Trending Topic

23 mins

Trending Topic

Developed by Touch
Mark CompleteCompleted
BookmarkBookmarked
Luke G Qin, Michael T Pierce, Rachel C Robbins

The uvea is a vascular stratum that includes the iris, ciliary body and choroid. Uveitis is defined as inflammation of a part of the uvea or its entirety, but it is also used to describe inflammatory processes of any part of the eye, such as the vitreous or peripheral retina. The clinical taxonomy of uveitis […]

Advances in the Medical Treatment of Thyroid Eye Disease: Current and Emerging Therapies

Clara Jiayun Men, Andrea Lora Kossler
Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF
Published Online: Apr 18th 2024 touchREVIEWS in Ophthalmology. 2024;18(1):33-40 DOI: https://doi.org/10.17925/USOR.2024.18.1.7
Select a Section…
1

Abstract

Overview

Thyroid eye disease (TED) is a complex, autoimmune condition that can be sight-threatening and disfiguring. This disease poses significant diagnostic and therapeutic challenges, with limited therapies available. Recent advances in our understanding of the pathophysiology of TED have shifted the focus of treatment towards early intervention with targeted biological therapies. Biologics have the advantage of precise immune modulation, with potentially better safety profile and greater efficacy compared with traditional approaches. Currently, teprotumumab is the only US Food and Drug Administration-approved therapy for active, moderate-to-severe TED. While teprotumumab is a promising new drug, it is limited by its adverse event profile, cost of therapy and need for access to an infusion centre. New molecular targets are under investigation which address some of the current limitations to therapy. This article will cover recent insights into the understanding of the pathophysiology of TED, the current treatment paradigm and novel therapies under investigation.

Keywords
2

Article

Thyroid eye disease (TED) is an autoimmune condition that can lead to significant visual impairment, facial disfigurement and decreased quality of life. It affects 16 out of every 100,000 females and 2.9 out of every 100,000 males. Risk factors for TED include age, female gender, smoking and radioactive iodine therapy.1 TED typically begins with a progressive inflammatory phase (previously termed ‘active’) that can last from 6 to 36 months. Common symptoms include dry eyes, periorbital pain and swelling and eyelid retraction. Some patients may develop disfiguring proptosis, diplopia and vision loss. Over time, patients enter a non-progressive chronic phase (previously termed ‘inactive’) characterized by fibrosis. An accurate diagnosis is based on clinical assessment of disease activity and severity, laboratory testing for dysthyroid states and orbital imaging.2

Targeted therapies have changed the treatment landscape for TED. Historically, corticosteroids and/or orbital radiation therapy were used to decrease inflammation in the active phase of the disease followed by surgical rehabilitation once the patient entered the non-progressive chronic phase. In January 2020, teprotumumab, an antibody targeted against the insulin-like growth factor-1 receptor (IGF-1R), became the first US Food and Drug Administration (FDA)-approved therapy for TED.3 Clinical trials demonstrated that teprotumumab therapy improves the clinical activity score (CAS), proptosis, diplopia and quality of life for patients with TED.4 Following the success of teprotumumab, several other investigational drugs are currently in development. With the advent of new therapies, it is important to understand each drug’s mechanism of action, safety profile and efficacy to safely and effectively customize our treatments for patients with TED.

Pathophysiology

TED is characterized by autoinflammation resulting from complex and incompletely understood mechanisms. Several processes contributing to TED have been identified, including cellular immunity, cytokine upregulation, glycosaminoglycan (GAG) synthesis and adipogenesis.5–10 Exploration of potential molecular mediators of TED has revealed that the insulin-like growth factor-1 (IGF-1) pathway is implicated in many autoimmune diseases, including TED.11,12 IGF-1 is a cell surface protein widely expressed in most tissues in the human body. The IGF-1 pathway acts synergistically with thyroid-stimulating hormone (TSH), and once activated, the thyroid-stimulating hormone receptor (TSHR)–IGF-1R complex leads to the production of cytokines and expression of genes that result in orbital tissue reactivity and remodelling.10,13–15 The cytokine released recruits inflammatory cells into the orbit and stimulates fibroblasts to secrete GAGs, resulting in adipose and muscle expansion.16 The activated fibroblasts can also differentiate into adipocytes and myofibroblasts, further expanding orbital tissue volume and fibrosis.16

Additionally, B and T lymphocytes have been implicated in the pathophysiology of TED. Antigen-presenting cells present the autoantigen to CD4+ helper T cells, leading to T-cell activation and proliferation. The T cells then may induce B cells to produce more antibodies against the autoantigen.17–21 CD20 is a surface antigen involved in B-cell maturation, which helps in antigen presentation and cytokine production.17 The cycle continues as memory B cells are involved in autoantibody production, which then leads to cellular dysfunction and inflammation.18 T cells may also directly lead to autoreactivity. Activated T cells may express CD145, which binds to CD40, leading to stimulation of both orbital fibroblasts and T cells.19 This, in turn, leads to cellular proliferation, GAG secretion and production of proinflammatory cytokines, including interleukin-6 (IL-6) and IL-8.19,20 T-helper 1 (Th1) cells dominate in the early phase, with a cytokine expression profile consisting of IL-2, interferon-γ and tumour necrosis factor-α (TNF-α).21 Later in disease, Th2 cytokines, such as IL-4, IL-6, IL-10 and IL-13, predominate.9,18,22,23 Cytokine release leads to the activation of the CD40:CD154 signalling pathway in orbital fibroblasts and B-cell proliferation, increasing autoantibody production.21,24,25 IL-6 can also promote adipogenesis and increase the expression of TSHR on orbital fibroblasts.26 Further studies into the signalling networks and molecular triggers involved in TED pathogenesis will help to improve our understanding of TED and direct future therapeutic development.

Medical management for progressive inflammatory (active) thyroid eye disease

Mild thyroid eye disease

Treatment for TED depends on the patient’s disease activity and severity.27 Mild TED can be managed with conservative intervention. Treatment involves optimization of the ocular surface with lubricants, management of risk factors that can exacerbate TED and thyroid hormone control under the guidance of the endocrinologist. Modifiable risk factors for TED progression include tobacco use, radioactive iodine treatment, high total cholesterol and low-density lipoprotein levels and vitamin D deficiency.28–30 A randomized clinical trial (RCT) found that the antioxidant, selenium, is associated with decreased soft-tissue inflammation and slowed the progression of disease when given at a dose of 100 μg twice a day for 6 months.31 However, the study enrolled patients with TED from selenium-deficient areas. In areas without selenium deficiency, such as the USA, this therapy may not have the same beneficial effects.

Moderate-to-severe thyroid eye disease

Corticosteroids

Historically, the first-line treatment option for active, moderate-to-severe TED was corticosteroids.32 Intravenous (IV) corticosteroids are more effective and better tolerated than oral corticosteroids.33,34 Patients with TED treated with methylprednisolone IV 500 mg weekly for six doses followed by 250 mg weekly for six doses achieved a response rate of 77% versus 51% of those treated with oral prednisone.33 An investigation of the optimal cumulative dosing for IV corticosteroid therapy found that improvement was more common with higher-dose regimens (52% in the 7.47 g group, 35% in the 4.98 g group and 28% in the 2.25 g group – doses were selected by the authors as amounts that resulted in efficacy while still safely below the threshold to cause hepatotoxicity).35 However, these differences were lost by 24 weeks, and major adverse events were slightly more common in the highest dose group.35 Studies have not reported a significant improvement in proptosis or diplopia with corticosteroid therapy. Patients receiving a cumulative dose greater than 8 g of methylprednisolone or equivalent may develop hepatotoxicity, which is a potentially fatal complication.36 Contraindications to steroid therapy include liver dysfunction, recent hepatitis, severe hypertension, cardiovascular disease, poorly controlled diabetes and severe steroid-responsive glaucoma.32

