Prevention of Orbitopathy by Oral or Intravenous Steroid Prophylaxis in Short Duration Graves' Disease Patients Undergoing Radioiodine Ablation: A Prospective Randomized Control Trial Study.

Background: Radioiodine (RAI) is a known risk factor for activation or de novo occurrence of Graves' orbitopathy (GO). Several studies demonstrated that GO can be prevented by glucocorticoids (GCs) in patients with pre-existing GO. We have previously shown that Graves' disease duration (GDd) <5 years is a risk factor for RAI-induced GO. We studied the effect of prophylaxis with either oral GCs (OGCs) or intravenous GCs (IVGCs) on GO activation in patients with GDd. Methods: In total, 99 hyperthyroid patients without GO or with pre-existing inactive GO with GDd <5 years were randomized to receive IVGCs (N = 49) or OGCs (N = 50) before RAI; 22 patients with GDd >5 did not receive steroids and were studied as controls. All patients underwent ophthalmological assessment before and 45, 90, 180 days and for a 5-year follow-up after RAI. Serum thyrotropin (TSH) receptor antibodies (TRAbs), thyroid hormones, and thyroid volume (TV) were also measured in response to RAI therapy and steroid prophylaxis. Results: No patient on prophylaxis developed GO after RAI. One woman of the control group, without steroid prophylaxis, and who had a marked elevation of her TSH, showed transient reactivation of GO, which spontaneously improved after restoring euthyroidism. On follow-up at 12 and 20 months after RAI, two patients developed overt optic neuropathy. A smaller TV was associated with a higher prevalence of RAI-induced hypothyroidism. Serum TRAbs increased significantly after RAI (p < 0.0001) but less in patients receiving steroids than in those without prophylaxis at 45 days (p < 0.01). Conclusions: The risk of RAI-induced GO can be prevented in all patients with GDd <5 years by steroids. Such treatment may not be necessary in patients with GDd >5 years. The blunting of TRAb elevation after RAI may be related to the prophylactic effect of steroids.

[Interaction between cigarette smoking and glucocorticoids therapy and therapeutic doses of radioiodine (131I) in patients with Graves' disease].

The present study evaluated the effects of smoking on the amount of therapeutic doses of radioiodine ((131)I) given to patients with Graves' disease (GB). The study also retrospectively analyzed the relationship between the onset of symptoms of thyroid ophthalmopathy (OT) after treatment with (131)I within 2 years and changes of TSHR-Abs levels, and the impact of prednisone administration before and after the therapy on OT development in both smoking and non-smoking patients. Materials and Methods: The study group included 116 patients, 97 women and 19 men, aged 28 ÷ 77 years (average 51 years) who were diagnosed with GB and treated with therapeutic doses of (131)I. Of the 116 patients treated, 85 patients were given a single dose of (131)I, whereas in 31 patients, due to recurrent hyperthyroidism, there was a need for a second dose of (131)I. In the group of 85 studied patients who received a single therapeutic dose of (131)I, 34 patients were smokers, including 27 women and 7 men, whereas in the group of 31 patients with recurrent hyperthyroidism who received repeated doses of 131I, 21 patients were smokers, 17 women and 4 men. Patients qualified for the therapy with (131)I and diagnosed with mild OT, were given prednisone, administered orally with an initial dose of 0.4 - 0.5 mg/kg daily tapering within 4-6 weeks. Results: The results of the study demonstrated that there was a statistically significant relationship (p<0.05) between cigarette smoking and the number of administered therapeutic doses of (131)I in patients with GD. Smoking patients needed to be given the second therapeutic dose of (131)I more frequently. The relationship between the onset of symptoms of OT in patients with GD and the TSHRAb in serum within two years after (131)I administration was highly significant (p<0.0001). The results obtained in our study showed that efficacy of therapy was lower in smokers with GD when compared with non-smokers Since the increased titer of TSHR-Ab was associated with higher risk of OT development, especially in smokers, its routine measurement after (131)I administration could be considered in all treated patients with GD. Steroid prophylaxis should be recommended for each smoking GD patient with mild OT qualified for (131)I therapy.

Statin reduces orbitopathy risk in patients with Graves' disease by modulating apoptosis and autophagy activities.

Statins use has been associated with reduced risk for developing orbitopathy among patients with Graves' disease. We hypothesize that statin reduces orbitopathy risk mainly by modulating both apoptosis and autophagy activities in patients with Graves' disease.

