Possible Treatment for Grave’s Ophthalmopathy: A Sight for Sore Eyes

Kyle Savio, Mercer University College of Pharmacy

Graves’ ophthalmopathy (GO) is considered a sight-threatening condition that can occur with hyperthyroidism, and a greater risk in Graves’ hyperthyroidism. Symptoms may include dry and gritty ocular sensation, photophobia, excessive tearing, double vision, and a pressure sensation behind the eyes. Distinguishable features include orbital erythema/edema, retraction of upper eyelids, and proptosis. [1]

Guideline recommendations include surgery, radiation, anti-thyroid drugs, and corticosteroids. [2] Biological therapies are being explored to target receptors of interest in GO. The insulin-like growth factor 1 receptor (IGF-1R) has demonstrated increased expression on orbital fibroblasts in GO patients. Thyroid autoantibodies that are overproduced in Graves’ disease may activate these receptors to cause upregulation of inflammatory mediators such as interleukin (IL)-1, IL-6, and prostaglandins. [1] Teprotumumab is believed to bind to IGF-1R and block thyroid autoantibodies from stimulating inflammation. [3]

Teprotumumab for Thyroid-Associated Ophthalmopathy [3]
Design Randomized, multicenter, placebo-controlled, double-blind; N= 87
Objective To determine the efficacy and safety of teprotumumab in patients with active, moderate-to-severe ophthalmopathy
Study Groups Teprotumumab (n= 43); placebo (n= 44)
Methods Inclusion criteria were the following: patients 18 to 75 years old, ophthalmopathy diagnosed <9 months after the onset of symptoms, clinical activity score (CAS) of 4 or more, and no prior surgical or medical treatment (with the exception of oral glucocorticoids with a 6-week washout period). Exclusion criteria included optic neuropathy, severe ocular surface damage, or an improved CAS of 2 points or more between screening and baseline. The teprotumumab group received eight IV infusions: 10 mg/kg once, then 20 mg/kg every 3 weeks.

The clinical activity score consisted of seven components: spontaneous retrobulbar pain, pain on eye movements, conjunctival redness, redness of eyelids, chemosis, swelling of the caruncle/plica, and swelling of the eyelids. Each component was scored as present or absent, 1 or 0. The sum of the scores was on a range of 0-7, where 0 or 1 constituted inactive disease and 7 severe active ophthalmopathy. A change of two or more points was considered clinically meaningful.

Quality of life score (0-100) was measured by GO–specific quality-of-life questionnaire (GO-QOL). Higher GO-QOL scores indicated improved or better quality of life

Duration Three phases: screening (2 to 6 weeks), intervention (24 weeks), and follow-up (48 weeks)
Primary Outcome Measure Composite of reduction of ≥ 2 points in the CAS and a reduction of ≥ 2 mm in proptosis
Secondary Outcome Measures Proptosis and CAS (both measured as continuous variables over time) and quality of life assessment score
Baseline Characteristics
Teprotumumab Placebo
Average age, years (SD) 51.6 (10.6) 54.7 (13.0)
Female, n (%) 28 (65) 36 (82)
Median time since initiation of thyroid treatment, months 8 15
Treatment for thyroid disease, n (%)
       Antithyroid drugs 15 (35) 20 (45)
       Levothyroxine 26 (60) 23 (52)
       Thyroid extract 1 (2) 3 (7)
Mean duration of eye symptoms, months (SD) 4.7 (2.1) 5.2 (2.3)
Median duration of Graves’ disease, months 10.7 10.8

 

Results
Teprotumumab Placebo Odds ratio (95% CI) p value
Primary outcome at week 24, n (%) 29 (69) 9 (20) 8.86 (3.29-23.8) <0.001
Proptosis, mm (SD)
Baseline 23.4 (3.2) 23.1 (2.9)
Change from baseline at week 24 -2.46 (0.20) -0.15 (0.19) <0.001
Clinical Activity Score
Baseline 5.1 (0.97) 5.2 (0.74)
Change from baseline at week 24 -3.43 (0.18) -1.85 (0.17) <0.001
GO-QOL Score, n (SD)
Baseline 34.5 (7.3) 34.5 (6.8)
Change from baseline at week 24 +17.7 (2.4) +6.8 (2.3) <0.01

 

Adverse Events Common Adverse Events: nausea, muscle spasms, diarrhea, hyperglycemia (>5%)
Serious Adverse Events: N/A
Discontinued due to Adverse Events: n= 4 (reason not specified)
Study Author Conclusions A 24-week course of teprotumumab therapy provided clinical benefit in patients with active, moderate-to-severe thyroid-associated ophthalmopathy.

 

Only patients with moderate-severe GO were included in the study, leaving out potential treatment in patients with mild or stable disease. The study was also only done over the course of 24 weeks when longer lengths of time would be needed to properly assess adverse events and drug resistance. Additionally, researchers and manufacturer did their parts to limit bias by using independent reviewers and academic investigators. This study shows promise for a disease where current therapies either do little for prevention and progression of symptoms or have limiting side effects that patients can not tolerate.

 

References

[1] Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362(8):726-38.

[2] Ross DS., Burch HB, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. October 2016, 26(10): 1343-1421.

[3] 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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