Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III).

BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Thyroid Eye Disease: Epidemiology, Natural History, and Risk Factors.

BACKGROUND: Thyroid eye disease (TED) is an autoimmune disorder of the orbit and the most frequent extrathyroidal manifestation of Graves' disease but it may rarely occur in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis. EPIDEMIOLOGY: TED is a relatively infrequent disorder, particularly in its severe forms. Men tend to have more severe TED at an older age. The prevalence of TED is lower than in the past among patients with recent onset Graves' hyperthyroidism, and moderate-to-severe forms requiring aggressive treatments are no more than 5% to 6% of all cases. NATURAL HISTORY: After an initial inflammatory (active) phase and a plateau phase, TED stabilizes and eventually inactivates (inactive or burnt-out phase) after an estimated period of 18-24 months. Minimal-to-mild TED often remits spontaneously, but complete restitutio ad integrum almost never occurs when TED is more than mild. RISK FACTORS: Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important of them, but thyroid dysfunction (both hyper- and hypothyroidism), radioactive iodine therapy (if not accompanied by low-dose steroid prophylaxis), elevated thyrotropin receptor antibodies, and, probably, hypercholesterolemia represent relevant modifiable risk factors. Early diagnosis, control and removal of modifiable risk factors, and early treatment of mild forms of GO (local treatment and selenium) may effectively limit the risk of progression to more severe forms.

Heterogeneity of TPIT expression in ACTH-secreting extra-pituitary neuroendocrine tumors (NETs) supports the existence of different cellular programs in pancreatic and pulmonary NETs.

Extra-pituitary ACTH secretion is associated with a variety of neoplastic conditions and may cause the so-called ectopic ACTH-dependent Cushing syndrome (CS). The clarification of the mechanisms of extra-pituitary ACTH expression would provide potential therapeutic targets for this complex and severe disease. In the adenohypophysis, the transcription factor TPIT, co-operating with other molecules, induces POMC expression and ACTH production. However, no data are currently available on the presence and role of TPIT expression in extra-pituitary ACTH-producing neoplasms. This study was designed to explore TPIT expression in a series of pulmonary and pancreatic ACTH-producing tumors, either CS-associated or not. Forty-one extra-pituitary ACTH-producing neuroendocrine tumors (NETs) were included in the study, encompassing 32 NETs of the lung (LuNETs), 7 of the pancreas (PanNETs), and 2 pheochromocytomas. Of these, 9 LuNETs, all PanNETs, and the two pheochromocytomas were CS-associated. For comparison, 6 NETs of the pituitary gland (PitNETs; 3 ACTH-secreting and 3 ACTH-negative) and 35 ACTH-negative extra-pituitary NETs (15 Lu-NETs and 20 PanNETs) were analyzed. Immunohistochemistry with specific anti-TPIT antibodies and quantitative real-time PCR (qRT-PCR) were performed using standard protocols. TPIT expression was completely absent (protein and mRNA) in PanNETs, pheochromocytomas, and all ACTH-negative NETs. In contrast, it was expressed in 16/32 LuNETs, although with lower levels than in PitNETs. No definite relationship was found between immunohistochemistry TPIT expression and NET grade or the presence of Cushing syndrome. This study further highlights the clinical and biological heterogeneity of extra-pituitary ACTH secretion and suggests that the differences between ACTH-secreting PanNETs and LuNETs may mirror distinct molecular mechanisms underlying POMC expression. Our results point towards the recognition of a real corticotroph-like phenotype of ACTH-producing LuNETs, that is not a feature of ACTH-producing PanNETs.

A potential role of human RNASET2 overexpression in the pathogenesis of Graves' disease.

