD scores (difference from reference group) were: physical functioning 58 +/- 31 (-28), role functioning 72 +/- 40 (-15), social functioning 78 +/- 25 (-14), mental health 67 +/- 18 (-10), health perceptions 46 +/- 22 (-26), and bodily pain 68 +/- 28 (-6). MOS-24 and SIP scores did not correlate with the duration, severity, or activity of the ophthalmopathy. In conclusion, we have shown that mild to moderately severe GO has a large influence on the quality of life of these patients. The negative impact on well-being seems not to be related to the usual clinical assessment. These results underscore the need for quality-of-life measurements in clinical trials.
Antithyroid treatment for Graves' hyperthyroidism restores euthyroidism clinically within 1–2 months, but it is well known that TSH levels can remain suppressed for many months despite normal free T4 and T3 levels. This has been attributed to a delayed recovery of the pituitary-thyroid axis. However, we recently showed that the pituitary contains a TSH receptor through which TSH secretion may be down-regulated via a paracrine feedback loop. In Graves' disease, TSH receptor autoantibodies may also bind this pituitary receptor, thus causing continued TSH suppression. This hypothesis was tested in a rat model. Rat thyroids were blocked by methimazole, and the animals were supplemented with l-T4. They were then injected with purified human IgG from Graves' disease patients at two different titers or with IgG from a healthy control (thyroid hormone binding inhibitory Ig, 591, 127, and < 5 U/liter). Despite similar T4 and T3 levels, TSH levels were indeed lower in the animals treated with high TSH receptor autoantibodies containing IgGs; the 48-h mean TSH concentration (mean ± sem; n = 8) was 11.6 ± 1.3 ng/ml compared with 16.2 ± 0.9 ng/ml in the controls (P < 0.01). The intermediate strength TSH receptor autoantibody-treated animals had levels in between the other two groups (13.5 ± 2.0 ng/ml). We conclude that TSH receptor autoantibodies can directly suppress TSH levels independently of circulating thyroid hormone levels, suggesting a functioning pituitary TSH receptor.
Radiotherapy is often used in Graves’ ophthalmopathy, but its efficacy has been doubted. We compared its efficacy with sham irradiation in mild ophthalmopathy. In a double-blind randomized trial, 44 patients received orbital irradiation, and 44 were sham-irradiated. The primary outcome was assessed using major and minor criteria. As secondary outcome, we used a disease-specific quality of life questionnaire (the GO-QoL) and compared cost-effectiveness and need for follow-up treatment. The primary outcome was successful in 23 of 44 (52%) irradiated patients vs. 12 of 44 (27%) sham-irradiated patients at 12 months after treatment (relative risk, 1.9; 95% confidence interval, 1.1–3.4; P = 0.02). Radiotherapy was effective in improving eye muscle motility and decreasing the severity of diplopia. However, quality of life improved similarly in both groups. In the radiotherapy group there was less need for follow-up treatment; 66% vs. 84% of the patients needed further treatment (P = 0.049). Retrobulbar irradiation did not prevent worsening of ophthalmopathy, which occurred in 14% of the irradiated and 16% of the sham-irradiated patients. Radiotherapy is an effective treatment in mild ophthalmopathy. However, the improvement upon irradiation may not be associated with an increase in quality of life or a reduction in treatment costs.
Increased serum cytokine levels have been reported in patients with autoimmune thyroid disease, but less is known about their levels in patients with Graves' ophthalmopathy (GO). It is not known whether GO is a cell-mediated or humoral autoimmune disease. We investigated whether serum cytokines are elevated in GO patients and whether the cytokines were Th1- or Th2-derived. In addition, elevated cytokines might reflect the activity of GO, and thus we investigated whether cytokine levels could predict the clinical response to orbital radiotherapy. We studied 62 consecutive patients with moderately severe untreated GO and 62 healthy controls, matched for sex, age and smoking habits. Serum concentrations of IL-1RA, sIL-2R, IL-6, sIL-6R, tumour necrosis factor-alpha (TNF-alpha) RI and II and sCD30 were measured using highly sensitive ELISAs, in the patients before and 3 and 6 months after radiotherapy. All patients were euthyroid, with anti-thyroid drugs, before and during the entire study period. All baseline cytokine and cytokine receptor levels were significantly elevated in GO patients compared with healthy controls, except for IL-1RA. The levels did not correlate with parameters of the thyroid disease, nor with the duration, activity or severity of GO. However, backward logistic regression analysis showed that IL-6, sCD30 and TNFalphaRI were able to predict a beneficial response to orbital radiotherapy. We therefore conclude that both Th1- and Th2-derived cytokines are elevated in GO patients compared with its controls. IL-6, sCD30 and TNFalphaRI had some value for predicting therapeutic outcome to orbital irradiation, and may thus reflect active eye disease.
In most patients with Graves' hyperthyroidism the eye signs are self-limiting and mostly subclinical. However, about one-third of the patients have clinically relevant ophthalmopathy, which can be disabling and disfiguring. The mechanical causes of the symptoms and signs of the eye disease are largely understood, but the best way to manage the ophthalmopathy is still a matter of much debate. Adequate treatment of hyperthyroidism can aleviate the eye symptoms to some extent, but it is less clear which kind of antithyroid treatment is to be preferred in patients with ophthalmopathy. There is particular controversy about the possibly deleterious effect of radioiodine therapy on the ophthalmopathy; in view of the present evidence it seems prudent to refrain from using 131I and to prefer antithyroid drugs in patients with clinical ophthalmopathy. Further medical management can include immunosuppressive treatment (such as corticosteroids) that results in improvement in roughly two-thirds of the patients. Orbital irradiation appears to be the first choice for treatment in moderately severe ophthalmopathy because it is equally effective and much better tolerated than classical corticosteroid treatment. However, to really improve the efficacy of such interventions we should be able to select those patients that are likely to respond to immunomodulatory therapy. Disease activity is probably the prime determinant of response and it is a challenge for the future to develop reliable parameters of disease activity on the basis of which patients can be selected for further medical treatment, or can be subjected to rehabilitative surgery without prior immunosuppression.
The negative impact of the visual limitations and disfigurement associated with Graves' ophthalmopathy (GO) for a patient's daily life has always been acknowledged in clinical practice. However, only recently have the effects of GO on health-related quality of life (HRQL) been quantified using validated questionnaires. In this article, a state of the art is presented on the aims, methodology and application of HRQL assessment in GO research. HRQL assessment is important in cross-sectional studies aimed at describing the severity of GO on multiple outcome levels, including the impact of GO on patients' daily functioning and perception of health in general, and in longitudinal studies aimed at the evaluation of treatment efficacy or comparison of the effects of different treatments on HRQL. Only a few studies have measured the effects of GO on HRQL directly. Patients with GO have a relatively low HRQL, not only in the period that they are diagnosed and treated for the disease, but their low HRQL persists even many years after the final treatment. Because the current therapies for GO are primarily directed at improving (visual) functioning and appearance, these treatments should be evaluated for their effectiveness on HRQL outcomes. At the moment, the recently developed GO-QOL questionnaire is the only validated disease-specific instrument available to measure HRQL in patients with GO. The GO-QOL is recommended as an instrument to measure GO treatment effects on HRQL.
