Review Article

Graves Orbitopathy: Update on Diagnosis and Therapy Eugen Melcescu, MD, William B. Horton, MD, Daniel Kim, MD, Vani Vijayakumar, MD, James J. Corbett, MD, Kimberly W. Crowder, MD, Karen T. Pitman, MD, Gabriel I. Uwaifo, MD, and Christian A. Koch, DrMedHabil Abstract: Graves orbitopathy (GO) is an autoimmune disorder representing the most frequent extrathyroidal manifestation of Graves disease. It is rare, with an age-adjusted incidence of approximately 16.0 cases per 100,000 population per year in women and 2.9 cases per 100,000 population per year in men. GO is an inflammatory process characterized by edema and inflammation of the extraocular muscles and an increase in orbital connective tissue and fat. Despite recent progress in the understanding of its pathogenesis, GO often remains a major diagnostic and therapeutic challenge. It has become increasingly important to classify patients into categories based on disease activity at initial presentation. A Hertel exophthalmometer measurement of 92 mm above normal for race usually categorizes a patient as having moderate-to-severe GO. Encouraging smoking cessation and achieving euthyroidism in the individual patient are important. Simple treatment measures such as lubricants for lid retraction, nocturnal ointments for incomplete eye closure, prisms in diplopia, or botulinum toxin injections for upper-lid retraction can be effective in mild cases of GO. Glucocorticoids, orbital radiotherapy, and decompression/rehabilitative surgery are generally indicated for moderate-to-severe GO and for sight-threatening optic neuropathy. Future therapies, including rituximab aimed at treating the molecular and immunological basis of GO, are under investigation and hold promise for the future.

Key Words: glucocorticoids, Graves disease, orbitopathy, rituximab, thyroid-stimulating immunoglobulin

A

s an autoimmune disorder, Graves orbitopathy (GO) represents the most common and most important extrathyroidal manifestation of Graves disease, which at times can be associated with other autoimmune disorders and thyroid cancer.1Y5 Most hyperthyroid patients with Graves disease do not have GO, although approximately 20% have mild and inactive GO, 6% have moderate-to-severe and active GO, and fewer than 1% have sight-threatening GO with dysthyroid optic neuropathy (ON).6 In a few patients (initially euthyroid or hypothyroid), GO precedes hyperthyroidism.7Y10 Rather than being a complication of Graves disease, GO seems to be a concomitant expression of the same underlying pathological autoimmune process directed against cross-reactive autoantigens in the thyroid and retrobulbar tissues.5,11Y13 The prevalence of GO is 2.9 cases per 100,000 population per year in men and 16.0 cases per 100,000 population per year in women, with a peak in the fifth and seventh decades.5,13,14

Risk Factors for Developing GO From the Departments of Medicine, Radiology/Nuclear Medicine, Neurology, and Ophthalmology, University of Mississippi Medical Center, Jackson, the Department of Ophthalmology, GV (Sonny) Montgomery VA Medical Center, Jackson, Mississippi, and the Department of Medicine/Endocrinology, Louisiana State University Health Sciences Center, New Orleans. Reprint requests to Prof Christian A. Koch, Department of Medicine, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216. Email: [email protected] G.I.U. receives grant funding from Johnson & Johnson, Boehringer Ingelheim, and Eli Lilly. C.A.K. is a member of the advisory boards for Ipsen Pharmaceutical, Corcept Therapeutics, and GLC; he received grant funding from Otsuka for a clinical trial; he is a member of the speakers’ bureau for Ipsen Pharmaceutical and the American Association of Clinical Endocrinologists; and he receives royalties from Springer Publishing and payments for the development of educational presentations for ENDOTEXT.org:emedicine. The other authors have no financial relationships to disclose and no conflicts of interest to report. Accepted June 4, 2013. Copyright * 2014 by The Southern Medical Association 0038-4348/0Y2000/107-34 DOI: 10.1097/SMJ.0000000000000038

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Women are more predisposed than men to develop GO, with a 3.4:1 female:male ratio in those without apparent ocular involvement, a 2.1:1 ratio for those with GO, and a 0.7:1 ratio

Key Points & Graves orbitopathy is the most frequent extrathyroidal manifestation of Graves disease, which occurs most frequently in the hyperthyroid state but can occur in euthyroid and hypothyroid patients. & Therapy is chosen based on scoring of active inflammation and evidence of disease progression. & Traditional nonsurgical therapies include immunosuppression with glucocorticoids and orbital radiotherapy. Future therapies, including rituximab aimed at treating the molecular and immunological basis of Graves orbitopathy, are under investigation and hold promise for the future.

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Review Article

for those with euthyroid Graves disease.7 The disease also tends to be more severe in women.4 Severe manifestations of GO may include loss of vision (sight-threatening dysthyroid ON) or corneal breakdown.1,5 Complex interactions among genetic, environmental, endogenous, and local factors could influence the development and severity of GO.13,15 Several risk factors have been shown to contribute to the progression of orbitopathy after radioactive iodine (RAI) therapy for Graves disease, including cigarette smoking; severe hyperthyroidism (serum triiodothy ronine concentration Q5 nmol/L); high levels of thyroid-stimulating hormone receptor (TSH-R) antibodies, especially TSH-R-stimulating antibodies; and poorly controlled hypothyroidism after RAI therapy.16Y20 There is a 1.3-fold increase in the risk of developing clinical orbitopathy and 3.1-fold increase in the risk of developing proptosis and diplopia for smokers. Current smokers seem to have a higher risk for GO than former smokers.21 The treatment of GO with orbital radiotherapy and high-dose steroids appears to be negatively influenced by cigarette smoking.18 Patients with euthyroid function seem to have a mild disease course.16,20,22,23 Increased TSH-R activation (by thyroidstimulating immunoglobulin [TSI] in hyperthyroidism and TSH in hypothyroidism) leads to an increased expression and release of antigens, followed by an autoimmune reaction directed against them in the thyroid and orbit, resulting in progression of GO.1 Radioiodine treatment carries a small risk of causing progression of eye disease in approximately 15% of cases.24

