A Research Guide for
Understanding Thyroid Eye Disease

FDA-APPROVED EMA-APPROVED Teprotumumab was the first FDA- and EMA-approved disease-modifying treatment for thyroid eye disease, and it is no longer the only one — the FDA approved a second IGF-1R antibody, veligrotug (Lumvoa), in June 2026. It is a monoclonal antibody that blocks the IGF-1 receptor (IGF-1R), a key driver of the autoimmune process in TED. The phase 2 trial (NCT01868997), OPTIC (NCT03298867), and OPTIC-X (NCT03461211) clinical trials showed that teprotumumab significantly reduces proptosis (eye bulging) by an average of approximately 3 mm, with over 80% of patients showing a meaningful proptosis response. It also improved diplopia (double vision) and quality of life. Treatment consists of 8 intravenous infusions given every 3 weeks over 24 weeks.

Important caveats:

• Cost: Approximately $300,000 per course. Insurance coverage varies and prior authorization is often required.
• Hearing side effects: Hearing loss and tinnitus occur in approximately 10% of patients, and in some cases these effects have been irreversible. An audiogram before and during treatment is recommended.
• International availability: FDA-approved in the US (January 2020) and EMA-approved in the EU (June 2025, following CHMP positive opinion April 2025). The initial EMA marketing application was withdrawn in September 2023 due to hearing loss concerns and cost-effectiveness doubts, but a subsequent application succeeded (EC approval 19 June 2025). Teprotumumab is also now approved in Japan (MHLW, September 2024), the UK (MHRA, May 2025), and Australia (TGA, 2025), with Canada under review. In several of these countries access depends on reimbursement/health-technology-assessment decisions (e.g. the pending NICE appraisal in England) rather than on approval.
• Hyperglycemia: Can worsen blood sugar control in patients with diabetes or pre-diabetes. Close glucose monitoring is required.
• An easier-to-give under-the-skin version is in late-stage testing. Teprotumumab is currently given only as an intravenous (IV) infusion at an infusion center. In April 2026 the maker (Amgen) reported positive results from a large phase 3 trial (TEPEZZA OBI, NCT06248619) of a subcutaneous (under-the-skin) version given by an on-body injector every 2 weeks. About 77% of people had a meaningful reduction in eye bulging versus about 20% on placebo, with side effects similar to the IV form. This subcutaneous version is not yet FDA-approved — these are trial results only — but if approved it could make treatment easier to receive.

GUIDELINE The European Group on Graves’ Orbitopathy (EUGOGO) published updated clinical practice guidelines in 2021 (Bartalena et al., Eur J Endocrinol 2021), establishing IV methylprednisolone combined with mycophenolate mofetil as the preferred first-line treatment for moderate-to-severe active TED in Europe. This standardized treatment approach provides an effective alternative pathway for patients worldwide who do not have access to teprotumumab.

EVIDENCE-BASED The Marcocci et al. randomized controlled trial published in the New England Journal of Medicine in 2011 showed that selenium supplementation (100 mcg twice daily for 6 months) in patients with mild TED slowed disease progression and improved quality of life compared to placebo. This simple, inexpensive intervention is recommended by EUGOGO 2021 guidelines specifically for patients in selenium-deficient areas (not as a universal recommendation), but remains inconsistently adopted in US practice.

INVESTIGATIONAL Growing evidence supports the use of tocilizumab (an anti-IL-6 receptor antibody) and rituximab (an anti-CD20 antibody) as off-label alternatives for steroid-refractory TED or patients ineligible for teprotumumab. Small randomized controlled trials and real-world case series show CAS improvement with tocilizumab. Rituximab is used in European centers as an alternative to repeated steroid courses and to teprotumumab.

Your eye specialist will assess:

• Proptosis (exophthalmos): Measured with an exophthalmometer. Values above 20–21 mm (or asymmetry ≥2 mm between eyes) are significant.
• Eyelid retraction: The most common sign of TED. Upper lid margin above the superior limbus (the top of the colored part of the eye).
• Soft tissue signs: Lid swelling, conjunctival redness and swelling (chemosis), caruncle swelling.
• Eye movement restriction: Tested in all directions of gaze. The inferior rectus (limiting upward gaze) is most commonly affected.
• Visual acuity, color vision, and visual fields: To assess for compressive optic neuropathy.
• Corneal exposure: Inability to fully close the eyelids (lagophthalmos) can lead to corneal damage.

• TSH, free T4, free T3: To assess thyroid function status
• TSH receptor antibodies (TRAb/TSI): Elevated in most TED patients, even those with euthyroid TED. TRAb levels correlate with TED severity and can be used to monitor disease activity.
• Thyroid peroxidase antibodies (TPO): May be elevated in autoimmune thyroid disease
• Complete blood count, liver function tests: Baseline before starting immunosuppressive therapy

• CT scan of the orbits: Shows enlarged extraocular muscles (particularly the inferior and medial rectus), increased orbital fat, and can assess the degree of crowding at the orbital apex (relevant for compressive optic neuropathy).
• MRI of the orbits: Can distinguish active inflammation (muscle edema on T2-weighted/STIR sequences, contrast enhancement) from chronic fibrosis. This is particularly useful when the clinical activity score is borderline.
• Ultrasound of the thyroid: To assess thyroid size and nodules if not previously done.

Imaging is not required for every TED patient but is essential when compressive optic neuropathy is suspected, when the diagnosis is uncertain, or when planning surgery.

Ask: "Do I need an orbital MRI or CT now — and if there is any concern about my optic nerve, can the scan be arranged urgently rather than routinely?"

The only part of TED that cannot wait is compressive optic neuropathy, which this guide notes affects about 5% of TED patients. The warning signs are loss of visual sharpness, colors (especially red) looking washed out or dimmer in one eye, or a new blind spot — not simply more bulging. Eye bulging can be minimal or absent when the optic nerve is being compressed.

If any of those are present, this is the sentence that gets you seen rather than scheduled:

Ask: “My vision has dimmed and colors look washed out in one eye — can I be assessed today for compressive optic neuropathy rather than waiting for a routine appointment?”

Two measurements determine which treatments are even on the table: your Clinical Activity Score (active vs. inactive) and your thyroid status. This guide notes that both hyperthyroidism and hypothyroidism worsen TED, and that smokers carry 7–8 times the risk and respond worse to steroid therapy.

Ask: “What is my Clinical Activity Score out of 7, what are my TSH, free T4, and TRAb, and am I euthyroid right now?”

Ask: “Since smokers respond worse to steroids and orbital radiotherapy, can you refer me to a smoking-cessation program at this visit rather than at the next one?”

This guide notes that TED needs an ophthalmologist experienced in orbital disease — an oculoplastic surgeon or neuro-ophthalmologist. The second half of this step matters just as much: without a recorded baseline, nobody can tell later whether you are progressing or stable, and that judgment is what decides whether you are offered drugs or surgery.

Ask: “Can you refer me to an oculoplastic surgeon or neuro-ophthalmologist who sees TED regularly, and can we record my exophthalmometry measurement in millimeters and take baseline photographs today so we can tell later whether I am progressing?”

If teprotumumab is under discussion, the FDA label (revised 11/2025) directs that hearing be assessed before, during, and after treatment, and that blood glucose be assessed prior to infusion and monitored during treatment. A baseline audiogram obtained after the first infusion cannot tell anyone what your hearing was before the drug — which is the entire point of a baseline.

