The role of TNF - α signaling pathway in rheumatoid arthritis and the therapeutic progress of TNF-α monoclonal antibodies

Authors

  • Tianhao Fan

DOI:

https://doi.org/10.61173/364zk362

Keywords:

Rheumatoid Arthritis, Cytokine, Monoclonal Antibodies

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis and progressive joint destruction. Tumor necrosis factor - α (TNF - α) plays a central regulatory role in its inflammatory network. At present, biological agents such as TNF - α monoclonal antibodies (mAbs) have been widely used in clinical practice, significantly improving the prognosis of RA patients. But some patients have problems with poor treatment efficacy or infection. The differences and safety issues between different drugs still need further research. This article analyzes the immune imbalance mechanism of RA and the activation process of TNF - α signaling pathway, explores the mechanism of action and safety characteristics of TNF - α inhibitor drugs (adalimumab, infliximab, etanercept), and reviews the research progress of new inhibitors such as biosimilars. TNF - α inhibitors can effectively block downstream inflammatory signals and alleviate joint damage. However, there are significant differences in patients' response to treatment, and issues related to infection risk and immunogenicity limit the long-term use of drugs. This study provides a theoretical reference for investigating the mechanism of TNF - α targeted therapy for rheumatoid arthritis. At the same time, future research should focus on exploring biomarkers for predicting treatment response, optimizing individualized combination therapy, and developing new drugs for nontumor necrosis factor pathways to cover a wider range of patients.

References

[1] Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018, 4:18001.

[2] Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017, 46(2):183–196.

[3] Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016, 12(1):49–62.

[4] Mitoma H, Horiuchi T, Tsukamoto H, Ueda N. Molecular mechanisms of action of anti-TNF-α agents—comparison among therapeutic TNF-α antagonists. Cytokine. 2018, 101:56–63.

[5] Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2019 update of the American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2019, 71(1):1–25.

[6] Wu Y, et al. The role of anti-citrullinated protein antibody in pathogenesis of RA. Clin Exp Med, 2024, 24(1):153.

[7] Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. 2018, 281(1):8–27.

[8] Arend WP, Dayer JM. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 1995, 38(2):151–160.

[9] Siegmund D, et al. TNF and TNF receptors as therapeutic targets for rheumatic diseases and beyond. Nat Rev Rheumatol, 2023, 19(9):576-591.

[10] Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006, 54(1):26–37.

[11] Lipsky PE, van der Heijde DMFM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000, 343(22):1594–1602. Dean&Francis ISSN 2959-409X

[12] Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004, 363(9410):675–681.

[13] Ota R, Hirata A, et al. Incidence of serious infections in the working-age Japanese adult population with RA treated with TNF-α inhibitors and IL-6 inhibitors: A nationwide retrospective cohort study. Pharmacotherapy, 2024, 44:570-580.

[14] Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A, et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2010, 69(3):522–528.

[15] Fernandez CA. Pharmacological strategies for mitigating anti-TNF biologic immunogenicity in rheumatoid arthritis patients. Curr Opin Pharmacol, 2023, 68:102320.

[16] Rezk MF, Pieper B. Unlocking the value of anti-TNF biosimilars: reducing disease burden and improving outcomes in chronic immune-mediated inflammatory diseases. Adv Ther. 2020, 37(9):3732–3745.

[17] Smolen JS, Choe JY, Prodanovic N, Niebrzydowski J, Staykov I, Dokoupilova E, et al. Radiographic progression based on baseline characteristics from studies comparing biosimilar TNF inhibitors with reference products in rheumatoid arthritis. Arthritis Res Ther. 2020, 22:206.

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Published

2026-08-13