influence the course of disease in the early, active intraorbital inflammatory phase. GO is characterized by edema and inflammation of the extraocular muscles, and an increase in orbital connective tissue and fat. The most common clinical appearance is upper and lower eyelid retraction of varying degrees (Fig. 1). The increased orbital volume leads to increased pressure within the orbit, resulting in a secondary decrease in venous and lymphatic drainage of the orbit.26 The T helper 1 (TH1) pattern (interleukin [IL]-1, IL-2, interferon-F, tumor necrosis factor->) appears to predominate in recent-onset GO, whereas the TH2 pattern (IL-4, IL-5, IL-10) more often is associated with remission.13,27 This underscores the importance of TH1 chemokines in the initiation of GO. Cytokine stimulation can furthermore lead to the release of CXCL9 and CXCL11 chemokines from thyrocytes and retrobulbar cell types from patients with Graves disease.28,29 An interaction between the activated CD4 T cells and local fibroblasts results in the release of cytokines into surrounding tissue, stimulating the expression of immunomodulatory proteins in orbital fibroblasts. The increase in connective tissue volume and the fibrotic restriction of extraocular muscle involvement resulting from fibroblast stimulation leads to the clinical manifestation of orbitopathy. The orbital cell target of the autoimmune processes is represented primarily by fibroblasts and adipocytes; however, eye muscle cells (with their antigens) may play a secondary role in maintaining the ongoing autoimmune reactions in the orbit.1,14

Pathogenesis

Diagnostic Markers and Imaging in Thyroid-Associated Orbitopathy

GO is an inflammatory process in which orbital connective tissue becomes inflamed and accumulates the glycosaminoglycan hyaluronan. This accumulation leads to extensive remodeling of orbital tissue with resultant ophthalmic and orbital sequelae.25 The disease presents with well-known stages and immunosuppressive or immunomodulatory treatment may

Serum Markers of GO Graves diseaseYspecific antibodies include TSH-R antibodies and TSI. TBII is another name for TSH-R antibodies and its use is fading in the literature. TSI is a bioassay, detects lower

Fig. 1. Signs of eyelid retraction seen in Graves orbitopathy (occurs in 50% of patients). A, Demonstrates bilateral lid retraction without associated proptosis. B, Shows bilateral lid retraction with bilateral proptosis. C, Exhibits unilateral lid retraction and unilateral proptosis. D, Shows lid lag in down gaze. Southern Medical Journal

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Melcescu et al

& Graves Orbitopathy: Update on Diagnosis and Therapy

levels of TSH-R autoantibodies, and is used to differentiate Graves disease from Hashimoto thyroiditis and to evaluate subclinical Graves disease during pregnancy.30 There is good correlation between TSI and clinical activity.31 Serial TSI measurements during the clinical inflammatory phase may help direct clinical decision making.32 Downward trends in TSI levels and GO scores indicate initiation of the cicatricial phase, which prompts consideration of rehabilitative surgery. Retrobulbar cell types participate in the self-perpetuation of inflammation by releasing chemokines under the influence of cytokines. It has been suggested that CXCL10 is a marker of active GO.33

Imaging in GO Orbital computed tomography (OCT) is a modern investigative tool with moderate cost and good resolution for imaging orbital structures. Low-density (fat) and higher-density images (eg, orbital muscle, optic nerve) with 1-mm slice thickness are useful in identifying the kind of remodeling taking place in the orbit.25,34,35 Mean values for the volume of normal extraocular muscle and orbital fat have been defined.36 Unilateral GO, by clinical examination, appears to be bilateral in 50% to 75% of patients by OCT, with an asymmetric extraocular muscle enlargement in approximately 30% of the cases. Some of the OCT findings that are most suggestive of GO are increased volume

of the extraocular muscles (spindle-like thickening 94 mm), recti muscle involvement (inferior 9 medial 9 superior), vascular engorgement, sinus involvement, occasional slight bowing of the medial orbital wall (‘‘Coca-Cola sign’’), and compression of the optic nerve by enlarged extraocular muscles and rarely by lacrimal gland enlargement.34 Magnetic resonance imaging (MRI) provides high-quality orbital anatomic detail and helps clinicians to assess disease activity in patients with GO. Compared with CT, MRI provides better tissue differentiation and is more sensitive to alterations in water content or hydrogen concentration. T2-weighted images yield great information about tissue composition within the orbit and provide high sensitivity for demonstrating edema within extraocular rectus eye muscles and orbital fat. Orbital MRI is indicated in patients with thyroid disease and decreased vision, for delineation of inflammatory from fibrotic disease when it is uncertain whether medical or surgical intervention is appropriate, and to monitor the progress of disease or response to treatment.34 Another useful investigative tool for GO has been octreoscan (Mallinckrodt, Hazelwood, MO), which is considered extremely sensitive for assessing orbital tissue inflammation and response to medical treatment. It also is useful for evaluating disease activity when clinical signs are not clear, if MRI is not available, and occasionally before initiation of medical therapy.34

Fig. 2. Bilateral optic nerve and retinal striae seen in Graves orbitopathy. A, Demonstrates optic nerve swelling and retinal striae seen in a patient’s right eye before treatment. Visual acuity at this time was 20/100. B, Shows the patient’s left eye before treatment with visual acuity of 20/200. C, Shows the right eye posttreatment with visual acuity restored to 20/20. D, Demonstrates the left eye posttreatment with visual acuity restored to 20/20.

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Review Article

Orbital ultrasound (performed with A and B scans) is useful in the detection of extraocular muscle defects, but it is less reliable than MRI.37 It may, however, accurately diagnose GO and measure orbital muscle thickness in patients after radiotherapy.38 Color doppler imaging is useful for assessing blood flow velocity of orbital vessels. Pathological findings in GO are related to an enhanced blood flow velocity in the orbital artery and a low blood flow velocity in the superior orbital vein in patients with moderate-to-severe disease. As in other disorders involving the central nervous system, measurement of visual evoked cortical potentials (VECPs) are important in the assessment of optic nerve impairment and ON in GO.

