Teprotumumab

Teprotumumab, a monoclonal antibody targeted against the insulin-like growth factor 1 (IGF-1) receptor, was recently approved by the United States Food and Drug Administration for the treatment of thyroid eye disease (TED). Phase 1 studies of teprotumumab for the treatment of malignancies demonstrated an acceptable safety profile but limited effectiveness. Basic research implicating the IGF-1 receptor on the CD-34+ orbital fibrocyte in the pathogenesis of TED renewed interest in the drug. Two multicenter, randomized, double-masked, clinical trials (phase 2 and 3) evaluated the efficacy of 8 infusions of teprotumumab every 3 weeks versus placebo in 170 patients with recent-onset active TED, as defined by a clinical activity score (CAS) of at least 4. Teprotumumab was superior to placebo for the primary efficacy end points in both studies: overall responder rate as defined by a reduction of 2 or more CAS points and a reduction of 2 mm or more in proptosis (69% vs. 20%; P < 0.001; phase 2 study) and proptosis responder rate as defined by a reduction of 2 mm or more in proptosis (83% vs. 10%; P < 0.001; phase 3 study). In both studies, treatment with teprotumumab compared with placebo achieved a significant mean reduction of proptosis (–3.0 mm vs. –0.3 mm, phase 2 study; –3.32 mm vs. –0.53 mm, phase 3 study) and CAS (–4.0 vs. –2.5, phase 2 study; –3.7 vs. –2.0, phase 3 study). Teprotumumab also resulted in a greater proportion of patients with a final CAS of 0 or 1, higher diplopia responder rate, and a larger improvement in the Graves' Ophthalmopathy Quality of Life overall score. More than half of patients (62%, phase 2 trial; 56%, phase 3 trial) who were primary end point responders maintained this response at 51 weeks after the last dose of therapy. The most common adverse events reported with teprotumumab included muscle spasms (25%), nausea (17%), alopecia (13%), diarrhea (13%), fatigue (10%), hearing impairment (10%), and hyperglycemia (8%). Teprotumumab is contraindicated for those with inflammatory bowel disease and who are pregnant. Although the current dosing regimen has proven effective for TED, dose-ranging studies including variable concentrations, infusion frequencies, and durations of teprotumumab therapy in the setting of TED have not been performed. Teprotumumab, a monoclonal antibody targeted against the insulin-like growth factor 1 (IGF-1) receptor, was recently approved by the United States Food and Drug Administration for the treatment of thyroid eye disease (TED). Phase 1 studies of teprotumumab for the treatment of malignancies demonstrated an acceptable safety profile but limited effectiveness. Basic research implicating the IGF-1 receptor on the CD-34+ orbital fibrocyte in the pathogenesis of TED renewed interest in the drug. Two multicenter, randomized, double-masked, clinical trials (phase 2 and 3) evaluated the efficacy of 8 infusions of teprotumumab every 3 weeks versus placebo in 170 patients with recent-onset active TED, as defined by a clinical activity score (CAS) of at least 4. Teprotumumab was superior to placebo for the primary efficacy end points in both studies: overall responder rate as defined by a reduction of 2 or more CAS points and a reduction of 2 mm or more in proptosis (69% vs. 20%; P < 0.001; phase 2 study) and proptosis responder rate as defined by a reduction of 2 mm or more in proptosis (83% vs. 10%; P < 0.001; phase 3 study). In both studies, treatment with teprotumumab compared with placebo achieved a significant mean reduction of proptosis (–3.0 mm vs. –0.3 mm, phase 2 study; –3.32 mm vs. –0.53 mm, phase 3 study) and CAS (–4.0 vs. –2.5, phase 2 study; –3.7 vs. –2.0, phase 3 study). Teprotumumab also resulted in a greater proportion of patients with a final CAS of 0 or 1, higher diplopia responder rate, and a larger improvement in the Graves' Ophthalmopathy Quality of Life overall score. More than half of patients (62%, phase 2 trial; 56%, phase 3 trial) who were primary end point responders maintained this response at 51 weeks after the last dose of therapy. The most common adverse events reported with teprotumumab included muscle spasms (25%), nausea (17%), alopecia (13%), diarrhea (13%), fatigue (10%), hearing impairment (10%), and hyperglycemia (8%). Teprotumumab is contraindicated for those with inflammatory bowel disease and who are pregnant. Although the current dosing regimen has proven effective for TED, dose-ranging studies including variable concentrations, infusion frequencies, and durations of teprotumumab therapy in the setting of TED have not been performed. Teprotumumab, a monoclonal antibody to the insulin-like growth factor 1 (IGF-1) receptor, was recently approved to treat thyroid eye disease (TED) and is marketed under the name Tepezza by Horizon Therapeutics. The following article describes the state of medical management of TED before the approval of teprotumumab, explains the current understanding of the pathophysiologic features of TED, presents an overview of IGF-1 and its physiologic roles throughout the body, discusses the preclinical and clinical trials of teprotumumab, and draws conclusions and discusses future directions. The Institutional Review Boards approved the study and waived the requirement for informed consent because of the retrospective nature of the study. All research adhered to the tenets of the Declaration of Helsinki. The prevalence of Graves' disease (GD) is approximately 2% to 3% in women and 0.2% in men.1Furszyfer J. Kurland L.T. McConahey W.M. et al.Epidemiologic aspects of Hashimoto's thyroiditis and Graves' disease in Rochester, Minnesota (1935–1967), with special reference to temporal trends.Metabolism. 1972; 21: 197-204Abstract Full Text PDF PubMed Google Scholar,2Tunbridge W.M. Evered D.C. Hall R. et al.The spectrum of thyroid disease in a community: the Whickham survey.Clin Endocrinol (Oxf). 1977; 7: 481-493Crossref PubMed Google Scholar Approximately 15% to 30% of patients with GD will experience clinically significant thyroid eye disease (TED), also known as Graves' orbitopathy or thyroid-associated orbitopathy.3Lazarus J.H. Epidemiology of Graves' orbitopathy (GO) and relationship with thyroid disease.Best Pract Res Clin Endocrinol Metab. 2012; 26: 273-279Crossref PubMed Scopus (80) Google Scholar,4Bartley G.B. Fatourechi V. Kadrmas E.F. et al.The incidence of Graves' ophthalmopathy in Olmsted County, Minnesota.Am J Ophthalmol. 1995; 120: 511-517Abstract Full Text PDF PubMed Google Scholar Thyroid eye disease is associated with eyelid retraction, exophthalmos, extraocular muscle dysfunction, facial disfigurement, reduced quality of life, and psychologic distress.5Bartley G.B. Fatourechi V. Kadrmas E.F. et al.Clinical features of Graves' ophthalmopathy in an incidence cohort.Am J Ophthalmol. 1996; 121: 284-290Abstract Full Text PDF PubMed Google Scholar In rare cases (3%–6%), TED can result in vision-threatening optic neuropathy or corneal exposure.5Bartley G.B. Fatourechi V. Kadrmas E.F. et al.Clinical features of Graves' ophthalmopathy in an incidence cohort.Am J Ophthalmol. 1996; 121: 284-290Abstract Full Text PDF PubMed Google Scholar,6Tanda M.L. 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: 1443-1449Crossref PubMed Scopus (131) Google Scholar Unlike most autoimmune diseases, TED is usually a self-limited process, with a 12- to 24-month active period followed by inactivity or quiescence.7Naik V.M. Naik M.N. Goldberg R.A. et al.Immunopathogenesis of thyroid eye disease: emerging paradigms.Surv Ophthalmol. 2010; 55: 215-226Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Recurrences can be expected in 15% to 22% of patients.8Patel D.K. Duncan M.S. Shah A.S. et al.Association of cardiac rehabilitation with decreased hospitalization and mortality risk after cardiac valve surgery.JAMA Cardiol. 2019; 4: 1250-1259Crossref PubMed Scopus (14) Google Scholar Rundle and Wilson9Rundle F.F. Wilson C.W. Development and course of exophthalmos and ophthalmoplegia in Graves' disease with special reference to the effect of thyroidectomy.Clin Sci. 1945; 5: 177-194PubMed Google Scholar first graphically described the relationship between duration of disease and measurements of TED severity. They found that over the course of approximately 2 years, both exophthalmos and extraocular muscle limitation worsen during the first 6 to 15 months and then begin to improve, plateauing by 18 to 24 months. Although these changes often improve with time, they rarely return to the predisease state.9Rundle F.F. Wilson C.W. Development and course of exophthalmos and ophthalmoplegia in Graves' disease with special reference to the effect of thyroidectomy.Clin Sci. 1945; 5: 177-194PubMed Google Scholar, 10Bartley G.B. Rundle and his curve.Arch Ophthalmol. 