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.

• Tofacitinib (Drug): 5 mg tablet administered orally twice daily (BID) for a continuous period of 24 weeks.

Primary outcomes

• Overall Response Rate (ORR) [Week12，24]: Percentage of participants classified as responders in the study eye. A responder is defined as a patient who achieves at least one of the following criteria without deterioration in the fellow eye: (1) Reduction in proptosis>=2 mm; (2) Reduction in Clinical Activity Score (CAS) >= 2 points (on a 7-point scale).

Secondary outcomes

• Change in Proptosis [Baseline, Week 4, 12, 24, and 36]: Mean change in proptosis from baseline in the study eye, measured by Hertel exophthalmometer in millimeters (mm).
• Change in Clinical Activity Score (CAS) [Baseline, Week 4, 12, 24, and 36]: Mean change in Clinical Activity Score (CAS) from baseline. CAS is assessed on a 7-point scale (1 point for each: spontaneous retrobulbar pain, pain on gaze, eyelid erythema, eyelid swelling, conjunctival injection, chemosis, inflammation of caruncle/plica), where higher scores indicate more active inflammation.
• Diplopia Response [12W,24W]: ercentage of participants with improvement in diplopia. Improvement is defined as a reduction of at least one grade in the Gorman diplopia score (Grades: absent, intermittent, inconstant, constant)
• Change in Graves' Orbitopathy Quality of Life (GO-QOL) Score [Baseline and Week4，12，24，36]: Mean change in the Graves' Orbitopathy Quality of Life (GO-QOL) questionnaire score from baseline. The GO-QOL measures two subscales: visual functioning and appearance. For each subscale, the minimum score is 0 and the maximum score is 100. Higher scores indicate a better quality of life.
• Incidence of Adverse Events [From baseline through Week 36]: Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0, including specific monitoring for infections, herpes zoster, venous thromboembolism, and lipid profile alterations.

Sex: All, ages: 18 Years to 75 Years

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

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• Fangsen Xiao, MD, Principal investigator, The First Affiliated Hospital of Xiamen University