The goal of this prospective single-arm open-label trial is to learn about efficacy and safety of Bortezomib in treating patients with difficult-to-treat rheumatoid arthritis. The main questions it aims to answer are:

• Is Bortezomib an effective treatment option for patients with difficult-to-treat rheumatoid arthritis?
• Is Bortezomib safe enough in treating patients with difficult-to-treat rheumatoid arthritis?

Participants will:

• Receive Bortezomib 2 mg per week subcutaneously for twelve weeks in total.
• Follow-up at weeks 4, 12, and 24, while biosamples will be collected.

Inclusion Criteria:

• Age >18 years and <70 years;
• Absolute neutrophil count ≥1.0×10^9/L, platelet count ≥100×10^9/L, aspartate transaminase and total bilirubin within 3 times and 1.5 times the normal upper limit, respectively, and serum creatinine clearance >60 ml/min;
• Voluntarily sign an informed consent form.

Exclusion Criteria:

• Individuals with concomitant autoimmune diseases;
• Presence of severe, poorly controlled cardiovascular, cerebrovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neuropsychiatric diseases, or laboratory abnormalities that the investigator deems an unacceptable risk for the participant's involvement in the study;
• History of malignant tumors (or clinical cure time less than 5 years);
• Subjects who are pregnant or lactating, or planning to become pregnant or start breastfeeding during the study period;
• Vaccination with live virus vaccines within the 4 weeks prior to study entry;
• Allergy to Borussertib or mannitol;
• Participation in any other investigational drug trial in the 12 weeks before the start of this study medication;
• Presence of active hepatitis or a history of severe liver disease at screening: defined as a positive test for hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus antibodies (HCVAb) (Note: If the result of hepatitis B core antibody (HBcAb) is positive and HBsAg is negative, hepatitis B virus (HBV) DNA testing will be performed. If HBV-DNA is negative, the patient is eligible.);
• Active herpes zoster infection, or occurrence of a severe infection in the 12 weeks before the start of the study medication (defined as requiring intravenous antibiotics or hospitalization);
• Other situations that investigators deem unsuitable for inclusion.