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CD40L Antagonism in Rheumatoid Arthritis (RA) (CONTROL-RA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05306353
Recruitment Status : Not yet recruiting
First Posted : April 1, 2022
Last Update Posted : November 23, 2022
Sponsor:
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
Patients with moderately-to-highly active Rheumatoid arthritis receive a 12-week VIB4920 treatment with Tumor necrosis factor alpha inhibitor (TNFi) compared to background disease-modifying (RA) therapy with TNFi and without the addition of VIB4920. The primary objective is to determine if the addition of a 12-week course of treatment with VIB4920 to a TNFi in patients with RA who have had an inadequate response to a TNFi results in improved clinical disease control.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Drug: Placebo for VIB4920 Drug: VIB4920 with TNFi Drug: VIB4920 without TNFi Phase 2

Detailed Description:

This study is a phase 2, multi-site, prospective, randomized, placebo-controlled, three-arm [two arms double-blinded, one arm evaluator-blinded (participant is aware of his/her treatment status, but evaluator is not)] trial of VIB4920 in 104 adults with seropositive Rheumatoid arthritis (RA) in the United States. Individuals will be eligible if they have moderate or high disease activity (Simplified Disease Activity Index [SDAI] ≥ 17) despite treatment with a TNFi (etanercept or adalimumab) for at least 12 weeks.

Study participation is divided into two phases: the study drug administration period (from week 0 to week 12) and the post-administration observation period (from week 12 to week 40).

Participants will be randomized into one of the following three study arms to assess the efficacy of adding VIB4920 to background disease modifying RA therapy including TNFi and replacing TNFi with VIB4920, as well as the safety of this combination of biologic agents compared to either agent alone.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Combining a CD40L-Binding Protein (VIB4920) With a TNF-alpha Inhibitor for the Treatment of Inadequately Controlled Rheumatoid Arthritis (ITN092AI)
Estimated Study Start Date : December 1, 2022
Estimated Primary Completion Date : August 2024
Estimated Study Completion Date : March 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: VIB4920 Placebo with TNFi
Participants will receive VIB4920 placebo in a blinded fashion intravenously at weeks 0, 2, 4, 8, and 12 and continue all background disease-modifying RA therapy, including the TNFi, through the study period VIB4920 placebo consists of 0.9% normal saline in 250mL bags.
Drug: Placebo for VIB4920
26 participants will receive VIB4920 placebo administered intravenously at weeks 0, 2, 4, 8, and 12 while continuing background rheumatoid arthritis (RA) therapy including tumor necrosis factor alpha inhibitor (TNFi) (double-blinded)

Experimental: VIB4920 with TNFi
Participants will receive VIB4920 in a blinded fashion intravenously at a dose of 1500 mg at weeks 0, 2, 4, 8, and 12 and continue all background disease-modifying RA therapy, including the TNFi, through the study period
Drug: VIB4920 with TNFi
52 participants will receive 1500 mg administered intravenously at weeks 0, 2, 4, 8, and 12 while continuing background rheumatoid arthritis (RA) therapy including Tumor necrosis factor alpha inhibitor (TNFi) (double blinded)

Experimental: VIB4920 without TNFi
Participants will stop TNFi after randomization to this arm, and receive VIB4920 in an evaluator-blinded fashion intravenously at a dose of 1500 mg at weeks 0, 2, 4, 8, and 12 while maintaining all other background disease-modifying RA therapy (e.g., methotrexate, hydroxychloroquine, etc.) through the study period. This arm is evaluator blinded (not aware of treatment status), with the participant aware of treatment status but evaluator is not, due to not using a TNFi placebo for this study
Drug: VIB4920 without TNFi
Participants will receive 1500 mg administered intravenously at weeks 0, 2, 4, 8, and 12 but discontinue necrosis factor alpha inhibitor (TNFi) while continuing all other background rheumatoid arthritis (RA) therapy (evaluator-blinded)




Primary Outcome Measures :
  1. Proportion of participants achieving low disease activity by Simplified Disease Activity Index (SDAI) [ Time Frame: Week 16 ]

    Defined by a Simplified Disease Activity Index (SDAI) <= 11

    Participants who escalate their disease-modifying therapy or take any prohibited medications for treatment of RA prior to Week 16 are considered to have failed the primary endpoint. The primary analysis will compare the primary endpoint between the two blinded study arms: VIB4920 with TNFi and VIB4920 placebo with TNFi study arms