Manifestations of ON Seen in GO

There also has been little uniformity among the grading systems used by various study groups. It is crucial to differentiate active disease from the cicatricial phase because treatment differs between the two stages. Patients with worsening deficits or persistent activity in the inflammatory phase need to be considered for additional treatments and intervention to limit their disability.34 Conversely, patients whose disease has entered the cicatricial phase will influence the decision to proceed with rehabilitative surgery.14 The clinical activity score (CAS) was introduced in 1989 to stage and grade the inflammatory phase of the disease.44 Spontaneous orbital/eye pain or pain on attempted up, lateral, or down gaze were considered inflammatory markers in this scale. The CAS also improved upon previous classification

ON occurs in approximately 5% of patients with GO. Early manifestations are defective color vision and a usually normal disc appearance; advanced manifestations are optic nerve swelling and retina striae (Fig. 2). ON is caused by optic compression at the orbital apex from enlarged extraocular muscles. The extenuation of the medial orbital wall by the medial rectus muscle results in the ‘‘Coca-Cola sign’’ (Fig. 3A). ON occurs in the presence (Fig. 3B) or absence of significant proptosis (Fig. 3C). Electrophysiological abnormalities have proven to be the most sensitive indicator of incipient ON.39 VECP is useful in the early detection of optic nerve abnormalities. In patients with GO affected by ON, vision loss occurs insidiously in the context of a congestive inflammatory orbitopathy. In the absence of visual loss, other signs have been suggested as possible indicators of ON development, such as changes in color vision and optic nerve head-on ophthalmoscopy and abnormal visual field examination.40 Prolonged latency of VECP is associated with hypothyroidism, with reversion to normal values seen by achieving euthyroidism with levothyroxine administration.41 Studies have shown that VECP in patients with GO could detect asymptomatic optic nerve dysfunction in the absence of deterioration of visual acuity. As a complimentary tool to visual field examination in the ophthalmological assessment, GO VECP could improve detection of the disease at an early stage.42 Positive VECP testing should trigger intraorbital imaging and close follow-up of patients.

Scoring and Grading Disease Activity At first, one should assess the thyroid volume by a simple clinical examination, because goiter size correlates with severity of Graves disease and GO. In addition, attention should be paid to possible coexisting thyroid dermopathy (occurring in 4%Y13% of patients), prompting the physical examination to include both shins.43 Various grading scales have been devised to aid the clinician in assessing GO. Some have attempted to grade the severity of the disease, whereas others have graded activity; however, most scales have not clearly differentiated between signs of acute inflammation and those of the subsequent cicatricial phase that occurs as the disease process resolves. Southern Medical Journal

Fig. 3. Manifestations of optic neuropathy occurring in Graves orbitopathy. A, Shows extenuation of the medial orbital wall by the medial rectal muscle (‘‘Coca-Cola sign’’). B, Optic neuropathy in the presence of significant proptosis. C, Optic neuropathy in the absence of significant proptosis.

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& Graves Orbitopathy: Update on Diagnosis and Therapy

Table 1. Parameters for clinical activity score Clinical finding Retrobulbar pain

Score 0Y1

Pain on eye movement

0Y1

Eyelid erythema

0Y1

Conjunctival injection

0Y1

Chemosis

0Y1

Swelling of the caruncle

0Y1

Eyelid edema

0Y1

Total

0Y2: inactive Graves orbitopathy 3Y7: active Graves orbitopathy

systems by addressing differences between the acute and cicatricial phases.45Y47 Studies have demonstrated good correlation between TSI and CAS.31,45 As an office-based tool, CAS assigns one point to each of seven signs or symptoms indicative of inflammation (Table 1). The VISA classification was developed by evaluating vision, inflammation, strabismus, and appearance,48 and these four parameters are used in the office setting to record clinical changes and guide/assess therapy. This classification system helps direct appropriate management in a logical sequence by targeting the most relevant aspect of the disease affecting the patient. Vision dysfunction from ON is the first priority. Inflammation is the next sign, and specific therapy will imply conservative measures, treatment with corticosteroids, immunosuppressive agents, radiotherapy, or a combination. Strabismus and appearance changes usually are managed medically and expectantly until signs of inflammation and disease progression have subsided. Once these have occurred, strabismus can be managed with prisms or routine surgery, whereas proptosis, eyelid retraction, dermatochalasis, or steatoblepharon would require special surgery. In clinical practice, it is advisable to understand the differences between CAS and VISA scoring. VISA eliminates caruncular edema as a separate sign and modifies CAS by widening the grade for chemosis and lid edema from 0 to 2 (Table 2).49 Chemosis is graded as 1 if the conjunctiva lies behind the gray line of the eyelid and 2 if it extends anterior to the gray line. Eyelid edema is scored as 1 if it is present but not causing the tissues to overhang and as 2 if it causes a roll in the eyelid skin, including festoons in the lower eyelid. The pain score is based on the patient’s report of deep orbital discomfort rather than ocular surface irritation (0 = no pain, 1 = pain with movement, 2 = pain at rest). The additional grading scores for chemosis and eyelid edema enable the clinician to document more subtle changes in inflammatory features between visits.48 Figure 4 demonstrates the chemosis and eyelid edema that occur in patients with GO. Periorbital and lid swelling (Fig. 4A), conjunctival hyperemia (Fig. 4B), chemosis (Fig. 4C), and superior limbic keratoconjunctivitis (Fig. 4D) all may be seen.

