Effect of Pirfenidone on TA Fibrosis

Inclusion criteria

• Patients who have signed the informed consents and meet the ACR 2022 classification criteria for Takayasu arteritis.
• Male or female, age between 18 and 60 years.
• Female patients must have a negative serum or urine pregnancy test and do not have pregnancy plans during the study period.
• Within the 3 months prior to enrollment, the patient's treatment regimen must consist of glucocorticoids and immunosuppressants (methotrexate). Biological agents (IL-6R, TNF, or monoclonal antibody) might be used based on clinical need. Other targeted therapies (such as CD20 monoclonal antibodies, JAK inhibitors, etc.) or cell-based therapies (such as CAR-T or stem cell therapy) are not permitted.
• During the 6-month follow-up period, the dosage and frequency of existing methotrexate and biologics (IL-6R monoclonal antibody, TNF monoclonal antibody, IL17 monoclonal antibody) must remain unchanged, except for adjustments of glucocorticoid doses based on clinical condition.
• After 3 months of the above combination glucocorticoid and immunosuppressants, patients must achieve remission of disease activity (NIH score <2) and meet at least 3 of the following 5 criteria:

i. Thickening of the affected vessel wall accompanied by luminal stenosis validated by angiographic examination.

ii. Carotid ultrasound showing medium-to-high echogenicity of the carotid artery wall.

iii. Progression in the thickness of the affected arterial wall compared to previous 3 months, with or without progression of luminal stenosis.

iv. Improvement in the thickness of the affected arterial wall of <10% compared to previous 3 months.

v. Within the 3 months prior to enrollment, the occurrence of new vascular ischemic symptoms or ischemic events, or worsening of pre-existing vascular ischemic symptoms. The ischemic symptoms or events must meet at least one of the criteria listed in the table below: Category (Criterion) Vascular Ischemic Signs

• New emerged vascular bruits (carotid, subclavian, or renal arteries).
• Newly emerged absent pulses (carotid, subclavian, brachial, radial, femoral, or dorsalis pedis arteries).
• New emerged systolic blood pressure difference ≥10 mmHg between left and right arms.
• New emerged systolic blood pressure difference ≥30 mmHg between ipsilateral upper and lower limbs.
• Intermittent claudication in upper or lower limbs.

Cardiac

• For non-hypertensive patients, blood pressure elevation to >140/90 mmHg.
• For hypertensive patients, an increase in diastolic blood pressure ≥20 mmHg from baseline.
• Ischemic angina.
• Myocardial infarction.
• Aortic valve insufficiency (moderate or severe).

Cerebral

• Ischemic stroke.
• New emerged ischemic symptoms: syncope, visual or auditory abnormalities such as decreased vision, visual field defects, etc.
• CT cerebral perfusion imaging indicating ischemic or infarcted areas (with a corresponding volume >10 ml detected by CTP software).

Renal Radionuclide renogram showing a decrease in glomerular filtration rate over 10%; or an increase in serum creatinine exceeding 50% compared with the baseline.

Exclusion criteria

• Presence of autoimmune diseases or autoinflammatory diseases other than Takayasu arteritis (e.g., systemic lupus erythematosus, ankylosing spondylitis, rheumatoid arthritis, etc.);
• Use of antifibrotic drugs or drugs with potential antifibrotic properties (such as acetylcysteine, nintedanib, pirfenidone, etc.) within 6 months prior to enrollment, or participation in other clinical trials involving antifibrotic therapies;
• Impaired liver function (elevated transaminases ALT/AST >2 times the upper limit of normal, or bilirubin exceeding the upper limit of normal), severe renal insufficiency (eGFR <15 mL/min/1.73m²), or requirement for psychotropic medications (excluding sleep medicine for sleep disorders);
• Any severe, progressive, or uncontrolled concurrent hematological, gastrointestinal, pulmonary, cardiac, neurological, or other medical conditions unrelated to Takayasu arteritis which could pose unpredictable risks, in the investigator's judgment;
• Allergy to the investigational drug or previous failure of regular pirfenidone treatment for 3 months;
• Due to pirfenidone's metabolism primarily via cytochrome P450 isoenzymes (particularly CYP1A2), use of CYP1A2 inducers or inhibitors prior to enrollment must be discontinued and avoided throughout the study period; such medications are also prohibited during the study unless deemed medically necessary by the investigator for managing adverse events;
• History of allergy to MRA contrast agents;
• Planned vascular surgery during the 6-month follow-up period which may interfere with assessment results.

CYP1A2 Inhibitors:

Acyclovir, amiodarone, atazanavir, caffeine, cimetidine, ciprofloxacin, enoxacin, famotidine, flutamide, fluvoxamine, lidocaine, lomefloxacin, mexiletine, moclobemide, norfloxacin, ofloxacin, perphenazine, propafenone, ropinirole, tacrine, ticlopidine, tocainide, verapamil

CYP1A2 Inducers:

Carbamazepine, esomeprazole, griseofulvin, lansoprazole, moricizine, omeprazole, rifampin, ritonavir