Thyroid Eye Disease
Pathogenesis, Red Flags & Treatment Ladder

1. What is thyroid eye disease?

TED is fundamentally autoimmune. The body mistakes the TSH receptor (TSH-R) for a threat and produces TRAbs (also called TSIs, thyroid-stimulating antibodies). These antibodies attack not only the thyroid (causing Graves' hyperthyroidism) but also orbital fibroblasts, preadipocytes, and extraocular muscles — all of which also express the TSH receptor.

① TSH-R / IGF-1R cross-talk

The TSH receptor forms a functional complex with the IGF-1 receptor. TRAb binding to TSH-R also triggers IGF-1R signalling, synergistically driving hyaluronic acid (a GAG) secretion, adipogenesis, and inflammation. This is the basis for teprotumumab, an IGF-1R monoclonal blocker (Krieger 2015 JCEM; Douglas 2020 NEJM).

② Osmotic edema + fibroblast proliferation

Hyaluronic acid binds water, swelling extraocular muscle and orbital fat. Because the bony orbit is a fixed-volume cavity (~30 mL), the extra soft tissue is forced to either:

• Push the globe forward → proptosis
• Compress the optic nerve at the apex → dysthyroid optic neuropathy (DON)

2. Who gets it? Epidemiology & risk factors

• Prevalence: About 20-25% of Graves' patients have clinically apparent eye disease — most are mild (~20%); about 5-6% are moderate-to-severe; fewer than 5% are sight-threatening. European data show an annual incidence of ~0.9-1.5 per 10 000 (Perros 2017 EUGOGO position statement).
• Sex: females ~4-6× more often, mirroring Graves' overall, but men tend to have more severe disease when affected, possibly due to later presentation, higher smoking rates and higher TRAb (Perros 1993 Clin Endocrinol).
• Age: typical onset 40-60; men's peak is 5-10 years later than women's.
• Smoking — the strongest modifiable risk factor. Both EUGOGO and ATA/ETA recognise current smokers as having about 7-8× higher risk of developing or progressing TED. Smoking also worsens response to glucocorticoids and orbital radiotherapy and amplifies post-radioiodine flare. The effect is dose-dependent (Wiersinga 2016; Khong 2016 JCEM).
• Radioiodine: RAI for Graves' hyperthyroidism can trigger or worsen TED, especially with pre-existing TED, smoking, high TRAbs, or untreated post-RAI hypothyroidism. RAI should be avoided in active TED; if needed, oral glucocorticoid prophylaxis is recommended.
• High TRAb titres: more than a diagnostic marker — also a prognostic marker. Higher TRAb correlates with greater incidence, severity and treatment resistance (Eckstein 2006 JCEM).
• Others: poorly controlled thyroid function (hyper or hypo can worsen TED), high serum cholesterol (statins may protect — Lanzolla 2021 STAGO trial), older age, stress. New-onset or reactivation TED after COVID-19 vaccination has been reported but causality remains uncertain.

3. Symptoms & red flags

Common symptoms (may be unilateral or bilateral; often asymmetric early):

• Gritty / foreign-body sensation, eye irritation, photophobia
• Proptosis / exophthalmos — patient or family notices the globes protruding from a side view, eyelids appearing wider
• Lid retraction — upper lids pulled up, sclera visible above iris (the classic 'stare')
• Lid lag — upper lid lags behind the globe on downgaze
• Eyelid edema, conjunctival injection, chemosis, swollen caruncle
• Deep retro-orbital pressure or pain, pain on eye movement
• Diplopia — typically horizontal or vertical, most often from inferior- and medial-rectus fibrosis
• Incomplete lid closure → corneal exposure, punctate keratopathy; corneal ulceration in severe disease

UpToDate emphasises that the correlation between symptoms and physical findings is often poor — some patients have marked proptosis but few complaints, others are very distressed by mild changes. Listening to the patient's subjective experience matters. EUGOGO has validated the GO-QoL questionnaire to quantify quality-of-life impact.

4. Active vs Inactive Staging (Rundle's curve)

Why does timing decide everything? Inflammatory activity in TED has a 'window' — once fibrosis sets in, no amount of immunomodulation can reverse it.

The natural history of TED was first described by Rundle in 1957 — the Rundle's curve — and remains the core concept guiding treatment timing:

5. The CAS score — am I still in the active phase?

The Clinical Activity Score (CAS), introduced by Mourits et al. (1989, 1997), is the activity assessment endorsed by both EUGOGO and ATA/ETA. It is bedside-friendly: each item scores 1 point (out of 7); CAS ≥ 3 indicates active disease:

An important caveat from UpToDate: a patient with longstanding fibrotic disease may have severe proptosis and restrictive strabismus yet score CAS < 3 — and is unlikely to respond to immunomodulation. CAS measures current immunological activity, not severity; rehabilitative surgery is the right path here.