2011; 129: 356-358Crossref PubMed Scopus (32) Google Scholar, 11Menconi F. Profilo M.A. Leo M. et al.Spontaneous improvement of untreated mild Graves' ophthalmopathy: Rundle's curve revisited.Thyroid. 2014; 24: 60-66Crossref PubMed Scopus (0) Google Scholar These observations agree with natural history studies that have demonstrated that after initial presentation, most patients with TED show improvement (45%–65%) or the disease remains stable (20%–45%), with the disease worsening in approximately 5% to 15% of patients.11Menconi F. Profilo M.A. Leo M. et al.Spontaneous improvement of untreated mild Graves' ophthalmopathy: Rundle's curve revisited.Thyroid. 2014; 24: 60-66Crossref PubMed Scopus (0) Google Scholar, 12Perros P. Kendall-Taylor P. Natural history of thyroid eye disease.Thyroid. 1998; 8: 423-425Crossref PubMed Google Scholar, 13Teng C.S. Yeo P.P.B. Occasional review. Ophthalmic Graves's disease: natural history and detailed thyroid function studies.Br Med J. 1977; : 273-275Crossref PubMed Scopus (37) Google Scholar Restorative surgery for TED is typically delayed until patients are in the inactive phase and the signs of TED have stabilized, except in cases of vision-threatening dysthyroid optic neuropathy (DON) or severe corneal exposure that require urgent intervention. The active phase of TED is often, although not always, accompanied by clinical signs of inflammation, including eyelid, caruncle, and conjunctiva swelling and erythema; retrobulbar pain either at rest or with eye movements; and diurnal variation in symptoms. Several indices have been created to quantify the extent of these inflammatory signs, including the clinical activity score (CAS) and the inflammatory index within the vision, inflammation, strabismus, and appearance (VISA) Classification for Graves' Orbitopathy (Table 1).14Mourits M.P. Prummel M.F. Wiersinga W.M. Koornneef L. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy.Clin Endocrinol (Oxf). 1997; 47: 9-14Crossref PubMed Google Scholar, 15Dolman P.J. Rootman J. VISA classification for Graves orbitopathy.Ophthalmic Plast Reconstr Surg. 2006; 22: 319-324Crossref PubMed Scopus (0) Google Scholar, 16Barrio-Barrio J. Sabater A.L. Bonet-Farriol E. et al.Graves' ophthalmopathy: VISA versus EUGOGO classification, assessment, and management.J Ophthalmol. 2015; 2015 (Epub 2015 Aug 17): 249125Crossref PubMed Scopus (90) Google Scholar Wiersinga17Wiersinga W.A. Immunosuppressive treatment of Graves' ophthalmopathy.Thyroid. 1992; 2: 229-233Crossref PubMed Google Scholar hypothesized that the amount of inflammation occurring during the active phase was directly related to the extent of disease severity and that an inflammatory curve exists whose peak precedes that of the severity (Rundle's) curve in time. By treating the inflammation early in the disease process, Wiersinga18Wiersinga W.M. Advances in medical therapy of thyroid-associated ophthalmopathy.Orbit. 1996; 15: 177-186Crossref Google Scholar posits that disease severity can be diminished. In contrast, treatments for TED administered at the top of the inflammatory curve and later are likely to have little effect on severity compared with the disease's natural history.18Wiersinga W.M. Advances in medical therapy of thyroid-associated ophthalmopathy.Orbit. 1996; 15: 177-186Crossref Google ScholarTable 1Clinical Activity ScoreAt the initial assessment, 1 point is given for each of the following 7 signs: Spontaneous retrobulbar pain Pain with eye movement Eyelid redness Conjunctival injection Eyelid edema Conjunctival edema (chemosis) Inflammation of the caruncle or plicaFor follow-up (after 1–3 mos), the CAS is scored out of 10 points by including these 3 conditions: Increase in measured proptosis > 2 mm over 1–3 mos Decrease in eye movement limit of > 80 over 1–3 mos Decrease in visual acuity (2 Snellen chart lines) over 1–3 mosBased on descriptions by Mourits et al (1997) and Barrio-Barrio et al (2015). Initial scores of ≥ 3 and follow-up scores of ≥ 4 are indicative of active thyroid eye disease. Open table in a new tab Based on descriptions by Mourits et al (1997) and Barrio-Barrio et al (2015). Initial scores of ≥ 3 and follow-up scores of ≥ 4 are indicative of active thyroid eye disease. Nunery and Tao,19Nunery W.R. Tao J. Thyroid orbitopathy.Ophthalmology. 