Ask: “If we are considering teprotumumab, the FDA label says to assess hearing before, during, and after treatment and to check blood glucose before infusions — who is arranging my baseline audiogram and my glucose testing, and will they be done before infusion one?”

Ask: “If my disease turns out to be inactive rather than active, which treatments come off the table for me, and why?”

This is the point at which monitoring tends to quietly lapse. If you are on IV methylprednisolone, this guide notes a cumulative ceiling of 8 g per course to avoid serious liver toxicity, with liver function tests before each infusion. If you are on teprotumumab, the FDA-labeled course is 8 infusions every 3 weeks, so month 3 falls mid-course — the “during treatment” hearing assessment the label calls for belongs here, not at the end.

Ask: “Has my Clinical Activity Score changed since we started, and by how much?”

Ask: “If I am on IV steroids, what is my cumulative methylprednisolone dose so far against the 8 g per course ceiling, and have my liver tests been checked before every infusion?”

Ask: “If I am on teprotumumab, the label says to assess hearing during treatment — when is my mid-course audiogram booked?”

A full teprotumumab course is 8 infusions given over roughly 24 weeks, so around month 6 you reach a decision point: surveillance, retreatment, or surgical planning. This guide notes that surgery is appropriate once disease has been inactive for at least 6 months with a CAS below 3, and that the surgical sequence is fixed — decompression, then strabismus, then eyelids.

Ask: “Now that the course is finished, what is my proptosis in millimeters compared with my baseline, what is my Clinical Activity Score, and are we moving to surveillance, retreatment, or surgical planning?”

• What is my Clinical Activity Score? Is my TED active or inactive?
• How severe is my TED according to the EUGOGO classification?
• Do I have any signs of compressive optic neuropathy?
• What are my TRAb levels, and what do they tell us?
• Is my thyroid function adequately controlled?
• Should I have orbital imaging (CT or MRI)?
• Am I a candidate for teprotumumab? If not, why not?
• If I smoke, what resources can you recommend for quitting?
• Is there a TED specialist or oculoplastic surgeon I should see?

Teprotumumab is a fully human monoclonal antibody that blocks the IGF-1 receptor on orbital fibroblasts. By inhibiting this receptor, it reduces:

• Production of glycosaminoglycans (reducing tissue swelling)
• Adipogenesis (fat cell formation in the orbit)
• Inflammation and immune cell recruitment
• Orbital tissue volume — resulting in measurable reduction of proptosis

• Infusion 1: 10 mg/kg IV
• Infusions 2–8: 20 mg/kg IV every 3 weeks
• Total treatment: 8 infusions over 24 weeks
• Each infusion takes approximately 60–90 minutes
• Administered at an infusion center; does not require hospitalization

Per the FDA label (revised 11/2025), the first two infusions are given over at least 90 minutes, and if well tolerated the minimum time for subsequent infusions can be reduced to 60 minutes. Because the dose is weight-based, your dose in milligrams is not the same as anyone else’s:

Ask: “The FDA label says 10 mg/kg for the first infusion and then 20 mg/kg every 3 weeks for 7 more — what is my dose in milligrams at my weight, and what is the date of each of my 8 infusions?”

The teprotumumab phase 2 trial (NCT01868997) provided the initial proof of concept. The OPTIC trial (Douglas et al., NEJM 2020, NCT03298867) was the pivotal phase 3 randomized controlled trial that led to FDA approval:

• Proptosis response (≥2 mm reduction): 83% with teprotumumab vs. 10% with placebo at week 24
• Mean proptosis reduction: ~3.3 mm with teprotumumab vs. ~0.5 mm with placebo
• Diplopia response: 68% vs. 29% (in those with baseline diplopia)
• CAS response (CAS 0 or 1): 59% vs. 21%

The OPTIC-X extension study (NCT03461211) showed that patients who initially received placebo responded well when crossed over to teprotumumab, and that retreatment for relapse was effective.

• Hearing impairment: Approximately 10% of patients experience hearing loss or tinnitus. In some cases, hearing changes have been irreversible. Audiometric testing is recommended before treatment, during treatment, and after completion.
• Hyperglycemia: Teprotumumab can worsen blood sugar control. Patients with diabetes or pre-diabetes require close glucose monitoring. Insulin adjustments may be needed.
• Infusion reactions: Generally mild (headache, muscle spasm, nausea)
• Inflammatory bowel disease: Teprotumumab may worsen pre-existing IBD. It is generally avoided in patients with active IBD.
• Pregnancy: Contraindicated during pregnancy and for 6 months after the last dose due to potential fetal harm.

The FDA label (revised 11/2025) states that TEPEZZA “may cause severe hearing impairment including hearing loss, which in some cases may be permanent,” and directs clinicians to assess hearing before, during, and after treatment and to consider the benefit-risk of treatment. The label does not set a numeric hearing threshold that automatically stops the drug — that judgment is made by you and your specialist together, which is exactly why noticing a change early, and reporting it before the next infusion rather than after the course, is the part that is in your hands.

Hearing stop rule: there is no automatic numeric cutoff, but new or worsening sensorineural hearing loss, tinnitus, autophony (your own voice sounding loud in your head), or ear fullness is a reason to hold the drug and discontinue if it does not settle — which is why the FDA label directs testing before, during, and after treatment.

Ask: “If I notice ringing, muffled hearing, or my own voice sounding loud in my head between infusions, who do I call that same day, and will my hearing be retested before the next infusion is given?”

Ask: “The label says to check blood glucose before infusions and monitor during treatment — what is my blood sugar now, and what reading would make you hold or delay an infusion?”

Ask: “The label says contraception before starting, during treatment, and for 6 months after my last dose — what does that mean for my situation, and is a pregnancy test needed before infusion one?”

Teprotumumab is generally considered for patients with:

• Active TED (CAS ≥3/7)
• Moderate-to-severe disease (proptosis ≥3 mm above normal)
• Symptom duration typically less than 2–3 years (though some patients with longer disease duration may benefit)

Relative contraindications:

• Active inflammatory bowel disease (Crohn’s, ulcerative colitis)
• Uncontrolled diabetes or hyperglycemia
• Pre-existing significant hearing impairment
• Pregnancy or planned pregnancy within 6 months
• Inability to obtain insurance coverage or afford the treatment

Ask: "Do I meet the usual teprotumumab criteria — active disease with a CAS of 3 or more and proptosis at least 3 mm above normal — and if my symptoms have lasted more than 2 to 3 years, is it still worth trying for me?"

The EUGOGO-recommended protocol is:

• Weeks 1–6: Methylprednisolone 500 mg IV once weekly (total 3.0 g)
• Weeks 7–12: Methylprednisolone 250 mg IV once weekly (total 1.5 g)
• Cumulative dose: 4.5 g over 12 weeks

Important safety limit: The cumulative dose of IV methylprednisolone should not exceed 8 g per course to avoid serious hepatotoxicity. Higher doses have been associated with fatal acute liver failure.

Stop rule: per the EUGOGO 2021 guideline, a course should stop if the cumulative methylprednisolone dose approaches the 8 g per-course ceiling, and clinicians discontinue if liver enzymes (ALT/AST) rise above roughly 2 to 3 times the upper limit of normal — a recognised warning of the fatal hepatotoxicity seen at high cumulative doses.

