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 (TSH-receptor antibodies; the stimulating subtype is called TSI, thyroid-stimulating immunoglobulin). 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 30% of Graves' patients have clinically apparent eye disease (ATA/ETA 2022: up to 40%; Bartalena 2025: about 30%), mostly mild; of all Graves' patients, about 6% have moderate-to-severe and about 0.5% sight-threatening disease (ATA/ETA 2022). EUGOGO 2021 cites an annual incidence of 0.54-0.9 per 100 000 in men and 2.67-3.3 per 100 000 in women; prevalence in Europe is about 10 per 10 000 (Perros 2017 EUGOGO position statement).
• Sex: females ~4-6× more often (Perros 1993: 4.05; Bartley 1995: 5.5), but men tend to have more severe disease when affected: after adjusting for age, men's severity index was 41% higher, and severity rises with age (Perros 1993 Clin Endocrinol).
• Age: bimodal — peaks at 40-44 and 60-64 years in women, about 5 years later in men (Bartley 1995, Minnesota, USA).
• Smoking — the strongest modifiable risk factor. Both EUGOGO and ATA/ETA list smoking as a major modifiable risk factor; in a case-control study, smokers had about 7-8× higher odds of TED (Prummel 1993: OR 7.7). Smoking also worsens response to glucocorticoids and orbital radiotherapy and amplifies post-radioiodine flare. Risk rises with the number of cigarettes smoked per day (EyeWiki).
• 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 moderate-to-severe active TED; in mild active TED, oral glucocorticoid prophylaxis is required if RAI is chosen (EUGOGO 2021).
• High TRAb titres: more than a diagnostic marker — also a prognostic marker. TRAb is an independent risk factor for TED; higher levels are usually associated with a more severe course and help predict outcome (Eckstein 2006 JCEM).
• Others: poorly controlled thyroid function (hyper or hypo can worsen TED), high serum cholesterol (statin users had less TED in retrospective studies, including a 2025 Taiwanese nationwide cohort in which patients over 40 who started a statin within 1 year of Graves' diagnosis had lower risk of moderate-to-severe TED (Chou 2025); in the STAGO RCT, adding atorvastatin to IV steroids improved response in hypercholesterolaemic patients (Lanzolla 2021)), 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 and Wilson in 1945 — 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 steroids or other immunomodulators. 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 and sex: upper limits White F/M ~20.1/21.7 mm, Black F/M ~23.0/24.7 mm (Migliori 1984); Hong Kong Chinese adults F/M ~19.7/20.9 mm (Cheung 2019). 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 are usually associated with a more severe course, and follow-up measurements can help assess prognosis in some patients (Eckstein 2006).
• 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 severe disease (to assess apical crowding), surgical planning, 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. EUGOGO 2021 indicates MRI for unilateral or strongly asymmetric proptosis, suspected optic neuropathy, and euthyroidism with normal thyroid serology, and CT before decompression surgery. 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 the head of the bed raised (e.g. extra pillows); sunglasses outdoors (reduces wind/light irritation)
• Smoking cessation — most important (see Section 9)
• Selenium formulation and dosing: Marcocci et al. (2011) used sodium selenite 100 µg twice daily for 6 months. EUGOGO discusses 200 µg sodium selenite per day (91.2 µg elemental selenium); this does not justify doubling an elemental-selenium dose. Benefit in selenium-replete regions is uncertain; formulation, dosing and duration require medical assessment. Beware of excess intake (see Myth 4).

② Moderate-to-severe active — immunomodulation

This is the most complex part of the treatment ladder. EUGOGO and ATA/ETA both treat IV glucocorticoids (IVMP) as a key option, 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 (except in sight-threatening disease) — 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. In MINGO, the prespecified week-12 outcome did not differ significantly (63% vs 49%); in a post-hoc analysis, week-24 response was 71% with combination vs 53% with IVMP alone (Kahaly 2018 Lancet Diabetes Endocrinol).
• ATA/ETA 2022 does not endorse this as first-line (the biggest divergence between guidelines), citing inconsistent RCT findings; one of the two, a single-centre Chinese trial, was retracted in 2023 (Bartalena 2025).