Orbital radiation

Orbital radiotherapy (ORT) presents another therapeutic option for active TED. Orbital lymphocytes have been found to be radio-sensitive, resulting in reduced inflammation.37,38 Proper patient selection is critical, as patients with early and progressing, active, moderate-to-severe TED show the highest response rates.39 Two RCTs comparing ORT with sham irradiation in moderate-to-severe TED demonstrated a response rate in a composite ophthalmic score of 50–60%.40,41 The main outcome improved was the diplopia score, with no significant effect on proptosis, CAS or eyelid aperture found.40,41 Potential side effects of ORT include conjunctivitis, dry eye, cataract formation and radiation retinopathy. Contraindications to ORT include diabetic retinopathy, severe hypertension and age under 35 years.38,42

Additionally, treatment with a combination of radiotherapy and corticosteroids can be more effective than either treatment alone.34,43 Concurrent ORT and corticosteroid therapy have been found to improve clinical scores, decrease the cumulative dose of steroids needed and reduce the overall length of therapy when compared with sequential treatment in moderate-to-severe TED.44 A prospective randomized study showed that ORT with oral prednisone (100 mg/day for 7 days, followed by 5–6 month taper) was more effective than ORT alone in active TED.43 ORT with IV steroids was also found to be more effective than ORT with oral steroids. In a study comparing ORT with oral prednisone (100 mg/day followed by 5-month taper) and ORT with methylprednisolone IV (15 mg/kg for four cycles followed by 7.5 mg/kg for four cycles) in active, moderate-to-severe TED, the ORT with IV steroid group resulted in a greater improvement in CAS (2.8 versus 2), fewer surgical procedures at follow-up (7 versus 22%) and lower rates of adverse events (56.1 versus 85.4%).45

Mycophenolate mofetil

Mycophenolate mofetil (MMF) has been used to treat TED by inhibiting the proliferation of T and B lymphocytes involved in inflammation.46 An RCT comparing MMF alone (500 mg twice a day for 24 weeks) with corticosteroids (methylprednisolone IV 0.5 g a day, 3 days a week, followed by an oral prednisone taper) in active, moderate-to-severe TED found that the MMF group demonstrated better CAS, diplopia and proptosis responses at 24 weeks, as well as a lower rate of disease reactivation on follow-up.46 MMF is commonly used in combination with other treatments for TED, in particular corticosteroids. The MINGO (Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves’ orbitopathy; EUDRACT number: 2008-002123-93) study, a multicentre, randomized observer-masked trial, found that the addition of MMF 360 mg twice a day for 24 weeks to methylprednisolone IV (500 mg/week for 6 weeks followed by 250 mg/week for 6 weeks) is superior to steroids alone in improving a composite ophthalmic index (including eyelid swelling, CAS, proptosis, eyelid width, diplopia and eye muscle motility) in patients with active, moderate-to-severe TED.47 The combination group showed fewer relapses at 36 weeks, and there was no difference in the rate of adverse events.47

Targeted therapies

Recently, the focus of the management of TED has shifted to novel biological therapies that target the immune cells and receptors implicated in the pathogenesis of TED. Compared with non-specific treatments, such as corticosteroids, these targeted therapies have potentially better safety profile and greater efficacy.48–53 Figure 1 shows the change in our current treatment paradigm with the advent of biological therapies.54

Figure 1: Treatment algorithm for active, moderate-to-severe thyroid eye disease

Figure 1: Treatment algorithm for active, moderate-to-severe thyroid eye disease

AE = adverse event; IV = intravenous.

Reproduced with permission from Kossler AL, et al., 2022 (https://creativecommons.org/licenses/by-nc-nd/4.0/).54

Rituximab

A monoclonal antibody targeting CD20, rituximab acts by depleting the body’s population of autoreactive B cells.55 Two RCTs have demonstrated mixed results in the use of rituximab for active, moderate-to-severe TED.56,57 Salvi et al. showed the superiority of rituximab (1,000 mg IV twice weekly ) compared with IV methylprednisolone in improving CAS at 24 weeks in 32 patients with eyelid retraction (13 versus 0%, respectively).56 No improvement in mean proptosis or diplopia was found in either group. Stan et al. showed no difference between rituximab (500 mg once) and placebo in 25 patients with CAS, proptosis, diplopia or eyelid retraction at 24 or 52 weeks.57 The study populations in the two studies differed in the percentage of smokers included (59 versus 16%), the average duration of TED (4 versus 12 months) and baseline CAS (≥3 versus ≥4), which may contribute to the difference in findings between the two RCTs. Notably, the rates of adverse events from rituximab therapy were high (8/13 patients and 13/15 patients) and included infusion reactions, transaminitis, hypotension, aggravation of inflammatory bowel disease and transient loss of vision.56,57

Adalimumab

Adalimumab is an anti-TNF-α agent that has been used to treat various autoimmune conditions, including active TED, with limited evidence. In a small retrospective study, 4 out of 10 patients reported subjective improvements in diplopia, pain and swelling, but no significant objective improvements on examination were measured.58 Larger and more rigorous studies are needed to establish the effectiveness of adalimumab in TED.

Infliximab

Infliximab is a monoclonal antibody that also targets TNF-α. Case reports of its use in patients with steroid-resistant, severe TED have shown improvements in visual acuity (VA) and CAS after one to three doses.59,60 Further investigation with larger studies is needed to determine the efficacy of infliximab in TED.

Tocilizumab

Tocilizumab is an IL-6 monoclonal antibody used to treat active TED. A proinflammatory cytokine, IL-6 is found in high concentrations in patients with TED.61,62 IL-6 stimulates the expression of TSHR in orbital fibroblasts, thereby potentiating the pathways implicated in disease.63 An RCT evaluated tocilizumab, administered as four infusions every 4 weeks, in 32 patients with corticosteroid-resistant, moderate-to-severe TED. Tocilizumab was found to significantly reduce CAS by two points or greater in 93% of patients at week 16 versus 59% in the placebo group.64 No improvement in diplopia was seen, and initial improvements in CAS and proptosis were lost at 40 weeks of follow-up.64 Furthermore, the recurrence rate was high, and side effects – such as hypercholesterolaemia, transaminitis, neutropenia and infections – were common, with more than one adverse event occurring in 60% of treated patients versus 24% of placebo.65

Teprotumumab

Teprotumumab, an antibody targeted against the IGF-1R, is the first FDA-approved therapy for active, moderate-to-severe TED.3 Teprotumumab reduces the production of proinflammatory cytokines by inhibiting both IGF-1R and TSHR signalling.66 The teprotumumab regimen consists of eight infusions administered every 3 weeks, with an initial dosing of 10 mg/kg for the first infusion, followed by 20 mg/kg for the remaining infusions.4 The OPTIC phase III trial (Treatment of Graves’ Orbitopathy [Thyroid Eye Disease] to Reduce Proptosis With Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study; ClinicalTrials.gov identifier: NCT03298867) showed that proptosis improved in 83% of the teprotumumab group versus 10% of the placebo group, with a mean improvement of 3.32 mm.4,67 Diplopia improved by one grade or more in 68% of the treatment group versus 29% of placebo. CAS reduced to 0 or 1 in 59% of the treatment group versus 21% of placebo.4

Durability data

Pooled long-term data from two randomized, placebo-controlled, multicenter trials (Teprotumumab [RV 001] Treatment in Patients With Active Thyroid Eye Disease. ClinicalTrials.gov identifier: NCT01868997; Treatment of Graves’ Orbitopathy [Thyroid Eye Disease] to Reduce Proptosis With Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC). ClinicalTrials.gov identifier: NCT03298867)67,68 showed proptosis response (defined as ≥2mm reduction in the study eye) in 62 of 71 patients (87%) 7 weeks after final dose of teprotumumab and 38 of 57 patients (67%) 51 weeks after. Diplopia response (≥1 Bahn-Gorman grade) was seen in 38 of 58 patients (66%) 7 weeks after and 33 of 48 patients (69%) 51 weeks after. The composite outcome (defined as improvement seen in at least 2 of the following: CAS, proptosis, lid aperture, diplopia, and/or globe motility) improved in 66 of 72 patients (92%) and 48 of 58 patients (83%) after 7 and 51 weeks, respectively.69

