Trial of Rituximab for Graves' Ophthalmopathy

Laboratory evidence suggests that autoantibodies targeting the thyrotropin receptor are
directly involved in the pathogenesis of Graves' ophthalmopathy (GO). This double-blind,
randomized, controlled study will determine whether rituximab, an anti-B-lymphocyte antigen
(CD20) monoclonal antibody that induces transient B-cell depletion, is an effective
treatment for moderate to severe, active GO.

Before any treatment is given, careful eye and thyroid physical examinations will be
performed and the patients will have several thyroid blood tests, a test to count the white
cells in the blood, and a CT scan of the head and eyes. A close-up photograph of the face
will be taken and patients will be given a short questionnaire about how their eyes are
feeling and how the eye disease is affecting their quality of life.

Each study subject will receive either 2 infusions of rituximab (each 1000 mg; given 2 weeks
apart) or 2 intravenous infusions of saline. Glucocorticoids (methylprednisolone 100 mg) or
saline will also be administered IV as premedication to the rituximab and placebo arm
respectively, in a blinded fashion but matching the randomization, to decrease the rate of
infusion-associated reactions. All antihypertensive medications will be held for the 12
hours prior to and during the infusion. Patients will return 2 weeks after the first
intravenous infusion in order to receive the second infusion.

Patients will be assessed at weeks 8, 16, 24 and 52 for eye disease severity, CAS, thyroid
stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), thyroid
autoantibodies (TRAB), thyroid peroxidase (TPO) and C19+B cell count. CT scan of the orbits
will be obtained at baseline and week 52 for orbital volume measurements and proptosis.
Thyroid ultrasound will be obtained at baseline, week 24 and week 52 for thyroid volume
measurements and color Doppler flow assessment.

Data analysis - Continuous variables were compared between the two treatment groups using t
test or the Wilcoxon rank sum test, while categorical variables were analyzed using the
chi-square /Fisher exact test. Non-parametric methods were used throughout where normality
and chi-squared assumptions did not hold. General linear models were used to access
treatment effect on change in CAS between baseline and 24 or 52 weeks. Patients who
discontinued the trial prior to week 52 were evaluated before discontinuation and those data
were carried forward to either 24 weeks (for the 5 patients who discontinued prior to or at
week 24) or 52 weeks (for the single patient discontinued from the trial after 24 weeks) as
the final evaluation for that patient. A p-value < 0.05 was considered significant.

Inclusion Criteria:

- Patients with clinical activity score (CAS) of ≥4 and moderate to severe disease
severity, as defined by thyroid eye disease severity scale based on the first letter
of the defining characteristic of each class, the classification is known as: 'no
signs or symptoms; only signs; soft tissue; proptosis; extraocular muscle; cornea;
sight loss' (NOSPECS) score

- Euthyroid for at least 6-8 weeks

- No immediate need for decompression surgery

- With disease progression over the previous 1-2 months or without evident improvement
in the prior 6 months.

Exclusion Criteria:

- Corticosteroid use in the preceding 4 weeks

- HIV, hepatitis C or hepatitis B infections

- Denied consent for HIV or hepatitis testing

- Mild or inactive Graves' ophthalmopathy

- Orbital radiotherapy within 18 months or orbital surgery within the past year

- Absolute neutrophil count < 1,500/mm^3

- Pregnant or nursing patients

- Coronary artery disease, congestive heart failure, significant arrhythmias,
significant infection or immunodeficiency, other serious illnesses