Comparative Efficacy of Four Treatments in Patients with Graves' Disease: a Network Meta-analysis.

BACKGROUND: The question of which treatment should be preferred for the treatment of Graves' disease is debatable, and pairwise meta-analyses could not obtain hierarchies of these treatments. Our intention was to integrate the evidence to provide hierarchies of the comparative efficacy of 4 treatments (radioiodine, radioiodine+prednisone, antithyroid drugs and surgery). METHODS: We conducted a Bayesian-framework network meta-analysis of randomized controlled trials (RCTs) to compare 4 treatments in patients with Graves' disease. The eligible RCTs were identified by searching Amed, the British Nursing Index, Embase, PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Google scholar, SIGLE, the National Technical Information Service, the National Research Register (UK) and the Current Controlled Trials databases. The data for 2 outcomes (e.g., ophthalmopathy and recurrence) were independently extracted by 2 authors. RESULTS: A total of 4 RCTs were ultimately included. Radioiodine+prednisone therapy showed statistical significance in reducing the incidence of new or deteriorative ophthalmopathy comparing with the other 3 therapies. Compared with radioiodine, therapy with antithyroid drugs therapy as well as surgery significantly decreased the incidence of new or deteriorative ophthalmopathy. Radioiodine therapy significantly reduced the rate of recurrence when compared to therapy with antithyroid drugs or surgery. For decreasing the incidence of new or deteriorative ophthalmopathy, the 4 treatments were ranked as follows: radioiodine+prednisone therapy, therapy with antithyroid drugs, surgery and radioiodine therapy. For reducing the rate of recurrence, 3 treatments were ranked as follows: radioiodine therapy, therapy with antithyroid drugs and surgery. CONCLUSIONS: Radioiodine+prednisone therapy might have the least probability of leading to an exacerbation or new appearance of ophthalmopathy, and radioiodine therapy might have the least probability of causing a recurrence.

Extrathyroidal manifestations of Graves' disease: a 2014 update.

INTRODUCTION: Graves' orbitopathy (GO), thyroid dermopathy (also called pretibial myxedema) and acropachy are the extrathyroidal manifestations of Graves' disease. They occur in 25, 1.5, and 0.3 % of Graves' patients, respectively. Thus, GO is the main and most common extrathyroidal manifestation. Dermopathy is usually present if the patient is also affected with GO. The very rare acropachy occurs only in patients who also have dermopathy. GO and dermopathy have an autoimmune origin and are probably triggered by autoimmunity to the TSH receptor and, likely, the IGF-1 receptor. Both GO and dermopathy may be mild to severe. MANAGEMENT: Mild GO usually does not require any treatment except for local measures and preventive actions (especially refraining from smoking). Currently, moderate-to-severe and active GO is best treated by systemic glucocorticoids, but response to treatment is not optimal in many instances, and retreatments and use of other modalities (glucocorticoids, orbital radiotherapy, cyclosporine) and, in the end, rehabilitative surgery are often needed. Dermopathy is usually managed by local glucocorticoid treatment. No specific treatment is available for acropachy. PERSPECTIVES: Novel treatments are presently being investigated for GO, and particular attention is paid to the use of rituximab. It is unknown whether novel treatments for GO might be useful for the other extrathyroidal manifestations. Future novel therapies shown to be beneficial for GO in randomized studies may be empirically used for dermopathy and acropachy.

Cohort study on radioactive iodine-induced hypothyroidism: implications for Graves' ophthalmopathy and optimal timing for thyroid hormone assessment.

