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.

Management of Graves ophthalmopathy - 2022 update.

Graves ophthalmopathy (GO) occurs in 25-50% cases of Graves disease. Most cases are just mild, only 5% represents eye threatening diseases. About 5-10% of cases could be euthyroid and 10% hypothyroid, respectively. All patients with GO should be assessed for activity (clinical activity score - CAS) and severity of the disease. Essential conditions of the successful treatment are well controlled thyroid dysfunction, smoking cessation and to refer patients with moderate to severe and sight threatening GO to specialized thyroid eye centers as soon as possible. Local therapy to maintain wet eye (lubricants) and supplementation of selenium deficiency is adequate in mild cases of GO. In cases of moderate to severe and sight threatening GO, administration of intravenous glucocorticoids in thyroid eye centers is first line treatment and a combination with mycophenolate or radiotherapy could be considered. When the first-line treatment fails or a contraindication/intolerance to them is present, non-steroid immunosuppressive drugs (mycophenolate, ciclosporin), rituximab, or radiotherapy could be considered. In rare cases of sight threatening GO urge surgical orbital decompression or tarsorrhaphy is warranted.

[REDUCTION OF MORBIDITY RATE IN THYROID EYE DISEASE PATIENTS].

INTRODUCTION: In their review, Vashdi and Gur present the clinical effect of lifestyle modification in patients with Thyroid Eye Disease )TED(. Smoking cessation, controlled levels of lipids and supplemental dietary selenium improved patients' quality of life and slowed TED progression.

[LIFESTYLE ADJUSTMENT AS THERAPEUTIC TOOL IN THYROID EYE DISEASE].

OBJECTIVES: Thyroid Eye Disease (TED), also known as Graves' ophthalmopathy, is the most frequent extrathyroidal manifestation of autoimmune dysthyroidism. The most common ocular signs are eyelid retraction, proptosis, and strabismus, alongside specific dermatopathies. This article aims to review the options to improve TED manifestation by lifestyle adjustment. RESULTS: Tobacco smoking is the strongest risk factor for the development of TED and is associated with increased incidence and severity of TED and reduction in response to treatment. Smoking cessation decreases the incidence of TED and compares the risk level of ex-smokers to the risk level of the general population. Selenium is a chemical element with anti-oxidative properties. Selenium levels were significantly lower in Graves' disease patients with TED compared with those without TED. A double-blinded, randomized-control trial demonstrated that supplementation of selenium was associated with improved quality of life, decreased ocular involvement, and slowed TED progression while taken for a limited period. Statins administration to thyroid patients is associated with a reduced risk of TED. Recently, a few studies have shown an increased risk of developing TED and increased severity depending on the level of lipids in the blood, which suggests that balancing blood lipid levels by statins or by low-fat diet can help prevent TED. CONCLUSIONS: Lifestyle adjustment might be critical for a significant portion of patients. By supporting smoking cessation, the recommendation of selenium supplementation for a limited period and reducing serum cholesterol levels can prevent the development of TED, reduce its severity, and improve the patient's quality of life.

[Graves' orbitopathy]. / Endokrine Orbitopathie.

BACKGROUND: Graves' orbitopathy (GO) is an autoimmune orbital disease which is mostly associated with Graves' disease and requires good interdisciplinary cooperation. To minimize irreversible damages a stage-adapted anti-inflammatory therapy is of great importance. MATERIAL AND METHODS: Discussion of the latest results of new findings of the pathogenesis, randomized controlled trials on anti-inflammatory treatments for Graves' orbitopathy and novel therapeutic concepts. RESULTS: In all patients with GO achieving euthyroidism, as well as cessation of smoking is very important to avoid prolongated diseases. Mild cases of GO can be treated with selenium supplementation and artificial tears. The moderate-to-severe, active form of GO requires primarily i. v. steroids in combination with orbital irradiation in case of impaired motility. In patients with insufficient therapeutic response after 6 weeks, treatment should be switched to other immunosuppressive agents. In severe sight-threatening cases even high-dose i. v. steroid treatments are often ineffective and bony orbital decompression is necessary. As latest research data have improved our understanding of the pathophysiology of GO, targeted therapies have been developed for GO. Teprotumumab, an IGF-1 receptor antibody, was shown effective in treating GO patients in a phase III trial and should soon be awarded approval for Europe. Inactive patients, who suffer from disturbing exophthalmos should be also treated with bony decompression before eye muscle or lid surgery. CONCLUSION: The current concept for Graves' orbitopathy is as follows: first anti-inflammatory therapy then surgical correction of the permanent defects. This might be modified in the future, due to the promising effects of targeted therapies.