Adverse events

Most adverse events reported in the clinical trials were mild to moderate, including muscle spasms, nausea, diarrhoea, fatigue, hyperglycaemia and alopecia.4,70 In the teprotumumab group, 5–12% of patients withdrew early from the study due to a serious adverse event, although half of them were categorized as likely unrelated to the treatment (such as pneumothorax, urinary retention and Escherichia sepsis).4,70 However, recent studies suggest that hearing impairment may be more prevalent and serious than previously reported.71 Sears et al. reported that 81.5% (22 of 27 patients) of patients who received at least four infusions of teprotumumab complained of otologic symptoms (tinnitus, autophony, ear plugging and hearing loss), with five patients developing objective sensorineural hearing loss and two patients with a significant decline in word recognition.72 After an average of 39.2-week post-treatment follow-up, these symptoms resolved in the majority of patients. However, 45.5% of patients with new-onset or worsening hearing loss remained symptomatic.72 Until the risk factors for hearing dysfunction are better understood, the authors recommend baseline audiogram testing prior to starting teprotumumab, repeat testing during therapy if otologic symptoms develop and post-treatment audiometry. The authors also recommend ear, nose and throat team involvement and discontinuation of teprotumumab if significant hearing loss develops during therapy. Among others, additional concerning adverse events include hyperglycaemia and the development or exacerbation of pre-existing inflammatory bowel disease after initiating teprotumumab therapy, underlining the importance for clinicians to exercise caution in patient selection.73–75 Providers must weigh the risks, benefits and alternatives to therapy and screen, educate and monitor all patients during therapy.

Teprotumumab for dysthyroid optic neuropathy

Several case reports describe the efficacy of teprotumumab in treating dysthyroid optic neuropathy (DON), with improvements in relative afferent pupillary defect (RAPD), VA, Humphrey visual fields, CAS, proptosis and extraocular muscle size after two to three infusions.76–79 In a case series of 10 patients with DON, 70% of patients showed improvement in RAPD and/or VA after two infusions.80 On average, patients achieved 5.25 points of CAS improvement and 4.7 mm of proptosis reduction, and six of the seven patients with colour deficiency recovered their colour vision.80 Additional clinical studies and long-term data are needed to further explore the efficacy of teprotumumab for sight-threatening TED.

Teprotumumab for long-disease-duration thyroid eye disease

The efficacy of teprotumumab in patients with long disease duration or who may need retreatment is currently being investigated. The OPTIC X clinical trial (Treatment of Graves’ Orbitopathy to Reduce Proptosis With Teprotumumab Infusions in an Open-Label Clinical Extension Study; ClinicalTrials.gov identifier: NCT03461211) enrolled patients who were proptosis non-responders in the earlier OPTIC trial, those who received placebo in OPTIC and those who met the criteria for re-treatment due to relapse in the follow-up period (defined as a loss of at least 2 mm of their week 24 proptosis improvement or substantial increase in the number of inflammatory signs).81 OPTIC X found that 89% of the OPTIC placebo patients (who had an average of 12-month duration of TED) were proptosis responders after treatment with teprotumumab.81 Five of the eight patients who relapsed after OPTIC experienced at least 2 mm of proptosis improvement with additional treatment, and of the five OPTIC non-responders, two benefitted from an additional course of teprotumumab in the OPTIC-X study.81

Other studies have reported the use of teprotumumab in long-disease-duration TED.82–84 A retrospective study of 31 patients with TED for longer than 2 years with CAS ≤3 and without any changes in the examination showed a mean reduction in proptosis by 3 mm, improvement in CAS by 1.8 and improvement in Gorman diplopia score by 0.5.83 An analysis of pre- and post-therapy imaging revealed reductions in the volume of both extraocular muscles and fat.83 A multicentre retrospective study, involving 66 patients with refractory, moderate-to-severe TED, of varying disease durations, who had failed prior therapy with corticosteroids, orbital radiation, surgical decompression, biologics or other steroid-sparing medications, demonstrated proptosis, CAS and diplopia responses of 85.9, 93.8, and 69.1%, respectively, which were comparable with response rates seen in treatment-naive patients.85 Patients experienced a mean reduction in proptosis of 3.1 ± 2.4 mm and a mean improvement in CAS of 3.8 ± 1.6. This study found no significant difference based on the disease duration or prior medical therapy used for TED, although patients with prior decompression surgery experienced significantly lower diplopia response (46.7% versus 77.5%, p = 0.014) and proptosis response (75.0% versus 90.9%, p = 0.045) when compared with nondecompression patients.85

Medical management for non-inflammatory (inactive) thyroid eye disease

Preliminary results from a phase IV clinical trial (A Study Evaluating TEPEZZA® Treatment in Patients With Chronic [Inactive] Thyroid Eye DiseaseClinicalTrials.gov identifier: NCT04583735)86 is evaluating the use of teprotumumab in patients with long-disease-duration TED (between 2 and 10 years) and low CAS (≤1) showed an average of 2.41 mm of proptosis reduction in the treatment group versus 0.92 mm in the placebo group at week 24. The secondary endpoint of ≥2 mm of proptosis reduction was met by 62% of patients in the treatment group versus 25% in the placebo group.87 The study did not find a significant improvement in the diplopia response rate between the two groups. This study excluded patients with prior orbital radiation, decompression surgery or strabismus surgery. Long-term studies are needed to assess the treatment response durability and potential reactivation or proptosis regression after therapy. Until then, teprotumumab can be considered a medical treatment alternative to orbital decompression for proptosis improvement in patients with non-inflammatory TED.

Emerging therapies

As our understanding of the pathophysiology underlying TED advances, new molecular targets are identified (see Figure 2).88 While teprotumumab is a promising new therapy, it is limited by its adverse event profile, cost of therapy and need for access to an infusion centre. New molecular targets are under investigation that address some of the limitations to current treatment options (see Table 1).89–95

Figure 2: Molecular targets for current and emerging medical therapies88

Figure 2: Molecular targets for current and emerging medical therapies88

CD = cluster of differentiation; CFZ533 = anti-CD40 antagonist; FcRn = neonatal Fc receptor; GTP = guanosine-5′-triphosphate; HA = hyaluronic acid; HAS2 = hyaluronan synthase 2; HBM9161 = FcRn antagonist; IGF-1R = insulin-like growth factor-1 receptorIL = interleukin; IMPDH = inosine 5′-monophosphate dehydrogenase; LDL = low-density lipoprotein; NF-kB = nuclear factor-κB; PGE2 = prostaglandin E2; PGHS-2 = prostaglandin-H synthase-2; RVT-1401 = FcRn antagonist; TNF-α = tumour necrosis factor-α; TSHR = thyroid stimulating hormone receptor; VRDN = a Viridian investigational drug.

Reproduced with permission from Smith TJ. 2022 (https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en).88

Table 1: Emerging therapies, their mechanisms of action, dosing, delivery and developmental stage

Drug name

Mechanism of action

Route of delivery

Dosing

Developmental stage

VRDN-001

Anti-IGF-1R monoclonal antibody

IV

Phase 1/2: Two infusions of 3,10, or 20 mg/kg vs placebo, given 3 weeks apart

Phase 3: Five invusions of 10mg/kg or placebo given 3 weeks apart.