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Therapy is chosen based on scoring of active inflammation (present or not) and evidence of progression. A VISA score of G4/8 with no other clinical findings is indicative of mild GO and can be managed conservatively, whereas a score of Q5/8 indicates moderate-to-severe disease, leading to more aggressive therapy (intravenous corticosteroids or decompression surgery).48 The release of the Consensus Statement of the European Group on Graves Orbitopathy in 2008 added refined recommendations to the management of GO. The authors recommended an initial stratification of patients into mild, moderate-to-severe, or sight-threatening categories, as well as an attempt to determine disease activity (Table 3).49,50

Treatment of GO There is no prophylaxis for GO and the treatment differs by stage of disease. Graves disease management should be individualized,4 with subtotal or total thyroidectomy for thyroid antigen elimination.51,52 Total thyroidectomy or bilateral subtotal thyroidectomy may not prevent the progression of GO, although TSH-R antibody titers may become undetectable in 50% of patients.53,54 Methimazole or thyroidectomy is the preferred therapy in patients with active and moderate-to-severe or sightthreatening GO. Most patients with Graves disease have declining or normalizing TSH-R antibody titers during medical therapy or after surgical therapy, whereas patients post-RAI treatment typically continue to have elevated titers of TSH-R antibody.55 Serial TSI measurements during the clinical inflammatory phases may help direct clinical decision making. Table 4 summarizes recommendations for the use of glucocorticoids in patients with Graves disease when RAI is used to treat hyperthyroidism. Hertel exophthalmometer measurements of both eyes should be performed in all patients by clinicians, taking into consideration racial differences. 56 Patients should be encouraged to abstain from active or passive smoking and to be compliant with levothyroxine intake, if it is needed. There are still many unknown variables regarding the likelihood of progression to severe GO. If a shared thyroidal and orbital antigen were involved in GO, its release by RAI could aggravate preexisting eye disease (Fig. 5); however,

Table 2. Parameters for VISA inflammatory score Clinical finding

Score

Orbital pain (none, at rest, with gaze) Chemosis

0Y2 0Y2

Eyelid edema

0Y2

Conjunctival injection

0Y1

Eyelid injection Total

0Y1 0Y8

G5/8, mild Graves orbitopathy; 94/8, moderate-to-severe Graves orbitopathy. VISA, vision, inflammation, strabismus, and appearance.

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Review Article

Fig. 4. Soft tissue involvement. A, Periorbital and lid swelling . B, Conjunctival hyperaemia. C, Chemosis. D, Superior limbic keratoconjunctivitis. ablation of the thyroid gland may in the long term improve eye disease by removing some or most of the antigen. The use of antithyroid drugs may be protective during the active inflammatory phase of the ophthalmopathy, and poor control of thyroid function may predispose to severe eye disease.20,22,23 Total or subtotal thyroidectomy for moderate to severe orbitopathy in hyperthyroid patients has been shown to be effective.57 Smoking, stage of disease, RAI treatment, and unstable thyroid function are possible factors exacerbating GO or compromising treatment outcome.16Y18,24,58,59 Smoking is associated with the deterioration of preexisting GO, more severe disease, and negatively affects the efficacy of various treatments. It also increases the risk of progression of GO after RAI treatment; therefore, physicians must be actively involved by helping patients to quit smoking and avoid exposure to passive smoking or making appropriate referrals to smoking cessation clinics if better outcome is the goal.21 The treatment of GO should be guided by the stage and activity of disease. The most useful indicators of active GO are represented by CAS Q3, eye muscle reflectivity of Q40% on A-mode ultrasonography, increased levels of glycosaminoglycans in serum or urine titer, prolonged T2 relaxation time on MRI, high orbital uptake of 111In on octreoscan, or a VISA score Q5.60Y65 Simple treatment measures such as lubricants for lid retraction, nocturnal ointments for incomplete eye closure, prisms in the situation of diplopia, or botulinum toxin injections for upper lid retraction could prove to be effective in mild cases of GO.1,66 A course of selenium may be helpful in mild GO.67Y69 Selenium is available over the counter and is believed to affect the formation of reactive oxygen species and assist in achieving euthyroidism. Glucocorticoids; orbital radiotherapy; orbital decompression (OD) either by removal of excess orbital fat or the expansion of the orbital of the walls, depending on radiographic and clinical findings; eye muscle surgery; and rehabilitative Southern Medical Journal

eyelid surgery are indicated generally for moderate-to-severe disease and for sight-threatening ON.

Glucocorticoids Glucocorticoids are the treatment of choice for ON and moderate-to-severe active disease, and numerous randomized trials and meta-analyses have proven their beneficial effects.49,70,71 Glucocorticoids and orbital radiotherapy are most effective for inflammatory manifestations of the disease such as periorbital edema and ocular discomfort, because both treatments inhibit the production of cytokines by activated mononuclear cells and orbital fibroblasts.1 In patients with active and severe GO, the response rate of intravenous glucocorticoid pulse therapy is approximately 80%.71 The recommended treatment for patients with active and moderate-to-severe GO is a course of 0.5 g intravenous methylprednisolone once weekly for 6 weeks,

Table 3. Severity classifications of GO Sight-threatening GO: Patients with dysthyroid optic neuropathy and/or corneal breakdown. This category requires immediate intervention. Moderate-to-severe GO: Patients without sight-threatening GO whose eye disease has enough impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). Patients within this classification usually have one or more of the following: lid retraction 92 mm, moderate-to-severe soft tissue involvement, exophthalmos 92 mm above normal for race1 and sex, or inconstant or constant diplopia. Mild GO: Patients whose symptoms of GO have only a minor impact on daily life and are insufficient to justify immunosuppressive or surgical treatment. Patients within this classification usually have one or more of the following: minor lid retraction G2 mm, mild soft tissue involvement, exophthalmos G3 mm above normal for race56 and sex, transient or no diplopia, or corneal exposure responsive to lubricants. GO, Graves orbitopathy.

