Takayasu arteritis is a severe vasculitis which could lead to significant disability and even death. While standard anti-inflammatory treatments can manage the systemic inflammation, they failed to stop a key driver of the disease: vascular fibrosis. This fibrosis could result in blood vessels thickening and narrowing, which continues to progress in many patients.

To tackle this critical treatment gap, the present project explores a new strategy. Building on pirfenidone's success in treating fibrosis in organs just like lungs and liver, along with promising early observations from our center, investigators believe adding this anti-fibrotic drug to standard therapy could improve vessel injury directly.

Therefore, investigators plan to conduct a clinical trial comparing pirfenidone with placebo in patients with Takayasu arteritis. The goal is to determine if this approach can successfully improve vascular injury and patient outcomes ultimately.

Inclusion Criteria:

1. Patients who have signed the informed consents and meet the ACR 2022 classification criteria for Takayasu arteritis.

2. Male or female, age between 18 and 60 years.

3. Female patients must have a negative serum or urine pregnancy test and do not have pregnancy plans during the study period.

4. 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.

5. 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.

6. 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

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

Cardiac

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

Cerebral

1. Ischemic stroke.
2. New emerged ischemic symptoms: syncope, visual or auditory abnormalities such as decreased vision, visual field defects, etc.
3. 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:

1. Presence of autoimmune diseases or autoinflammatory diseases other than Takayasu arteritis (e.g., systemic lupus erythematosus, ankylosing spondylitis, rheumatoid arthritis, etc.);
2. 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;
3. 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);
4. 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;
5. Allergy to the investigational drug or previous failure of regular pirfenidone treatment for 3 months;
6. 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;
7. History of allergy to MRA contrast agents;
8. 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