Monitoring: Liver function tests should be checked before each infusion. Blood glucose, blood pressure, and bone density should be monitored. Patients should be screened for tuberculosis, hepatitis B, and hepatitis C before starting treatment.

The 8 g ceiling is the number worth carrying in your head, because it is a hard safety limit rather than a preference, and cumulative dose is easy to lose track of across a 12-week course — particularly if a course is extended or repeated.

Ask: “What is my planned cumulative methylprednisolone dose for this whole course in grams, and how does it sit against the 8 g per course ceiling?”

Ask: “Will my liver function be checked before every infusion, and what result would make you stop the course rather than continue it?”

IV methylprednisolone pulse therapy is effective in approximately 70–80% of patients with active moderate-to-severe TED for reducing soft tissue inflammation, eye redness, and pain. However, it is less effective at reducing proptosis compared to teprotumumab. IV steroids primarily suppress inflammation rather than reversing the underlying tissue expansion.

IV steroids are significantly more effective and better tolerated than oral prednisone, which is why EUGOGO guidelines recommend the IV route as standard.

• Hepatotoxicity: Rare but potentially fatal acute liver failure at cumulative doses >8 g. Monitor liver function tests.
• Hyperglycemia: Steroids raise blood sugar. Diabetic patients need close monitoring.
• Insomnia and mood changes: Common during treatment weeks
• Weight gain and fluid retention
• Increased infection risk
• Osteoporosis risk with cumulative exposure
• Hypertension
• Gastric irritation: Proton pump inhibitor co-prescription is recommended

EUGOGO FIRST-LINE COMBINATION Mycophenolate mofetil (MMF, 1–2 g/day) combined with IV methylprednisolone is the EUGOGO-recommended first-line approach for moderate-to-severe active TED. The MINGO trial demonstrated that adding mycophenolate to IV steroids improved outcomes compared to steroids alone, with better CAS response and longer duration of benefit.

• Dose: Typically 500 mg twice daily, increasing to 1 g twice daily
• Duration: Usually 6–12 months
• Monitoring: Complete blood count every 2–4 weeks initially, then monthly
• Side effects: GI upset, increased infection risk, leukopenia
• Contraindication: Pregnancy (teratogenic)

Ask: "While I am on mycophenolate, how often will my complete blood count be checked, and because it is teratogenic, what contraception do I need until I stop it?"

Azathioprine (1–2 mg/kg/day) is an alternative immunosuppressant used for TED, particularly in settings where mycophenolate is not available. It can be used as maintenance therapy after an initial steroid course to prevent relapse. TPMT enzyme testing is recommended before starting to identify patients at risk for severe bone marrow suppression.

INVESTIGATIONAL Tocilizumab is an anti-IL-6 receptor monoclonal antibody approved for rheumatoid arthritis and other conditions. Small randomized trials and case series show benefit in steroid-refractory active TED, with improvement in CAS and some reduction in proptosis. It is used off-label at select centers, particularly in Europe. Standard dosing is typically 8 mg/kg IV every 4 weeks or 162 mg SC weekly.

INVESTIGATIONAL Rituximab is an anti-CD20 monoclonal antibody that depletes B cells. It is used off-label in European TED centers as an alternative to teprotumumab or for steroid-refractory cases. Randomized trial data is mixed, but real-world experience is generally favorable. It is typically given as either two 1000 mg IV infusions 2 weeks apart or a single 500 mg infusion. Infusion reactions can be significant, and rarely, reactivation of the disease has been reported.

• Am I a candidate for teprotumumab? If so, will my insurance cover it?
• If teprotumumab is not an option, what is the plan for IV steroid therapy?
• Should mycophenolate be added to my steroid protocol?
• What monitoring do I need during treatment (liver tests, blood sugar, hearing)?
• How will we know if the treatment is working?
• What happens if I don’t respond to first-line treatment?
• Are there clinical trials I should consider?
• Is my thyroid function well controlled?
• Am I doing everything I can to optimize my outcome (smoking cessation, thyroid control)?

• Moderate-to-severe active TED with significant diplopia or motility restriction
• As an adjunct to IV steroids for better outcomes
• Steroid-refractory or steroid-dependent disease
• When teprotumumab is not available or not tolerated

Contraindications:

• Diabetic retinopathy: Radiotherapy can worsen retinopathy. Generally contraindicated in patients with significant diabetic eye disease.
• Age under 35: Some guidelines advise caution due to long-term radiation risk

Orbital radiotherapy takes 2–3 weeks to complete and several months to show full benefit. It is generally well tolerated, with temporary mild dryness or irritation being the most common side effect.

Ask: "Before orbital radiotherapy, have I been checked for diabetic retinopathy, and am I over the age of 35 — the two situations where the EUGOGO guideline advises caution or avoidance?"

For mild TED only: Selenium 100 mcg twice daily for 6 months. Based on the Marcocci et al. NEJM 2011 randomized controlled trial, which showed that selenium slowed disease progression and improved quality of life in mild TED. EUGOGO 2021 guidelines recommend selenium specifically for patients in selenium-deficient areas (much of inland Europe), not as a universal recommendation for all mild TED patients. Less consistently adopted in the United States, where selenium dietary intake tends to be adequate.

Important: Selenium supplementation is supported only for mild TED. It should not replace immunosuppressive treatment for moderate-to-severe disease.

Ask: "Is my TED mild enough that selenium 100 mcg twice daily for 6 months is appropriate for me, and should my selenium level be checked first?"

• Artificial tears: Use preservative-free drops frequently (4–6 times daily or more) for dryness and irritation
• Lubricating eye ointment: Apply at bedtime, especially if you cannot fully close your eyelids at night (lagophthalmos)
• Moisture chambers or swimming goggles: Can help reduce evaporation, especially in dry climates or air-conditioned environments
• Tape eyelids closed at night: If significant lagophthalmos is present, taping the eyelids or using a moisture shield can protect the cornea

• Elevate the head of the bed: Sleeping with the head elevated (30–45 degrees) reduces periorbital edema and morning swelling
• Sunglasses: Wraparound sunglasses protect against wind, dust, and light sensitivity (photophobia)
• Cool compresses: Can provide temporary relief for swelling and discomfort
• Prism glasses: For patients with diplopia, prism lenses can be ground into regular glasses to temporarily correct double vision while awaiting definitive treatment
• Stop smoking: This cannot be emphasized enough — it is the single most impactful modifiable factor

If multiple surgeries are needed, they must be performed in a specific sequence because each procedure changes the anatomy for the next:

1. Orbital decompression (first): Removes bone walls of the orbit and/or orbital fat to reduce proptosis. This changes eye position and alignment, which is why it must be done before strabismus surgery.
2. Strabismus surgery (second, 3–6 months after decompression): Realigns the eye muscles to correct diplopia. Must wait for the new eye position after decompression to stabilize.
3. Eyelid surgery (last): Corrects lid retraction, excess skin, and cosmetic changes. Done last because both decompression and strabismus surgery alter eyelid position.

Ask: “Is my disease inactive enough to operate — how long has my CAS been below 3? And if I need more than one procedure, are we doing decompression first, then strabismus, then eyelids?”

Not all patients need all three surgeries. Some may only need one or two procedures. Your oculoplastic surgeon will determine the appropriate plan based on your specific situation.

Orbital decompression surgery enlarges the bony orbit to reduce proptosis and relieve pressure on the optic nerve. Several approaches exist:

• Balanced medial and lateral wall decompression: Most commonly performed. Removes portions of the medial and lateral orbital walls. Can achieve 4–7 mm of proptosis reduction.
• Fat decompression: Removes orbital fat without removing bone. Less proptosis reduction but lower risk of new diplopia.
• Floor decompression: Removes part of the orbital floor. Effective but higher risk of numbness (infraorbital nerve).
• Emergency decompression: Performed urgently for compressive optic neuropathy that does not respond to IV steroids within 1–2 weeks.

Recovery: Typically 2–4 weeks for swelling to subside. Most patients notice proptosis reduction immediately. New or worsened diplopia can occur (approximately 10–30% risk depending on technique) and may require subsequent strabismus surgery.

Ask: "For the decompression technique you are planning, what is my personal risk of new double vision — nearer the 10% or the 30% end — and would fat-only decompression lower that risk for me?"

Strabismus surgery corrects eye misalignment and diplopia caused by fibrotic, thickened extraocular muscles. In TED, the muscles are typically tight and restricted (restrictive strabismus) rather than weak. Surgery involves recessing (moving back) the affected muscles to improve alignment. Adjustable sutures are often used so that fine-tuning can be done in the early postoperative period.

Eyelid surgery addresses:

• Upper eyelid retraction: The most common TED sign. Surgically corrected by weakening or recessing the levator muscle or Müller muscle.
• Lower eyelid retraction: Can be corrected with spacer grafts or lateral canthal tightening.
• Blepharoplasty: Removes excess skin and fat deposits that accumulated during the active phase.

Eyelid surgery can dramatically improve appearance and comfort, reducing the “staring” look that many TED patients find distressing.

• Has my disease been stable long enough to safely proceed with surgery?
• Which surgeries do I need, and in what order?
• How much proptosis reduction can I expect from decompression?
• What is the risk of new or worsened diplopia after decompression?
• How many TED decompression surgeries has this surgeon performed?
• What is the expected recovery timeline?
• Will I need more than one surgical stage?
• Should I try teprotumumab before surgery to reduce proptosis medically?

• ClinicalTrials.gov (clinicaltrials.gov): Search for “thyroid eye disease” or “Graves ophthalmopathy” and filter by status (recruiting) and location.
• Graves’ Disease & Thyroid Foundation: gdatf.org — patient advocacy organization with trial information
• Your TED specialist or oculoplastic surgeon: Academic centers often run trials not widely advertised.
• ITEDS (International Thyroid Eye Disease Society): Professional organization that may list ongoing research.

Ask: "Are any TED trials — for example an oral IGF-1R drug such as linsitinib (NCT05276063), or an FcRn antibody — enrolling at this center or one you can refer me to?"

• RAI use for Graves’ disease: More common in the US; less common in Europe and Japan, partly due to awareness of TED exacerbation risk
• EUGOGO guidelines: The European standard emphasizes IV methylprednisolone + mycophenolate as first-line. Used across Europe, Australia, and many Asian countries.
• Japanese guidelines: Use lower-dose steroid pulse protocols and incorporate orbital radiotherapy earlier in the treatment algorithm
• Developing countries: Access to specialized TED centers and disease-modifying therapy varies enormously. Many patients have no access to teprotumumab or even to oculoplastic surgical expertise.
• ITEDS (International Thyroid Eye Disease Society): Working toward global consensus guidelines that bridge the US teprotumumab-centered approach and the European EUGOGO approach.

DE-PRIORITIZED Prolonged courses of high-dose oral prednisone were historically the mainstay of TED treatment. EUGOGO studies demonstrated that IV methylprednisolone pulse therapy is more effective, better tolerated, and associated with fewer side effects than oral prednisone. Oral steroids are still used occasionally for mild flares or as a bridge, but IV pulses are the standard route for moderate-to-severe active TED.

FAILED Cyclosporine as a single agent for TED showed disappointing results in controlled trials, with limited efficacy and significant side effects including nephrotoxicity and hypertension. It has largely been abandoned as monotherapy for TED. It was occasionally combined with steroids in older protocols but has been replaced by mycophenolate and newer agents.

FAILED Despite initial enthusiasm based on the presence of somatostatin receptors on orbital tissue, controlled trials of octreotide and lanreotide showed no significant benefit over placebo for TED. These agents are no longer recommended.

FAILED Colchicine was studied as an anti-inflammatory agent for TED but showed no meaningful benefit in controlled studies. It is not recommended.

• Acknowledge the emotional impact. Changes in facial appearance — eye bulging, lid retraction, asymmetry — cause real psychological distress. This is not vanity. TED patients have documented rates of depression and anxiety comparable to patients with cancer diagnoses. Validate their feelings.
• Help with daily tasks affected by vision changes. Double vision, light sensitivity, and difficulty reading are common. Offer practical support with driving (safety is paramount — diplopia may make driving unsafe), reading, and screen work.
• Encourage professional mental health support. Psychologists experienced with body image and chronic illness can be very helpful. Many TED patients benefit from counseling.

• Teprotumumab requires 8 infusions over 24 weeks. Help with scheduling, transportation to the infusion center, and managing time off work.
• Insurance navigation is often challenging. Prior authorization, appeals, and step therapy requirements are common for teprotumumab. The manufacturer (Amgen) has patient assistance programs. Ask the specialist’s office about insurance advocacy support.
• Keep records. Track CAS scores, proptosis measurements, and treatment responses. This documentation is essential for insurance appeals.

Diplopia (double vision) may make driving unsafe. This is a difficult conversation but an essential safety issue. Some patients can drive safely with prism glasses. Others should not drive until diplopia is corrected. Discuss driving safety with the specialist and respect their assessment, even when the patient wants to continue driving.

TED can affect work capacity through vision changes, light sensitivity, eye discomfort, and the emotional impact of visible facial changes. Accommodations may include:

• Adjusted lighting and screen filters
• Flexible scheduling for medical appointments and infusions
• Permission to wear sunglasses indoors
• Reduced screen time or frequent breaks
• Temporary work-from-home arrangements during active disease

• Studies consistently find that TED patients have significantly impaired quality-of-life scores (GO-QoL, SF-36) compared to age-matched controls and even compared to patients with other forms of thyroid disease without eye involvement
• The appearance domain of quality of life is particularly affected — even mild-moderate proptosis causes significant cosmetic distress that is not well-predicted by Hertel measurements alone
• Depression rates of 40–60% have been reported in TED cohorts, with anxiety rates similarly elevated; rates correlate with CAS score and visual symptoms but persist into the inactive phase
• The EUGOGO and American Thyroid Association now formally recognize QoL assessment as a component of TED management decisions, not merely a side concern
• Effective treatment (teprotumumab or surgical rehabilitation) improves QoL scores substantially; this improvement is now used as a primary outcome in clinical trials

• Graves’ Disease and Thyroid Foundation (GDTF): The primary US patient advocacy organization for TED. Website: gdatf.org; phone: 1-877-643-3123. Provides patient guides, local support groups, physician referral list, and a Graves’ thyroid disease newsletter. Annual patient conference includes TED-specific programming.
• TED Connect: An online patient community specifically for TED patients (tedconnect.com), supported by Amgen/Horizon. Connects TED patients with peers, provides educational content, and links to healthcare provider finders.
• European Graves’ Orbitopathy Network (EUGOGO) patient resources: eugogo.eu provides patient information in multiple languages for international patients.
• Body image therapy: CBT-based body image therapy adapted for people with chronic disfiguring conditions is evidence-based for improving self-esteem, social confidence, and reducing avoidance behavior. The "Changing Faces" organization (UK-based, available internationally through online programs) provides free resources. Visible Ink (US) provides workshops for people with appearance-altering conditions.
• Makeup and aesthetic strategies during active TED: Certain makeup techniques can minimize the appearance of proptosis and periorbital swelling during the active phase (before surgery is possible). Many online resources and YouTube channels are dedicated to makeup for TED patients. Tinted lenses in glasses provide an additional visual effect to reduce the appearance of proptosis. Cosmetic camouflage from the National Skin Centre or equivalent services offer free professional makeup training.
• When to seek professional mental health support: If depression or anxiety is significantly impairing function at work or in relationships, or if suicidal thoughts occur, please contact your primary care physician or call 988 (Suicide and Crisis Lifeline). Mental health crisis resources are available 24/7 and are appropriate for any severe distress from chronic illness.