A 'Real Life' Service Evaluation Model for Multidisciplinary Thyroid Eye Services.

Background/Aims: There is no universal consensus on the practical implementation and evaluation of the Amsterdam Declaration on Graves Orbitopathy in a Multidisciplinary Thyroid Eye Disease (MDTED) pathway. Recent recommendations from the UK TEAMeD-5 and BOPSS initiative highlight the importance of prevention, screening, and prompt referral of patients with moderate to severe and sight-threatening thyroid eye disease to multidisciplinary (MDTED) clinics and recommends annual auditing. We propose a practical service evaluation model with Key Performance Indicators (KPI) that are achievable and could be implemented across most TED pathways. Material and Methods: We conducted a service evaluation from an integrated TED pathway in London with three MDTED clinics. Data was collected retrospectively from consecutive TED patients included: 1) Patient demographics, 2) Referral to first appointment time, 3) Documented smoking cessation and selenium supplementation advice, 4) Presenting disease activity and severity, 5) Investigations and treatments, including radio-iodine, 6) Time from decision to treatment initiation, 7) Initial and subsequent thyroid status. Results: The median age was 49.0 yrs, 77.5% (183/236) were female and 49.5% (101/204) Afro-Caribbean or Asian. At their first clinic attendance, 47.6% (110/231) were biochemically euthyroid and 76.7% (79/103) at discharge. All 23.1% (52/225) current smokers received smoking cessation advice and 64.8% (153/236) received selenium supplementation advice. Intravenous methylprednisolone was given to 33.9% (80/236) patients and 12.7% (30/236) received second-line immunosuppression. All 7.2% (17/236) patients with sight-threatening disease received treatment within two weeks of diagnosis. Conclusions: This study forms a waymark for other units using TEAMeD-5 and BOPSS audit criteria. Dedicated electronic patient records with ongoing data capture, including quality of life assessments, and diagnostic coding would significantly aid future auditing, improve patient care, and facilitate a national audit of TED management. A future survey when the TED standards have become embedded would be instructive to see whether this has improved TED care.

A prospective randomized controlled clinical trial of Pingmu Decoction combined with acupuncture in the treatment of non-active thyroid-related ophthalmopathy.

BACKGROUND: Thyroid eye disease of orbital disease first, it is main and clinical expression with exophthalmos, visual impairment, serious influence patient's quality of life and beautiful, especially for the non-active Graves' ophthalmopathy, there is no effective treatment methods at home and abroad, for the non-active thyroid eye disease only recommended surgery, but the procedure pain, poor curative effect, postoperative recurrence, most patients are difficult to accept. Pingmu Decoction can effectively reduce the degree of exophthalmus and TCM syndrome integral, and The combination therapy with acupuncture and moxibustion on the basis of Pingmu Decoction has achieved remarkable clinical effect, but the lack of rigorous evidence of evidence-based medicine (ebm). The test is designed to further evaluate flat mesh in active soup combined with acupuncture treatment of thyroid related ophthalmopathy card belongs to the yang qi-deficiency, phlegm and blood stasis block syndrome in patients with clinical efficacy and safety. METHODS/DESIGN: A prospective, randomized controlled clinical trial will be conducted to evaluate the efficacy and safety of Pingmu Decoction combined with acupuncture in the treatment of non-active thyroid-related eye disease in patients with Yang qi deficiency and phlegm-blood stasis syndrome. A total of 120 patients with non-active thyroid-related eye disease, namely deficiency of Yang qi and blockage of phlegm and blood stasis, are randomly divided into 3 groups and treated for 12 weeks. All three groups will maintain basic western medicine treatment. The primary outcomes are to observe the degree of prominence of eyes, and the TCM syndrome scores. The secondary result is clinical efficacy. Free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), and thyroid stimulating hormone receptor antibody (TRAb)will be used as the observation indicators in this study. In addition, adverse reactions will be observed and recorded as safety indicators. DISCUSSION: The results of this trial will provide convincing evidence for the efficacy and safety of Pingmu Decoction combined with acupuncture in the treatment of patients with non-active thyroid-associated eye disease with deficiency of Yang qi and phlegm and blood stasis block, and it will expand the treatment options for patients with non-active thyroid-related eye disease. TRIAL REGISTRATION: Clinical Trials.gov ID: ChiCTR2000039626. Registered on 3 November 2020.