BACKGROUND: Graves' ophthalmopathy (GO) develops or worsens in up to one-third of patients treated with radioactive iodine (RAI) for Graves' hyperthyroidism. We sought to identify the prevalence of development or worsening of GO in patients treated with RAI for Graves' hyperthyroidism and to identify the risk factors associated with that outcome. METHODS: We identified a retrospective cohort of consecutive patients treated with RAI at Mayo Clinic (Rochester, MN) between 2005 and 2006. We assessed their medical records for evidence of hypothyroidism and development or worsening of GO in the year after therapy. Hypothyroidism was defined as thyrotropin >3.0 mIU/L or free thyroxine <0.8 ng/dL. RESULTS: We identified 291 consecutive patients who received RAI therapy during the study period, with 195 out of 291 having complete follow-up data for a one-year period. GO was present in 46 out of 195 patients (23.6%) at baseline. After RAI treatment, GO developed or worsened in 25 out of 195 patients (12.8%) and it was associated with hypothyroidism at first follow-up (p=0.011) with an odds ratio (OR) of 3.3 [95% confidence interval (CI) 1.3-8.7]. More smokers than nonsmokers developed new or worse GO (17.7% vs. 11.8%), but that difference did not reach statistical significance (p=0.35). Preexisting GO (24% of patients) was associated with a higher risk for negative GO outcome compared with patients who had no GO at baseline (11%; p=0.021). Both development of hypothyroidism by the first visit after RAI therapy (OR 3.6) and preexistent GO (OR 2.8) remained significant in a multivariate analysis. Development of hypothyroidism was more likely in patients with longer duration to first follow-up (p<0.001). By 6-8 weeks after RAI treatment, the prevalence of hypothyroidism was ∼40%, while that of hyperthyroidism was only 20%. CONCLUSIONS: The presence of hypothyroidism at the first assessment of thyroid function after RAI administration is a strong predictor for adverse GO outcome. This risk is highest in patients with preexisting GO. We suggest that in order to prevent clinical hypothyroidism and the associated risk for GO, the optimal time for first measurement of fT4 is before 6 weeks after RAI therapy.

Antifibrotic effects of quercetin in primary orbital fibroblasts and orbital fat tissue cultures of Graves' orbitopathy.

PURPOSE: We investigated the effects of quercetin on fibrotic markers and matrix metalloproteinases (MMPs) in primary cells and whole orbital tissues from Graves' orbitopathy (GO). METHODS: Orbital fat tissues were harvested from GO for primary cell and tissue cultures during orbital fat decompression. To determine noncytotoxic dose and time of quercetin treatment, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and LDH release assay were performed. The effects of quercetin on fibrosis were evaluated according to a scratch wound closure assay, and Western blotting for expression of fibronectin, collagen Iα, α-smooth muscle actin with or without TGF-ß stimulation, and MMP-2, -7, -9, and tissue inhibitor of metalloproteinase-1 with or without IL-1ß stimulation. The gelatinolytic activities of MMP-2 and MMP-9 were measured using gelatin zymography. In tissue cultures, MMP secretion and MMP and collagen Iα mRNA levels were determined by enzyme-linked immunosorbent assays and reverse transcription-polymerase chain reaction (RT-PCR), respectively. RESULTS: Quercetin significantly inhibited cell migration at nontoxic concentrations. In primary cells, quercetin dose-dependently downregulated expression of TGF-ß-stimulated fibronectin and collagen Iα, and IL-1ß-enhanced MMP-2 and MMP-9. However, without IL-1ß stimulation, 10-50 µM of quercetin increased MMP-2 expression and activity, but dose-dependently suppressed MMP-9 expression and activity. In tissue cultures, quercetin dose-dependently inhibited MMP-2 and -9 activity and secretion, but 30 and 50 µM of quercetin increased tissue MMP-2 mRNA. MMP-9 and collagen Iα mRNA levels were dose-dependently suppressed. CONCLUSIONS: Quercetin inhibited fibrotic markers and affected MMP-2 and MMP-9 activities in primary cell and orbital fat tissue cultures from GO at nontoxic concentrations. Our results support the potential use of quercetin for active inflammation and treatment or prevention of chronic fibrosis in GO.

Prevention of Graves' ophthalmopathy.

Smoking is the most important risk factor for the occurrence/progression of Graves' ophthalmopathy (GO), as well as for its lower/slower response to immunosuppression. Accordingly, refrain from smoking should be urged, both as primary prevention (removal of risk factors in Graves' patients without GO), secondary prevention (early detection and treatment of asymptomatic/very mild GO) and tertiary prevention (reduction of complications/disability of overt GO). A 6-month course of 200 µg/day sodium selenite can prevent progression of mild GO to more severe GO and is, therefore, a form of secondary prevention and, probably, primary prevention. Correction of thyroid dysfunction and stable maintenance of euthyroidism are important preventive measures. The optimal treatment for hyperthyroidism in patients with GO is uncertain, because evidence demonstrating the superiority of antithyroid drugs over thyroid ablation (radioiodine, thyroidectomy, or both) is lacking. If radioiodine is used, low-dose steroid prophylaxis is recommended, particularly in smokers, to prevent radioiodine-associated GO progression.

Incidence and clinical presentation of moderate to severe graves' orbitopathy in a Danish population before and after iodine fortification of salt.