Phase I/II and Phase III89

VRDN-002

Anti-IGF-1R monoclonal antibody (extended half-life)

SC and IV

Single dose of 300 mg/2 mL

Phase I90

Batoclimab

Anti-FcRn monoclonal antibody

SC

2-weekly 680 mg doses followed by 4-weekly 340 mg doses

Phase III91

Linsitinib

Anti-IGF-1R monoclonal antibody

Oral

Twice a day for 6 months

Phase IIb92

Lonigutamab

Anti-IGF-1R monoclonal antibody

SC

Single dose given at day 1 and day 21, weekly dosing and monthly dosing

Phase I/II93

K1-70

Anti-TSHR monoclonal antibody

IM and IV

Single IM injection (at 0.2, 1, 5 or 25 mg/dose) or IV infusion (at 50 or 150 mg/dose)

Phase I94

Secukinumab

Anti-IL-17A monoclonal antibody

SC

300 mg at baseline, week 1, week 2, week 3, week 4, week 8 and week 12

Phase II/III95

FcRn = neonatal Fc receptor;IGF-1R = insulin-like growth factor-1 receptor;IL = interleukin;IM = intramuscular;IV = intravenous;SC = subcutaneous;TSHR = thyroid stimulating hormone receptor;VRDN = a Viridian investigational drug.

VRDN-001, VRDN-002 and VRDN-003

VRDN-001, a monoclonal antibody against the IGF-1R, is under investigation as a treatment option for TED. The phase I/II clinical trial (A Safety, Tolerability and Efficacy Study of VRDN 001 in Healthy Volunteers and Persons With Thyroid Eye Disease [TED]; ClinicalTrials.gov identifier: NCT05176639) evaluated the efficacy of varying doses of the drug at 3 and 10 mg/kg.96 The 3 mg/kg treatment group showed a mean reduction of 1.5 mm in proptosis from baseline, 33% proptosis response rate and CAS improvement by 2.0. The 10 mg/kg group showed a mean reduction of 1.8 mm in proptosis, 50% proptosis response rate and CAS improvement of 1.8.96 None of the patients with diplopia at baseline achieved the resolution of their symptoms. There were no serious adverse events, discontinuations or infusion reactions reported.96

VRDN-002 is an anti-IGF-1R antibody compound with a modified Fc region engineered to extend the half-life of the drug. In phase I clinical trials involving healthy volunteers, VRDN-002 showed an approximately four times half-life extension when compared with VRDN-001, and patients’ measured IGF-1 serum levels were elevated when compared with placebo.90 Additionally, VRDN-003 is another half-life-extended version of VRDN-001. In preclinical studies involving monkeys, VRDN-003 was found to have a similar pharmacology to VRDN-001, with twice the half-life when delivered intravenously and subcutaneously.97 The increased half-lives of VRDN-002 and VRDN-003 may enable therapeutic levels of the drugs to be achieved with low-volume subcutaneous (SC) delivery, potentially decreasing the burden of care for patients with TED. Studies are ongoing, evaluating these potential therapeutic options.

Batoclimab

Batoclimab is a monoclonal antibody targeting the neonatal Fc receptor (FcRn) that has been proposed for the treatment of several autoimmune diseases, including TED.98 FcRn transports immunoglobulin G (IgG) and prevents their lysosomal degradation.99 Batoclimab blocks FcRn-mediated recycling of IgG and increases the catabolism of IgG in the body. In TED, this may increase the degradation of pathogenetic autoantibodies against the TSHR and IGF-1R. Administered as a weekly SC injection, batoclimab allows for the possibility of at-home treatment. Proof-of-concept, randomized, double-blind placebo-controlled trials (A Proof-of-Concept Study to Assess Batoclimab in Participants With Graves’ Disease; ClinicalTrials.gov identifier: NCT05907668) evaluated 2-weekly 680 mg SC doses of batoclimab followed by 4-weekly 340 mg SC doses of batoclimab in 77 adult patients with moderate-to-severe active TED.91 Both trials showed significant decreases in anti-TSHR antibody and total IgG serum levels with batoclimab. The batoclimab group showed a significant decrease in orbital muscle volume and an improvement in quality of life when compared with the placebo group. The study found no statistically significant difference in the proptosis response between the treatment and placebo groups; however, the trial was terminated early due to an unanticipated increase in serum cholesterol. The increase in lipids is reversed upon discontinuation of the drug.100 A phase III RCT (Study to Assess Batoclimab in Participants With Active Thyroid Eye Disease; ClinicalTrials.gov identifier: NCT05524571) is currently underway to evaluate the safety and efficacy of the treatment of TED.101

Linsitinib

Linsitinib is a small-molecule inhibitor of IGF-1R. In an experimental mouse model of TED, it was found to prevent autoimmune hyperthyroidism in the early stage of the disease and reduce the infiltration of orbital tissues by T cells and macrophages.92 The drug is currently in phase IIb clinical trials (A Phase 2b, Study of Linsitinib in Subjects With Active, Moderate to Severe Thyroid Eye Disease [LIDS]ClinicalTrials.gov identifier: NCT05276063).102 It is administered orally twice daily for 6 months to patients with active, moderate-to-severe TED.

Lonigutamab

Lonigutamab is another anti-IGF-1R monoclonal antibody designed to have a strong binding affinity to its target, thereby potentially enabling a small-volume SC injection. The drug is currently in phase I/II clinical trials, which will randomize patients to one of the three different treatment doses (Efficacy and Safety of Lonigutamab in Subjects With Thyroid Eye DiseaseClinicalTrials.gov identifier: NCT05683496).93

K1-70

K1-70 is a human monoclonal antibody targeting TSHR. In a phase I clinical trial, 18 patients with Graves’ disease were treated with a single intramuscular (IM) injection (at 0.2, 1, 5 or 25 mg/dose) or IV infusion (at 50 or 150 mg/dose). T3, T4 and TSH levels progressed into hypothyroid ranges with an IM dose of 25 mg or an IV dose of 50 or 150 mg. There were no serious adverse events that required discontinuation, dose reduction or dose interruption of therapy. Additional studies are needed to determine the efficacy of TSHR inhibition in patients with TED.94

Secukinumab

Secukinumab is a human monoclonal anti-IL-17A antibody already approved for the treatment of psoriatic arthritis, ankylosing spondylitis and severe plaque psoriasis.103,104 IL-17 is a group of proinflammatory cytokines secreted by T cells, mast cells and neutrophils, with IL-17A being the key effector cytokine. The binding of IL-17 to its receptor activates downstream pathways involved in the amplification of other cytokines, including TNF-α, cellular hyperproliferation and T-cell infiltration, leading to an increased inflammatory response.105 By blocking IL-17A, secukinumab may potentially decrease the expression of cytokines and prevent the inflammatory processes involved in TED. Secukinumab is now currently in phase II/III clinical trials for patients with active, moderate-to-severe TED. It is delivered as an SC injection of 300 mg at baseline, week 1, week 2, week 3, week 4, week 8 and week 12 (A Study of the Efficacy and Safety of Secukinumab 300 mg in Patients With Thyroid Eye DiseaseClinicalTrials.gov identifier: NCT04737330).95

Conclusions

Recent advances in our understanding of the molecular underpinnings of TED have changed the treatment landscape. Teprotumumab, the only FDA-approved therapy for TED, has shown efficacy in improving proptosis, diplopia and inflammatory signs in patients with active moderate-to-severe disease. Questions remain regarding its cost-effectiveness, ease of access and severity of adverse events. Several emerging therapies under investigation similarly target IGF-1R, each with different binding affinities, dosing regiments and delivery approaches. Other therapies target TSHR, active cytokines in the TED inflammatory pathway or the neonatal FcRn. Investigating treatment options may bring new insights into the pathophysiology of TED and address the limitations of current treatment options, including cost, access, safety and limited efficacy in certain types of TED. Additional research identifying different phenotypes of TED, risk factors for adverse events to therapy, objective testing parameters, biomarkers for better diagnosis and measurement of response to therapy and the role of surgery for TED with or without combination with medical treatment are needed.

3

References

List View
Grid View
1
Copy DOIDOI Copied
Visit DOI Link

 Sikder SWeinberg RSThyroid eye disease: Pathogenesis and treatmentOphthalmologica2010;224:199203. DOI10.1159/000260224.

2
Copy DOIDOI Copied
Visit DOI Link

 Rundle FFWilson CWDevelopment and course of exophthalmos and ophthalmoplegia in Graves’ disease with special reference to the effect of thyroidectomyClin Sci1945;5:17794.

3
Copy DOIDOI Copied
Visit DOI Link

 U.S. Food and Drug AdministrationFDA approves first treatment for thyroid eye disease2020Available atwww.fda.gov/news-events/press-announcements/fda-approves-first-treatment-thyroid-eye-disease (Date last accessed12 April 2024).

4
Copy DOIDOI Copied
Visit DOI Link

 Douglas RSKahaly GJPatel Aet alTeprotumumab for the treatment of active thyroid eye diseaseN Engl J Med2020;382:34152DOI10.1056/NEJMoa1910434.

5
Copy DOIDOI Copied
Visit DOI Link

 Yang DHiromatsu YHoshino Tet alDominant infiltration of T(H)1-type CD4+ T cells at the retrobulbar space of patients with thyroid-associated ophthalmopathyThyroid1999;9:30510DOI10.1089/thy.1999.9.305.

6
Copy DOIDOI Copied
Visit DOI Link

 Förster GOtto EHansen Cet alAnalysis of orbital T cells in thyroid-associated ophthalmopathyClin Exp Immunol1998;112:42734DOI10.1046/j.1365-2249.1998.00613.x.

7
Copy DOIDOI Copied
Visit DOI Link

 Smith TJOrbital fibroblasts exhibit a novel pattern of responses to proinflammatory cytokines: Potential basis for the pathogenesis of thyroid-associated ophthalmopathyThyroid2002;12:197203DOI10.1089/105072502753600133.

8
Copy DOIDOI Copied
Visit DOI Link

 Kumar SBahn RSRelative overexpression of macrophage-derived cytokines in orbital adipose tissue from patients with Graves’ ophthalmopathyJ Clin Endocrinol Metab2003;88:424650DOI10.1210/jc.2003-030380.

9
Copy DOIDOI Copied
Visit DOI Link

 Hiromatsu YYang DBednarczuk Tet alCytokine profiles in eye muscle tissue and orbital fat tissue from patients with thyroid-associated ophthalmopathyJ Clin Endocrinol Metab2000;85:11949DOI10.1210/jcem.85.3.6433.

10
Copy DOIDOI Copied
Visit DOI Link

 Tsui SNaik VHoa Net alEvidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: A tale of two antigens implicated in Graves’ diseaseJ Immunol2008;181:4397405. DOI10.4049/jimmunol.181.6.4397.

11
Copy DOIDOI Copied
Visit DOI Link

 Smith TJInsulin-like growth factor-I regulation of immune function: A potential therapeutic target in autoimmune diseases Pharmacol Rev2010;62:199236DOI10.1124/pr.109.002469.

12
Copy DOIDOI Copied
Visit DOI Link

 Smith TJTsai CCShih M-Jet alUnique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathyThyroid2008;18:9838DOI10.1089/thy.2007.0404.

13
Copy DOIDOI Copied
Visit DOI Link

 Tramontano DCushing GWMoses ACIngbar SHInsulin-like growth factor-I stimulates the growth of rat thyroid cells in culture and synergizes the stimulation of DNA synthesis induced by TSH and Graves’-IgG. Endocrinology. 1986;119:9402. DOI10.1210/endo-119-2-940.

14
Copy DOIDOI Copied
Visit DOI Link

 Krieger CCPerry JDMorgan SJet alTSH/IGF-1 receptor cross-talk rapidly activates extracellular signal-regulated kinases in multiple cell typesEndocrinology2017;158:367683DOI10.1210/en.2017-00528.

15
Copy DOIDOI Copied
Visit DOI Link

 Pritchard JHan RHorst Net alImmunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves’ disease is mediated through the insulin-like growth factor I receptor pathwayJ Immunol2003;170:634854DOI10.4049/jimmunol.170.12.6348.

16
Copy DOIDOI Copied
Visit DOI Link

 Longo DLSmith TJHegedüs LGraves’ diseaseN Engl J Med2016;375:155265DOI10.1056/NEJMra1510030.

17
Copy DOIDOI Copied
Visit DOI Link

 Boye JElter TEngert AAn overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol. 2003;14:52035. DOI10.1093/annonc/mdg175.

18
Copy DOIDOI Copied
Visit DOI Link

 Strianese DRossi FInterruption of autoimmunity for thyroid eye disease: B-cell and T-cell strategy. Eye. 2019;33:1919. DOI10.1038/s41433-018-0315-9.

19
Copy DOIDOI Copied
Visit DOI Link

 Hwang CJAfifiyan NSand Det alOrbital fibroblasts from patients with thyroid-associated ophthalmopathy overexpress CD40: CD154 hyper induces IL-6, IL-8, and MCP-1Invest Ophthalmol Vis Sci2009;50:22628. DOI10.1167/iovs.08-2328.

20
Copy DOIDOI Copied
Visit DOI Link

 Sempowski GDRozenblit JSmith TJPhipps RPHuman orbital fibroblasts are activated through CD40 to induce proinflammatory cytokine productionAm J Physiol1998;274:C70714DOI10.1152/ajpcell.1998.274.3.C707.

21
Copy DOIDOI Copied
Visit DOI Link

 Aniszewski JPValyasevi RWBahn RSRelationship between disease duration and predominant orbital T cell subset in Graves’ ophthalmopathyJ Clin Endocrinol Metab2000;85:77680DOI10.1210/jcem.85.2.6333.

22
Copy DOIDOI Copied
Visit DOI Link

 Fang SLu YHuang Yet alMechanisms that underly T cell immunity in Graves’ orbitopathyFront Endocrinol. 2021;12:648732. DOI10.3389/fendo.2021.648732.

23
Copy DOIDOI Copied
Visit DOI Link

 Fang SHuang YWang Net alInsights into local orbital immunity: Evidence for the involvement of the Th17 cell pathway in thyroid-associated ophthalmopathyJ Clin Endocrinol Metab2019;104:1697711DOI10.1210/jc.2018-01626.

24
Copy DOIDOI Copied
Visit DOI Link

 Feldon SEPark DJJO’Loughlin CWet alAutologous T-lymphocytes stimulate proliferation of orbital fibroblasts derived from patients with Graves’ ophthalmopathyInvest Ophthalmol Vis Sci2005;46:391321DOI10.1167/iovs.05-0605.

25
Copy DOIDOI Copied
Visit DOI Link

 Zhao L-QWei R-LCheng J-Wet alThe expression of intercellular adhesion molecule-1 induced by CD40-CD40L ligand signaling in orbital fibroblasts in patients with Graves’ ophthalmopathyInvest Ophthalmol Vis Sci. 2010;51:465260. DOI10.1167/iovs.09-3789.

26
Copy DOIDOI Copied
Visit DOI Link

 Jyonouchi SCValyasevi RWHarteneck DAet alInterleukin-6 stimulates thyrotropin receptor expression in human orbital preadipocyte fibroblasts from patients with Graves’ ophthalmopathyThyroid2001;11:92934. DOI10.1089/105072501753210984.

27
Copy DOIDOI Copied
Visit DOI Link

 Bartalena LKahaly GJBaldeschi Let alThe 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathyEur J Endocrinol2021;185:G4367. DOI10.1530/EJE-21-0479.

