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

A Single-Arm, Open-Label, Exploratory Study of Tofacitinib in Patients With Glucocorticoid-Resistant or Intolerant Moderate-to-Severe Active Thyroid Eye Disease

Thyroid Eye Disease (TED), also known as Graves' orbitopathy, is an autoimmune condition that causes inflammation and tissue expansion behind the eyes, leading to bulging eyes (proptosis), double vision, and pain. Currently, intravenous glucocorticoids (steroids) are the standard first-line treatment. However, approximately 20-30% of patients do not respond to steroids, or cannot tolerate their side effects.

This study aims to evaluate the safety and efficacy of Tofacitinib, an oral medication known as a Janus kinase (JAK) inhibitor, as a rescue therapy for these difficult-to-treat cases. Tofacitinib works by blocking specific signaling pathways (JAK-STAT) that drive inflammation and fibrosis in the eye socket. In this study, patients with moderate-to-severe active TED who are resistant to or intolerant of steroids will receive Tofacitinib tablets (5 mg twice daily) for 24 weeks. The researchers will assess whether the treatment can effectively reduce eye bulging and improve clinical activity scores.

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:

1. Age and Gender: Male or female participants aged 18 to 75 years (inclusive).
2. Diagnosis: Clinical diagnosis of Graves' orbitopathy (GO) consistent with EUGOGO criteria.
3. Severity: Moderate-to-severe GO as defined by EUGOGO guidelines (impact on daily life, but not sight-threatening).
4. Activity: Active disease, defined as a Clinical Activity Score (CAS) >=3 points (on the 7-point scale).
5. 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.
6. Thyroid Function: Euthyroid or mild hypothyroidism/hyperthyroidism maintained on stable antithyroid drugs or thyroxine replacement therapy for at least 4 weeks prior to baseline.
7. 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.
8. 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