• Linsitinib (OPK-88003): An oral, small-molecule IGF-1R inhibitor being evaluated in the LIDS phase 3 trial for active moderate-to-severe TED. Oral administration would eliminate the need for IV infusion center visits (the major logistics challenge with teprotumumab). Early phase 2 results showed meaningful proptosis reduction; phase 3 results are expected in 2025–2026. Clinical trial: NCT05276063.
• Batoclimab (IMVT-1402) and nipocalimab (J&J/Momenta): Anti-FcRn (neonatal Fc receptor) antibodies that reduce circulating IgG antibody levels, including TRAb (the antibodies driving TED). By lowering TRAb levels, these drugs target the upstream driver of TED rather than blocking its downstream effects. Batoclimab subcutaneous injection is in phase 3 trials for TED (CIRCULATE trial) and other antibody-mediated diseases. This approach could be useful both for active TED and to prevent TED development after Graves’ diagnosis.
• Iscalimab (CFZ533, anti-CD40L): Blocks the CD40/CD40L costimulatory pathway that activates T and B cells, reducing the autoimmune drive behind TED. In early clinical trials for TED with encouraging preliminary results.
• Subcutaneous teprotumumab: Amgen is developing a subcutaneous (under-the-skin injection) formulation of teprotumumab to enable self-administration at home, eliminating the need for infusion center visits. This would represent a major convenience improvement while maintaining efficacy.
• Mycophenolate mofetil (MMF, CellCept): An immunosuppressant already used in transplant medicine, MMF has been evaluated in combination with IV glucocorticoids for TED. The EUGOGO MINGO trial (PMID 29396246) showed that adding MMF to IV steroids significantly reduced relapse rates after steroid completion compared to steroids alone. Some centers use MMF as a bridge treatment between acute steroid therapy and elective surgical correction.

An exciting frontier in TED research is moving from treating established orbital disease to preventing it in Graves’ patients at high risk. Current understanding identifies high TRAb, active smoking, and RAI treatment without steroid prophylaxis as the major modifiable risk factors for TED development or worsening. Emerging strategies include:

• Early teprotumumab treatment in Graves’ hyperthyroidism patients with elevated TRAb, BEFORE orbital disease becomes clinically apparent — "pre-emptive" TED treatment
• Anti-FcRn antibodies to reduce TRAb levels early in Graves’ disease course, potentially preventing TED altogether
• Biomarkers of TED risk — galectin-9, periostin, and cytokine profiles — to identify Graves’ patients most likely to develop TED and prioritize them for early intervention
• Better orbital imaging (dynamic MRI, contrast-enhanced MRI for muscle inflammation) to detect subclinical TED and guide treatment timing

• TED in men: Although Graves’ disease is predominantly a condition of women (8:1 female:male ratio), men with Graves’ disease have more severe TED than women. This is not fully explained by smoking rates alone. Men with Graves’ hyperthyroidism should be specifically counseled about TED risk and the particular importance of avoiding smoking. Men may also present later in the TED course because dry eye and mild proptosis may be less readily recognized.
• TED in older adults (>65 years): TED tends to be more severe and takes longer to reach the inactive phase in older adults. The inflammatory phase may be less distinct (lower CAS despite significant proptosis), and DON risk is higher due to potentially narrower orbital apices and less orbital fat for cushioning. Older adults also tolerate high-dose IV steroids less well (glucose control, bone loss, hypertension amplified). Teprotumumab may be preferred over steroids in older adults with comorbidities, though hearing assessment is important as age-related hearing loss may make teprotumumab-associated hearing changes harder to assess.
• Euthyroid Graves’ (TED without hyperthyroidism): Approximately 5–10% of TED patients have no thyroid dysfunction at diagnosis — so-called "euthyroid Graves’" disease. These patients have positive TRAb but normal thyroid hormone levels. The orbital disease behaves identically to TED in hyperthyroid Graves’ patients. All management decisions are based on ophthalmic findings, not thyroid status. These patients are often initially misdiagnosed as having other orbital diseases (orbital pseudotumor, lymphoma) because TED is not suspected without overt hyperthyroidism; awareness of euthyroid Graves’ is critical for early correct diagnosis.
• TED in Hashimoto’s thyroiditis: Rare but recognized. Hashimoto’s-associated TED patients typically have lower TRAb levels, milder disease, and a shorter active phase than Graves’-associated TED. The pathophysiology involves similar orbital fibroblast activation by IGF-1R antibodies rather than TSH-R antibodies.

• Graves’ disease in pregnancy: Graves’ hyperthyroidism can develop or worsen during pregnancy, particularly in the first trimester. Untreated maternal hyperthyroidism causes preterm birth, low birth weight, and fetal loss. Propylthiouracil (PTU) is preferred in the first trimester (methimazole carries a small risk of aplasia cutis in the fetus); methimazole is safer from the second trimester onward. Neonatal hyperthyroidism can result from transplacental TRAb transfer.
• TED course during pregnancy: TED commonly improves during pregnancy (likely due to immunotolerance and immune suppression in the second and third trimesters), then worsens or rebounds 3–6 months postpartum as immune activity surges. This postpartum flare is a major at-risk period for TED progression.
• Teprotumumab and pregnancy: Teprotumumab is contraindicated in pregnancy and nursing. If a woman with active TED becomes pregnant, teprotumumab must be stopped. IV glucocorticoids can be used at the lowest effective dose for severe active TED in pregnancy with appropriate neonatology oversight. Planning pregnancy should involve ophthalmology, endocrinology, and obstetrics jointly.

• Ophthalmology visits: During active TED (CAS ≥3/7), ophthalmology follow-up every 4–8 weeks is typically recommended to assess disease activity (CAS), proptosis (Hertel measurement), visual acuity, color vision, and optic nerve function (formal visual fields if any concern for DON). Closer monitoring (every 2–4 weeks) if the disease is rapidly progressing or there is any optic nerve risk.
• Endocrinology visits: TRAb (TSH receptor antibody) levels every 3–6 months during active disease. TSH and free T4 every 3 months while on antithyroid drugs or immediately post-RAI/thyroidectomy. Target TSH in low-normal range (0.5–1.5 mIU/L) — hypothyroidism and hyperthyroidism can both worsen TED.
• Orbital imaging: MRI of orbits (preferred over CT due to no radiation and better soft tissue detail) at diagnosis and when optic neuropathy is suspected. CT of orbits is used pre-operatively for decompression planning (bone anatomy visualization). Repeat imaging is not routinely needed during follow-up unless clinical concern arises.
• TRAb normalization as a guide: TRAb levels correlate with disease activity better than any single clinical sign. Falling TRAb levels signal disease becoming inactive; rising TRAb predicts relapse. In patients who had teprotumumab, TRAb monitoring post-treatment predicts who may relapse and need re-treatment.