28
Copy DOIDOI Copied
Visit DOI Link

 Bartalena LBaldeschi LBoboridis Ket alThe 2016 European Thyroid Association/European Group on Graves’ orbitopathy guidelines for the management of Graves’ orbitopathyEur Thyroid J2016;5:926DOI10.1159/000443828.

29
Copy DOIDOI Copied
Visit DOI Link

 Sabini EMazzi BProfilo MAet alHigh serum cholesterol is a novel risk factor for Graves’ orbitopathy: Results of a cross-sectional studyThyroid2018;28:38694DOI10.1089/thy.2017.0430.

30
Copy DOIDOI Copied
Visit DOI Link

 Heisel CJRiddering ALAndrews CAKahana ASerum vitamin D deficiency is an independent risk factor for thyroid eye diseaseOphthalmic Plast Reconstr Surg2020;36:1720DOI10.1097/IOP.0000000000001437.

31
Copy DOIDOI Copied
Visit DOI Link

 Marcocci CKahaly GJKrassas GEet alSelenium and the course of mild Graves’ orbitopathyN Engl J Med. 2011;364:192031. DOI10.1056/NEJMoa1012985.

32
Copy DOIDOI Copied
Visit DOI Link

 Zang SPonto KAKahaly GJClinical review: Intravenous glucocorticoids for Graves’ orbitopathy: Efficacy and morbidityJ Clin Endocrinol Metab2011;96:32032DOI10.1210/jc.2010-1962.

33
Copy DOIDOI Copied
Visit DOI Link

 Kahaly GJPitz SHommel GDittmar MRandomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathyJ Clin Endocrinol Metab2005;90:523440DOI10.1210/jc.2005-0148.

34
Copy DOIDOI Copied
Visit DOI Link

 Stiebel-Kalish HRobenshtok EHasanreisoglu Met alTreatment modalities for Graves’ ophthalmopathy: Systematic review and metaanalysisJ Clin Endocrinol Metab2009;94:270816DOI10.1210/jc.2009-0376.

35
Copy DOIDOI Copied
Visit DOI Link

 Bartalena LKrassas GEWiersinga Wet alEfficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves’ orbitopathyJ Clin Endocrinol Metab2012;97:445463DOI10.1210/jc.2012-2389.

36
Copy DOIDOI Copied
Visit DOI Link

 Marinó MMorabito EBrunetto MRet alAcute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathyThyroid2004;14:4036. DOI10.1089/105072504774193276.

37
Copy DOIDOI Copied
Visit DOI Link

 Bartalena LMarcocci CTanda MLet alOrbital radiotherapy for Graves’ ophthalmopathyThyroid2002;12:24550DOI10.1089/105072502753600223.

38
Copy DOIDOI Copied
Visit DOI Link

 Tanda MLBartalena LEfficacy and safety of orbital radiotherapy for Graves’ orbitopathyJ Clin Endocrinol Metab2012;97:385765DOI10.1210/jc.2012-2758.

39
Copy DOIDOI Copied
Visit DOI Link

 Chundury RVWeber ACPerry JDOrbital radiation therapy in thyroid eye diseaseOphthalmic Plast Reconstr Surg2016;32:839DOI10.1097/IOP.0000000000000544.

40
Copy DOIDOI Copied
Visit DOI Link

 Mourits MPvan Kempen-Harteveld MLGarcía MBet alRadiotherapy for Graves’ orbitopathy: Randomised placebo-controlled studyLancet2000;355:15059DOI10.1016/S0140-6736(00)02165-6.

41
Copy DOIDOI Copied
Visit DOI Link

 Prummel MFTerwee CBGerding MNet alA randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves’ ophthalmopathyJ Clin Endocrinol Metab2004;89:1520DOI10.1210/jc.2003-030809.

42
Copy DOIDOI Copied
Visit DOI Link

 Bartalena LBaldeschi LDickinson AJet alConsensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathyThyroid2008;18:33346DOI10.1089/thy.2007.0315.

43
Copy DOIDOI Copied
Visit DOI Link

 Marcocci CBartalena LBogazzi Fet alOrbital radiotherapy combined with high dose systemic glucocorticoids for Graves’ ophthalmopathy is more effective than radiotherapy alone: Results of a prospective randomized studyJ Endocrinol Invest1991;14:85360DOI10.1007/BF03347943.

44
Copy DOIDOI Copied
Visit DOI Link

 Limone PPBianco LMellano Met alIs concomitant treatment with steroids and radiotherapy more favorable than sequential treatment in moderate-to-severe Graves orbitopathy Radiol Med2021;126:33442. DOI10.1007/s11547-020-01244-5.

45
Copy DOIDOI Copied
Visit DOI Link

 Marcocci CBartalena LTanda MLet alComparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves’ ophthalmopathy: Results of a prospective, single-blind, randomized studyJ Clin Endocrinol Metab2001;86:35627DOI10.1210/jcem.86.8.7737.

46
Copy DOIDOI Copied
Visit DOI Link

 Ye XBo XHu Xet alEfficacy and safety of mycophenolate mofetil in patients with active moderate-to-severe Graves’ orbitopathyClin Endocrinol (Oxf)2017;86:24755DOI10.1111/cen.13170.

47
Copy DOIDOI Copied
Visit DOI Link

 Kahaly GJRiedl MKönig Jet alEuropean Group on Graves’ orbitopathy (EUGOGO). mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves’ orbitopathy (MINGO): A randomised, observer-masked, multicentre trialLancet Diabetes Endocrinol2018;6:28798DOI10.1016/S2213-8587(18)30020-2.

48
Copy DOIDOI Copied
Visit DOI Link

 Roos JCPMurthy RUpdate on the clinical assessment and management of thyroid eye diseaseCurr Opin Ophthalmol2019;30:4016DOI10.1097/ICU.0000000000000596.

49
Copy DOIDOI Copied
Visit DOI Link

 Liou VDYoon MKAdvances in steroid sparing medical management of active thyroid eye diseaseSemin Ophthalmol2020;35:21623DOI10.1080/08820538.2020.1791911.

50
Copy DOIDOI Copied
Visit DOI Link

 Khong JJMcNab AMedical treatment in thyroid eye disease in 2020Br J Ophthalmol2021;105:299305. DOI10.1136/bjophthalmol-2020-316051.

51
Copy DOIDOI Copied
Visit DOI Link

 Honavar SGMedical management of thyroid eye disease – A paradigm shiftIndian J Ophthalmol. 2020;68:1515. DOI10.4103/ijo.IJO_2386_20.

52
Copy DOIDOI Copied
Visit DOI Link

 Kahaly GJImmunotherapies for thyroid eye diseaseCurr Opin Endocrinol Diabetes Obes2019;26:2505. DOI10.1097/MED.0000000000000493.

53
Copy DOIDOI Copied
Visit DOI Link

 Taylor PNZhang LLee RWJet alNew insights into the pathogenesis and nonsurgical management of Graves orbitopathyNat Rev Endocrinol2020;16:10416DOI10.1038/s41574-019-0305-4.

54
Copy DOIDOI Copied
Visit DOI Link

 Kossler ALDouglas RDosiou CTeprotumumab and the evolving therapeutic landscape in thyroid eye diseaseThe Journal of clinical endocrinology and metabolism2022;107:S3646DOI10.1210/clinem/dgac168.

55
Copy DOIDOI Copied
Visit DOI Link

 El Fassi DNielsen CHHasselbalch HCHegedüs LThe rationale for B lymphocyte depletion in Graves’ disease. Monoclonal anti-CD20 antibody therapy as a novel treatment optionEur J Endocrinol2006;154:62332. DOI10.1530/eje.1.02140.

56
Copy DOIDOI Copied
Visit DOI Link

 Salvi MVannucchi GCurrò Net alEfficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves’ orbitopathy: A randomized controlled studyJ Clin Endocrinol Metab2015;100:42231DOI10.1210/jc.2014-3014.

