Activated Peripheral Blood B Cells in Rheumatoid Arthritis and Their Relationship to Anti-Tumor Necrosis Factor Treatment and Response: A Randomized Clinical Trial of the Effects of Anti-Tumor Necrosis Factor on B Cells
Nida Meednu, Jennifer Barnard, Kelly Callahan, Andreea Coca, Bethany Marston, Ralf Thiele, Darren Tabechian, Marcy Bolster, Jeffrey Curtis, Meggan Mackay, Jonathan Graf, Richard Keating, Edwin Smith, Karen Boyle, Lynette Keyes-Elstein, Beverly Welch, Ellen Goldmuntz, Jennifer H Anolik, Nida Meednu, Jennifer Barnard, Kelly Callahan, Andreea Coca, Bethany Marston, Ralf Thiele, Darren Tabechian, Marcy Bolster, Jeffrey Curtis, Meggan Mackay, Jonathan Graf, Richard Keating, Edwin Smith, Karen Boyle, Lynette Keyes-Elstein, Beverly Welch, Ellen Goldmuntz, Jennifer H Anolik
Abstract
Objective: B cells can become activated in germinal center (GC) reactions in secondary lymphoid tissue and in ectopic GCs in rheumatoid arthritis (RA) synovium that may be tumor necrosis factor (TNF) and lymphotoxin (LT) dependent. This study was undertaken to characterize the peripheral B cell compartment longitudinally during anti-TNF therapy in RA.
Methods: Participants were randomized in a 2:1 ratio to receive standard dosing regimens of etanercept (n = 43) or adalimumab (n = 20) for 24 weeks. Eligible participants met the American College of Rheumatology 1987 criteria for RA, had clinically active disease (Disease Activity Score in 28 joints >4.4), and were receiving stable doses of methotrexate. The primary mechanistic end point was the change in switched memory B cell fraction from baseline to week 12 in each treatment group.
Results: B cell subsets remained surprisingly stable over the course of the study regardless of treatment group, with no significant change in memory B cells. Blockade of TNF and LT with etanercept compared to blockade of TNF alone with adalimumab did not translate into significant differences in clinical response. The frequencies of multiple activated B cell populations, including CD21- double-negative memory and activated naive B cells, were higher in RA nonresponders at all time points, and CD95+ activated B cell frequencies were increased in patients receiving anti-TNF treatment in the nonresponder group. In contrast, frequencies of transitional B cells-a putative regulatory subset-were lower in the nonresponders.
Conclusion: Overall, our results support the notion that peripheral blood B cell subsets are remarkably stable in RA and not differentially impacted by dual blockade of TNF and LT with etanercept or single blockade of TNF with adalimumab. Activated B cells do associate with a less robust response.
Trial registration: ClinicalTrials.gov NCT00837434.
© 2021, American College of Rheumatology.
Figures
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8795463/bin/nihms-1729405-f0001.jpg)
![Figure 2.. Clinical response at 12 and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8795463/bin/nihms-1729405-f0002.jpg)
![Figure 3.. Core B cell subsets over…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8795463/bin/nihms-1729405-f0003.jpg)
Figure 4.. RA responders have lower frequencies…
Figure 4.. RA responders have lower frequencies of activated memory B cells and more proliferating…
Figure 5.. Frequency of T1/T2 B cells…
Figure 5.. Frequency of T1/T2 B cells is higher in RA responders at all time…
- A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness.Chen YF, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, Fry-Smith A, Burls A. Chen YF, et al. Health Technol Assess. 2006 Nov;10(42):iii-iv, xi-xiii, 1-229. doi: 10.3310/hta10420. Health Technol Assess. 2006. PMID: 17049139 Review.
- Down-titration and discontinuation strategies of tumor necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity.van Herwaarden N, den Broeder AA, Jacobs W, van der Maas A, Bijlsma JW, van Vollenhoven RF, van den Bemt BJ. van Herwaarden N, et al. Cochrane Database Syst Rev. 2014 Sep 29;(9):CD010455. doi: 10.1002/14651858.CD010455.pub2. Cochrane Database Syst Rev. 2014. PMID: 25264908 Updated. Review.
- Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor.Kobie JJ, Zheng B, Bryk P, Barnes M, Ritchlin CT, Tabechian DA, Anandarajah AP, Looney RJ, Thiele RG, Anolik JH, Coca A, Wei C, Rosenberg AF, Feng C, Treanor JJ, Lee FE, Sanz I. Kobie JJ, et al. Arthritis Res Ther. 2011;13(6):R209. doi: 10.1186/ar3542. Epub 2011 Dec 16. Arthritis Res Ther. 2011. PMID: 22177419 Free PMC article.