Secondary Outcome Measures :
  1. Proportion of participants who achieve sustained remission [ Time Frame: Week 16 to Week 40 ]
    Defined by Simplified Disease Activity Index (SDAI) <= 3.3

  2. Proportion of participants achieving low disease activity by Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) [ Time Frame: Week 16 ]
    Defined by Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) <= 3.2

  3. Proportion of participants achieving remission defined by SDAI [ Time Frame: Week 16 ]
    Defined by Simplified Disease Activity Index (SDAI) <= 3.3. Participants who escalate their disease-modifying therapy or take prohibited medications for treatment of their RA prior to week 16 are considered to have failed this secondary endpoint

  4. Proportion of participants achieving remission defined by DAS28-CRP [ Time Frame: Week 16 ]
    Defined by Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) < 2.6. Participants who escalate their disease-modifying therapy or take prohibited medications for treatment of their Rheumatoid Arthritis (RA) prior to week 16 are considered to have failed this secondary endpoint

  5. The proportion of participants achieving an ACR20 response [ Time Frame: Week 16 ]
  6. The proportion of participants achieving an ACR50 response [ Time Frame: Week 16 ]
  7. The proportion of participants achieving an ACR70 response [ Time Frame: Week 16 ]
  8. The proportion of participants achieving an ACR20 response [ Time Frame: Week 40 ]
  9. The proportion of participants achieving an ACR50 response [ Time Frame: Week 40 ]
  10. The proportion of participants achieving an ACR 70 response [ Time Frame: Week 40 ]
  11. Time to first occurrence of low disease activity as defined by SDAI [ Time Frame: Week 0 to Week 40 ]
    Defined by SDAI <= 11; for participants who fail to achieve low disease activity or remission prior to escalating their disease-modifying therapy or taking a prohibited medication for treatment of RA, we will assume low disease activity and remission is not achievable.

  12. Time to first occurrence of low disease activity as defined by DAS28-CRP [ Time Frame: Week 0 to Week 40 ]
    Defined by Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) <= 3.2; for participants who fail to achieve low disease activity or remission prior to escalating their disease-modifying therapy or taking a prohibited medication for treatment of RA, we will assume low disease activity and remission is not achievable.

  13. Time to first occurrence of remission as defined by SDAI [ Time Frame: Week 0 to Week 40 ]
    Defined by Simplified Disease Activity Index (SDAI) <= 3.3; for participants who fail to achieve low disease activity or remission prior to escalating their disease-modifying therapy or taking a prohibited medication for treatment of RA, we will assume low disease activity and remission is not achievable.

  14. Time to first occurrence of remission as defined by DAS28-CRP [ Time Frame: Week 0 to Week 40 ]
    Defined by Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) < 2.6; for participants who fail to achieve low disease activity or remission prior to escalating their disease-modifying therapy or taking a prohibited medication for treatment of RA, we will assume low disease activity and remission is not achievable.

  15. Time to loss of low disease activity defined by SDAI [ Time Frame: Week 16 ]
    Defined by Simplified Disease Activity Index (SDAI) > 11 for the subset of individuals achieving low disease activity by the SDAI criteria. Participants who escalate their disease-modifying therapy or take prohibited medications for treatment of their RA will be considered to have lost the low disease activity or remission response

  16. Time to loss of low disease activity defined by DAS28-CRP [ Time Frame: Week 16 ]
    Defined by Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) > 3.2 for the subset of individuals achieving low disease activity by the DAS28-CRP criteria. Participants who escalate their disease-modifying therapy or take prohibited medications for treatment of their RA will be considered to have lost the low disease activity or remission response

  17. Time to loss of remission defined by SDAI [ Time Frame: Week 16 ]
    Defined by Simplified Disease Activity Index (SDAI) > 3.3 for the subset of individuals achieving remission by the SDAI criteria. Participants who escalate their disease-modifying therapy or take prohibited medications for treatment of their RA will be considered to have lost the low disease activity or remission response

  18. Time to loss of remission defined by DAS28-CRP [ Time Frame: Week 16 ]
    Defined by DAS28-CRP >= 2.6 for the subset of individuals achieving remission by the DAS28-CRP criteria. Participants who escalate their disease-modifying therapy or take prohibited medications for treatment of their RA will be considered to have lost the low disease activity or remission response