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& Graves Orbitopathy: Update on Diagnosis and Therapy

Table 4. Use of oral glucocorticoids for prevention of GO development or progression when RAI is used to treat Graves’ hyperthyroidism RAI with oral glucocorticoids No GO (nonsmoker)

RAI without glucocorticoids

Not recommended

Recommended

V

Insufficient data

GO present-inactive (smoker or nonsmoker)

Not recommended

Recommended

GO present-active and mild (nonsmoker)

Acceptable

GO present-active and mild (smoker) GO present-active and moderate-to-severe or sight-threatening (smoker or nonsmoker)

Recommended

Not recommended

Insufficient data to recommend for or against

Not recommended

No GO (smoker)

Acceptable

GO, Graves’ orbitopathy; RAI, radioactive iodine. Reproduced with permission from the American Association of Clinical Endocrinologists.52

followed by 0.25 g/week for 6 weeks (cumulative dose 4.5 g).49,71 If there is negative clinical response, intravenous glucocorticoid treatment may be stopped after 6 weeks of 0.5 g/week dosing. Although effective, this treatment may be accompanied by adverse effects, including liver dysfunction, hypertension, peptic ulcer disease, diabetes, infection, psychosis, or glaucoma.72Y75 As such, careful patient selection (evaluation for autoimmune and other forms of hepatitis) and routine monitoring during treatment are necessary. The total cumulative dose of intravenous glucorticoids should not exceed 8 g, and it is preferable that single doses not be administered on consecutive days.71 Of note, oral therapy with glucocorticoids is widely used in daily practice, and prednisone at a dose of 0.2 mg/kg per body weight started 1 day after RAI and withdrawn after 6 weeks can prevent RAI-induced exacerbation of initially mild or absent GO.76

inflammation has subsided and the restrictive component has stabilized.77,82 Orbital radiotherapy may cause temporary ocular irritation and increased soft tissue inflammation from approximately 2 weeks following therapy and continuing for at least 24 to 36 weeks; therefore, oral steroids should be continued during the course of radiotherapy and tapered slowly for 3 months. If vision deteriorates despite steroids and radiation treatment, then surgical decompression is warranted.80 Optic nerve compression must be treated emergently with intravenous glucocorticoids or surgical decompression of the orbit.72,73,82,83 Radiotherapy has a limited role in treating nonYsight-threatening GO and should be limited to improving or halting progression of vertical ocular dysmotility.84 For progressive GO, radiotherapy should be avoided in people younger than 35 years old, but it remains relatively safe, with a 0.2% lifetime risk of cancer, a risk of definite radiation retinopathy within 10 years of 1% to 2%, and a 1% incidence of retinopathy in patients with diabetes mellitus.84 Radiotherapy reduces restriction and improves fields of single binocular vision, and it can prevent decompression surgery or prevent relapses after OD (when muscles continue to enlarge postdecompression for dystrophic ON).

OD OD is a surgical procedure that can be performed either by removing parts of the orbital walls, thereby increasing space for the orbital contents, or by orbital fat removal, leaving the bony orbit intact. The choice of surgery is dependent on a combination of individual surgeon’s preference and intersubject variability in orbital morphology.57,85 Immediate OD has no advantage over intravenous steroid therapy with relation to improvement of visual acuity in the short term,86 and surgical manipulation may worsen orbital inflammation if performed during the active

Radiotherapy Orbital irradiation (OI) is advocated in active GO associated with diplopia and restricted motility.77 Orbital lymphocytes and fibroblasts are sensitive to ionizing radiation1 and cumulative doses between 10 and 20 Gy may be effective.78 Irradiation must be avoided in diabetic retinopathy, severe hypertension, and patients younger than 35 years old.79Y81 Limited clinical trials support the idea of a more effective treatment when a combination of oral glucocorticoids and OI is used rather than either treatment alone.1 The best results with radiotherapy are found in patients in whom irradiation was given shortly after the onset of symptoms. Radiotherapy decreases eyelid and conjunctival swelling and improves motility during the active, inflammatory phase. It is ineffective against fibrotic extraocular muscle restriction or strabismus and has no effect on chronic proptosis. Strabismus may not resolve entirely; however, strabismus surgery or OD is effective when

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Fig. 5. Conjunctival and periorbital edema seen in a male patient with Graves orbitopathy after treatment with radioactive iodine (without glucocorticoid coverage) leading to acute exacerbation of GO. * 2014 Southern Medical Association

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Review Article

phase. By contrast, high-dose steroids can reduce local edema, ameliorate optic nerve compression, and allow surgery to be performed during an inactive phase.86 Other surgical modalities used in the treatment of GO are extraocular muscle surgery for strabismus and eyelid surgery (performed after OD and strabismus surgery, if either or both are needed).

Future Trends in Treatment Despite extensive research, GO remains a problematic disease with a broad range of clinical manifestations and a highly variable natural history. Managing such patients requires a multidisciplinary approach, including endocrinologists, ophthalmologists, head and neck surgeons, and nuclear medicine physicians with a special expertise in GO. Current treatments rely on systemic immunosuppression, OI, and surgery to relieve the mechanical effects of the disease such as optic nerve compression, proptosis, strabismus, and lid retraction and swelling. Future therapies aimed at the molecular and immunological bases of the disease are more likely to be beneficial. A key component would be the ability to detect the disease at its earliest stage or recognize predisposing factors. Various compounds such as somatostatin analogs, azathioprine, ciamexone, selenium, and intravenous immunoglobulins have been used with marginal effectiveness. Immunomodulators such as rituximab or etanercept also may prove to be effective therapies for GO, but randomized studies are required.67,87Y93 Of 34 patients with active GO and 3 patients with inactive GO, 92% improved, with a reduction of CAS from 5.3 to 1.3. Time to improvement is approximately 6 weeks when the standard rheumatoid arthritis regimen of 1000 mg of rituximab on day 1 and on day 14 is used.94 There is evidence that a combination of glucocorticoids and immunosuppressant therapy may be more beneficial than either treatment alone.95,96 Direct or indirect inhibitors of glycosaminoglycans also may be useful. IL-1> has a potent effect in stimulating the synthesis of glycosaminoglycans and the proliferation of orbital fibroblasts. As such, new pharmacological compounds (eg, cyclooxygenase inhibitors, anti-IL-1 antibodies, IL-1-receptor antagonists) with the ability to decrease titers or the action of IL-1>, or those that inhibit the expression of various immunomodulatory proteins, may provide a new approach to the management of GO by interrupting disease progression.97

References 1. Bartalena L, Pinchera A, Marcocci C. Management of Graves’ ophthalmopathy: reality and perspectives. Endocr Rev 2000;21:168Y199. 2. Melcescu E, Kemp EH, Majithia V, et al. Graves’disease, hypoparathyroidism, systemic lupus erythematosus, alopecia, and angioedema: autoimmune polyglandular syndrome variant or coincidence? Int J Immunopathol Pharmacol 2013;26:217Y222. 3. Antonelli A, Fallahi P, Tolari S, et al. Thyroid-associated ophthalmopathy and TSH receptor autoantibodies in nonmetastatic thyroid cancer after total thyroidectomy. Am J Med Sci 2008;336:288Y290. 4. Brent GA. Graves’ disease. N Engl J Med 2008;358:2594Y2605. 5. Bartalena L, Tanda ML. Clinical practice. Graves’ ophthalmopathy. N Engl J Med 2009;360:994Y1001.