- Efficacy and retention rate of adalimumab in rheumatoid arthritis and psoriatic arthritis patients after first-line etanercept failure: the FEARLESS cohort.Favalli EG, Becciolini A, Carletto A, Conti F, Amato G, Fusaro E, Quartuccio L, Egan CG, Lo Monaco A, Benucci M, Salaffi F, Semeraro A, Parisi S, Ceccarelli F, Piazza I, Foti R. Favalli EG, et al. Rheumatol Int. 2020 Feb;40(2):263-272. doi: 10.1007/s00296-019-04416-3. Epub 2019 Aug 21. Rheumatol Int. 2020. PMID: 31435754
- Anti-TNF-α effects on anemia in rheumatoid and psoriatic arthritis.Corrado A, Di Bello V, d'Onofrio F, Maruotti N, Cantatore FP. Corrado A, et al. Int J Immunopathol Pharmacol. 2017 Sep;30(3):302-307. doi: 10.1177/0394632017714695. Epub 2017 Jun 12. Int J Immunopathol Pharmacol. 2017. PMID: 28604144 Free PMC article. Clinical Trial.
- Single-Cell Sequencing in Rheumatic Diseases: New Insights from the Perspective of the Cell Type.Ding L, Li X, Zhu H, Luo H. Ding L, et al. Aging Dis. 2022 Dec 1;13(6):1633-1651. doi: 10.14336/AD.2022.0323. eCollection 2022 Dec 1. Aging Dis. 2022. PMID: 36465169 Free PMC article.
- NAC1 modulates autoimmunity by suppressing regulatory T cell-mediated tolerance.Yang JM, Ren Y, Kumar A, Xiong X, Das JK, Peng HY, Wang L, Ren X, Zhang Y, Ji C, Cheng Y, Zhang L, Alaniz RC, de Figueiredo P, Fang D, Zhou H, Liu X, Wang J, Song J. Yang JM, et al. Sci Adv. 2022 Jul;8(26):eabo0183. doi: 10.1126/sciadv.abo0183. Epub 2022 Jun 29. Sci Adv. 2022. PMID: 35767626 Free PMC article.
- Precision medicine in rheumatoid arthritis.Bhamidipati K, Wei K. Bhamidipati K, et al. Best Pract Res Clin Rheumatol. 2022 Mar;36(1):101742. doi: 10.1016/j.berh.2022.101742. Epub 2022 Mar 2. Best Pract Res Clin Rheumatol. 2022. PMID: 35248489 Free PMC article. Review.
- Interactions of B-lymphocytes and bone cells in health and disease.Grčević D, Sanjay A, Lorenzo J. Grčević D, et al. Bone. 2023 Mar;168:116296. doi: 10.1016/j.bone.2021.116296. Epub 2021 Dec 21. Bone. 2023. PMID: 34942359 Review.
- Local and systemic reactogenicity of COVID-19 vaccine BNT162b2 in patients with systemic lupus erythematosus and rheumatoid arthritis.Bartels LE, Ammitzbøll C, Andersen JB, Vils SR, Mistegaard CE, Johannsen AD, Hermansen MF, Thomsen MK, Erikstrup C, Hauge EM, Troldborg A. Bartels LE, et al. Rheumatol Int. 2021 Nov;41(11):1925-1931. doi: 10.1007/s00296-021-04972-7. Epub 2021 Sep 2. Rheumatol Int. 2021. PMID: 34476603 Free PMC article.
- Clinical Trial, Phase IV
- Multicenter Study
- Randomized Controlled Trial
- Research Support, N.I.H., Extramural
- Adalimumab / pharmacology*
- Adalimumab / therapeutic use
- Adult
- Aged
- Antirheumatic Agents / pharmacology*
- Antirheumatic Agents / therapeutic use
- Arthritis, Rheumatoid / blood
- Arthritis, Rheumatoid / drug therapy
- Arthritis, Rheumatoid / immunology*
- B-Lymphocytes / drug effects*
- B-Lymphocytes / physiology*
- Etanercept / pharmacology*
- Etanercept / therapeutic use
- Female
- Humans
- Male
- Middle Aged
- Single-Blind Method
- Tumor Necrosis Factor Inhibitors / pharmacology*
- Tumor Necrosis Factor Inhibitors / therapeutic use
- Antirheumatic Agents
- Tumor Necrosis Factor Inhibitors
- Adalimumab
- Etanercept
- ClinicalTrials.gov/NCT00837434
- Full Text Sources
- Medical
- Research Materials
- Miscellaneous
![Figure 4.. RA responders have lower frequencies…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8795463/bin/nihms-1729405-f0004.jpg)
Figure 5.. Frequency of T1/T2 B cells…
Figure 5.. Frequency of T1/T2 B cells is higher in RA responders at all time…
![Figure 5.. Frequency of T1/T2 B cells…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8795463/bin/nihms-1729405-f0005.jpg)
Source: PubMed