  19. Longitudinal trends in Simplified Disease Activity Index (SDAI) [ Time Frame: Week 0 to Week 40 ]
  20. Longitudinal trends in Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) [ Time Frame: Week 0 to Week 40 ]
  21. Change in the Health Assessment Questionnaire - Disability Index (HAQ-DI) [ Time Frame: Week 0 to 16 ]
  22. Change in the Health Assessment Questionnaire - Disability Index (HAQ-DI) [ Time Frame: Week 0 to 40 ]
  23. Change in Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) Profile scores [ Time Frame: Week 0 to Week 40 ]
  24. Change in Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) Profile scores [ Time Frame: Week 0 to 16 ]
  25. Incidence of grade 2 or higher adverse events (AEs) [ Time Frame: Week 0 to Week 40 ]

    Liver chemistry abnormalities will be graded using protocol specific criteria, defined relative to the upper limit of normal (ULN):

    • Aspartate aminotransferase [AST] increased: Grade 2: > 3.0x ULN - 5.0x ULN, Grade 3: > 5.0x ULN - 20.0x ULN, Grade 4: > 20.0x ULN
    • Alanine aminotransferase [ALT] increased: Grade 2: > 3.0x ULN - 5.0x ULN, Grade 3: > 5.0x ULN - 20.0x ULN, Grade 4: > 20.0x ULN
    • Alkaline phosphatase [ALP] increased: Grade 2: > 2.5x ULN - 5.0x ULN, Grade 3: > 5.0x ULN - 20.0x ULN, Grade 4: > 20.0x ULN
    • Blood bilirubin increased: Grade 2: > 1.5x ULN - 3.0x ULN, Grade 3: > 3.0x ULN - 10.0x ULN, Grade 4: > 10.0x ULN

    All other AEs will be graded according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.


  26. Incidence of serious adverse events [ Time Frame: Week 0 to Week 40 ]

    An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the investigator or Sponsor (DAIT/NIAID), it results in any of the following outcomes (21 CFR 312.32(a)):

    1. Death.
    2. A life-threatening event: An AE or SAR is considered "life-threatening" if, in the view of either the investigator or Sponsor (DAIT/NIAID), its occurrence places the participant at immediate risk of death. It does not include an AE or SAR that, had it occurred in a more severe form, might have caused death.
    3. Inpatient hospitalization or prolongation of existing hospitalization.
    4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.
    5. Congenital anomaly or birth defect.

  27. Incidence of adverse events of special interest (AESI) [ Time Frame: Week 0 to Week 40 ]

    The following are considered Adverse Events of Special Interest (AESI):

    • Anaphylaxis and grade 3 or higher hypersensitivity reactions
    • Grade 3 or higher infusion reactions
    • AST or ALT >3xULN with serum total bilirubin > 2xULN (Hy's Law)
    • Thrombotic or embolic events except for superficial thrombophlebitis and transient ischemic attacks
    • Grade 3 or higher infection
    • Opportunistic infections including but not limited to reactivation of latent viral infections, invasive fungal infections, and TB
    • Malignant neoplasm
    • Immune complex disease



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participant or legally authorized representative must be able to understand and provide informed consent
  2. Adult 18-70 years of age
  3. Diagnosed with RA by fulfilling the ACR/EULAR 2010 Classification Criteria for Rheumatoid Arthritis (RA) >= 6 months prior to screening
  4. Documented positive test for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibody (ACPA)
  5. Simplified Disease Activity Index (SDAI) >= 17
  6. At least 4 tender and 4 swollen joints by a 44 joint count
  7. Tumor necrosis factor alpha inhibitor (TNFi) therapy:

    1. Current treatment with etanercept 50 mg SC weekly or adalimumab 40 mg SC every other week for at least 12 weeks
    2. Willing to continue or discontinue treatment with their current TNFi at the same dose depending upon study arm assignment
  8. If treated with leflunomide, sulfasalazine, or hydroxychloroquine, must be taking a stable dose for at least 12 weeks
  9. 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 SARS-CoV-2 vaccination as per American College of Rheumatology guidance
    2. Holding methotrexate for 1 or 2 weeks after influenza vaccination
  10. COVID-19 vaccination:

