A single-center randomized controlled study will be used to observe the efficacy and safety of pirfenidone on CTD-ILD patients for 24 months.

The main research endpoints is the lung function (FVC) at 6 months. The clinical dyspnea score, 6-minute walking distance, index of lung function and imaging indicators are evaluated, as well as primary disease activity and adverse reactions of therapy with glucocorticoid and immunosuppressants up to 24 months.

A total of 120 Chinese patients with connective tissue disease-associated interstitial lung disease (CTD-ILD), including inflammatory myopathy (IIM), rheumatoid arthritis (RA), systemic sclerosis (SSc), and other connective tissue diseases, will be enrolled to use Pirfenidone or not in this study according to 2:1 random entry. Glucocorticoid and immunosuppressants worked as background treatment.

The main research endpoint is the lung function (FVC) at 6 months. The clinical dyspnea score, 6-minute walking distance, lung function and imaging indicators, primary disease activity index are evaluated regularly until 24 months. The relationship of pirfenidone concentration, clinical effect and safety, immune function will be analyzed also.

1. Age ≥18 years;
2. Meet several CTD diagnostic criteria (RA, IIM, SSc) and UCTD/IPAF classification criteria;
3. HRCT diagnosis confirmed interstitial lung disease (ILD) with corresponding clinical manifestations;
4. Patients who were able to complete vital capacity (FVC) or carbon monoxide dispersion (DLco) tests (with Hb correction).
5. Patients with clinical deterioration more than 1 month after diagnosis of ILD history, or poor response or intolerance to Glucocorticoids or immunosuppressants treatment, or poor response or intolerance to other antifibrotic drugs (acetyl hemitrine, nidanib, etc.), or effective use of PFD, and exacerbation of clinical symptoms or ILD indicators more than 3 months after withdrawal of the drug.
6. Poor response was defined as no improvement in one of the following:

(1) Symptoms of dyspnea such as cough, chest tightness, breathlessness, shortness of breath after activity, or decreased activity endurance;

(2) the worst decrease in oxygen saturation as measured by pulse oxygen saturation (SpO2) observed during 6MWD;

(3) There was no improvement in pulmonary ventilation (FVC%) or lung dispersion (DLco%);

(4) HRCT findings: new onset, fibrosis tendency or density of ILD lesions were not decreased;

Clinical deterioration was defined as meeting one of three criteria:

1. Clinical deterioration or dyspnea within 4 weeks;
2. New or worsening radiological abnormalities on chest X-ray or high-resolution CT;
3. Objective deterioration of pulmonary function tests or gas exchange, defined as meeting at least one of the following criteria:

1) Start long-term oxygen therapy or increase oxygen supplementation by at least 1 L/min to maintain resting oxygen saturation of at least 90%;

2) FVC decreased by more than 5% compared with the previously measured value; Or a decrease in DLCO of more than 10% from previous measurements; Or a 20% decrease in 6MWD from previous measurements.

7. If concomitant therapy with immunosuppressants was used, the dose was stable for at least 4 weeks before the baseline period. The types of immunomodulator hydroxychloroquine (HCQ) or immunosuppressive agents are MMF, TAC, JAKi, CTX, LEF, AzA, iguratimod etc.

8. Concomitant glucocorticoids: IIM patients with glucocorticoids dose (calculated as the equivalent dose of prednisone) ≤60mg/d and relatively stable disease; For other CTD patients, the glucocorticoids dose (calculated as prednisone equivalent dose) was ≤40mg/ day for at least 1 month.

Exclusion Criteria:

1. Subjects have systemic vasculitis, other arthritis other than CTD or RA such AS psoriatic arthritis, SPA, AS, SLE and pSS;

2. ILD patients with other obvious causes, such as HIV, GVHD, etc.

3. Patients with obvious abnormal combined organ function;

1. Liver :AST, ALT, R-GT, bilirubin at 1.5 ULN, or previously diagnosed viral hepatitis;
2. Kidney: creatinine clearance rate 30ml /min;
3. Lung: airway obstruction (pre-bronchodilator FEV1/FVC & LT; 0.7), pleural effusion accounted for more than 20% of pleural effusion, severe pulmonary infection or other clinically significant pulmonary abnormalities;
4. Cardiovascular: myocardial infarction within 6 months;
5. gastrointestinal tract: active peptic ulcer or bleeding;
6. Blood system: severe anemia, leukopenia, thrombocytopenia;
7. Nervous system: patients with mental disorders; Cerebral thrombotic events (stroke and transient ischemic attack) within the last 1 year;

4. Tuberculosis, cancer, hereditary diseases and other diseases with poor prognosis;

5. Effective contraception cannot be guaranteed during pregnancy, lactation or childbearing age;

6. Evidence of alcohol or drug abuse, according to the researchers;

7. Allergic to glucocorticoids, immunosuppressants and PFD;

8. Unable to complete regular follow-up and post-treatment pulmonary function tests;

9. PFD users not included in the efficacy analysis but included in the safety analysis: those who had used PFD for less than 3 months 6 months before the primary endpoint; The duration of use was less than 3 months before the 24th month of the syudy and the total duration of use was less than 6 months.