Genetic variation of the gene encoding for the only human enzyme of the T2 ribonucleases family (RNASET2) emerged in genome-wide association studies as a putative risk hotspot for Graves' disease (GD). T2 ribonucleases activities include immune regulation, induction of cell apoptosis and differentiation. Several reports supported the hypothesis that RNASET2 represents a "danger" message addressed to the innate immune system in peculiar conditions. This was a longitudinal, case-control study. RNASET2 protein levels were assessed in blood samples from 34 consecutive newly diagnosed GD patients and in healthy controls. At enrollment, RNASET2 levels were significantly higher in GD patients (98.5 ± 29.1 ng/ml) compared to healthy controls (72.5 ± 27.9 ng/ml, p = 0.001). After 6 months of methimazole treatment, RNASET2 levels significantly decrease and return to levels similar to healthy controls (62.4 ± 22 ng/ml, p = 0.69). These preliminary results suggest that RNASET2 is overexpressed in patients with GD and might represent an "alarm signal" generated by thyroid cells in response to endogenous or environmental stress to alert the immune system.

Psychological complications in patients with acromegaly: relationships with sex, arthropathy, and quality of life.

PURPOSE: Current treatment of acromegaly restores a normal life expectancy in most cases. So, the study of persistent complications affecting patients' quality of life (QoL) is of paramount importance, especially motor disability and depression. In a large cohort of acromegalic patients we aimed at establishing the prevalence of depression, to look for clinical and sociodemographic factors associated with it, and to investigate the respective roles (and interactions) of depression and arthropathy in influencing QoL. METHODS: One hundred and seventy-one acromegalic patients (95 women and 76 men, aged 20-85 years) among those recruited in a cross-sectional Italian multicentric study were investigated. Each patient filled in three validated questionnaires: AcroQoL, WOMAC (measuring articular pain, stiffness and functionality), and AIMS (evaluating articular symptoms and depression). RESULTS: A very high (up to 28%) depression rate was detected in acromegalic subjects. Two patients showing pathological AIMS depression scores, committed suicide during the three years observational period. In our population poor psychological status was significantly associated with female sex. Furthermore, a significant strong correlation was found between AIMS depression score and WOMAC score. Both depression and arthropathy-related motor disability turned out to independently contribute with similar strength to the impairment of QoL. CONCLUSIONS: We report a high prevalence of depression in acromegaly, which is associated with female sex and arthropathy. Both depression and arthropathy strongly and independently contribute to the impaired QoL of patients. Our study shows that assessment and monitoring of psychological status is mandatory in acromegaly, also suggesting an inexpensive tool for this assessment.

Current concepts regarding Graves' orbitopathy.

Graves' orbitopathy (GO) is an orbital autoimmune disorder and the main extrathyroidal manifestation of Graves' disease, the most common cause of hyperthyroidism. GO affects about 30% of Graves' patients, although fewer than 10% have severe forms requiring immunosuppressive treatments. Management of GO requires a multidisciplinary approach. Medical therapies for active moderate-to-severe forms of GO (traditionally, high-dose glucocorticoids) often provide unsatisfactory results, and subsequently surgeries are often needed to cure residual manifestations. The aim of this review is to provide an updated overview of current concepts regarding the epidemiology, pathogenesis, assessment, and treatment of GO, and to present emerging targeted therapies and therapeutic perspectives. Original articles, clinical trials, systematic reviews, and meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, Graves' orbitopathy, thyroid eye disease, glucocorticoids, orbital radiotherapy, rituximab, cyclosporine, azathioprine, teprotumumab, TSH-receptor antibody, smoking, hyperthyroidism, hypothyroidism, thyroidectomy, radioactive iodine, and antithyroid drugs. Recent studies suggest a secular trend toward a milder phenotype of GO. Standardized assessment at a thyroid eye clinic allows for a better general management plan. Treatment of active moderate-to-severe forms of GO still relies in most cases on high-dose systemic-mainly intravenous-glucocorticoids as monotherapy or in combination with other therapies-such as mycophenolate, cyclosporine, azathioprine, or orbital radiotherapy-but novel biological agents-including teprotumumab, rituximab, and tocilizumab-have achieved encouraging results.

Management of Graves' hyperthyroidism: present and future.