2007; 114: 621-622Abstract Full Text Full Text PDF PubMed Google Scholar Nunery,20Nunery W.R. Ophthalmic Graves' disease: a dual theory of pathogenesis.Ophthalmol Clin North Am. 1991; 4: 73-87Google Scholar and Nunery et al21Nunery W.R. Martin R.T. Heinz G.W. Gavin T.J. The association of cigarette smoking with clinical subtypes of ophthalmic Graves' disease.Ophthalmic Plast Reconstr Surg. 1993; 9: 77-82Crossref PubMed Google Scholar separated TED into 2 distinct types. Type 1 disease is characterized by younger age, predominantly female sex distribution, symmetric proptosis, rare extraocular motility disturbance (except for extremes of gaze), low rates of DON, and minimal signs of inflammation. In contrast, type 2 disease has a more equal sex distribution, older age, higher rates of smoking, more asymmetric proptosis, frequent strabismus, higher rates of DON, and more overt signs of inflammation.21Nunery W.R. Martin R.T. Heinz G.W. Gavin T.J. The association of cigarette smoking with clinical subtypes of ophthalmic Graves' disease.Ophthalmic Plast Reconstr Surg. 1993; 9: 77-82Crossref PubMed Google Scholar,22Uddin J.M. Rubinstein T. Hamed-Azzam S. Phenotypes of thyroid eye disease.Ophthal Plast Reconstr Surg. 2018; 34: S28-S33Crossref PubMed Scopus (4) Google Scholar Orbital imaging of patients with type 1 disease is characterized by expansion of the orbital fat, whereas imaging in patients with type 2 disease demonstrates greater amounts of extraocular muscle hypertrophy.21Nunery W.R. Martin R.T. Heinz G.W. Gavin T.J. The association of cigarette smoking with clinical subtypes of ophthalmic Graves' disease.Ophthalmic Plast Reconstr Surg. 1993; 9: 77-82Crossref PubMed Google Scholar Uddin et al22Uddin J.M. Rubinstein T. Hamed-Azzam S. Phenotypes of thyroid eye disease.Ophthal Plast Reconstr Surg. 2018; 34: S28-S33Crossref PubMed Scopus (4) Google Scholar described 6 phenotypes: (1) congestive (active inflammatory), (2) white eye expansion, (3) hydraulic apex, (4) white eye apex, (5) cicatricial active, and (6) cicatricial passive. Three of these phenotypes do not present with overt signs of orbital inflammation.22Uddin J.M. Rubinstein T. Hamed-Azzam S. Phenotypes of thyroid eye disease.Ophthal Plast Reconstr Surg. 2018; 34: S28-S33Crossref PubMed Scopus (4) Google Scholar,23Rubinstein T.J. Hamed-Azzam S. Uddin J.M. Re: "Noninflammatory thyroid eye disease.Ophthalmic Plast Reconstr Surg. 2020; 36: 98Crossref PubMed Scopus (1) Google Scholar Regensburg et al24Regensburg N.I. Wiersinga W.M. Berendschot T.T.J.M. et al.Do subtypes of Graves' orbitopathy exist?.Ophthalmology. 2011; 118: 191-196Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar characterized 95 consecutive White patients with TED with respect to orbital fat expansion and extraocular muscle volume on computed tomography imaging. Most patients (70%) showed evidence of muscle enlargement that correlated with older age, impaired motility, more proptosis, and higher thyrotropin binding inhibitory immunoglobulin (TBII), similar to Nunery et al's type 2 patients. Twenty-five percent showed neither increased fat expansion nor muscle volume outside of an age-specific range, 8% were characterized by both fat expansion and muscle enlargement, and 5% showed fat expansion alone. The European Group on Graves Orbitopathy classification system separates the severity of TED into 3 broad categories.16Barrio-Barrio J. Sabater A.L. Bonet-Farriol E. et al.Graves' ophthalmopathy: VISA versus EUGOGO classification, assessment, and management.J Ophthalmol. 