Thyroid eye disease (TED) is an autoimmune inflammation of the orbital tissues that develops in up to 50% of patients with Graves' disease. Although about 80% respond to IVGC initially, the relapse rate is high and about 75% require further surgery despite initial response. Although the natural history of TED is associated with spontaneous remissions after about 1 to 3 years, many irreversible serious ophthalmic and orbital complications can arise during this time. Therefore, there is a need for improved intervention strategies in the early active inflammatory phase of TED, to avoid progression to the cicatricial stage where disease manifestations can only be addressed in a rehabilitative fashion. The primary immunopathogenesis of Graves' disease is considered to be activation of B cells that then produce autoantibody against thyrotropin receptors in the thyroid (TRAb). Like in many autoimmune diseases, the inflammatory CD4+ T cell subset known as Th17 cells is also increased in blood of patients with active Graves' disease; the putative Th17 cytokine, IL-17, is also increased in serum and tears of TED patients. There is also an emerging pathogenic role for Th17 cells that co-express the chemokine receptor CXCR5 and drive autoantibody production. The contribution of Th17 cells to TED is not well defined. This study is an observational, longitudinal, prospective study of patients receiving treatment for thyroid eye disease.

All enrolled subjects will receive Intravenous Glucocorticoid (IVGC) therapy, which is currently the standard of care for TED patients. Subjects will receive the IVGC therapy at a facility chosen by them and their physician. If their disease does not respond to IVGC therapy, they will receive rituximab and/or surgical decompression and/or radiation which is also currently standard of care at a facility chosen by them and their physician. Prior to initiation of treatment and during the course of treatment, study patients will get research labs done along with routine labs and fill out questionnaires regarding their disease symptoms.

We will obtain 30 mL or 2 tablespoons of blood from subjects at initial evaluation and approximately Wk4, Wk 12, Wk 26, Wk 38, and Wk 52 (this may vary depending on when the patient comes in for their follow up visits, but the schedule approximates what is typical for standard of care in these patients) for mechanistic studies.

Inclusion Criteria:

1. Willing and able to give informed consent
2. Age 18 to 75 years of age
3. Diagnosis of Thyroid Eye Disease (TED) with a CAS of ≥ 3. (Thyroid status can be euthyroid, hyper or hypothyroid.)
4. Willingness to practice birth control for at least 12 months post treatment.
5. Normal organ function, except if abnormal due to tumor involvement.
6. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months after completion of treatment.
7. Subject has provided written informed consent.
8. Documentation of CD20 + status (for B cell malignancies).
9. ANC: > 1000/mm3
10. Adequate bone marrow function as indicated by a total white blood cell count of > 4 x 109/, hemoglobin of > 7 g/dl or a platelet count >100,000/mm³
11. Adequate renal function as indicated by creatinine of <2.5.
12. Adequate liver function, as indicated by AST or ALT <2x Upper Limit of normal unless related to primary disease.

Exclusion Criteria:

Patients will be excluded from the study based on the following criteria:

1. Brittle insulin dependent diabetes [The term "brittle" refers to cases of diabetes in which there is an instability that leads to a disruption of life and often recurrent and/ or prolonged hospitalization]
2. Pregnant or nursing patients
3. Significant medical comorbidities that would make the risk of high dose steroids intolerable such as severe CHF, CAD, arrhythmias, renal insufficiency, infection or immune deficiency, systemic autoimmune disease, severe glaucoma etc.
4. Absolute neutrophil count < 1500/mm³.
5. Contraindication to use of rituximab
6. Positive PPD and/or Quantiferon Gold TB test without prior anti-tuberculous therapy; active TB
7. HIV or hepatitis infection or declined consent for HIV or hepatitis testing
8. Use of rituximab in the prior 24 months for any reason other than TED
9. Unwillingness to practice birth control for at least 12 months post treatment
10. Pregnancy (a negative serum pregnancy test should be performed for all women of childbearing potential within 7 days of treatment), or lactating.
11. Inability to comply with study and/or follow-up procedures.
12. History of HIV.
13. Presence of active infection.
14. Presence of CNS metastases.
15. New York Heart Association Classification III or IV heart disease (See Appendix D).
16. Concomitant malignancies or previous malignancies within the last five years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
17. History of psychiatric disorder.
18. At the Investigator's discretion, receipt of a live vaccine within 4 weeks prior to randomization.

The study will be introduced during a clinic visit with one of the physicians who are investigators on this study. These will be subjects who are being referred for intravenous glucocorticoid (IVGC) therapy due to the severe nature of their thyroid eye disease.