6. EUGOGO severity classification

EUGOGO uses a three-tier classification, adopted by the ATA/ETA 2022 consensus and continued in the 2025 ETJ comparative review:

Normal proptosis values (Hertel exophthalmometer) differ by ethnicity: White F/M 19/21 mm; Black F/M 23/24 mm; Chinese F/M ~18/19 mm (Cheung 2019, Hong Kong). Diagnostic cut-offs should use ethnicity-specific norms.

7. Work-up

• Thyroid function: TSH, free T4, total T3 — usually already on file; if not, obtain at evaluation.
• TRAbs (TSH-receptor antibodies): dual diagnostic and prognostic role; higher levels predict more severe disease and worse response (Eckstein 2006). Also useful for monitoring.
• CAS: rescore at every visit.
• Hertel exophthalmometry: objective measurement; ≥ 2 mm change is clinically significant.
• Visual acuity and colour vision: standard chart + red-desaturation test — abnormality should immediately raise concern for DON.
• Visual fields (Humphrey 30-2 / 24-2): detects central or paracentral defects (early DON).
• OCT (optic nerve / RNFL): monitors axonal damage from DON.
• Ocular motility / diplopia: Hess chart quantifies extraocular-muscle restriction and deviation.
• Slit-lamp + cornea: fluorescein staining for exposure keratopathy; tear break-up time.
• Orbital imaging (CT or MRI): not required for all TED — main indications are moderate-severe, sight-threatening, or atypical presentations (unilateral, euthyroid). ATA/ETA 2022 distinguishes two contexts: (A) diagnosis / differential (rule out non-TED lesions, assess activity): contrast CT or MRI is preferred, with MRI STIR sequence detecting muscle edema indicating active inflammation; (B) planning decompression surgery: non-contrast CT is preferred for bony detail and orbital-volume norms. EUGOGO 2021 indicates imaging mainly for asymmetric, euthyroid, suspected DON, or surgical planning. Contrast warning: iodinated contrast in untreated hyperthyroidism worsens thyrotoxicosis.

🔍 Atypical TED — what to rule out: unilateral, painless, slowly-progressive proptosis warrants imaging to exclude lacrimal gland tumors (e.g. adenoid cystic carcinoma), cavernous hemangioma, IgG4-related disease, and other orbital pathologies.

8. The treatment ladder

The 2021 EUGOGO and 2022 ATA/ETA guidelines share the same overall framework — therapy is selected by severity and activity — but differ on first-line drug choice. The 2025 ETJ comparative review (Bartalena et al.) summarises convergences and divergences.

① Mild — supportive care & consider selenium

• Preservative-free artificial tears in daytime + ointment at night (protect cornea)
• Sleep with head elevated 30°; sunglasses outdoors (reduces wind/light irritation)
• Smoking cessation — most important (see Section 9)
• Selenium 6-month course: Marcocci 2011 NEJM (CATCH, European cohort) showed QoL improvement and slowing of progression in mild active TED. Dosing differs slightly between guidelines: the original CATCH trial used sodium selenite 200 µg/day (≡ 91.2 µg elemental selenium) once daily; ATA/ETA 2022 Key Point 6.1.1 recommends selenium selenite 100 µg BID × 6 months; EUGOGO 2021 follows the original once-daily protocol. Total elemental selenium is similar (~90-100 µg/day). Europe is generally selenium-deficient, so supplementation is favored; ATA/ETA and UpToDate consider the evidence weaker in selenium-replete populations (e.g., US) — optional use. Do not extend beyond 6 months — excess selenium has been associated with type-2 diabetes, skin cancer and all-cause mortality (SELECT trial, etc.).

② Moderate-to-severe active — immunomodulation

This is the most complex part of the treatment ladder. EUGOGO and ATA/ETA both anchor first-line on IV glucocorticoids (IVMP), but their first-line choices diverge significantly — see the comparison table below, then the per-item details.

◆ First-line A: IV methylprednisolone (IVMP)

• Standard regimen (4.5 g cumulative): 500 mg weekly × 6, then 250 mg weekly × 6.
• High-dose (7.5 g cumulative): 750 mg weekly × 6, then 500 mg weekly × 6 — EUGOGO Rec #23 for the most severe (constant / inconstant diplopia, severe soft tissue, proptosis > 25 mm).
• Safety ceilings (critical): weekly single dose ≤ 750 mg, cumulative ≤ 8 g per cycle, avoid consecutive-day dosing — exceeding raises hepatotoxicity and cardiovascular risk.
• Contraindications: acute viral hepatitis, significant liver dysfunction, severe cardiovascular disease, uncontrolled hypertension / diabetes, untreated psychiatric disorders. Pre-treatment liver / infection / cardiovascular work-up is required.