57
Copy DOIDOI Copied
Visit DOI Link

 Stan MNGarrity JACarranza Leon BGet alRandomized controlled trial of rituximab in patients with Graves’ orbitopathyJ Clin Endocrinol Metab2015;100:43241DOI10.1210/jc.2014-2572.

58
Copy DOIDOI Copied
Visit DOI Link

 Ayabe RRootman DBHwang CJet alAdalimumab as steroid-sparing treatment of inflammatory-stage thyroid eye diseaseOphthalmic Plast Reconstr Surg2014;30:4159DOI10.1097/IOP.0000000000000211.

59
Copy DOIDOI Copied
Visit DOI Link

 Durrani OMReuser TQMurray PIInfliximab: A novel treatment for sight-threatening thyroid associated ophthalmopathyOrbit2005;24:1179DOI10.1080/01676830590912562.

60
Copy DOIDOI Copied
Visit DOI Link

 Strianese DUpdate on Graves disease: Advances in treatment of mild, moderate and severe thyroid eye diseaseCurr Opin Ophthalmol2017;28:50513DOI10.1097/ICU.0000000000000402.

61
Copy DOIDOI Copied
Visit DOI Link

 Hamed Azzam SKang SSalvi MEzra DGTocilizumab for thyroid eye diseaseCochrane Database Syst Rev. 2018;11:CD012984. DOI10.1002/14651858.CD012984.pub2.

62
Copy DOIDOI Copied
Visit DOI Link

 Slowik MUrbaniak-Kujda DBohdanowicz-Pawlak Aet alCD8+ CD28-lymphocytes in peripheral blood and serum concentrations of soluble interleukin 6 receptor are increased in patients with Graves’ orbitopathy and correlate with disease activityEndocr Res2012;37:8995DOI10.3109/07435800.2011.635622.

63
Copy DOIDOI Copied
Visit DOI Link

 Kumar SSchiefer RCoenen MJBahn RSA stimulatory thyrotropin receptor antibody (M22) and thyrotropin increase interleukin-6 expression and secretion in Graves’ orbital preadipocyte fibroblastsThyroid2010;20:5965. DOI10.1089/thy.2009.0278.

64
Copy DOIDOI Copied
Visit DOI Link

 Perez-Moreiras JVGomez-Reino JJManeiro JRet alEfficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves orbitopathy: A randomized clinical trialAm J Ophthalmol2018;195:18190. DOI10.1016/j.ajo.2018.07.038.

65
Copy DOIDOI Copied
Visit DOI Link

 Sears CMAzad ADTopping KLet alRecurrent disease and adverse events after Tocilizumab treatment for thyroid eye disease51st ASOPRS Fall Scientific Symposium, Virtual21 November 2020Abstr Narrated Presentation #8.

66
Copy DOIDOI Copied
Visit DOI Link

 Chen HMester TRaychaudhuri Net alTeprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytesJ Clin Endocrinol Metab2014;99:E163540DOI10.1210/jc.2014-1580.

67
Copy DOIDOI Copied
Visit DOI Link

 ClinicalTrials.govTreatment of Graves’ Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis With Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC)2022Available athttps://classic.clinicaltrials.gov/ct2/show/NCT03298867 (Date last accessed12 April 2024).

68
Copy DOIDOI Copied
Visit DOI Link

 ClinicalTrials.govTeprotumumab (RV 001) Treatment in Patients With Active Thyroid Eye Disease2018Available athttps://classic.clinicaltrials.gov/ct2/show/NCT01868997 (Date last accessed12 April 2024).

69
Copy DOIDOI Copied
Visit DOI Link

 Kahaly GJDouglas RSHolt RJet alTeprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trialsLancet Diabetes Endocrinol2021;9:36072DOI10.1016/S2213-8587(21)00056-5.

70
Copy DOIDOI Copied
Visit DOI Link

 Smith TJKahaly GJEzra DGet alTeprotumumab for thyroid-associated ophthalmopathyN Engl J Med. 2017;376:174861./ DOI10.1056/NEJMoa1614949.

71
Copy DOIDOI Copied
Visit DOI Link

 Chern ADagi Glass LRGudis DAThyroid eye disease, teprotumumab, and hearing loss: An evolving role for otolaryngologistsOtolaryngol Head Neck Surg2021;165:7578DOI10.1177/01945998211004240.

72
Copy DOIDOI Copied
Visit DOI Link

 Sears CMAzad ADAmarikwa Let alHearing dysfunction after treatment with teprotumumab for thyroid eye diseaseAm J Ophthalmol2022;240:113DOI10.1016/j.ajo.2022.02.015.

73
Copy DOIDOI Copied
Visit DOI Link

 Safo MBSilkiss RZA case of ulcerative colitis associated with teprotumumab treatment for thyroid eye disease. Am J Ophthalmol Case Rep. 2021;22:101069. DOI10.1016/j.ajoc.2021.101069.

74
Copy DOIDOI Copied
Visit DOI Link

 Ashraf DCJankovic IEl-Nachef Net alNew-onset of inflammatory bowel disease in a patient treated with teprotumumab for thyroid associated ophthalmopathyOphthalmic Plast Reconstr Surg2021;37:e1604. DOI10.1097/IOP.0000000000001943.

75
Copy DOIDOI Copied
Visit DOI Link

 Amarikwa LMohamed AKim SHet alTeprotumumab-related hyperglycemiaJ Clin Endocrinol Metab2023;108:85864. DOI10.1210/clinem/dgac627.

76
Copy DOIDOI Copied
Visit DOI Link

 Sears CMAzad ADDosiou CKossler ALTeprotumumab for dysthyroid optic neuropathy: Early response to therapyOphthalmic Plast Reconstr Surg2021;37:S15760DOI10.1097/IOP.0000000000001831.

77
Copy DOIDOI Copied
Visit DOI Link

 Hwang CJNichols EEChon BHPerry JDBilateral dysthyroid compressive optic neuropathy responsive to teprotumumabEur J Ophthalmol2022;32:469DOI10.1177/1120672121991042.

78
Copy DOIDOI Copied
Visit DOI Link

 Chiou CAReshef ERFreitag SKTeprotumumab for the treatment of mild compressive optic neuropathy in thyroid eye disease: A report of two casesAm J Ophthalmol Case Rep2021;22:101075DOI10.1016/j.ajoc.2021.101075.

79
Copy DOIDOI Copied
Visit DOI Link

 Slentz DHSmith TJKim DSJoseph SSTeprotumumab for optic neuropathy in thyroid eye diseaseJAMA Ophthalmol2021;139:2447DOI10.1001/jamaophthalmol.2020.5296.

80
Copy DOIDOI Copied
Visit DOI Link

 Sears CMWang YBailey LAet alEarly efficacy of teprotumumab for the treatment of dysthyroid optic neuropathy: A multicenter studyAm J Ophthalmol Case Rep2021;23:101111DOI10.1016/j.ajoc.2021.101111.

81
Copy DOIDOI Copied
Visit DOI Link

 Douglas RSKahaly GJUgradar Set alTeprotumumab efficacy, safety, and durability in longer-duration thyroid eye disease and re-treatment: OPTIC-X studyOphthalmology2022;129:43849DOI10.1016/j.ophtha.2021.10.017.

82
Copy DOIDOI Copied
Visit DOI Link

 Ozzello DJKikkawa DOKorn BSEarly experience with teprotumumab for chronic thyroid eye diseaseAm J Ophthalmol Case Rep2020;19:100744DOI10.1016/j.ajoc.2020.100744.

83
Copy DOIDOI Copied
Visit DOI Link

 Ugradar SKang JKossler ALet alTeprotumumab for the treatment of chronic thyroid eye diseaseEye (Lond). 2022;36:15539. DOI10.1038/s41433-021-01593-z.