CONTEXT: Population-based data on the incidence and clinical presentation of moderate to severe Graves' orbitopathy (GO) are scarce, and virtually nothing is known on the effect of an iodization program on the incidence and presentation of GO. OBJECTIVE: The objective of the study was to characterize incident moderate to severe GO in North Jutland County, Denmark, during the period 1992-2009, before and after the Danish salt iodization program. DESIGN AND PATIENTS: The design of the study was a prospective register of patients with incident moderate to severe GO in a population during 8.9 million persons × years of observation. SETTING: The study was conducted at a thyroid-eye clinic of university hospital. MAIN OUTCOME MEASURES: Clinical presentation and incidence before and after the year 2000 initiation of the mandatory Danish iodization of salt were measured. The incidence of GO was related to the incidence of Graves' hyperthyroidism (GH) in the same population. RESULTS: The incidence rate of moderate to severe GO was 16.1/million per year (women: 26.7; men: 5.4), with no change associated with iodization of salt. The moderate to severe GO incidence was 4.9% of the incidence of GH. The incidence rate ratio between women and men with GO (4.9) was not different from the ratio in GH. Compared with GH, only a few patients (<2%) suffered from moderate and severe GO below the age of 40 yr, whereas GO was relatively common in age groups 40-60 yr (∼8%). CONCLUSIONS: Approximately 5% of the patients with Graves' disease develop moderate to severe GO, with a similar risk in women and men with Graves' disease. The risk of GO is much higher in patients aged 40-60 yr than in young patients with Graves' disease. Salt iodization was not associated with a change in the incidence of GO.

Randomized clinical trial of bilateral subtotal thyroidectomy versus total thyroidectomy for Graves' disease with a 5-year follow-up.

BACKGROUND: The extent of thyroid resection in Graves' disease remains controversial. The aim of this study was to evaluate long-term results of bilateral subtotal thyroidectomy (BST) compared with total thyroidectomy (TT) in patients with Graves' disease and mild active ophthalmopathy. METHODS: Participants were assigned randomly to BST or TT, and followed for 5 years after surgery. The primary endpoints of the study were the prevalence of recurrent hyperthyroidism and changes in Graves' ophthalmopathy. Secondary endpoints were postoperative transient and permanent paresis of the recurrent laryngeal nerve, and postoperative hypocalcaemia and hypoparathyroidism. RESULTS: Two hundred patients were included, of whom 191 (BST 95, TT 96) completed the 5-year follow-up. Recurrent hyperthyroidism occurred in nine patients after BST and in none after TT (P = 0·002). Progression of Graves' ophthalmopathy was observed in nine patients after BST compared with seven following TT (P = 0·586). Transient hypoparathyroidism occurred in 13 and 24 patients respectively (P = 0·047). Permanent hypoparathyroidism was diagnosed in no patient after BST and in one after TT (P = 0·318). No differences were noted in transient or permanent recurrent laryngeal nerve injury. CONCLUSION: TT for Graves' disease prevented recurrent hyperthyroidism but did not prevent the progression of ophthalmopathy compared with BST.

Thyroid associated orbitopathy--medication, radioiodine or operation?

This paper presents the current state of knowledge on the treatment of ophthalmopathy in the process of the Grave's disease. The question of prevention occupies a special place in the process of treatment as it has been clearly shown that exophthalmos is strongly associated with cigarette smoking. Therefore, before proceeding with any treatment, the patient should be advised to quit smoking as soon as possible. Further on in the publication, various forms of therapy are presented. Because of the unknown etiology, only symptomatic treatment can be applied, which includes steroids, radiotherapy and surgery. Patient care of patients with ophthalmopathy is a challenge even for an experienced clinician. Each case requires an individual approach that would take into account the severity of eye changes.

The tale of radioiodine and Graves' orbitopathy.