INTRODUCTION: Graves' disease (GD) is an autoimmune disorder due to loss of tolerance to the thyrotropin receptor (TSHR) and ultimately caused by stimulatory TSHR antibodies (TSHR-Ab). GD may be associated with extrathyroidal manifestations, mainly Graves' orbitopathy. Treatment of GD relies on antithyroid drugs (ATDs), radioactive iodine (RAI), thyroidectomy. The major ATD limitation is the high recurrence rate after treatment. The major drawback of RAI and thyroidectomy is the inevitable development of permanent hypothyroidism. AREAS COVERED: Original articles, clinical trials, systematic reviews, meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, management of Graves' disease, antithyroid drugs, radioactive iodine, thyroidectomy, Graves' orbitopathy, thyroid-eye disease. EXPERT OPINION: ATDs are the first-line treatment worldwide, are overall safe and usually given for 18-24 months, long-term treatment may decrease relapses. RAI is safe, although associated with a low risk of GO progression, particularly in smokers. Thyroidectomy requires skilled and high-volume surgeons. Patients play a central role in the choice of treatment within a shared decision-making process. Results from targeted therapies acting on different steps of the autoimmune process, including iscalimab, ATX-GD-59, rituximab, blocking TSHR-Ab, small molecules acting as antagonists of the TSHR, are preliminary or preclinical, but promising in medium-to-long perspective.

Epidemiology, Natural History, Risk Factors, and Prevention of Graves' Orbitopathy.

GO is the most frequent extrathyroidal manifestation of Graves' disease, although it may rarely occur in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis. It is a relatively infrequent disorder, and men tend to have more severe ocular involvement at an older age. The prevalence of GO is lower than in the past among patients with recent onset Graves' hyperthyroidism, and moderate-to-severe forms requiring aggressive treatments are no more than 5-6% of all cases of GO. After an initial inflammatory (active) phase and a phase of stabilization (plateau phase), GO tends to improve and eventually inactivates (inactive or burnt-out phase). Minimal-to-mild GO often remits spontaneously, but complete restitutio ad integrum almost never occurs when GO is more than mild. Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important of them. Early diagnosis, control and removal of modifiable risk factors, early treatment of mild forms of GO may effectively limit the risk of progression to more severe forms, which have a profound and dramatic impact on the quality of life of affected individuals, and remain a therapeutic challenge, often requiring long-lasting and multiple medical and surgical therapies.

Duration of Exposure to Thyrotoxicosis Increases Mortality of Compromised AIT Patients: the Role of Early Thyroidectomy.

CONTEXT: Patients with amiodarone-induced thyrotoxicosis (AIT) and severely reduced left ventricular ejection fraction (LVEF) have a high mortality rate that may be reduced by total thyroidectomy. Whether in this subset of patients thyroidectomy should be performed early during thyrotoxicosis or later after restoration of euthyroidism has not yet been settled. OBJECTIVES: Mortality rates, including peritreatment mortality and 5-year cardiovascular mortality, and predictors of death, evaluated by Cox regression analysis. METHODS: Retrospective cohort study of 64 consecutive patients with AIT selected for total thyroidectomy from 1997 to 2019. Four groups of patients were identified according to serum thyroid hormone concentrations and LVEF: Group 1 (thyrotoxic, LVEF <40%), Group 2 (thyrotoxic, LVEF ≥40%), Group 3 (euthyroid, LVEF < 40%), Group 4 (euthyroid, LVEF ≥40%). RESULTS: Among patients with low LVEF (Groups 1 and 3), mortality was higher in patients undergoing thyroidectomy after restoration of euthyroidism (Group 3) than in those submitted to surgery when still thyrotoxic (Group 1): peritreatment mortality rates were 40% versus 0%, respectively (P = .048), whereas 5-year cardiovascular mortality rates were 53.3% versus 12.3%, respectively (P = .081). Exposure to thyrotoxicosis was longer in Group 3 than in Group 1 (112 days, interquartile range [IQR] 82.5-140, vs 76 days, IQR 24.8-88.5, P = .021). Survival did not differ in patients with LVEF ≥40% submitted to thyroidectomy irrespective of being thyrotoxic (Group 2) or euthyroid (Group 4): in this setting, peritreatment mortality rates were 6.3% versus 4% (P = .741) and 5-year cardiovascular mortality rates were 12.5% and 20% (P = .685), respectively. Age (hazard ratio [HR] 1.104, P = .029) and duration of exposure to thyrotoxicosis (HR 1.004, P = .039), but not presurgical serum thyroid hormone concentrations (P = .577 for free thyroxine, P = .217 for free triiodothyronine), were independent predictors of death. CONCLUSIONS: A prolonged exposure to thyrotoxicosis resulted in increased mortality in patients with reduced LVEF, which may be reduced by early thyroidectomy.