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6. Tanda ML, Piantanida E, Liparulo L, et al. Prevalence and natural history of Graves’ orbitopathy in a large series of patients with newly diagnosed Graves’ hyperthyroidism seen at a single center. J Clin Endocrinol Metab 2013;98:1443Y1449. 7. Lesho E, Jones RE. Hypothyroid Graves’ disease. South Med J 1997;90: 1201Y1203. 8. Khoo DH, Eng PH, Ho SC, et al. Graves’ ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels: prevalence, natural history, and thyrotropin receptor antibody levels. Thyroid 2000;10:1093Y1100. 9. Marcocci C, Bartelena L, Bogazzi F, et al. Studies on the occurrence of ophthalmopathy in Graves’ disease. Acta Endocrinol (Copenh) 1989;120: 473Y478. 10. Melcescu E, Horton WB, Pitman KT, et al. Euthyroid Graves’ orbitopathy and incidental papillary thyroid microcarcinoma. Hormones (Athens) 2013;12:298Y304. 11. Fernando R, Atkins S, Raychaudhuri N, et al. Human fibrocytes coexpress thyroglobulin and thyrotropin receptor. Proc Natl Acad Sci U S A 2012; 109:7427Y7432. 12. Gillespie EF, Papagerogiou KI, Fernando R, et al. Increased expression of TSH receptor by fibrocytes in thyroid-associated ophthalmopathy leads to chemokine production. J Clin Endocrinol Metab 2012;97:E70YE76. 13. Bahn RS. Graves’ ophthalmopathy. N Engl J Med 2010;362:726Y738. 14. Bartley GB, Fatourechi V, Kadrmas EF, et al. The incidence of Graves’ ophthalmopathy in Olmsted County, Minnesota. Am J Ophthalmol 1995; 120:511Y517. 15. Guarneri F, Benvenga S. Environmental factors and genetic background that interact to cause autoimmune thyroid disease. Curr Opin Endocrinol Diabetes Obes 2007;14:398Y409. 16. Tallstedt L, Lundell G, Torring O, et al. Occurrence of ophthalmopathy after treatment for Graves’ hyperthyroidism: the thyroid study group. N Engl J Med 1992;326:1733Y1738. 17. Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med 1998;338:73Y78. 18. Bartalena L, Marcocci C, Tanda ML, et al. Cigarette smoking and treatment outcomes in Graves’ ophthalmopathy. Ann Intern Med 1998;129:632Y635. 19. Eckstein AK, Plicht M, Lax H, et al. Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metab 2006;91:3464Y3470. 20. Tallstedt L, Lundell G, Blomgren H, et al. Does early administration of thyroxine reduce the development of Graves’ ophthalmopathy after radioiodine treatment? Eur J Endocrinol 1994;130:494Y497. 21. Pfeilschifter J, Ziegler R. Smoking and endocrine ophthalmopathy: impact of smoking severity and current vs lifetime cigarette consumption. Clin Endocrinol (Oxf ) 1996;45:477Y481. 22. Prummel MF, Wiersinga WM, Mourits MP, et al. Amelioration of eye changes of Graves’ ophthalmopathy by achieving euthyroidism. Acta Endocrinol (Copenh) 1989;121:185Y189. 23. Prummel MF, Wiersinga WM, Mourits MP, et al. Effect of abnormal thyroid function on the severity of Graves’ ophthalmopathy. Arch Intern Med 1990;150:109Y1101. 24. Bartalena L, Marcocci C, Pinchera A. Graves’ ophthalmopathy: a preventable disease? Eur J Endocrinol 2002;146:457Y461. 25. Dragan LR, Seiff SR, Lee DC. Longitudinal correlation of thyroidstimulating immunoglobulin with clinical activity of disease in thyroidassociated orbitopathy. Ophthal Plast Reconstr Surg 2006;22:13Y19. 26. Bahn RS, Heufelder AE. Mechanisms of disease: pathogenesis of Graves’ophthalmopathy. N Engl J Med 1993;329:1468Y1475. 27. Hiromatsu Y, Yang D, Bednarczuk T, et al. Cytokine profiles in eye muscle tissue and orbital fat tissue from patients with thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2000;85:1194Y1199. 28. Antonelli A, Ferrari SM, Fallahi P, et al. Monokine induced by interferon gamma (IFNgamma) (CXCL9) and IFNgamma inducible T-cell alpha-chemoattractant (CXCL11) involvement in Graves’disease and ophthalmopathy: modulation

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Melcescu et al

29.

30.

31.

32.

33.

34. 35. 36.

37.

38.

39. 40. 41. 42.

43. 44.

45.

46. 47.

48. 49.

50. 51. 52.