Most TED progression is slow enough to be managed at regularly scheduled visits. However, certain symptoms represent potential emergencies requiring immediate contact with your ophthalmologist:

• Sudden vision loss or blurring — especially color desaturation (colors appearing washed out, particularly red) or a new central visual field defect: these suggest optic nerve compression (dysthyroid optic neuropathy/DON) and require same-day evaluation
• Corneal pain, significant redness, or new light sensitivity — may indicate corneal ulceration from exposure keratopathy
• Inability to close the eye during sleep combined with a red, painful, or cloudy cornea in the morning — urgent corneal exposure complication
• Sudden increase in diplopia or inability to look in any direction — may suggest acute muscle entrapment or orbital apex syndrome
• Severe orbital pain unresponsive to usual analgesics — orbital inflammation may be rapidly escalating

Who to call: Your ophthalmologist’s after-hours line for vision symptoms; if unavailable, go directly to an emergency room with ophthalmology on call. Many academic medical centers have 24-hour ophthalmology emergency coverage. Do not wait for the next scheduled appointment if you experience any of the above.

After the active phase resolves and TED is stable (≥6 months inactive), ophthalmology visits can be reduced to every 6–12 months to monitor for relapse and manage residual complications. Thyroid hormone levels should still be monitored annually or as directed by your endocrinologist.

Ask: "Now that my TED is inactive, how often should I be seen — is every 6 to 12 months right for me — and which symptoms should make me call the same day rather than wait for that visit?"

Dry eye is nearly universal in TED. Proptosis and lid retraction reduce the ability to fully close the eye, and TED-related lacrimal gland inflammation reduces tear production. Management:

• Artificial tears (lubricating eye drops): Use preservative-free drops frequently — at least 4 times per day, and every 1–2 hours during screen work. Preserved drops (those containing benzalkonium chloride/BAK) cause cumulative corneal toxicity with frequent use. Preservative-free unit-dose vials (Refresh Plus, Systane Ultra PF, Bion Tears, TheraTears) are preferred for high-frequency use. Thicker gels (GenTeal Gel, Lacrilube ointment) are used at night; ointment blurs vision but protects the cornea during sleep when lagophthalmos (inability to close the eye) is present.
• Moisture chamber goggles: Sealed or semi-sealed goggles worn during sleep, or in dry/windy environments, dramatically reduce corneal desiccation. Available through optical shops; some patients sleep with swim goggles as a low-cost option.
• Eyelid taping: If lagophthalmos is causing corneal exposure during sleep, tape the eyelid gently shut with paper surgical tape (Micropore) until definitive eyelid surgery can be performed. Your ophthalmologist can demonstrate the technique.
• Punctal plugs: Small silicone plugs inserted into the tear drainage canals (puncta) reduce tear drainage and increase tear film retention on the eye surface. A simple office procedure that can significantly improve dry eye comfort.

• Driving with diplopia: Binocular diplopia (double vision with both eyes open) is a significant driving safety risk. During active TED with uncontrolled diplopia, driving should be avoided. Temporary prism glasses (Fresnel prism stickers applied to one spectacle lens) can sometimes compensate for small-angle diplopia and allow safe driving; see an orthoptist or neuro-ophthalmologist for evaluation. Many patients with severe or uncompensated diplopia must stop driving temporarily or permanently until strabismus surgery is performed.
• Screen work and light sensitivity: Photophobia (light sensitivity) and visual fatigue from dry eye and extraocular muscle restriction make prolonged screen use difficult. Blue-light filtering glasses, frequent breaks (20-20-20 rule: every 20 minutes, look at something 20 feet away for 20 seconds), and adjusting screen brightness and position help. A humidifier in the workspace reduces evaporative dry eye.
• Psychological impact: Studies consistently show significantly impaired quality of life in TED patients, driven by changes in facial appearance, visual symptoms, and the burden of a prolonged disease course with uncertain timeline to resolution. Depression and social anxiety are common. Cognitive behavioral therapy (CBT) addressing body image and illness adaptation is recommended. Peer support through the Graves’ Disease and Thyroid Foundation (GDTF) patient community (gdatf.org) provides connection with others who share the TED experience. The Eye Cancer Network and TED Connect communities are additional resources.
• Support organizations: The Graves’ Disease and Thyroid Foundation (gdatf.org, 1-877-643-3123), the American Thyroid Association (thyroid.org), and TED Connect (tedconnect.com) provide patient resources, physician directories, and peer support for people living with TED.

Three treatments are available for Graves’ hyperthyroidism: antithyroid drugs (methimazole/propylthiouracil), radioactive iodine (RAI), and thyroidectomy. Each has different implications for TED:

• Antithyroid drugs (ATDs) — methimazole: The most common first-line treatment outside the US. Methimazole (or less commonly PTU) reduces thyroid hormone production and is continued for 12–18 months. In some patients (∼30–50%), Graves’ remission occurs after a course of ATD therapy. ATDs have the least TED risk of the three treatment options and are preferred in patients with active TED who require thyroid treatment. They do not appear to worsen TED. Methimazole side effects: rash, liver toxicity (rare), and agranulocytosis (rare, <0.3%; presents as sudden severe sore throat — seek blood count immediately).
• Radioactive iodine (RAI) — RISK for TED: RAI (I-131) ablates thyroid tissue and permanently renders the patient hypothyroid. Critically, RAI is associated with development or worsening of TED in approximately 15–33% of patients, particularly in: current smokers; patients with high TRAb (TSH receptor antibody) titers before RAI; and patients with pre-existing TED. This risk can be significantly mitigated by prophylactic oral prednisone given concomitantly with RAI (current European TED guideline recommendation). If you have active TED or significant TED risk factors, discuss RAI risk with your endocrinologist before proceeding. Stabilization with ATDs before RAI is sometimes recommended.
• Thyroidectomy (total thyroidectomy) — lowest TED risk: Surgical removal of the entire thyroid gland renders the patient permanently hypothyroid and removes the main antigenic stimulus driving TSH-R antibody production. Thyroidectomy is associated with the most rapid fall in TRAb levels of any treatment option and appears to have the lowest risk of TED worsening. Current EUGOGO guidelines favor thyroidectomy over RAI in patients with moderate-to-severe TED, particularly active TED, when definitive thyroid treatment is required. Risks: hypocalcemia (parathyroid injury), recurrent laryngeal nerve injury (voice change), need for lifelong levothyroxine.
• After definitive therapy: Monitor TRAb levels every 6 months after RAI or thyroidectomy until they normalize. Persistently elevated TRAb after definitive thyroid treatment is associated with ongoing TED activity. Target TSH in the low-normal range (0.5–1.5 mIU/L); both hypothyroidism and hyperthyroidism can worsen TED.

Ask: "Given my TED activity and my TRAb level, is thyroidectomy a better choice than radioactive iodine for protecting my eyes — and either way, what is my target TSH?"