When primary hyperparathyroidism comes as good news.

SUMMARY: Brown tumors are osteoclastic, benign lesions characterized by fibrotic stroma, intense vascularization and multinucleated giant cells. They are the terminal expression of the bone remodelling process occurring in advanced hyperparathyroidism. Nowadays, due to earlier diagnosis, primary hyperparathyroidism keeps few of the classical manifestations and brown tumors are definitely unexpected. Thus, it may happen that they are misdiagnosed as primary or metastatic bone cancer. Besides bone imaging, endocrine evaluation including measurement of serum parathyroid hormone and calcium (Ca) levels supports the pathologist to address the diagnosis. Herein, a case of multiple large brown tumors misdiagnosed as a non-treatable osteosarcoma is described, with special regards to diagnostic work-up. After selective parathyroidectomy, treatment with denosumab was initiated and a regular follow-up was established. The central role of multidisciplinary approach involving pathologist, endocrinologist and oncologist in the diagnostic and therapeutic work-up is reported. In our opinion, the discussion of this case would be functional especially for clinicians and pathologists not used to the differential diagnosis in uncommon bone disorders. LEARNING POINTS: Brown tumors develop during the remodelling process of bone in advanced and long-lasting primary or secondary hyperparathyroidism. Although rare, they should be considered during the challenging diagnostic work-up of giant cell lesions. Coexistence of high parathyroid hormone levels and hypercalcemia in primary hyperparathyroidism is crucial for the diagnosis. A detailed imaging study includes bone X-ray, bone scintiscan and total body CT; to rule out bone malignancy, evaluation of bone lesion biopsy should include immunostaining for neoplastic markers as H3G34W and Ki67 index. If primary hyperparathyroidism is confirmed, selective parathyroidectomy is the first-line treatment. In advanced bone disease, treatment with denosumab should be considered, ensuring a strict control of Ca levels.

Disease heterogeneity in IgG4-related hypophysitis: report of two histopathologically proven cases and review of the literature.

IgG4-related hypophysitis (IgG4-RH) is a rare disease, which can occur singularly or as manifestation of a systemic IgG4-related disease (IgG4-RD). Less than one hundred cases have been reported in the literature, very few of which were histopathologically documented. We analyzed the clinical, radiological, and histopathological features of two cases of IgG4-RH, the former observed in a 66-year-old man in the context of an IgG4-RD, and the latter affecting a 21-year-old woman, as an isolated lesion. In addition, we performed a comprehensive review of the previously published histopathologically documented cases of IgG4-RH. Pituitary samples from both patients showed dense lymphoplasmacytic infiltration, interstitial and storiform fibrosis, and high numbers of IgG4-positive plasma cells, consistent with IgG4-RH. From the literature review, we retrieved 18 papers reporting a total of 22 cases of histopathologically documented IgG4-RH. The revision of these cases, also including the two reported herein, showed an equal distribution of IgG4-RH in the two sexes, albeit significant clinico-pathological variation was found between cases arisen in female and male patients, respectively. In detail, IgG4-RH females were affected in their second-third decade of life, with a solitary pituitary lesion, low IgG4 serum level, and frequent association with autoimmune disorders. By contrast, IgG4-RH in men was a disease of the elderly, often in the context of a systemic IgG4-RD, with high IgG4 serum levels. Our study shows that IgG4-RH, as currently defined, is a clinically heterogenous disease, with different features in the two sexes. Indeed, cases diagnosed in young women, as our case 2, mostly do not present other evidence of IgG4-RD and might be better classified as lymphocytic hypophysitis with abundant IgG4+ plasma cells. For this reason, the histopathological examination of the pituitary lesion, particularly in female patients, may still be useful for a correct differential diagnosis with other variants of primary hypophysitis.

Thyroid cancer with tracheal invasion: a pathological estimation.