Current and Emerging Treatment Strategies for Graves' Orbitopathy.

Graves' orbitopathy is a debilitating disorder which occurs in patients with autoimmune thyroid disease, mainly Graves' disease, and adds layers of complexity to management of both conditions. We conducted a comprehensive review of literature for publications relating to established and new management options for Graves' orbitopathy and have summarized key articles in this review. Initial evaluation of patients with Graves' disease should also include clinical evaluation for orbitopathy. If eye disease is present, patients are best managed by a multi-specialty team including an endocrinologist and ophthalmologist. All patients with Graves' orbitopathy benefit from risk factor modification and normalization of thyroid function tests. Patients with active, mild disease generally benefit from local therapies and selenium, while patients with moderate-to-severe disease usually require the addition of intravenous glucocorticoid therapy. If there is an inadequate response to glucocorticoid therapy, several second-line therapies have been investigated for use, including orbital radiotherapy (with additional glucocorticoids), rituximab, cyclosporine, mycophenolate mofetil, and methotrexate. Use of new biologic agents, mainly teprotumumab and tocilizumab, have demonstrated impressive reductions in disease activity and severity. If these results are confirmed, the treatment paradigm is likely to change in the future. Finally, there are several novel immunotherapies being investigated for Graves' disease, which may have treatment implications for Graves' orbitopathy as well. Overall, there are many encouraging advances in the therapy of Graves' orbitopathy that are making the future more promising for patients suffering from this disease.

Changing trend in referral to secondary care specialist thyroid eye disease clinic following the Amsterdam declaration.

INTRODUCTION: Early diagnosis and treatment of thyroid eye disease (TED) improves outcomes. Previous studies have highlighted delays in diagnosis and referral to specialist centres. The Amsterdam declaration (2009) aimed to halve the time from presentation to diagnosis and from diagnosis to referral to a specialist centre in five years. A recent study from the European group on Graves' orbitopathy tertiary centres showed a trend for earlier referral of patients to the centres. It is unknown whether similar improvements are occurring in secondary care hospitals in the UK. AIM: To study the trend in referral to a UK secondary care specialist TED clinic since the Amsterdam declaration. METHODS: We carried out a prospective audit of patients who attended the specialist TED clinic after the Amsterdam declaration (2010-2015). We compared their clinical characteristics, including duration of symptoms, disease activity and severity, with those of the patients (n = 114) from an earlier audit attending the clinic during 2004-2008. RESULTS: During 2010-2015, 126 patients with TED (97 females, median age 55 years, 39 current smokers) attended the clinic. The median time from onset of symptoms to being seen in the clinic was 5 months, reduced from 12 months in 2004-2008 (p < 0.001). As compared to the 2004-2008 cohort, significantly more patients in the current cohort presented with mild disease (72 vs. 52%, p = 0.002). Twenty-seven per cent patients had active TED (clinical activity score ≥3/7) compared to 18% in 2004-2008 (p = 0.1). CONCLUSIONS: The trend in referral to secondary care specialist TED clinic is changing in line with the Amsterdam declaration aims.

[Endocrine orbitopathy: the present view of a clinical endocrinologist]. / Endokrinní orbitopatie: aktuální pohled klinického endokrinologa.

