Tofacitinib for Glucocorticoid-Resistant Moderate-to-Severe Thyroid Eye Disease

Thyroid Eye Disease (TED) involves complex pathogenesis where orbital fibroblasts are activated by autoantibodies targeting the TSH receptor (TSHR) and the Insulin-like Growth Factor-1 receptor (IGF-1R). Current evidence suggests that TSHR and IGF-1R form a physical and functional complex that activates downstream signaling cascades, prominently the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway. The activation of STAT3, in particular, is a critical driver of hyaluronan synthesis, adipogenesis (fat expansion), and inflammation within the orbital tissue.

While intravenous glucocorticoids (IVGC) are the standard first-line treatment, they primarily exert broad anti-inflammatory effects and may fail to adequately suppress the tissue remodeling (adipogenesis and fibrosis) driven by these specific signaling pathways. Consequently, a significant proportion of patients become "steroid-resistant."

This study proposes the use of Tofacitinib, a small-molecule JAK inhibitor, as a targeted rescue therapy. By inhibiting the JAK-STAT pathway, Tofacitinib is hypothesized to suppress both the inflammatory cytokine release and the orbital tissue remodeling that persists despite steroid treatment.

Participants will enter a 24-week treatment phase receiving oral Tofacitinib (5 mg twice daily). Clinical assessments will be performed at Baseline, Week 4, 12, 24, and a follow-up visit at Week 36. Key exploratory components of this study include: 1. Quantitative Orbital Imaging: Use of Orbital MRI to objectively measure changes in extraocular muscle volume and orbital fat volume to distinguish between anti-inflammatory and anti-remodeling effects. 2. Durability of Response: A 12-week post-treatment observation period (Weeks 24-36) to monitor for disease relapse or "rebound" phenomena after drug cessation. 3. Safety in Comorbidities: Close monitoring of coagulation profiles and lipid levels, given the known safety profile of JAK inhibitors, specifically in this population with potential metabolic comorbidities.

Inclusion criteria

• Age and Gender: Male or female participants aged 18 to 75 years (inclusive).
• Diagnosis: Clinical diagnosis of Graves' orbitopathy (GO) consistent with EUGOGO criteria.
• Severity: Moderate-to-severe GO as defined by EUGOGO guidelines (impact on daily life, but not sight-threatening).
• Activity: Active disease, defined as a Clinical Activity Score (CAS) >=3 points (on the 7-point scale).
• Refractory Status (Must meet ONE of the following):Glucocorticoid-Resistant: Failure to respond (no significant improvement in proptosis or CAS) after receiving a cumulative dose of at least 3g of intravenous methylprednisolone (or equivalent).Glucocorticoid-Intolerant: Documented contraindications to high-dose systemic glucocorticoids (e.g., uncontrolled diabetes mellitus, severe osteoporosis, glaucoma, severe psychiatric disorders) or history of severe adverse events leading to discontinuation.
• Thyroid Function: Euthyroid or mild hypothyroidism/hyperthyroidism maintained on stable antithyroid drugs or thyroxine replacement therapy for at least 4 weeks prior to baseline.
• Contraception: Women of childbearing potential must agree to use effective contraception during the study period and for at least 4 weeks after the last dose of the study drug.
• Consent: Willing and able to provide written informed consent and comply with study procedures.

Exclusion criteria

• 1.Sight-Threatening Disease: Presence of Dysthyroid Optic Neuropathy (DON) or severe corneal breakdown requiring immediate surgical intervention.

2.Chronic/Inactive Disease: Fibrotic or burnout stage of GO with a Clinical Activity Score (CAS) < 3.

3.Prior Orbital Treatment:Orbital radiotherapy at any time.Orbital surgical decompression at any time.Strabismus surgery or eyelid surgery within 3 months prior to baseline.

4.Concomitant Immunomodulation: Use of other biologic agents (e.g., Teprotumumab, Rituximab, Tocilizumab) within 3 months prior to baseline.

5.Active Infection Risk (Critical for JAK Inhibitors):Active tuberculosis (TB) or untreated latent TB.Active or chronic Hepatitis B or Hepatitis C infection.Human Immunodeficiency Virus (HIV) infection.History of disseminated herpes zoster or herpes simplex.Any severe active infection requiring hospitalization or IV antibiotics within 4 weeks of baseline.

6.Thrombosis Risk: History of venous thromboembolism (VTE), including deep vein thrombosis (DVT) or pulmonary embolism (PE), or known coagulation disorders.

8.Malignancy: History of any malignancy within the past 5 years (except adequately treated basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix).

9.Laboratory Abnormalities:Absolute Neutrophil Count (ANC) < 1.0 *10^9/L and/or Absolute Lymphocyte Count (ALC) < 0.5 *10^9/L and /or Hemoglobin < 90 g/L and/or AST or ALT > 2* Upper Limit of Normal (ULN) and/or Estimated Glomerular Filtration Rate (eGFR) < 60 mL/min/1.73 m²