We review the clinical and pathologic features of seven cases of papillary carcinoma of the thyroid that invaded the trachea and were treated by thyroidectomy, airway resection with reconstructive surgery over an interval of 15 years. We depicted the peculiarity of invasion of well differentiated papillary thyroid carcinoma (PTC) cells is perpendicularly oriented to the tracheal lumen, in between cartilaginous rings, along blood vessels and collagen fibers. Tracheal rings appear non-infiltrated in all histological sections of well differentiated PTC infiltrating the trachea. Similar description of inter-cartilage PTC infiltration into the trachea was first provided by Shin et al. in 1993. Interestingly, our pathological revision support the estimation by Shin et al., though that cartilage rings infiltration did occur in poorly differentiated thyroid cancers with exiguous prognosis.

Minimally invasive follicular thyroid cancer (MIFTC)--a consensus report of the European Society of Endocrine Surgeons (ESES).

BACKGROUND: This paper aims to review controversies in the management of minimally invasive follicular thyroid carcinoma (MIFTC) and to reach an evidence-based consensus. METHOD: MEDLINE search of the literature was conducted using keywords related to MIFTC. The search term was identified in the title, abstract, or medical subject heading. Available literature meeting the inclusion criteria were assigned the appropriate levels of evidence and recommendations in accordance with accepted international standards. Results were discussed at the 2013 Workshop of the European Society of Endocrine Surgeons devoted to MIFTC. RESULTS: Published papers on MIFTC present inadequate power with a III­IV level of evidence and C grade of recommendation. Several issues demanded a comparison of published studies from different medical reports regarding MIFTC definition, specimen processing, characteristics, diagnosis, prognoses, and therapy. As a consequence, it is difficult to make valuable statements on MIFTC with a sufficient recommendation rating. MIFTC diagnosis requires clearer, unequivocal, and reproducible criteria for pathologist, surgeons, and endocrinologists to use in the management of these patients. If the distinction between MIFTC and WIFTC cannot be made, an expert in thyroid pathologist should be consulted. CONCLUSION: According to published papers, the following conclusions can be drawn. (a) Candidates for hemithyroidectomy are MIFTC with exclusive capsular invasion, patients <45 years old at presentation, tumor size <40 mm, without vascular invasion, and without any node or distant metastases. (b) Candidates for total thyroidectomy are MIFTC in patients ≥45 years at presentation, tumor size ≥40 mm, vascular invasion present, positive nodes, and positive distant metastases. (c) In the absence of clinical evidence for lymph node metastasis, patients with MIFTC do not require prophylactic lymph node dissection. (d) Radio iodine ablation is indicated in elderly patients (>45 years), large tumor size (>40 mm), extensive vascular invasion, presence of distant synchronous or metachronous metastasis, positive nodes, and if recurrence is noted at follow-up.

Continuous monitoring of the recurrent laryngeal nerve in thyroid surgery: a critical appraisal.

BACKGROUND AND PURPOSE: Intraoperative neuromonitoring (IONM) contributes in several ways to recurrent laryngeal nerve (RLN) protection. Notwithstanding these advantages, surgeons must be aware that the current, intermittent, mode of IONM (I-IONM) has relevant limitations. To overcome these I-IONM limitations, a continuous IONM (C-IONM) technology has been proposed. METHODS: A PubMed indexed literature review of the current limitations of I-IONM is presented and a commentary about C-IONM is provided presenting the preliminary results of research on this topic. MAIN FINDINGS: I-IONM, despite the advantages it produces, presents some important limitations; to overcome these drawbacks a C-IONM technology has been introduced. CONCLUSIONS: RLN traction injury is still the most common cause of RLN injury and is difficult to avoid with the application of I-IONM in thyroid surgery. C-IONM is useful to prevent the imminent traction injury by detecting progressive decreases in electromyographic amplitude combined with progressive latency increases. C-IONM seems to be a technological improvement. Likely, C-IONM by vagal nerve stimulation should enhance the standardization process, RLN intraoperative information, documentation, protection, training, and research in modern thyroid surgery. Although C-IONM is a promising technology at the cutting edge of research in thyroid surgery, we need more studies to assess in an evidence-based way all its advantages.

Efficacy and safety of orbital radiotherapy for graves' orbitopathy.