2015; 2015 (Epub 2015 Aug 17): 249125Crossref PubMed Scopus (90) Google Scholar Mild TED usually includes 1 or more of the following: minor eyelid retraction (< 2 mm), mild soft tissue involvement, exophthalmos of less than 3 mm above normal, transient or no diplopia, and corneal exposure treatable with lubrication. Moderate to severe TED impacts daily life and usually includes 1 or more of the following: eyelid retraction ≥ 2 mm, moderate or severe soft tissue involvement, exophthalmos of 3 mm or more above normal, and diplopia. Patients with DON, severe corneal exposure, globe subluxation, choroidal folds, or transient visual obscurations are categorized as having sight-threating TED. A number of therapies have been used in an attempt to diminish inflammation during the active phase of TED, with the ultimate goal of reducing severity and altering the natural history of the disease. Based on Wiersinga's hypothesis, clinical trials need to be performed in cohorts of patients whose disease state is before the peak of the active phase and who have significant signs of inflammation. Studies performed with patients whose disease process is later in its course are potentially past the point at which reducing inflammation will alter disease severity when compared with the disease's natural history. Similarly, studies in which a significant portion of patients have minimal signs of inflammation are also likely to show negative results from medications that reduce inflammation. Unfortunately, several published clinical trials for TED lack 1 or both of these requisite conditions, making interpretation of their findings quite difficult. In a European randomized, placebo-controlled trial, Marcocci et al25Marcocci C. Kahaly G.J. Krassas G.E. et al.Selenium and the course of mild Graves' orbitopathy.N Engl J Med. 2011; 364: 1920-1931Crossref PubMed Scopus (299) Google Scholar demonstrated that 100 μg twice daily of the antioxidant selenium improves quality of life (P < 0.001), is associated with less eyelid retraction and soft tissue signs (P ≤ 0.04), and slows the progression of Graves' orbitopathy (P = 0.01) compared with placebo in patients with mild, active TED. In addition, CAS decrease was greater in those taking selenium at 6 months (–1.9) and 12 months (–2.2) than in those taking placebo (P < 0.001). No difference was found in terms of proptosis or extraocular muscle involvement. No adverse events (AEs) associated with selenium treatment occurred. The patients in the study experienced symptoms of TED for an average of 6 to 7 months. Selenium deficiency is not uncommon in Europe, where this study was performed. However, in the United States, selenium deficiency is rare, limiting the usefulness of supplementation in this population. For the past 65 years, corticosteroid therapy has been the primary method used to reduce inflammation in TED. A review of the published literature in English disclosed an overall corticosteroid-mediated treatment response of 66.9% in a total of 834 treated patients who had moderate or severe TED.26Zoumalan C.I. Cockerham K.P. Turbin R.E. et al.Efficacy of corticosteroids and external beam radiation in the management of moderate to severe thyroid eye disease.J Neuro-Ophthalmology. 2007; 27: 205-214Crossref PubMed Scopus (0) Google Scholar Numerous studies and meta-analyses have demonstrated that intravenous corticosteroids are more effective and better tolerated than oral steroids.27Kahaly G.J. Pitz S. Hommel G. Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves' orbitopathy.J Clin Endocrinol Metab. 2005; 90: 5234-5240Crossref PubMed Scopus (243) Google Scholar, 28Zhao L.Q. Yu D.Y. Cheng J.W. Intravenous glucocorticoids therapy in the treatment of Graves' ophthalmopathy: a systematic review and metaanalysis.Int J Ophthalmol. 2019; 12: 1177-1186Crossref PubMed Scopus (3) Google Scholar, 29Aktaran S. Akarsu E. Erbağci I. et al.Comparison of intravenous methylprednisolone therapy vs. oral methylprednisolone therapy in patients with Graves' ophthalmopathy.Int J Clin Pract. 2007; 61: 45-51Crossref PubMed Scopus (0) Google Scholar, 30van Geest R.J. Sasim I.V. Koppeschaar H.P.F. et al.Methylprednisolone pulse therapy for patients with moderately severe Graves' orbitopathy: a prospective, randomized, placebo-controlled study.Eur J Endocrinol. 