BACKGROUND: Autoimmunity against the thyrotropin receptor (TSH-R) is a key pathogenic element in Graves' disease (GD) and the autoimmune aberration may be modified by antithyroid treatment. An association between radioactive iodine (RAI) therapy for GD and the development or worsening of Graves' orbitopathy (GO) is widely quoted. RAI-associated leakage of thyroid antigen(s) leads to an increased production of TSH-R antibodies that may initiate the eye injury. SUMMARY: RAI therapy leads to prolonged worsening of autoimmunity against the TSH-R, and the number of patients entering remission of TSH-R autoimmunity is considerably lower than with other antithyroid therapies. Scientific evidence has indicated that RAI treatment for GD is associated with increased risk of occurrence or progression of GO compared with antithyroid drugs (ATD) and thyroid surgery. The risks of developing new GO or worsening of preexisting GO is around 20% after RAI and around 5% after ATD. The risk of developing severe GO after RAI is around 7%. Smoking, high levels of pretreatment serum triiodothyronine, and post-RAI hypothyroidism are associated with increased risk of GO, whereas a high TSH-R autoantibody titer is an independent risk factor for the progression of GO. In patients with mild preexisting GO, steroid prophylaxis is effective in preventing deterioration of GO. Also, routine use of prophylactic oral steroids with RAI therapy should be considered in GD patients without overt GO, but even more so in those at higher risks of eye complications such as smokers, old men, and those with severe hyperthyroidism or high TSH-R antibody titers. CONCLUSION: In contrast to ATD, remission of TSH-R autoimmunity after RAI therapy is less common, and RAI for GD is associated with definite increased risk of GO. Oral steroids are beneficial for patients with preexisting GO, particularly smokers.

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.

Antifibrotic effect of Pirfenidone on orbital fibroblasts of patients with thyroid-associated ophthalmopathy by decreasing TIMP-1 and collagen levels.

PURPOSE: The aim of this study was to determine the antifibrotic effects of pirfenidone in orbital fibroblasts of patients with thyroid-associated ophthalmopathy (TAO). METHODS: The effects of interleukin (IL)-1beta and of fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor (TGF)-beta on the induction of tissue inhibitors of metalloproteinases (TIMP)-1 were assessed in orbital fibroblasts of TAO patients. TIMP-1 protein levels were measured by ELISA and Western blot analyses, and TIMP-1 activity was assessed by reverse zymography. The effect of pirfenidone on TIMP-1 induction in orbital fibroblasts was evaluated with the same methods using dexamethasone as a reference agent. A hydroxyproline assay was used to determine the effect of pirfenidone and dexamethasone on collagen production in orbital fibroblasts, and the tetrazolium-based MTT assay was used to assess pirfenidone cytotoxicity. RESULTS: IL-1beta strongly and dose dependently increased the level of active TIMP-1 protein, whereas FGF, PDGF, and TGF-beta did not significantly induce TIMP-1 protein. Pirfenidone was more effective than dexamethasone in inhibiting IL-1beta-induced increases in TIMP-1, reducing TIMP-1 levels to less than those in untreated controls at a minimal concentration (5 mM). Moreover, pirfenidone effectively decreased hydroxyproline levels in orbital fibroblasts, whereas dexamethasone had no effect on hydroxyproline levels. Pirfenidone exhibited no toxicity in orbital fibroblasts at the concentrations used. CONCLUSIONS: These results indicate that nontoxic concentrations of pirfenidone have significant antifibrotic effects on orbital fibroblasts from patients with TAO.

Graves' orbitopathy activation after radioactive iodine therapy with and without steroid prophylaxis.

CONTEXT: The reactivation of Graves' orbitopathy (GO) after radioiodine (RAI) for Graves' disease (GD) is a known effect, and its clinical relevance is controversial. Prevention of RAI-induced GO activation is possible in at-risk patients with oral glucocorticoids (OGC). OBJECTIVES: The aim of the study was to analyze the effects of RAI on GO with or without prophylactic steroids based on known risk factors and to compare the effectiveness of prophylaxis with iv glucocorticoids (IVGC) and OGC. DESIGN: We conducted a retrospective study in which patients were assessed before and 1-12 months after RAI. PATIENTS AND SETTING: A total of 113 patients were included in the study; 83 underwent RAI without prophylactic steroids for the absence of risk of activation, and 30 were treated with either OGC (n = 21) or IVGC (n = 9). MAIN OUTCOME MEASURES: We analyzed the prevalence of GO activation with or without steroid prophylaxis and the difference in the prevalence of GO activation after OGC or IVGC. RESULTS: GO activation was observed in 7.2% of patients without and 33.3% of patients with steroid prophylaxis (P < 0.0001), for an overall prevalence of 14.6%. GO activation occurred in 47.6% of patients treated with OGC but in none of the nine patients treated with IVGC (P = 0.0001). Disease activation was more prevalent in males (P < 0.02) and in older patients (P = 0.04) with a shorter duration of GD (P < 0.01) and time from GO onset (P < 0.01). CONCLUSIONS: GO may occur after RAI in approximately 15% of patients also in the absence of signs of active GO. Prophylactic OGC did not prevent GO activation in a large proportion of patients, compared to IVGC.