Orbital decompression creates more space within the orbit by removing one or more walls of the orbit (usually the medial and/or inferior wall, and sometimes orbital fat). This allows the proptotic eye to recede back into the socket. Indications include:

• Sight-threatening: Dysthyroid optic neuropathy (DON) that has not responded to or is not suitable for IV glucocorticoids; urgent/emergent procedure
• Corneal exposure: Proptosis causing corneal exposure keratopathy not managed with lubricants/moisture chambers
• Cosmetic/quality-of-life: Significant proptosis causing distress, especially after the inflammatory phase has resolved

Most decompression for proptosis reduction removes the medial and/or inferior orbital walls (bone decompression) plus varying amounts of orbital fat (fat decompression). The degree of proptosis reduction achieved depends on the approach and individual anatomy, typically 3–6 mm. Potential complications include new or worsened diplopia (due to disruption of orbital anatomy and muscle relationships), altered sensation below the eye, and rarely, cerebrospinal fluid leak. Performed by oculoplastic or orbital surgeons at major academic and specialty eye centers.

• Strabismus surgery (eye muscle surgery): TED-associated strabismus (diplopia) is caused by fibrotic, restrictive enlargement of the extraocular muscles (particularly inferior and medial rectus). It can rarely be corrected with prisms in spectacles alone; most patients require surgery on the eye muscles to realign the eyes. TED strabismus surgery involves recessing (weakening) the tight, fibrotic muscle(s) to allow the eye to move into proper alignment. Because TED strabismus can be unpredictable and complex, and because orbital decompression itself can change the eye position, strabismus surgery is performed AFTER orbital decompression has been stable for 3–6 months. Adjustable suture techniques (where suture tension is adjusted in the recovery room with the patient awake) improve surgical accuracy in complex cases.
• Eyelid surgery: Eyelid retraction (upper and/or lower lid) is the most common cosmetic manifestation of TED. Upper eyelid retraction surgery involves weakening the levator palpebrae aponeurosis and/or Müller’s muscle; lower lid retraction surgery uses spacer grafts (hard palate mucosa, AlloDerm) to lengthen the retracted lower lid. Eyelid surgery is performed LAST in the surgical sequence because changes from decompression and strabismus surgery can affect lid position. Blepharoplasty (excess eyelid skin removal) and ptosis repair are common adjuncts once TED is stable.
• Botulinum toxin (Botox): Can be injected into the levator palpebrae to temporarily reduce upper lid retraction during the active inflammatory phase when definitive surgery is not yet possible. Also useful for testing the anticipated result of surgery. Effect lasts 2–3 months; repeat injections are needed for ongoing benefit.
• Finding a surgeon: TED surgery requires specialized expertise in orbital, oculoplastic, and strabismus surgery. Major academic ophthalmology centers, the Graves’ Disease and Thyroid Foundation (gdatf.org), and the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) provide referral resources.

Teprotumumab (brand name Tepezza) is a fully human monoclonal antibody against IGF-1R (insulin-like growth factor-1 receptor). Approved by the FDA in January 2020 for active, moderate-to-severe TED, teprotumumab represents the first treatment that directly reverses the orbital changes of TED — not merely suppresses inflammation.

Clinical trial results (OPTIC and OPTIC-X trials):

• Proptosis reduction: 83% of patients achieved ≥2 mm proptosis reduction (the primary endpoint) after 8 infusions over 24 weeks, compared to 10% in the placebo group. Mean proptosis reduction was 3.0 mm (vs. 0.3 mm placebo).
• Clinical activity score: 78% of teprotumumab patients achieved CAS of 0 or 1 (inactive disease) vs. 7% placebo. Teprotumumab appears to move patients into the inactive phase significantly faster than other treatments.
• Diplopia improvement: 68% of patients with diplopia at baseline had improvement or resolution (vs. 29% placebo), including improvement in extraocular muscle restriction on imaging.
• Durability: The OPTIC-X extension study showed that responses were maintained for 51 weeks after the last infusion in most patients; a subset needed re-treatment.

Practical details: Teprotumumab is given as 8 IV infusions over 24 weeks (20–90 minutes each, depending on tolerance of infusion rate). It must be infused at an infusion center. Key side effects include muscle cramps (25%), nausea (17%), hearing changes/tinnitus (12%), and hyperglycemia (5–10%) — the last is important in patients with diabetes. Hearing loss can be permanent in rare cases; baseline audiologic assessment is recommended. Teprotumumab is not recommended in pregnancy.

Insurance and cost: Teprotumumab costs approximately $400,000 for a full 8-infusion course. Most commercial insurers cover it for FDA-labeled active moderate-to-severe TED; some require documented CAS ≥4/7 and failure or contraindication to IV glucocorticoids. Horizon Therapeutics (now Amgen) offers a patient assistance program (TepezzaSupport.com).

• Intravenous (IV) methylprednisolone: High-dose IV glucocorticoids (1 g IV weekly for 6 weeks, then 0.5 g weekly for 6 weeks — the EUGOGO recommended protocol; total cumulative dose ≤8 g) remain a standard treatment for active, moderate-to-severe TED, particularly where teprotumumab is not available or affordable. Response rate is approximately 80% for orbital inflammation and 60% for diplopia; proptosis improves less reliably. Oral prednisone has less efficacy and more systemic side effects than IV methylprednisolone and is not preferred. Monitor liver function (rare hepatotoxicity with high cumulative doses), blood pressure, blood glucose, and bone density.
• Selenium (selenomethionine) for MILD active TED: A large European RCT (Marcocci et al., NEJM 2011) showed that selenium 200 mcg/day for 6 months significantly improved mild active TED compared to placebo, with a minor adverse event profile. Selenium is recommended by EUGOGO for mild active TED in selenium-deficient populations (selenium deficiency is common in Europe; baseline selenium levels should be checked). Selenium supplementation does not have established efficacy in moderate-to-severe TED.
• Orbital radiation (radiotherapy): Low-dose external beam orbital radiation (20 Gy in 10 fractions over 2 weeks) can reduce orbital inflammation and improve diplopia in active TED. Meta-analyses suggest it is most effective for diplopia and extraocular muscle involvement; it has modest effect on proptosis. It is often combined with IV glucocorticoids. Contraindicated in patients with diabetic retinopathy (risk of radiation retinopathy) and in those under age 35 (radiation-induced malignancy risk). Requires referral to a radiation oncology center experienced in treating orbital disease.

The Clinical Activity Score (CAS) is the most widely used tool to assess TED activity in clinical practice. Developed by Mourits et al. and validated in multiple studies, the CAS assesses 7 signs and symptoms of orbital inflammation. Each present sign scores 1 point:

1. Spontaneous orbital pain (pain in or behind the eye)
2. Pain on up-gaze or down-gaze
3. Redness of the eyelid
4. Redness of the conjunctiva (covering 2 quadrants or more)
5. Eyelid edema (swelling)
6. Conjunctival edema (chemosis)
7. Caruncle or plica involvement (redness/swelling of the inner corner of the eye)

A CAS ≥3/7 is generally considered indicative of active disease; a CAS ≥4/7 is the threshold used in most clinical trials for immunosuppressive treatment eligibility. CAS is assessed at each ophthalmology appointment.