2008; 158: 229-237Crossref PubMed Scopus (0) Google Scholar In a comparison of intravenous versus oral corticosteroid treatment in TED, Zang et al31Zang S. Ponto K.A. Kahaly G.J. Intravenous glucocorticoids for Graves' orbitopathy: efficacy and morbidity.J Clin Endocrinol Metab. 2011; 96: 320-332Crossref PubMed Scopus (0) Google Scholar found that in 5 randomized trials, the combined overall response rate was 82% versus 53.4% in the intravenous and oral steroid groups, respectively. In a separate meta-analysis, Stiebel-Kalish et al32Stiebel-Kalish H. Robenshtok E. Hasanreisoglu M. et al.Treatment modalities for Graves' ophthalmopathy: systematic review and metaanalysis.J Clin Endocrinol Metab. 2009; 94: 2708-2716Crossref PubMed Scopus (0) Google Scholar found that oral corticosteroids were associated with higher rates of AEs, including weight gain (26%), hypertension (8%), and Cushingoid features (7%). Intravenous steroids were more often associated with palpitations (8%), flushes (20%), and transient dyspepsia (15%). In a randomized, double-masked trial comparing multiple cumulative doses of intravenous corticosteroids, Bartalena et al33Bartalena L. Krassas G.E. Wiersinga W. et al.Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves' orbitopathy.J Clin Endocrinol Metab. 2012; 97: 4454-4463Crossref PubMed Scopus (167) Google Scholar found that 48% of patients experienced an improvement in quality of life after 12 weekly infusions of methylprednisolone (cumulative dose, 4.98 g) and that CAS decreased by 2 or more in 83% of patients. At the end of the 12-week intervention, 65% of patients showed TED inactivation, as defined by a CAS of 2 or less; an average decrease in exophthalmos of 0.4 mm was found; and 26%, 46%, and 34% had improved, unchanged, and worsened diplopia, respectively. Patients in this group experienced a 12.4-month duration of TED symptoms and an initial CAS of 4 before starting steroids. At 24 weeks, 21% of patients who showed initial improvements at 12 weeks relapsed after withdrawal of steroids, indicating that 51% could expect a durable effect from treatment. Very few randomized trials have compared placebo versus corticosteroids. Van Geest et al30van Geest R.J. Sasim I.V. Koppeschaar H.P.F. et al.Methylprednisolone pulse therapy for patients with moderately severe Graves' orbitopathy: a prospective, randomized, placebo-controlled study.Eur J Endocrinol. 2008; 158: 229-237Crossref PubMed Scopus (0) Google Scholar published the results of a placebo-controlled trial of 500 mg intravenous methylprednisolone delivered daily over 3 consecutive days in 4 cycles, each 4 weeks apart (6 g total). Five of the 6 patients (83%) who received steroid and 1 of 9 patients (11%) who received placebo showed a treatment response. During the first year after the trial, 33% in the methylprednisolone group and 89% in the placebo group required orbital decompression. No patient in the methylprednisolone group and 33% in the placebo group underwent strabismus surgery. Eyelid retraction repair was performed in 33% in the methylprednisolone group and 22% in the placebo group. Reviewing published data from 1045 patients receiving intravenous steroids, the combined morbidity and mortality rates were 6.5% and 0.6%, respectively.31Zang S. Ponto K.A. Kahaly G.J. Intravenous glucocorticoids for Graves' orbitopathy: efficacy and morbidity.J Clin Endocrinol Metab. 2011; 96: 320-332Crossref PubMed Scopus (0) Google Scholar Serious events were associated with daily or alternate-day doses of more than 0.5 g methylprednisolone. Fatal liver injury has been reported in patients who received cumulative doses of 10 to 24 g of methylprednisolone. For these reasons, many authors advocate for 500-mg intravenous methylprednisolone delivered weekly for 6 weeks followed by 250 mg weekly for an additional 6 weeks, yielding a cumulative dose of 4.5 g. Liver function test results and viral hepatitis antibody levels are evaluated before beginning treatment because pre-existing liver injury may increase the risk of complications related to intravenous steroids. Although orbital radiotherapy (ORT) has been used in the treatment of TED for more than 75 years, its effectiveness is debated.26Zoumalan C.I. Cockerham K.P. Turbin R.E. et al.Efficacy of corticosteroids and external beam radiation in the management of moderate to severe thyroid eye disease.J Neuro-Ophthalmology. 