CD40L Antagonism in Rheumatoid Arthritis (RA)

Inclusion Criteria: 1. Participant or legally authorized representative must be able to understand and provide informed consent 2. Adults ≥ 18 years of age 3. Diagnosed with RA by fulfilling the ACR/EULAR 2010 Classification Criteria for RA ≥ 6 months prior to screening (Appendix 9) 4. Documented positive test for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibody (ACPA) 5. SDAI ≥ 17 6. At least 4 tender and 4 swollen joints by a 44 joint count (Appendix 5) 7. Receiving treatment with an FDA-approved TNFi (including biosimilars) that is dosed subcutaneously at an FDA-approved dosing regimen for at least 12 weeks. 8. Willing to continue or discontinue treatment with their current TNFi at the same dose depending upon study arm assignment 9. If treated with leflunomide, sulfasalazine, or hydroxychloroquine, must be taking a stable dose for at least 12 weeks 10. If treated with methotrexate, must be taking a stable dose for at least 12 weeks. The following exceptions are permitted within the 12 weeks prior to screening: 1. Holding methotrexate after COVID-19 vaccination as per American College of Rheumatology guidance (https://rheumatology.org/) 2. Holding methotrexate for 1 or 2 weeks after influenza vaccination 11. All participants who engage in sexual activity that could lead to pregnancy must agree to use abstinence or an FDA-approved contraception for the duration of the study to prevent pregnancy Exclusion Criteria: 1. Inability or unwillingness to give written informed consent or comply with the study protocol 2. Prior or ongoing systemic inflammatory or autoimmune disease (other than RA and secondary Sjögren's syndrome) requiring or potentially requiring other systemic immunomodulatory therapy during the 40-week study period 3. Use of glucocorticoid and/or disease-modifying therapies as specified below: 1. Prior treatment with any B cell depleting therapy (e.g., rituximab) 2. Treatment with other biologic therapy (i.e., not targeting TNF-α), including abatacept, tocilizumab, or sarilumab within the previous 12 weeks 3. Treatment with a JAK inhibitor within the previous 12 weeks 4. Concurrent use of methotrexate and leflunomide in combination 5. Prednisone \> 10 mg a day or equivalent glucocorticoid use within the previous 4 weeks 6. Intramuscular, intra-articular, or intravenous glucocorticoids within the previous 4 weeks 7. Other immunomodulatory medications within the previous 12 weeks except for methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine 4. Lack of any subjective or objective clinical response (i.e., complete non-responder) to treatment with the current TNFi, in the opinion of the study investigator based on available documentation in the medical record and/or history provided by the patient and/or referring rheumatologist 5. Use of an investigational agent including VIB4920 in the past 30 days or 5 half-lives, whichever is longer 6. History of a severe allergy, hypersensitivity reaction, or infusion reaction to any component of the VIB4920 formulation 7. History of Felty's syndrome 8. History of interstitial lung disease with FVC \< 70% predicted, DLCO \< 70% predicted, or requiring supplemental oxygen 9. Arterial or deep venous thromboembolism including pulmonary embolism in the prior two years 10. Infection: a. Evidence of current or prior infection with hepatitis B, as indicated by a positive test for the hepatitis B surface antigen (HBsAg) or a positive test for the hepatitis B core antibody (HBcAb) b. Positive HCV serology unless treated with an anti-viral regimen resulting in a sustained virologic response (undetectable viral load 24 weeks after cessation of therapy) c. Evidence of HIV infection d. Evidence of active tuberculosis, untreated or incompletely treated latent tuberculosis, or recent close contact with a person who has active tuberculosis e. Positive QuantiFERON-TB Gold, QuantiFERON-TB Gold Plus, or T-SPOT-TB test without history of previous treatment for active or latent TB f. Indeterminate QuantiFERON-TB Gold, QuantiFERON-TB Gold Plus, or T-SPOT.TB test which remains indeterminate on repeat testing, and any of the following additional required screening which indicates an increased risk of TB infection: i. History of tuberculosis exposure ii. History of travel to an area where tuberculosis is endemic iii. Findings on chest radiograph suggestive of prior exposure to tuberculosis (e.g., granulomas or apical scarring) obtained at screening or within the past 3 months iv. Positive purified protein derivative (PPD) skin test for tuberculosis obtained in the past 3 months, either obtained at screening or within the past 3 months v. Prior history of a positive QuantiFERON-TB Gold, QuantiFERON-TB Gold Plus, T- SPOT.TB, or purified protein derivative (PPD) test without history of previous treatment for latent TB g. Symptoms of presumed or documented SARS-CoV-2 infection in the past 30 days h. More than one episode of herpes zoster in the past 12 months i. An opportunistic infection in the past 12 months j. Acute or chronic infection, including current use of suppressive systemic anti-microbial therapy for chronic or recurrent bacterial or fungal infection, hospitalization for treatment of infection in the past 60 days, or parenteral anti-microbial (including anti-bacterial, anti-viral, or anti-fungal agents) use in the past 60 days for infection k. History of bronchiectasis with recurrent pulmonary infections 11. History of a primary immunodeficiency disorder 12. Vaccination with a live vaccine within the past 30 days 13. Women who are pregnant or breast-feeding 14. White Blood Cell (WBC) count \< 3.0 x 103/μl 15. Absolute neutrophil count \< 1.5 x 103/μl 16. Hemoglobin \< 9 g/dL 17. Platelet count \< 100 x 103/μl 18. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2x the upper limit of normal (ULN) 19. History of malignant neoplasm within the last 5 years, except for basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterine cervix treated locally 20. Current, diagnosed mental illness or current, diagnosed or self-reported drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements 21. Any new or uncontrolled condition occurring within the past 12 weeks which, in the judgment of the investigator, could interfere with participation in the trial (e.g., diabetes mellitus with HbA1c ≥ 9.0%, myocardial infarction, or stroke) 22. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements, or that may impact the quality or interpretation of the data obtained from the study 23. Inability to comply with study and follow-up procedures