EUGOGO (European Group on Graves’ Orbitopathy) classifies TED into 3 severity levels, guiding management decisions:

• Mild: Minimal impact on daily life; one or more of: minor lid retraction (<2 mm), mild proptosis (<3 mm above normal), transient or absent diplopia, corneal irritation responsive to lubricants
• Moderate-to-severe: Significant impact without immediate sight threat; lid retraction ≥2 mm, proptosis ≥3 mm above normal, intermittent or constant diplopia, corneal exposure not responding to lubricants alone
• Sight-threatening: Dysthyroid optic neuropathy (DON) and/or corneal breakdown; requires urgent intervention

Cigarette smoking is the most important modifiable risk factor for developing TED, and for the severity and treatment response in established TED. Key evidence:

• Smokers with Graves’ hyperthyroidism are 7–8 times more likely to develop TED than non-smokers with Graves’
• TED is more severe in smokers than non-smokers across all EUGOGO severity categories
• Response to IV glucocorticoid therapy is approximately 30% lower in smokers than non-smokers
• Radioactive iodine (RAI) treatment for Graves’ hyperthyroidism increases the risk of TED development or worsening — this risk is further amplified in smokers. Current guidelines recommend prophylactic IV steroids with RAI in active smokers with Graves’.
• Smoking cessation before or early in TED is associated with a milder disease course and better treatment response. Even cessation during active TED improves outcomes.

Smoking cessation support: varenicline (Chantix/Champix), combination nicotine replacement therapy (patch + gum/lozenge), and bupropion SR are the most effective pharmacological options. For TED patients, the conversation about smoking cessation should be reinforced at every ophthalmology and endocrinology visit — the benefit in TED is greater than in almost any other smoking-related condition.

TED is driven by autoantibodies against the TSH receptor (TSH-R Ab, also measured as TRAb or TRAB). These same antibodies cause Graves’ hyperthyroidism by overstimulating the thyroid gland. In the orbit, TSH receptors are expressed on orbital fibroblasts — the connective tissue cells that produce the structural matrix of the orbit. When TSH-R antibodies activate orbital fibroblasts, they:

• Differentiate into adipocytes (fat cells), expanding the orbital fat volume
• Produce large amounts of hyaluronic acid and glycosaminoglycans (GAGs), which are hydrophilic molecules that absorb water and cause the orbital muscles and connective tissues to swell
• Attract inflammatory cells (T cells, B cells, macrophages) that sustain and amplify the inflammatory process

The combined effect — expanded orbital fat volume and swollen extraocular muscles — increases the total volume of tissue within the fixed bony orbit. Since the orbit cannot expand (it is surrounded by bone on three sides and the eyelids on the fourth), increased orbital volume pushes the eyeball forward (proptosis/exophthalmos) and can compress the optic nerve at the orbital apex (causing vision loss in severe disease).

The insulin-like growth factor 1 receptor (IGF-1R) plays an important co-stimulatory role in orbital fibroblast activation, forming a complex with TSH-R. Teprotumumab (Tepezza) targets IGF-1R and is the first FDA-approved drug that directly reverses the orbital changes of TED.

• Proptosis (exophthalmos): Forward protrusion of the eye from expanded orbital contents. Even a few millimeters of proptosis can cause significant cosmetic distress; severe proptosis (>24 mm, measured by Hertel exophthalmometer) risks corneal exposure and desiccation because the eyelids cannot fully cover the globe.
• Eyelid retraction: Inflammation and scarring of the levator palpebrae muscle (which raises the upper eyelid) and Müller’s muscle cause the upper and/or lower eyelids to retract, exposing more of the white of the eye (sclera). Lid retraction and proptosis together create the "staring" appearance characteristic of TED.
• Diplopia (double vision): Swelling and fibrosis of the extraocular muscles (particularly the inferior and medial rectus muscles) restricts eye movement, causing misalignment of the two eyes and double vision. Inferior rectus enlargement causes limitation of upward gaze; medial rectus causes limitation of lateral gaze.
• Optic neuropathy: The most serious TED complication. The swollen extraocular muscles compress the optic nerve at the orbital apex (where it exits the eye socket through a narrow bony opening). Optic neuropathy causes reduced visual acuity, color desaturation, afferent pupillary defect, and visual field defects. It is a medical emergency requiring urgent intervention (high-dose IV steroids and/or surgical orbital decompression).
• Dry eye and exposure keratopathy: Proptosis and lid retraction impair the ability to fully close the eye, causing corneal exposure — particularly during sleep. Chronic corneal exposure leads to dryness, irritation, and eventually corneal scarring. Lubricating eye drops (preservative-free, used generously), nighttime eye ointment or gel, and moisture chamber goggles during sleep are the cornerstones of exposure management.

• Manufacturer list price: Amgen’s published Wholesale Acquisition Cost is $19,451.83 per 500 mg vial (stated accurate as of 25 June 2026). Dosing is weight-based, so the number of vials — and the billed total — depends on your weight.
• Full 8-infusion course: commonly quoted at approximately $300,000 to $400,000 before any rebates or discounts.
• Commercially insured out-of-pocket: Amgen states eligible patients “may pay as little as $0 per dose” through its co-pay program; government-insured patients (Medicare, Medicaid, VA, TRICARE) are excluded and typically face coinsurance, which on a six-figure course can still run into thousands of dollars.

Ask: "What is my expected out-of-pocket cost per infusion in dollars — not the billed charge — and am I eligible for the Amgen co-pay program, or an alternative if my insurance is government-funded?"

The EUGOGO 2021 first-line alternative to teprotumumab is built largely from inexpensive generic drugs; most of the cost is facility and monitoring time rather than the medicines themselves.

• IV methylprednisolone (the drug itself): generic; the medication for a full 4.5 g EUGOGO course often totals under $500, though infusion-suite and monitoring fees add more.
• Mycophenolate mofetil (generic CellCept): roughly $30 to $100 per month.
• Selenium 100 mcg twice daily: an over-the-counter supplement, roughly $5 to $15 per month across the 6-month mild-TED course.
• Preservative-free artificial tears: roughly $10 to $25 per box, an ongoing cost for most patients.
• Smoking-cessation medication (generic varenicline or bupropion): often $30 to $150 per month, and frequently covered as a preventive benefit.

Ask: "If teprotumumab is out of financial reach, what does the IV methylprednisolone and mycophenolate pathway cost me out of pocket, and is it a reasonable option for my severity?"

• Baseline and follow-up audiogram (needed around teprotumumab): roughly $100 to $500 each.
• Orbital MRI or CT: commonly $500 to $3,000 depending on facility and contrast.
• Orbital decompression surgery: surgeon and facility fees together commonly run $10,000 to $30,000 or more per side, largely covered by insurance when medically indicated.
• Strabismus surgery and eyelid rehabilitation: each additional staged procedure typically adds several thousand to over $15,000.

Because TED surgery is staged — decompression, then strabismus, then eyelids — the costs arrive in sequence over many months, which matters both for budgeting and for meeting more than one insurance deductible year.

Ask: "Which of my planned procedures and infusions fall in this insurance year versus next, and roughly what will each cost me after my deductible?"

• “thyroid eye disease teprotumumab OPTIC”
• “Graves ophthalmopathy IV methylprednisolone EUGOGO”
• “thyroid eye disease mycophenolate MINGO”
• “thyroid eye disease orbital decompression”
• “teprotumumab hearing loss side effects”
• “thyroid eye disease selenium supplementation”
• “Graves orbitopathy tocilizumab rituximab”
• “thyroid eye disease FcRn inhibitor batoclimab”
• “thyroid eye disease clinical trial 2026”