◆ First-line B: mycophenolate (MMF) — EUGOGO only

• EUGOGO 2021 Rec #22 / #15: oral mycophenolate sodium 0.72 g/day (or mofetil 1 g/day) for 24 weeks combined with standard IVMP 4.5 g. Combination 71% vs IVMP-alone 53% response at week 24 (Kahaly 2018 Lancet Diabetes Endocrinol).
• ATA/ETA 2022 does not endorse this as first-line (the biggest divergence between guidelines), citing inconsistent RCT findings.

◆ First-line C: teprotumumab (Tepezza) — ATA/ETA for proptosis/diplopia

◆ Second-line (after inadequate IVMP — EUGOGO Rec #24, six pathways)

1. Second IVMP cycle starting 0.75 g per dose (cumulative ≤ 8 g).
2. Oral GC + cyclosporine or azathioprine (steroid-sparing).
3. Orbital radiotherapy + GC: 20 Gy per orbit / 10 fractions / 2 weeks — particularly for diplopia-dominant disease. Contraindicated: age < 35 years; diabetic or hypertensive retinopathy.
4. Teprotumumab.
5. Rituximab (anti-CD20): 500 mg single or 2 × 1000 mg; contraindicated if at risk for DON (cases of DON triggering and cytokine release syndrome reported).
6. Tocilizumab (IL-6R blocker): consider in GC-resistant patients.

Oral glucocorticoids alone: not recommended first-line by either guideline (less effective, more systemic toxicity) — reserved for those who cannot receive IVMP. EUGOGO regimen: 100 mg/day prednisone or 1 mg/kg/day, taper 5-10 mg/week off (4-6 months total).

③ Sight-threatening — ophthalmic emergency

Sight-threatening TED comprises (a) dysthyroid optic neuropathy (DON) — usually from apical muscle compression (< 5% from globe stretch, which doesn't respond to drugs and needs direct surgery); (b) severe corneal exposure / breakdown; (c) globe subluxation — rare, requires immediate decompression.

• Step 1 (within 24-72 h): high-dose IV methylprednisolone — EUGOGO 2021 Rec #26: 500-1000 mg per dose for 3 consecutive days, OR preferably on alternate days for 1 week (can be repeated for another week) — alternate-day dosing is safer than consecutive-day dosing for hepatic and cardiovascular events.
• If no improvement within 1-2 weeks → emergency orbital decompression. ATA/ETA 2022 prefers deep medial wall + orbital floor (transcaruncular or transnasal endoscopic) to relieve apical compression. Visual improvement can occur within days; even severe or longstanding DON may have partial recovery.
• Corneal exposure / breakdown is managed by escalating measures: lubricants → tarsorrhaphy → corneal gluing → keratoplasty; globe subluxation goes directly to decompression.

④ Inactive — rehabilitative surgery, order matters!

Once CAS < 3 has persisted for at least 6 months, symptoms are stable, and thyroid function is controlled, rehabilitative surgery can reshape function and appearance. Order is critical — each step alters the anatomy for the next:

1. Orbital decompression — remove orbital wall(s) and/or fat to retropose the globe; improves proptosis.
2. Strabismus surgery — must wait until strabismus measurements are stable for at least 6 months (ATA/ETA 2022) so the deviation can be measured reliably. Adjustable sutures are commonly used, allowing fine-tuning after surgery based on patient feedback.
3. Eyelid surgery — upper-lid recession, lower-lid elevation, blepharoplasty. Last in sequence because prior steps shift lid position.

Mnemonic: decompression → strabismus → eyelid — globe first, alignment next, lid last. Not every patient needs all three; tailor to individual functional and cosmetic needs.

9. Smoking cessation — the strongest modifiable risk factor

If you remember only one sentence from this article, remember this one: smokers have a 7-8× higher risk of TED than non-smokers. Why does it matter so much?

