What is the recommended steroid dosing regimen for active Graves ophthalmopathy?

Graves' Ophthalmopathy Steroid Dosing

For active moderate-to-severe Graves' ophthalmopathy, administer intravenous methylprednisolone 500 mg weekly for 6 weeks, followed by 250 mg weekly for 6 weeks (cumulative dose 4.5 g over 12 weeks), as this regimen provides optimal efficacy with acceptable safety. 1

Initial Assessment and Treatment Selection

• Confirm that the ophthalmopathy is both active (Clinical Activity Score ≥3/7) and moderate-to-severe before initiating IV glucocorticoids, as mild disease does not warrant systemic steroids. 1

• Ensure the patient is euthyroid before starting treatment; antithyroid drugs are the preferred method for managing Graves' hyperthyroidism in patients with ophthalmopathy. 1

• Screen for contraindications to high-dose steroids: check hepatitis B and C serology, liver function tests, and assess for active infections, uncontrolled diabetes, severe osteoporosis, or psychiatric disorders. 1, 2

First-Line IV Methylprednisolone Protocol

Standard Regimen (4.5 g cumulative dose)

• Administer 500 mg IV methylprednisolone weekly for 6 weeks, then 250 mg weekly for 6 weeks (total 12 infusions over 12 weeks). 1, 3

• Each infusion should be given in 500 mL isotonic saline over approximately 2 hours. 4

• This weekly protocol is superior to daily protocols in both efficacy (77% response rate vs 41%) and safety, with significantly fewer relapses during treatment. 3

Higher-Dose Regimen for Severe Cases (7.5 g cumulative dose)

• For the most severe cases with constant diplopia or impending optic neuropathy, consider escalating to a cumulative dose of 7.47 g: 750 mg weekly for 6 weeks, then 375 mg weekly for 6 weeks. 1, 5

• This higher dose provides greater short-term improvement in ocular motility (52% response vs 28% with lower doses) but carries slightly increased toxicity risk. 5

• Do not exceed 8 g cumulative dose due to unacceptable hepatotoxicity risk (0.8% fatal liver failure with doses of 9-12 g). 1, 2

Combination Therapy (Preferred First-Line)

• Add mycophenolate sodium 360 mg twice daily starting with the first IV methylprednisolone infusion and continue for 24 weeks; this combination is more effective than IV steroids alone and is now recommended as first-line treatment. 1

• The combination approach allows for lower cumulative steroid doses while maintaining or improving efficacy. 1

Sight-Threatening Ophthalmopathy (Dysthyroid Optic Neuropathy)

• Administer 500-1000 mg IV methylprednisolone daily for 3 consecutive days, then repeat this 3-day pulse weekly for several weeks. 1, 4

• If no improvement occurs within 1-2 weeks, proceed immediately to urgent orbital decompression surgery rather than continuing ineffective medical therapy. 1

Monitoring During Treatment

• Check liver function tests before each infusion for the first 6 weeks, then every 2 weeks; discontinue immediately if transaminases exceed 3× upper limit of normal. 1, 2

• Measure Clinical Activity Score, proptosis, ocular motility, visual acuity, and color vision at weeks 4,12, and 24 to assess response. 1, 3

• Monitor blood glucose, blood pressure, and potassium at each visit, as hyperglycemia and hypertension are common adverse effects. 2

Oral Steroid Bridging (Alternative Protocol)

• If using the older pulse-plus-oral protocol: give 500 mg IV methylprednisolone for 3 days, followed by oral prednisone 40 mg daily tapered to 10 mg over 4 weeks, then repeat the IV pulse. 4

• This approach is now considered second-line because the weekly IV-only protocol (without oral bridging) is more effective and safer. 3

Second-Line Treatments for Non-Responders

• If no improvement after 12 weeks of first-line therapy, options include:
  • A second course of IV methylprednisolone (7.5 g cumulative) after careful hepatic and ophthalmologic evaluation. 1
  • Orbital radiotherapy (20 Gy in 10 fractions) combined with oral or IV glucocorticoids. 1
  • Teprotumumab 10 mg/kg IV every 3 weeks for 8 infusions (if available and reimbursed). 1
  • Rituximab 1000 mg IV on days 1 and 15. 1

Critical Pitfalls to Avoid

• Do not use daily IV methylprednisolone protocols (e.g., 500 mg daily for 5 days); these cause more relapses when transitioning to oral steroids and have worse safety profiles. 3

• Do not start with oral prednisone alone for moderate-to-severe disease; IV methylprednisolone is significantly more effective (77% response) and better tolerated than oral glucocorticoids. 1

• Do not exceed 8 g cumulative IV methylprednisolone due to hepatotoxicity risk; fatal liver failure has been reported with 9-12 g doses. 1, 2

• Do not delay orbital decompression in sight-threatening cases if high-dose IV steroids fail within 1-2 weeks; vision loss may become irreversible. 1

• Do not omit mycophenolate sodium from the initial regimen; the combination is now preferred first-line therapy based on superior long-term outcomes. 1