42

& Graves Orbitopathy: Update on Diagnosis and Therapy

by peroxisome proliferator-activated receptor-gamma agonists. J Clin Endocrinol Metab 2009;94:1803Y1809. Antonelli A, Ferrari SM, Frascerra S, et al. CXCL9 and CXCL11 chemokines modulation by peroxisome proliferator-activated receptor-alpha agonists secretion in Graves’ and normal thyrocytes. J Clin Endocrinol Metab 2010; 95:E413YE420. Leschik JJ, Diana T, Olivo PD, et al. Analytical performance and clinical utility of a bioassay for thyroid-stimulating immunoglobulins. Am J Clin Pathol 2013;139:192Y200. Gerding MN, van der Meer JW, Broenink M, et al. Association of thyrotropin receptor antibodies with the clinical features of Graves’ ophthalmopathy. Clin Endocrinol (Oxf ) 2000;52:267Y271. Schott M, Minich WB, Willenberg HS, et al. Relevance of TSH receptor stimulating and blocking autoantibody measurement for the prediction of relapse in Graves’ disease. Horm Metab Res 2005;37:741Y744. Antonelli A, Rotondi M, Ferrari SM, et al. Interferon-gamma-inducible alpha-chemokine CXCL10 involvement in Graves’ ophthalmopathy: modulation by peroxisome proliferator-activated receptor gamma agonists. J Clin Endocrinol Metab 2006;91:614Y620. Kahaly GJ. Imaging in thyroid-associated orbitopathy. Eur J Endocrinol 2001;145:107Y118. Mu¨ller-Forell W, Kahaly GJ. Neuroimaging of Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab 2012;26:259Y271. Forbes G, Gorman CA, Brennan MD, et al. Ophthalmopathy of Graves’ disease: computerized volume measurements of the orbital fat and muscle. Am J Neuroradiol 1986;7:651Y656. Werner SC, Coleman DJ, Franzen LA. Ultrasonographic evidence of a consistent orbital involvement in Graves’ disease. N Engl J Med 1974;290: 1447Y1450. Erickson BA, Harris GJ, Lewandowski MF, et al. Echographic monitoring of response of extraocular muscles to irradiation in Graves’ ophthalmopathy. Int J Rad Oncol Biol Phys 1995;31:651Y660. Batch JA, Lepre F. Early diagnosis of Graves’ optic neuropathy using visual evoked responses. Postgrad Med J 1990;66:664Y666. Gasser P, Flammer J. Optic neuropathy of Graves’disease. Ophthalmologica 1986;192:22Y27. Ladenson PW, Stakes JW, Ridgway EC. Reversible alteration of the visual evoked potential in hypothyroidism. Am J Med 1984;77:1010Y1014. Salvi M, Spaggiari E, Neri F, et al. The study of visual evoked potentials in patients with thyroid-associated ophthalmopathy identifies asymptomatic optic nerve involvement. J Clin Endocrinol Metab 1997;82:1027Y1030. Fatourechi V. Thyroid dermopathy and acropachy. Best Pract Res Clin Endocrinol Metab 2012;26:553Y565. Mourits MP, Koorneef L, Wiersinga WM, et al. Clinical criteria for the assessment of disease activity in Graves’ ophthalmopathy: a novel approach. Br J Ophthalmol 1989;73:639Y644. Gerding MN, Prummel MF, Kalmann R, et al. The use of colour slides in the assessment of changes in soft tissue involvement in Graves’ ophthalmopathy. J Endocrinol Invest 1998;21:459Y462. Mourits MP, Prummel MF, Wiersinga WM, et al. Measuring eye movements in Graves’ ophthalmopathy. Ophthalmology 1994;101:1341Y1346. Mourits MP, Prummel MF, Wiersinga WM, et al. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol (Oxf ) 1997;47:9Y14. Dolman PJ, Rootman J. VISA classification for Graves orbitopathy. Ophthal Plast Reconstr Surg 2006;22:319Y324. Bartalena L, Baldeschi L, Dickinson AJ, et al. Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid 2008;18:333Y346. Griepentrog GJ, Garrity JA. Update on the medical treatment of Graves’ ophthalmopathy. Int J Gen Med 2009;2:263Y269. Bradley EL 3rd, DiGirolamo M. Remnant function after subtotal thyroidectomy for Graves’disease. South Med J 1975;68:1245Y1258. Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid

53.

54.

55.

56.

57.

58. 59. 60.

61. 62.

63. 64.

65.

66.

67. 68. 69. 70.

71. 72.

73.

74.

Association and American Association of Clinical Endocrinologists. Endocr Pract 2011;17:456Y520. Barczynski M, Konturek A, Hubalewska-Dydejczyk A, et al. Randomized clinical trial of bilateral subtotal thyroidectomy versus total thyroidectomy for Graves’ disease with a 5-year follow-up. Br J Surg 2012;99:515Y522. Jarhult J, Rudberg C, Larsson E, et al. Graves’disease with moderate-severe endocrine ophthalmopathyVlong term results of a prospective randomized study of total or subtotal thyroid resection. Thyroid 2005;15:1157Y1165. Laurberg P, Wallin G, Tallstedt L, et al. TSH-receptor autoimmunity in Graves’ disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur J Endocrinol 2008;158:69Y75. Migliori ME, Gladstone GJ. Determination of the normal range of exophthalmometric values for black and white adults. Am J Ophthalmol 1984;98:438Y442. Wu CH, Chang TC, Liao SL. Results and predictability of fat-removal orbital decompression for disfiguring Graves’ exophthalmos in an Asian patient population. Am J Ophthalmol 2008;145:755Y759. Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy. Thyroid 2002;12:855Y860. Thornton J, Kelly SP, Harrison RA, et al. Cigarette smoking and thyroid eye disease: a systematic review. Eye (Lon) 2007;21:1135Y1145. Frueh BR. Why the NOSPECS classification of Graves’ eye disease should be abandoned, with suggestions for the characterization of this disease. Thyroid 1992;2:85Y88. Gorman CA. The measurement of change in Graves’ ophthalmopathy. Thyroid 1998;8:539Y543. Prummel MF, Suttorp-Schulten MS, Wiersinga WM, et al. A new ultrasonographic method to detect disease activity and predict response to immunosuppressive treatment in Graves’ ophthalmopathy. Ophthalmology 1993;100: 556Y561. Kahaly G, Forster G, Hansen C. Glycosaminoglycans in thyroid eye disease. Thyroid 1998;8:429Y432. Utech CI, Khatibnia U, Winter PF, et al. T2 relaxation time for the assessment of retrobulbar inflammation in Graves’ ophthalmopathy. Thyroid 1995;5: 185Y193. Postema PTE, Krenning EP, Wijngaarde R, et al. [111In-DTPA-D-Phe1] octreotide scintigraphy in thyroidal and orbital Graves’ disease: a parameter for disease activity? J Clin Endocrinol Metab 1994;79:1845Y1851. Uddin JM, Davies PD. Treatment of upper eyelid retraction associated with thyroid eye disease with subconjunctival botulinum toxin injection. Ophthalmology 2002;109:1183Y1187. Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of mild Graves’ orbitopathy. N Engl J Med 2011;364:1920Y1931. Marcocci C, Marino M. Treatment of mild, moderate-to-severe and very severe Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab 2012;26:325Y337. Drutel A, Archambeaud F, Caron P. Selenium and the thyroid gland: more good news for clinicians. Clin Endocrinol 2013;78:155Y164. Stiebel-Kalish H, Robenshtok E, Hasanreisoglu M, et al. Treatment modalities for Graves’ ophthalmopathy: systematic review and metaanalysis. J Clin Endocrinol Metab 2009;94:2708Y2716. Zang S, Ponto KA, Kahaly GJ. Intravenous glucocorticoids for Graves’ orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab 2011;96:320Y332. Marcocci C, Bartalena L, Tanda ML, et al. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in management of severe Graves’ ophthalmopathy: results of a prospective, single-blind, randomized study. J Clin Endocrinol Metab 2001; 86:3562Y3567. Kahaly GJ, Pitz S, Hommel G, et al. Randomized, single-blind trial of intravenous v oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab 2005;90:5234Y5240. Marino M, Morabito E, Brunetto MR, et al. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathy. Thyroid 2004;14:403Y406.

