Graves' Orbitopathy (GO) is a disabling and disfiguring condition associated with Graves' Disease, due to autoimmunity against antigens expressed by the thyroid and orbital tissues, and resulting in orbital fibroblast proliferation and release of glycosaminoglycans. The current treatments available, especially glucocorticoids, are not effective in all patients. Two cases of patients with GO treated with Sirolimus have been reported with an excellent response to the drug.

The rationale for the use of Sirolimus lies in its mechanisms of action. Sirolimus is able to inhibit T-cell activation as well as fibroblast proliferation. In addition, acts indirectly on the Insulin-Like Growth Factor-1 (IGF-1) pathway, and recent clinical trials have shown that a monoclonal antibody against the IGF-1 receptor (Teprotumumab) is effective in patients with GO. Thus, Sirolimus could be used in GO as monotherapy in patients with GO.

The aim of the present drug vs standard treatment, observational study is to evaluate the efficacy of Sirolimus as a second-line treatment in patients with moderately severe, active GO.

Study Design: observational

Thirty consecutive patients with moderate-to-severe and active GO treated with sirolimus (15 patients) or methylprednisolone (15 patients) observance 18 consecutive months will be compared.

Study Timeline

Baseline visit - (Time 0) Treatment period (week 1-week 12): daily administration of the trial agent (Sirolimus) or weekly administration of the standard treatment (methylprednisolone) Outcome visit (week 24)

Inclusion Criteria:

1. Patients willing and capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
2. A moderate-to-severe GO, defined as the presence of at least one of the following criteria: an exophthalmos ≥2 mm compared with normal values for sex and race; presence of inconstant to constant diplopia; a lid retraction ≥2 mm
3. Active GO: CAS (4) ≥2 out of 7 points in the most affected eye
4. Previous GO treatment with glucocorticoids and/or orbital radiotherapy and/or orbital decompressive surgery, performed more than 24 weeks before the current treatment
5. Male and female patients of age: 18-75 years

Exclusion Criteria:

1. Optic neuropathy
2. Treatment with glucocorticoids or other immunosuppressive medications, and/or selenium, and/or orbital radiotherapy and/or orbital decompressive surgery in the 24 weeks preceding the current treatment
3. Mental illness that prevents patients from comprehensive, written informed consent

Consecutive patients with moderate-to-severe, active Graves' orbitopathy treated with either sirolimus of methyprednisolone as a second-line treatment after a previous course of methyprednisolone, over 18 consecutive months