Thyroid eye disease (TED), also known as Graves' orbitopathy or thyroid-associated
ophthalmopathy is a rare debilitating autoimmune condition in which immune cells attack the
eye muscles and connective tissues within the eye socket, leading to proptosis, pain,
diplopia, periorbital and orbital erythema and edema, exposure keratopathy and lagophthalmos,
decreased vision, and compressive optic neuropathy. It has an incidence of 1.9 cases per
10,000 population per year. Approximately 25% of patients with autoimmune thyroid disease
develop TED within 18 months of diagnosis. Severe optic neuropathy will affect 10% of
patients with TED, leading to irreversible vision loss.
The natural history of TED involves an initial active phase, during which the autoimmune
process causes the above mentioned morbidity, followed by a quiescent phase. The active
period usually lasts 2-3 years and requires monitoring until the disease is quiescent. Until
now, treatment during the active period focuses on preserving sight and providing treatment
for double vision. Emergent orbital decompression or radiation treatment is reserved for
compressive optic neuropathy. Alternative therapies, such as glucocorticoids, have little
effect on proptosis and can have dose-limiting side effects. When the active phase "burns"
out, the treatment for thyroid eye disease involves rehabilitative surgeries for orbital
decompression, followed by strabismus surgery, followed by eyelid recession surgery;
altogether, this may involve multiple surgeries which don't reverse the damage of the ocular
and orbital tissues.
Tepezza®, or teprotumumab, is a fully human monoclonal insulin-like growth factor-1 receptor
(IGF-1R) inhibitor antibody which blocks the inflammatory/autoimmune pathophysiology that
underlies thyroid eye disease. It is the first FDA-approved medication for the treatment of
adults with thyroid eye disease, reversing inflammatory changes of proptosis and diplopia. In
clinical trials, 83% of patients receiving teprotumumab demonstrated a greater than 2 mm
reduction in proptosis compared to 10% of participants who received placebo (between-group
difference, 73% points; 95% CI = 59-88; P<0.001). Teprotumumab had a quick improvement on
each outcome, which was evident at the first postbaseline evaluation at week 6, and the
results improved during the 24-week treatment period. This therapy could potentially replace
surgery for many patients, including those with more advanced disease.
The investigators propose a retrospective observational chart review of a cohort of adults
with active TED without compressive optic neuropathy necessitating urgent orbital
decompression or radiation who are undergoing treatment with Tepezza®. Inclusion criteria are
patients with a clinical diagnosis of autoimmune thyroid disease and moderate-severe TED with
clinical activity including symptoms of proptosis, diplopia, orbital pain, lid/orbital edema,
or lid/orbital erythema, and with circulating thyroid stimulating or anti-thyroid
auto-antibodies present within the last 18 months from the initiation of treatment. Exclusion
criteria include patients with a history of compressive optic neuropathy necessitating urgent
orbital decompression or external beam radiation, patients with a history of uncontrolled
diabetes, uncontrolled inflammatory bowel disease, patients under 18 years old, and patients
who are pregnant or trying to become pregnant.
The primary outcome is CAS score improvement and TSI level.
HLA has been associated with Graves disease and TED in different populations. In White
patients, C07:01, DQA105:01, DRB103, and DQB102:01 are associated with GD risk while
DRB107:01 and DQA102:01 may be protective. However, in Asian patients, GD was noted to be
mostly associated with B46:01, 05:01, DRB108:02/03, DRB116:02, DRB114:03, DRB104:05,
DQB05:02 and DQB103:03, while DRB107:01 DRB101:01, DRB113:02, and DRB112:02 are
potentially protective. Likewise, HLA-B38:02, DRB116:02, DQA101:02, and DQB105:02 have
been linked to increased TED risk in Asian patients while HLA-B*54:01 may be protective for
TED in White patients.
In this study, the investigators analyze the HLA subtypes and correlate these with responders
and non-responders to teprotumumab therapy.