CONTEXT: Graves' orbitopathy (GO), when moderate-to-severe and active, requires medical treatment. High-dose glucocorticoids (GCs) represent the first-line treatment. Orbital radiotherapy (OR) has been used for decades, alone or in combination with GCs, but opinions on its efficacy are conflicting. EVIDENCE ACQUISITION: The major source of data acquisition included PubMed strategies. Original articles, systemic reviews and metaanalyses, and other relevant citations were screened. EVIDENCE SYNTHESIS: Randomized clinical trials evaluating the efficacy of OR are limited. However, available data suggest that OR is a safe treatment, which seems to be effective particularly on ocular motility impairment, especially if it is of recent onset. OR seems to be effective also on soft tissue changes, whereas exophthalmos and long-standing extraocular muscle dysfunction are poorly affected. OR efficacy on dysthyroid optic neuropathy is uncertain. The combination of OR and oral GCs is more effective than either treatment alone, suggesting a synergistic effect of the two treatments. There is no available evidence that the addition of OR to iv GCs provides an advantage over iv GCs alone. CONCLUSIONS: OR can be considered a safe second-line treatment for patients with moderate-to-severe and active GO but less effective than GCs. A possible strategy may include its use in combination with iv GCs in patients whose GO has only partially responded to a first-course of iv GCs alone and is still active. Future studies might address the question of whether the combination of iv GCs and OR might represent the first-line treatment for active GO.

Novel treatment modalities for Graves' orbitopathy.

Non-surgical treatments for moderate to severe and active Graves' orbitopathy (systemic glucocorticoids with or without orbital radiotherapy) have limited effects on the underlying autoimmune process causing the disease. Although the clinical responses to treatment are often good, at least one third of patients with Graves' orbitopathy are eventually dissatisfied with the treatment outcome. Progress in our understanding of the autoimmune basis of Graves' orbitopathy (although still incomplete) made it possible, similar to other autoimmune disorders, to envision the use of novel immunomodulating drugs. Among the currently available biologic agents, the CD20+ B cell-depleting agent, rituximab, and tumor necrosis factor-alpha inhibitors are presently the drugs that have the best chance of being employed in the future for the treatment of Graves' orbitopathy. However, randomized, controlled clinical trials to support their use are warranted.

Lower dose prednisone prevents radioiodine-associated exacerbation of initially mild or absent graves' orbitopathy: a retrospective cohort study.

CONTEXT: Radioiodine (RAI) therapy may cause progression of mild or absent Graves' orbitopathy (GO), preventable by oral prednisone. Optimal doses of prednisone are undefined. OBJECTIVE: The aim of this study was to compare the effectiveness of reported doses [starting dose, >0.3 mg/kg body weight (bw)], and lower (<0.3 mg/kg bw)] doses of prednisone. DESIGN AND SETTING: We conducted a retrospective matched cohort study at a University Center. PATIENTS: Of 111 RAI-treated Graves' patients with mild or no GO, 35 received no steroid prophylaxis (absence of GO and/or risk factors for RAI-associated GO progression); 28 received low-dose prednisone (starting dose, 0.16-0.27 mg/kg bw; mean +/- sd, 0.22 +/- 0.03 mg/kg bw; group 1); and 48 received higher doses (group 2). Among the latter, 28 (starting dose, 0.32-0.56 mg/kg bw; mean +/- sd, 0.36 +/- 0.05 mg/kg bw) were matched with group 1 according to several relevant variables. Prednisone was started 1 d after RAI and withdrawn after 6 wk. MAIN OUTCOME MEASURES: We assessed ocular changes (1, 3, and 6 months after RAI) and side effects of prednisone. RESULTS: Two of 35 patients not receiving steroid prophylaxis (6%) developed mild-to-moderate GO (clinical activity score, 2/7 and 3/7) after RAI. No patients in group 1 or group 2 had GO progression. Side effects were very mild and inconstant, although more frequent in group 2. Both groups showed an increase in bw, an increase that was significantly higher in group 2. CONCLUSION: Lower doses of oral prednisone (about 0.2 mg/kg bw) are as effective as previously reported doses (0.3-0.5 mg/kg bw). A shorter treatment period (6 wk) is probably sufficient. The increase in bw is less using lower doses of prednisone.