◆ 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 in 10 fractions over 2 weeks — particularly for diplopia-dominant disease. Should be avoided in: age < 35 years (theoretical long-term tumor risk); diabetic or hypertensive retinopathy.
4. Teprotumumab.
5. Rituximab (anti-CD20): EUGOGO suggests a single 500 mg dose (or a low single 100 mg dose); 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 optic-nerve stretch due to proptosis, which doesn't respond to drugs and needs direct surgery); (b) severe corneal exposure / breakdown; (c) globe subluxation — rare, requires immediate decompression.

• Step 1 (immediately): 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 the disease is inactive (CAS < 3) and clinically stable, and euthyroidism has been achieved and maintained (EUGOGO 2021: rehabilitative surgery is for 'inactive residual GO manifestations'; ATA/ETA 2022: once the disease is inactive, clinical stability has been maintained and euthyroidism achieved; neither specifies how long), 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 about 7-8× higher odds of TED than non-smokers (Prummel 1993). Why does it matter so much?

• Dose-dependent: more cigarettes per day → higher risk (EyeWiki).
• Reduces treatment response: smokers have a delayed or worse response to immunosuppressive treatment such as IVMP and to orbital radiotherapy (EUGOGO 2021).
• 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).
• Risk does not vanish right after quitting: in the Australian ATOR study, ex-smokers' odds ratio (2.07) was similar to current smokers' (2.22), both above never-smokers (Khong 2016); but quitting is linked to lower risk (EyeWiki) and may improve outcomes even with established TED (EUGOGO 2021). Earlier is better.
• Secondhand smoke: ATA/ETA 2022 advises patients to avoid second-hand smoke; household members quitting reduces exposure.
• Taiwan resources: HPA quit-line 0800-636363; smoking-cessation clinics (family medicine / chest); for medications (varenicline, bupropion, nicotine patches), Taiwan NHI drug reimbursement rules (updated 2026-10-22) section 1.2.1.1 excludes bupropion used for smoking cessation, and the rules do not list varenicline or nicotine replacement as covered; ask the cessation clinic about costs and available subsidies.

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) — EUGOGO 2021 recommends ATDs for moderate-to-severe active or sight-threatening TED until eye treatment is completed, possibly longer than the usual 18-24 months; long-term ATD therapy lowers TRAb and benefits TED. ATA/ETA 2022 says little on this. Dose-titrated.
• Radioiodine (RAI): avoid in moderate-to-severe active TED. In mild active TED or patients with risk factors, oral prednisone prophylaxis is required if RAI is chosen. 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: per EUGOGO 2021, small studies suggest early thyroidectomy may improve the response of moderate-to-severe active TED to immunosuppression; two RCTs of total thyroid ablation (thyroidectomy plus RAI remnant ablation) with IV steroids showed short-term but not long-term benefit — not standard first choice.
• Avoid hypothyroidism: start levothyroxine promptly after RAI or thyroidectomy — both hyper- and hypothyroidism worsen TED (EUGOGO 2021).
• Multidisciplinary team: EUGOGO recommends referring all but the mildest cases (and mild cases at risk of worsening) to combined thyroid-eye clinics with endocrine and ophthalmic expertise (adding oculoplastics and radiation oncology when needed).

11. Taiwan NHI Coverage (updated 22 October 2026)

Taiwan NHI coverage status of TED-related medications:

* Source: Taiwan NHI drug reimbursement rules (updated 2026-10-22), sections 14.5, 14.9.3, 1.5.1, 1.2.1.1, 8.2.1, 8.2.4 and 8.2.7. Surgery/radiotherapy are outside these drug reimbursement rules; for costs, rely on your hospital's pre-service explanation. Teprotumumab licence: TFDA drug-licence open data; NHI listing: NHIA drug-item open data (both checked 2026-10-16). Confirm latest at NHIA.

12. Common myths — Q&A

Key references

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