Graves orbitopathy (GO) occurs in 25-50 % cases of Graves disease. Only in 5 % of patients the eye threatening GO is present. About 5-10 % and 10 % cases are present in euthyroid and hypothyroid patients respectively. All patients with GO should be assessed for activity (clinical activity score - CAS) and severity of the disease. Basic preconditions of the treatment are maintenance of euthyroidism, an effort to stop smoking, and referring of patients with moderate to severe and sight threatening GO to specialized thyroid eye centers. The first line treatment includes maintenance of wet eye (lubricants), supplementation of selenium deficiency, intravenous glucocorticoids, radiotherapy and surgery. Cases with moderate to severe GO should be treated with intravenous glucocorticoids in thyroid eye centers, however, the risk/benefit ratio in all cases should be considered. Cases with sight threatening GO should be immediately referred to thyroid eye centers, high-dose intravenous glucocorticoids are administered, and when the clinical response is absent within 2 weeks, surgical orbital decompression is recommended. Other immunosuppressive drugs (cyclosporine, mycophenolate mofetil) or biological therapy (teprotumumab) are not routinely recommended because of lack of evidence obtained by randomized controlled trials.Key words: clinical activity score - dysthyroid optic neuropathy - Graves orbitopathy - intravenous glucocorticoids - mycophenolate mofetil.

Bilateral optic nerve edema presenting as initial manifestation of thyroid eye disease.

A 48-year-old smoker with a history of hyperthyroidism treated 10 years prior to presentation with radioactive iodine ablation of the thyroid gland presented to his ophthalmologist with a 2-week history of transient loss of vision in the right eye occurring for 1 to 2 hours each morning. He denied ocular pain, diplopia or change in the prominence of one or both eyes. Examination revealed 2 mm of relative proptosis on the right, bilateral temporal flare and lower lid retraction. There was minimal upper lid retraction and no evidence of lid lag. Ocular motility was full. Dilated fundoscopic examination revealed bilateral optic nerve edema, right more than left. CT of the orbit demonstrated enlargement of the extraocular muscles bilaterally with marked enlargement of the right medial rectus and left inferior rectus muscles resulting in crowding at the orbital apex bilaterally. Laboratory testing revealed the patient to be hyperthyroid. The patient was treated with high dose oral steroids followed by orbital radiation. Hyperthyroidism was managed by the patient's primary care physician. Visual symptoms rapidly improved with oral steroids and orbital radiation. Optic nerve edema completely resolved. Repeat CT imaging demonstrated a reduction in the enlargement of the extraocular muscles with relief of bilateral optic nerve compression.

[Graves' ophthalmopathy]. / Endokrine Orbitopathie.

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease and the full clinical picture can impair the quality of life of the patients considerably. Active inflammation can often be effectively treated by intravenous steroids/immunosuppression, however does not lead to full remission, since inflammation rather quickly results in irreversible fibrosis and increase of orbital fat. Very important is the control of risk factors (smoking cessation, good control of thyroid function, selenium supplementation) to prevent progression to severe stages. Treatment should rely on a thorough assessment of activity and severity of GO. Rehabilitative surgery (orbital decompression, squint surgery, eyelid surgery) is needed in many patients to restore function and appearance. Anti-thyroid-stimulating hormone (TSH) receptor antibodies do specifically occur in these patients and correlate to the course of thyroid and eye disease. The levels of these antibodies can be used for treatment decisions at certain time points of the disease.

[Thyroid orbitopathy, an overview with special attention to the role of radiotherapy]. / Orbitopatía tiroidea, una visión global con atención especial al papel de la radioterapia.

Thyroid orbitopathy is the most prevalent non-thyroid symptom in Graves' syndrome. It has a high incidence and particularly affects young women. Smoking is clearly involved in its development and progress, and in its response to different treatments. This autoimmune condition usually has a benign course, independent from hyperthyroidism, but its severe, progressive forms represent a major therapeutic challenge. Clinical evaluation poses great difficulties, as there is no truly objective rating scale representing disease activity. New molecular or inflammation markers may prove to be useful in this regard. This review reports new findings about its pathophysiology and the different techniques used for treatment over time. Discussion particularly focuses on the immunomodulatory role of radiotherapy, as well as on its role together with corticosteroids.