84
Copy DOIDOI Copied
Visit DOI Link

 Diniz SBCohen LMRoelofs KARootman DBEarly experience with the clinical use of teprotumumab in a heterogenous thyroid eye disease populationOphthalmic Plast Reconstr Surg2021;37:58391. DOI10.1097/IOP.0000000000001959.

85
Copy DOIDOI Copied
Visit DOI Link

 Men CJAmarikwa LPham Bet alTeprotumumab for the treatment of recalcitrant thyroid eye disease. Ophthalmic Plast Reconstr Surg2023 Nov 16Epub ahead of printDOI10.1097/IOP.0000000000002564.

86
Copy DOIDOI Copied
Visit DOI Link

 Clinicaltrials.GovA Study Evaluating TEPEZZA® Treatment in Patients With Chronic (Inactive) Thyroid Eye Disease. ClinicalTrials.gov identifier: NCT045837352024Available athttps://classic.clinicaltrials.gov/ct2/show/NCT04583735 (Date last accessed12 April 2024).

87
Copy DOIDOI Copied
Visit DOI Link

 Horizon Therapeutics Plc ANNOUNCES positive Topline data from TEPEZZA® (Teprotumumab-Trbw) phase 4 clinical trial in patients with chronic/low clinical activity score (CAS)2023Available atwww.ophthalmologytimes.com/view/horizon-therapeutics-announces-positive-topline-data-from-teprotumumab-trbw-phase-4-clinical-trial-in-patients-with-chronic-clinical-activity-score-ted (Date last accessed10 April 2023).

88
Copy DOIDOI Copied
Visit DOI Link

 Smith TJUnderstanding pathogenesis INTERSECTS with effective treatment for thyroid eye diseaseJ Clin Endocrinol Metab2022;107:S1326DOI10.1210/clinem/dgac328.

89
Copy DOIDOI Copied
Visit DOI Link

 Clinicaltrials.GovTolerability and Efficacy Study of VRDN 001 in Healthy Volunteers and Persons With Thyroid Eye Disease (TED). ClinicalTrials.gov identifier: NCT051766392024Available athttps://clinicaltrials.gov/study/NCT05176639?intr=VRDN%20-001&rank=1 (Date last accessed12 April 2024).

90
Copy DOIDOI Copied
Visit DOI Link

 Foster KShe ASummerfelt Ret alVRDN-002, a next-generation half-life extended antagonist antibody to IGF-1 receptor for thyroid eye disease (TED): safety and pharmacokinetic/pharmacodynamic (PK/PD) results in healthy volunteersPresented atAssociation for Research in Vision and Ophthalmology 2023 Annual Meeting, , 2023.

91
Copy DOIDOI Copied
Visit DOI Link

 ClinicalTrials.govA Proof-of-Concept Study to Assess Batoclimab in Participants With Graves’ Disease. ClinicalTrials.gov identifier: NCT059076682023Available athttps://clinicaltrials.gov/study/NCT05907668 (Date last accessed28 March 2024).

92
Copy DOIDOI Copied
Visit DOI Link

 Gulbins AHorstmann MDaser Aet alLinsitinib, an IGF-1R inhibitor, attenuates disease development and progression in a model of thyroid eye diseaseFront Endocrinol (Lausanne). 2023;14:1211473. DOI10.3389/fendo.2023.1211473.

93
Copy DOIDOI Copied
Visit DOI Link

 ClinicalTrials.govEfficacy and Safety of Lonigutamab in Subjects With Thyroid Eye Disease (TED) (TED). ClinicalTrials.gov identifier: NCT05683496 Available athttps://clinicaltrials.gov/study/NCT05683496 (Date last accessed28 March 2024).

94
Copy DOIDOI Copied
Visit DOI Link

 Furmaniak JSanders JSanders Pet alTSH receptor specific monoclonal autoantibody K1-70Tm targeting of the TSH receptor in subjects with Graves’ disease and Graves’ orbitopathy – Results from a phase I clinical trialClin Endocrinol (Oxf)2022;96:87887DOI10.1111/cen.14681.

95
Copy DOIDOI Copied
Visit DOI Link

 ClinicalTrials.govA Study of the Efficacy and Safety of Secukinumab 300 mg in Patients With Thyroid Eye Disease (TED) (ORBIT). ClinicalTrials.gov identifier: NCT047373302023Available athttps://clinicaltrials.gov/study/NCT04737330 (Date last accessed28 March 2024).

96
Copy DOIDOI Copied
Visit DOI Link

 Ophthalmology TimesViridian announces positive data from ongoing phase 1/2 trial evaluating VRDN-001 in patients with chronic thyroid eye disease (TED)2023Available atwww.ophthalmologytimes.com/view/viridian-announces-positive-data-from-ongoing-phase-1-2-trial-evaluating-vrdn-001-in-patients-diagnosed-with-chronic-ted (Date last accessed10 July 2023).

97
Copy DOIDOI Copied
Visit DOI Link

 Foster KDickinson BBedian VPreclinical pharmacokinetics and clinical exposure prediction for VRDN-003, a next-generation half-life extended antibody to the IGF-1 receptor for thyroid eye disease. EJEA. 2023. DOI10.1530/endoabs.92.OP-09-02.

98
Copy DOIDOI Copied
Visit DOI Link

 Zuercher AWSpirig RBaz Morelli Aet alNext-generation FC receptor-targeting biologics for autoimmune diseasesAutoimmun Rev2019;18:102366DOI10.1016/j.autrev.2019.102366.

99
Copy DOIDOI Copied
Visit DOI Link

 Wang YTian ZThirumalai DZhang XNeonatal FC receptor (FcRn): A novel target for therapeutic antibodies and antibody engineeringJ Drug Target2014;22:26978DOI10.3109/1061186X.2013.875030.

100
Copy DOIDOI Copied
Visit DOI Link

 Kahaly GJDolman PJWolf Jet alProof-of-concept and randomized, placebo-controlled trials of an FcRn inhibitor, batoclimab, for thyroid eye diseaseJ Clin Endocrinol Metab2023;108:312234DOI10.1210/clinem/dgad381.

101
Copy DOIDOI Copied
Visit DOI Link

 ClinicalTrials.govStudy to Assess Batoclimab in Participants With Active Thyroid Eye Disease. ClinicalTrials.gov identifier: NCT055245712024Available athttps://clinicaltrials.gov/study/NCT05524571 (Date last accessed28 March 2024).

102
Copy DOIDOI Copied
Visit DOI Link

 ClinicalTrials.govA Phase 2b, Study of Linsitinib in Subjects With Active, Moderate to Severe Thyroid Eye Disease (TED) (LIDS). ClinicalTrials.gov Identifier: NCT052760632023Available athttps://classic.clinicaltrials.gov/ct2/show/NCT05276063 (Date last accessed12 April 2024).

103
Copy DOIDOI Copied
Visit DOI Link

 NovartisNovartis receives two new FDA approvals for Cosentyx to treat patients with ankylosing spondylitis and psoriatic arthritis in the US2016Available atwww.novartis.com/news/media-releases/novartis-receives-two-new-fda-approvals-cosentyx-treat-patients-ankylosing-spondylitis-and-psoriatic-arthritis-us (Date last accessed12 April 2024).

104
Copy DOIDOI Copied
Visit DOI Link

 NovartisNovartis announces FDA approval for first IL-17A antagonist Cosentyx(TM) (secukinumab) for moderate-to-severe plaque psoriasis patients2015Available atwww.novartis.com/news/media-releases/novartis-announces-fda-approval-first-il-17a-antagonist-cosentyxtm-secukinumab-moderate-severe-plaque-psoriasis-patients (Date last accessed12 April 2024).

105
Copy DOIDOI Copied
Visit DOI Link

 Frieder JKivelevitch DMenter ASecukinumab: A review of the anti-IL-17A biologic for the treatment of psoriasisTher Adv Chronic Dis2018;9:521DOI10.1177/2040622317738910.