• Dose-dependent: more cigarettes per day → higher risk (Wiersinga 2016; Khong 2016 JCEM).
• Reduces treatment response: smokers respond worse to both IVMP and orbital radiotherapy.
• Amplifies post-radioiodine flare: smoking + RAI is one of the highest-risk combinations for TED progression.
• Mechanism: cigarette smoke stimulates orbital fibroblast GAG secretion and adipogenesis dose-dependently in vitro (Cawood 2007 JCEM) and alters T-cell regulation.
• Risk persists after quitting but drops substantially: ex-smokers have higher risk than never-smokers but lower than current smokers; earlier is better. Even with established TED, quitting still improves prognosis.
• Secondhand smoke: EUGOGO 2021 and ATA/ETA 2022 both recommend household contacts also quit, to avoid passive exposure.
• Taiwan resources: HPA quit-line 0800-636363; smoking-cessation clinics (family medicine / chest); varenicline, bupropion and nicotine patches are NHI-covered.

10. Thyroid control — collaborate with endocrinology

Both EUGOGO and ATA/ETA emphasise that thyroid stabilisation is foundational. Both hyper- and hypothyroidism worsen TED.

• First-line: antithyroid drugs (ATDs, e.g., methimazole) — preferred by both EUGOGO 2021 and ATA/ETA 2022 in active TED, as ATDs are most neutral for eye disease. Typical course 12-18 months, dose-titrated.
• Radioiodine (RAI): avoid in active TED. If unavoidable (ATD intolerance, relapse), oral prednisone prophylaxis is required. EUGOGO 2021 Recommendation #5 specifies two regimens: (A) high-risk patients (smokers, high TRAb, severe hyperthyroidism, pre-existing TED): start 0.3-0.5 mg/kg/day, taper, withdraw at 3 months; (B) low-risk patients: start 0.1-0.2 mg/kg/day, taper, withdraw at 6 weeks. Patients with longstanding stably-inactive TED and no risk factors can have RAI without prophylaxis. Promptly start levothyroxine for any post-RAI hypothyroidism.
• Total / near-total thyroidectomy: an option in severe active TED or those intolerant of ATDs/RAI. The Salvi 'total ablation' strategy (thyroidectomy + RAI remnant + IVMP) lowers TRAb and stabilises some severe cases, but is not first-line standard.
• Avoid hypothyroidism: start levothyroxine promptly after RAI or thyroidectomy — hypothyroid intervals can rebound TRAb and worsen TED.
• Multidisciplinary team: EUGOGO strongly recommends a joint or co-managed clinic of ophthalmology + endocrinology + oculoplastics (and radiation oncology when needed) for all moderate-severe TED.

11. Taiwan NHI Coverage (April 2026)

Taiwan NHI coverage status of TED-related medications:

* Source: NHIA Drug Coverage Regulations, April 2026, Sections 14.5, 14.9.3, and 1.5.1. Surgery/radiotherapy fall under separate medical-payment regulations. Confirm latest at NHIA.

12. Common myths — QA

Key references

1. [EUGOGO 2021 主要指引] Bartalena L, Kahaly GJ, Baldeschi L, et al. The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy. Eur J Endocrinol. 2021;185(4):G43-G67. doi:10.1530/EJE-21-0479
2. [ATA/ETA 2022 共識聲明] Burch HB, Perros P, Bednarczuk T, et al. Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the European Thyroid Association. Thyroid. 2022;32(12):1439-1470. doi:10.1089/thy.2022.0251
3. [2025 兩大指引比較性回顧] Bartalena L, et al. Comparing 2021 EUGOGO and 2022 ATA-ETA guidelines: convergences and divergences in management of Graves' orbitopathy. Eur Thyroid J. 2025; ETJ-25-0318.
4. Davies TF, Burch HB. Clinical features and diagnosis of thyroid eye disease. UpToDate (literature review through Apr 2026). Last updated Aug 2024.
5. Davies TF, Burch HB. Treatment of thyroid eye disease. UpToDate (literature review through Apr 2026).
6. Gandhi R, Eyley K, Phelps M, et al. Thyroid Eye Disease. American Academy of Ophthalmology EyeWiki. Updated April 14, 2026.
7. Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med. 2017;376(18):1748-1761.
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9. Kahaly GJ, Riedl M, König J, et al. Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. Lancet Diabetes Endocrinol. 2018;6(4):287-298.
10. Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of mild Graves' orbitopathy (CATCH trial). N Engl J Med. 2011;364(20):1920-1931.
11. Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf). 1997;47(1):9-14.
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16. Lanzolla G, Sabini E, Leo M, et al. Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial. Lancet Diabetes Endocrinol. 2021;9(12):733-742.
17. Cawood TJ, Moriarty P, O'Farrelly C, O'Shea D. Smoking and thyroid-associated ophthalmopathy: A novel explanation of the biological link. J Clin Endocrinol Metab. 2007;92(1):59-64.
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