2007; 27: 205-214Crossref PubMed Scopus (0) Google Scholar In 2001, Gorman et al34Gorman C.A. Garrity J.A. Fatourechi V. et al.A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy.Ophthalmology. 2001; 108: 1523-1534Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar published the results of a prospective, randomized, crossover trial involving 42 TED patients treated with 20 Gy of ORT to 1 orbit followed by ORT to the contralateral orbit 6 months later. The study demonstrated no effect on volume of extraocular muscle and fat, proptosis, ductions, area of diplopia fields, or eyelid fissure width. Critics of the study cite that although patients began the study with a mean CAS of 6.2, the average duration of TED symptoms before ORT was 1.3 years (range, 0.2–16 years), indicating that many participants were likely in the inactive phase of disease. In addition, in several of the patients, corticosteroid therapy had failed previously and these patients would be unexpected to benefit from ORT.35Bartalena L. Marcocci C. Pinchera A. Editorial: orbital radiotherapy for Graves' ophthalmopathy.J Clin Endocrinol Metab. 2004; 89: 13-14Crossref PubMed Scopus (0) Google Scholar Moreover, the spillover radiation to the contralateral orbit, estimated at 0.4 Gy, may also have anti-inflammatory effects, essentially causing both orbits to be treated.36Large M. Hehlgans S. Reichert S. et al.Study of the anti-inflammatory effects of low-dose radiation: the contribution of biphasic regulation of the antioxidative system in endothelial cells.Strahlenther Onkol. 2015; 191: 742-749Crossref PubMed Scopus (13) Google Scholar,37Wunderlich R. Ernst A. Rödel F. et al.Low and moderate doses of ionizing radiation up to 2 Gy modulate transmigration and chemotaxis of activated macrophages, provoke an anti-inflammatory cytokine milieu, but do not impact upon viability and phagocytic function.Clin Exp Immunol. 2015; 179: 50-61Crossref PubMed Scopus (63) Google Scholar In a double-blind, randomized trial of 88 patients receiving ORT versus sham irradiation, Prummel et al38Prummel M.F. Terwee C.B. Gerding M.N. et al.A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves' ophthalmopathy.J Clin Endocrinol Metab. 2004; 89: 15-20Crossref PubMed Scopus (0) Google Scholar demonstrated a significant improvement in 52% of the irradiated patients versus 27% of the sham-irradiated patients 12 months after treatment (P = 0.02). Orbital radiotherapy was most effective at reducing severity of diplopia and improving extraocular motility. However, neither improvement in quality of life nor prevention of worsening of ophthalmopathy associated with ORT were observed. Prummel et al39Prummel M.F. Berghout A. Wiersinga W.M. et al.Randomised double-blind trial of prednisone versus radiotherapy in Graves' ophthalmopathy.Lancet. 1993; 342: 949-954Abstract PubMed Scopus (0) Google Scholar also investigated oral corticosteroid treatment versus ORT in a double-blind, randomized trial comparing 3 months of oral corticosteroid treatment with sham ORT versus 20 Gy of ORT and oral placebo in 56 patients with moderate to severe TED. Fifty percent of patients receiving steroids and 46% of patients receiving ORT showed a clinical response; however, patients receiving ORT showed greater improvement of motility at 24 weeks, whereas those receiving prednisone did not (P = 0.003). Marcocci et al40Marcocci C. Bartalena L. Bogazzi F. et al.Orbital radiotherapy combined with high dose systemic glucocorticoids for Graves' ophthalmopathy is more effective than radiotherapy alone: results of a prospective randomized study.J Endocrinol Invest. 1991; 14: 853-860Crossref PubMed Google Scholar showed that that the combination of ORT with corticosteroid therapy was more effective than ORT alone. A number of biologic agents targeting inflammatory cells and cytokines involved in TED have been reported. Rituximab, a monoclonal antibody directed against the CD20 antigen on B cells, has been used in the treatment of he