[Novel treatment opportunities in Graves' orbitopathy]. / Új lehetoségek az endokrin orbitopathia kezelésében.

Graves' orbitopathy is the most common extrathyroidal manifestation of Graves' disease. Up to now, curative treatment modalities for the most severe sight-threatening cases have not been developed. Here the authors summarize the treatment protocol of Graves' orbitopathy and review novel therapeutic options. They review the literature on this topic and present their own clinical experience. The authors point out that anti-CD20 antibody could positively influence the clinical course of Graves' orbitopathy. Selenium is efficient in mild cases. Further prospective investigations are warranted.

Management of patients in a combined thyroid eye clinic in secondary care.

The European Group on Graves' Orbitopathy (EUGOGO) recommends the use of specialised multidisciplinary clinics for the management of thyroid eye disease (TED). In the UK, many patients with TED are managed outside of specialised clinics. We describe the organisation of a combined TED clinic in a secondary care setting and present the result of a prospective audit of the patient characteristics and outcomes during the first four years of a combined TED clinic. Of a total of 132 patients referred to the TED clinic, 114 (86 %) had TED (90 females, median age 56 years; range 17-90 years). At presentation, 77 (67 %) were current or ex-smokers and 99 (87 %) were biochemically euthyroid. Median duration of eye symptoms was 12 months. Fifty-two percent, 45 and 3 had mild, moderate-to-severe and sight-threatening TED, respectively. Only 18 % of patients had a clinical activity score (CAS) of ≥3. Sixty-nine patients (61 %) required follow-up appointments in the TED clinic. In those who required follow-up, 43 % (n = 30) received either immunosuppressive or surgical treatment. CAS improved from first to final visit, with 29 % (n = 20) having a CAS of ≥3 at the first visit and 1 % (n = 1) at the final visit (p = 0.0001). There was also a decrease in prevalence of smoking and thyroid dysfunction at the final visit. A multidisciplinary specialised TED clinic offers an optimal setting for managing patients with TED; however, patients are often referred late to a specialist TED clinic.

Immunotherapy in miscellaneous medical disorders Graves ophthalmopathy, asthma, and regional painful syndrome.

In Graves ophthalmopathy, immunotherapy is offering an opportunity of reducing bad outcomes that lead to disfigurement and impairment of vision. These therapies are not perfect; however, we now have a chance to achieve better outcomes. In asthma, immune therapy using passive immunity targeting key proinflammatory cytokine/chemokines and medications of their effects has opened an avenue of research into a safe and durable therapy. Omalizumab appears to be safe and effective in clinical use. In regional pain syndrome, immune mechanisms may be involved in sustaining long-standing pain, and IVIG may moderate pain sensitivity by reducing immune activation.

Treatment of mild, moderate-to-severe and very severe Graves' orbitopathy.

Treatment of Graves' orbitopathy (GO) is better performed through a multidisciplinary approach. Euthyroidism should be promptly restored. Antithyroid drug and thyroidectomy are not disease-modifying treatments, whereas radioiodine may be associated with worsening of GO. This risk is eliminated by glucocorticoid prophylaxis. Treatments for GO differ depending on its severity and activity. Mild forms should be treated with local measures. In addition a course of selenium may be beneficial. Glucocorticoids (oral or intravenous) represent the main treatment of moderate-to-severe GO, the intravenous route being more effective. Weekly pulses of methylprednisolone are used and the cumulative dose should not exceed 8 g. Severe adverse events have been reported, particularly with higher doses. Orbital radiotherapy can be used either alone or associated with glucocorticoids. In very severe sight-threatening GO high dose intravenous glucocorticoid should be the initial treatment, orbital decompression being considered in nonresponding patients. Rehabilitative surgery should be deferred until GO becomes inactive.