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75. Le Moli R, Baldeschi L, Saeed P, et al. Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in patients with Graves’ ophthalmopathy. Thyroid 2007;17:357Y362. 76. Lai A, Sassi L, Compri E, et al. Lower dose prednisone prevents radioiodineassociated exacerbation of initially mild or absent Graves’ orbitopathy: a retrospective cohort study. J Clin Endocrinol Metab 2010;95:1333Y1337. 77. Mourits MP, van Kempen-Harteveld ML, Garcia MB, et al. Radiotherapy for Graves’ orbitopathy: randomized placebo-controlled study. Lancet 2000;355:1505Y1509. 78. Kahaly GJ, Rosler HP, Pitz S, et al. Low- versus high-dose radiotherapy for Graves’ ophthalmopathy: a randomized, single blind trial. J Clin Endocrinol Metab 2000;85:102Y108. 79. Marcocci C, Bartalena L, Rocchi R, et al. Long-term safety of orbital radiotherapy for Graves’ ophthalmopathy. J Clin Endocrinol Metab 2003; 88:3561Y3566. 80. Wakelkamp IM, Tan H, Saeed P, et al. Orbital irradiation for Graves’ ophthalmopathy: is it safe? A long-term follow-up study. Ophthalmology 2004; 111:1557Y1562. 81. Robertson DM, Buettner H, Gorman CA, et al. Retinal microvascular abnormalities in patients treated with external radiation for Graves’ ophthalmopathy. Arch Ophthalmol 2003;121:652Y657. 82. Cockerham KP, Kennerdell JS. Does radiotherapy have a role in the management of thyroid orbitopathy? Br J Ophthalmol 2002;86:102Y104. 83. Ng CM, Yuen HK, Choi KL, et al. Combined orbital irradiation and systemic steroids compared with systemic steroids alone in the management of moderate-to-severe Graves’ ophthalmopathy: a preliminary study. Hong Kong Med J 2005;11:322Y330. 84. Bradley EA, Gower EW, Bradley DJ, et al. Orbital radiation for Graves’ ophthalmopathy: a report by the American Academy of Ophthalmology. Ophthalmology 2008;115:398Y409. 85. Borumandi F, Hammer B, Kamer L, et al. How predictable is exophthalmos reduction in Graves’ orbitopathy? A review of the literature. Br J Ophthalmol 2011;95:1625Y1630.

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86. Wakelkamp IM, Baldeschi L, Saeed P, et al. Surgical or medical decompression as a first-line treatment of optic neuropathy in Graves’ ophthalmopathy? A randomized controlled trial. Clin Endocrinol (Oxf ) 2005;63:323Y328. 87. Wemeau JL, Caron P, Beckers A, et al. Octreotide (long-acting release formulation) treatment in patients with Graves’ orbitopathy: clinical results of a four month, randomized, placebo-controlled, double-blind study. J Clin Endocrinol Metab 2005;90:841Y848. 88. Perros P, Weightman DR, Crombie AL, et al. Azathioprine in the treatment of thyroid-associated ophthalmopathy. Acta Endocrinol (Copenh) 1990;122:8Y12. 89. Kahaly G, Lieb W, Muller-Forell W, et al. Ciamexone in endocrine orbitopathy. A randomized, double-blind, placebo-controlled study. Acta Endocrinol (Copenh) 1990;122:13Y21. 90. Antonelli A, Saracino A, Alberti B, et al. High-dose intravenous immunoglobulin treatment in Graves’ ophthalmopathy. Acta Endocrinol (Copenh) 1992;126:13Y23. 91. Salvi M, Vannucchi G, Campi I, et al. Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol 2007;156:33Y40. 92. Paridaens D, van den Bosch WA, van der Loos TL, et al. The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye (Lond) 2005;19: 1286Y1289. 93. Madaschi S, Rossini A, Formenti I, et al. Treatment of thyroid-associated orbitopathy with rituximabVa novel therapy for an old disease: case report and literature review. Endocr Pract 2010;16:677Y685. 94. Salvi M, Vannucchi G, Curro N, et al. Small dose of rituximab for Graves’ orbitopathy: new insights into the mechanism of action. Arch Ophthalmol 2012;130:122Y124. 95. Kahaly G, Schrezenmeir J, Krause U, et al. Ciclosporin and prednisone vs. prednisone in treatment of Graves’ ophthalmopathy: a controlled, randomized and prospective study. Eur J Clin Invest 1986;16:415Y422. 96. Prummel MF, Mourits MP, Berghout A, et al. Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy. N Engl J Med 1989; 321:1353Y1359. 97. Dinarello CA, Wolff SM. The role of interleukin-1 in disease. N Engl J Med 1993;328:106Y113.

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