    1. Completion of a primary COVID-19 vaccination series based on current CDC recommendations for individuals who are moderately to severely immunocompromised. The primary vaccination series should include at least 2 doses of an mRNA vaccine, one dose of an adenovirus-based vaccine, or the primary series for any other authorized or approved vaccine.
    2. Receipt of at least one booster dose of a COVID-19 vaccine after the primary vaccine series if recommended by the CDC for individuals who are moderately to severely immunocompromised
    3. The last COVID-19 vaccine dose must have been administered at least 14 days prior the initiation of the study drug (Visit 0)
  11. All participants who engage in sexual activity that could lead to pregnancy must agree to use abstinence or an US Food and Drug Administration (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 Rheumatoid Arthritis (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. History of treatment with more than two Tumor necrosis factor alpha inhibitors (TNFi), including ongoing treatment with etanercept or adalimumab
    3. Treatment with other biologic therapy (i.e., not targeting TNF-alfa), including abatacept, tocilizumab, or sarilumab within the previous 12 weeks
    4. Treatment with a Janus kinase (JAK) inhibitor within the previous 12 weeks
    5. Concurrent use of methotrexate and leflunomide
    6. Prednisone > 10 mg a day or equivalent glucocorticoid use within the previous 4 weeks
    7. Intramuscular, intra-articular, or intravenous glucocorticoids within the previous 4 weeks
    8. 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 current TNFi use, in the opinion of the study investigator based on information provided by the patient and 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. Hypercoagulable state as specified below:

    1. Previous deep venous or arterial thrombosis or thromboembolism, or pulmonary embolism
    2. Known hypercoagulable state (e.g., inherited thrombin III deficiency, protein S deficiency, protein C deficiency, antiphospholipid antibody syndrome, MTHFR mutation)
    3. Risk factors for deep venous or arterial thromboembolism (e.g., immobilization or major surgery within 12 weeks prior to enrollment)
    4. Anti-phospholipid antibodies:

    i. Positive anti-cardiolipin IgG, IgM, or IgA antibodies at a moderate titer or higher (>= 40 U) ii. Positive anti-beta-2-glycoprotein I IgG, IgM, or antibodies at a moderate titer or higher (>= 40 U) iii. Positive lupus anticoagulant test

  10. Infection:

    1. 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)
    2. Positive Hepatitis C Virus (HCV) serology unless treated with an anti-viral regimen resulting in a sustained virologic response (undetectable viral load 24 weeks after cessation of therapy)
    3. Evidence of Human Immunodeficiency Virus (HIV) infection
    4. Evidence of active tuberculosis, untreated or incompletely treated latent tuberculosis, or recent close contact with a person who has active tuberculosis
    5. Positive QuantiFERON-TB Gold or QuantiFERON-TB Gold Plus test without history of previous treatment for active or latent TB
    6. Indeterminate QuantiFERON-TB Gold or QuantiFERON-TB Gold Plus test or TSPOT.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 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 tuberculosis (TB)

    g. Positive test for acute COVID-19 infection (e.g., PCR test for SARS-CoV-2 or alternative viral test according to CDC guidance)

    h. Symptoms of presumed or documented COVID-19 infection in the past 30 days

    i. More than one episode of herpes zoster in the past 12 months

    j. An opportunistic infection in the past 12 months

    k. 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

    l. 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 10^3/mcl
  15. Absolute neutrophil count < 1.5 x 10^3/mcl
  16. Hemoglobin < 9 g/dL
  17. Platelet count < 100 x 10^3/mcl
  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05306353


Locations
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United States, California
University of California San Francisco School of Medicine: Lupus Clinic and Rheumatology Clinical Research Center
San Francisco, California, United States, 94110
Providence Saint John's Health Center, California
Santa Monica, California, United States, 90404
United States, Colorado
University of Colorado School of Medicine: Division of Rheumatology
Aurora, Colorado, United States, 80045
United States, Massachusetts
Brigham & Women's Hospital: Department of Medicine, Rheumatology, Immunology
Boston, Massachusetts, United States, 02215
United States, Michigan
University of Michigan Health System: Department of Internal Medicine, Division of Rheumatology
Ann Arbor, Michigan, United States, 48109
United States, New York
Hospital for Special Surgery, New York: Division of Rheumatology
New York, New York, United States, 10021
United States, North Carolina
Duke University Medical Center: Division of Rheumatology and Immunology
Durham, North Carolina, United States, 27710
United States, Texas
Pop-Moody Clinic
Corpus Christi, Texas, United States, 78404
Metroplex Clinical Research Center: Division of Rheumatology
Dallas, Texas, United States, 75231
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
Investigators
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Study Chair: Eugene William St. Clair Duke University Medical Center: Division of Rheumatology and Immunology
Additional Information:
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT05306353    
Other Study ID Numbers: DAIT ITN092AI
First Posted: April 1, 2022    Key Record Dates
Last Update Posted: November 23, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The plan is to share data upon completion of the study in Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
Time Frame: On average, within 24 months after database lock for the trial
Access Criteria: Open access.
URL: http://www.immport.org/home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Rheumatoid arthritis
VIB4920
TNFi
Additional relevant MeSH terms:
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Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases