Integrated Clinical Study of Traditional Chinese and Western Medicine for Refractory Rheumatoid Arthritis

Inclusion Criteria

Subjects must meet all of the following criteria to be enrolled in this study:

1. Fully understand the purpose and requirements of the trial, voluntarily participate by signing written informed consent, and be willing and able to complete the study procedures, including medication administration and follow-up assessments;
2. Male patients aged ≥50 years with no fertility requirements, or postmenopausal female patients, younger than 70 years;
3. Patients diagnosed with rheumatoid arthritis (RA) according to the 1987 revised criteria of the American College of Rheumatology (ACR), or the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria;

4. Patients with RA of the "Wind-Damp Bi obstruction" pattern according to traditional Chinese medicine (TCM), defined as:

   • Primary symptoms: joint pain and swelling with a wandering nature; joint pain and swelling with intermittent occurrence.
   • Secondary symptoms: aversion to wind, or spontaneous sweating; headache; heaviness of the limbs.

   Tongue and pulse: pale-red tongue with thin white coating, slippery or floating pulse.Diagnosis requires at least 2 primary symptoms, or 1 primary symptom plus 2 secondary symptoms, in combination with tongue and pulse findings.

5. Patients with confirmed moderate to severe active RA at screening, defined as ≥6 tender joints (TJC, based on 68-joint count) and ≥6 swollen joints (SJC, based on 66-joint count), with erythrocyte sedimentation rate (ESR) >28 mm/h or C-reactive protein (CRP) >10 mg/L, and DAS28-CRP >3.2;
6. Prior inadequate response (DAS28-ESR >3.2) to at least two disease-modifying antirheumatic drug (DMARD) regimens (excluding methotrexate + JAK inhibitor + Kunxian capsule), each administered for at least 12 weeks.

Exclusion Criteria

Subjects meeting any of the following conditions will not be eligible for enrollment:

1. Suspected or confirmed allergy to the investigational drug (including excipients or drugs of the same class), or any other severe allergic disease (excluding RA itself) that, in the investigator's judgment, may compromise subject safety;
2. Presence of inflammatory diseases other than RA, including but not limited to psoriatic arthritis, ankylosing spondylitis, or systemic lupus erythematosus;
3. Severe, progressive, or uncontrolled diseases of the kidneys, liver, blood, gastrointestinal tract, endocrine system, lungs, heart, nervous system, psychiatric conditions, or brain; history of venous thromboembolism, diverticulitis, significantly abnormal or poorly controlled blood lipids;
4. History of lymphoproliferative disorders, or current or past malignancy;

5. Meeting any of the following criteria for tuberculosis screening, which require exclusion:

   • History of active tuberculosis;
   • Recent close contact with patients with active tuberculosis;
   • Signs or symptoms of active tuberculosis based on medical history and physical examination;
   • Chest CT scan within 3 months prior to enrollment showing evidence of active pulmonary tuberculosis;
   • Positive interferon-gamma release assay (IGRA) within 6 weeks prior to enrollment;

6. Presence or history of active infections, including:

   • Receipt of systemic anti-infective therapy within 4 weeks prior to randomization;
   • Pharyngalgia, nasal congestion, acute upper respiratory tract infection, or systemic acute infection within 2 weeks prior to randomization;
   • Recurrent, chronic, or other active infections at screening that, in the investigator's judgment, may increase subject risk;
7. History of recurrent herpes zoster, disseminated herpes zoster, or disseminated herpes simplex, or history of herpes zoster or herpes simplex within 2 months prior to randomization;
8. Positive hepatitis B surface antigen (HBsAg) and/or HBV DNA >50 IU/mL (or >500 copies/mL) at screening; positive hepatitis C virus antibody, human immunodeficiency virus (HIV) antibody, or Treponema pallidum antibody;
9. Receipt of, or planned receipt of, live or attenuated vaccines within 3 months prior to the first dose of study medication, during the study, or within 6 months after the last study dose;
10. Pregnant, breastfeeding, planning pregnancy, or planning fatherhood during the study or within 6 months after the last dose; females or males with fertility requirements;
11. Clinically significant abnormalities on 12-lead ECG at screening that may increase subject risk, in the investigator's judgment;
12. Any other disease at screening that may interfere with study assessments;

13. Laboratory abnormalities at screening, defined as:

    1. Hemoglobin <100.0 g/L in males, or <90.0 g/L in females;
    2. White blood cell (WBC) count <4.0 × 10⁹/L;
    3. Neutrophil count <1.5 × 10⁹/L;
    4. Platelet (PLT) count <100 × 10⁹/L;
    5. Lymphocyte count <0.5 × 10⁹/L;
    6. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), or serum creatinine (Scr) above the upper limit of normal;
    7. Hematology, liver function, or renal function abnormalities that, in combination with medical history and/or additional examinations, are deemed clinically significant by the investigator;

14. Prior use of any of the following drugs or treatments:

    1. Strong opioids within 1 week prior to randomization;
    2. Any JAK inhibitor within 2 weeks prior to randomization;
    3. Nonsteroidal anti-inflammatory drugs (NSAIDs) at the time of randomization with dosage adjustments within 2 weeks prior;
    4. Prednisone or equivalent corticosteroid >10 mg/day at randomization; or ≤10 mg/day with dosage adjustment within 4 weeks prior to randomization;
    5. Intra-articular, intramuscular, intravenous, trigger-point, bursal, or tendon-sheath corticosteroid injections within 4 weeks prior to randomization or during the study;
15. Concurrent participation in another drug clinical trial;
16. Any clinically significant abnormalities in clinical or laboratory examinations, or any other reason deemed inappropriate for study participation by the investigator.