This study aimed to determine the correlation of disease activity of rheumatoid arthritis (RA) with Th17/regulatory T cell (Treg) and Forkhead box protein 3 (Foxp3) cells ratio in patients under therapy with anti-tumor necrosis factor (TNF)-α. Totally, 84 patients with RA and 13 healthy controls were included in this case-control study. The patients were divided into four groups to receive only methotrexate (MTX) (n=25), monotherapy (anti-TNF) (n=18), and combined therapy (MTX+anti-TNF) (n=26); however, one group received no medications (n=15) and was regarded as a positive control. Other 13 healthy controls that were considered negative controls were also enrolled in this study. Patients with RA were attending Basrah General Hospital, Rheumatology Unit, Biological Therapy Center for receiving anti-TNF therapy. Flow cytometry was used for measuring Treg/Foxp3 and Th17 markers, and the DAS-28 score was utilized to measure RA disease activity. Anti-TNF inhibitors (e.g., infliximab and etanercept), as well as other inflammatory and hematological parameters (e.g., erythrocyte sedimentation rate, total white blood cells, lymphocytes, monocytes, and neutrophil counts), were also measured in this study. DAS-28 as a disease activity score was significantly correlated with Th17/Treg/Foxp3 ratio and the Th17 cells count. Statistically, Th17/Treg/Foxp3 ratio was not correlated with body mass index, morning stiffness, and duration of the disease. Th17/Treg/Foxp3 ratio correlated significantly with DAS-28 as an RA disease activity. The lower Treg/Foxp3 frequency led to the higher DAS score reflecting higher disease activity. In the combined therapy group, disease activity was found lower than that in other patient groups indicating the effect of this combination on the relationship between MTX and anti-TNF. This study demonstrated that the main advantage of this combined therapy in RA patients was the reversion of Th17 cell expansion. |
- Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity. 2013;38(3):414-23.
- Chen DY, Chen YM, Chen HH, Hsieh CW, Lin CC, Lan JL. Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-alpha therapy. Arthritis Res Ther. 2011;13(4):R126.
- Flores-Borja F, Jury EC, Mauri C, Ehrenstein MR. Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2008;105(49):19396-401.
- Lee GR. The Balance of Th17 versus Treg Cells in Autoimmunity. Int J Mol Sci. 2018;19(3):730.
- Aravena O, Pesce B, Soto L, Orrego N, Sabugo F, Wurmann P, et al. Anti-TNF therapy in patients with rheumatoid arthritis decreases Th1 and Th17 cell populations and expands IFN-gamma-producing NK cell and regulatory T cell subsets. Immunobiology. 2011;216(12):1256-63.
- Alzabin S, Abraham SM, Taher TE, Palfreeman A, Hull D, McNamee K, et al. Incomplete response of inflammatory arthritis to TNFalpha blockade is associated with the Th17 pathway. Ann Rheum Dis. 2012;71(10):1741-8.
- Lina C, Conghua W, Nan L, Ping Z. Combined treatment of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in patients with rheumatoid arthritis. J Clin Immunol. 2011;31(4):596-605.
- Thomas SS, Borazan N, Barroso N, Duan L, Taroumian S, Kretzmann B, et al. Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis. BioDrugs. 2015;29(4):241-58.
- Atiqi S, Hooijberg F, Loeff FC, Rispens T, Wolbink GJ. Immunogenicity of TNF-Inhibitors. Front Immunol. 2020;11:312.
- Bendtzen K. Immunogenicity of Anti-TNF-α Biotherapies: II. Clinical Relevance of Methods Used for Anti-Drug Antibody Detection. Front Immunol. 2015;6(109).
- Chen J, Li J, Gao H, Wang C, Luo J, Lv Z, et al. Comprehensive evaluation of different T-helper cell subsets differentiation and function in rheumatoid arthritis. J Biomed Biotechnol. 2012;2012:535361.
- Blache C, Lequerre T, Roucheux A, Beutheu S, Dedreux I, Jacquot S, et al. Number and phenotype of rheumatoid arthritis patients' CD4+CD25hi regulatory T cells are not affected by adalimumab or etanercept. Rheumatology (Oxford). 2011;50(10):1814-22.
- Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057-61.
- Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 2007;8(3):277-84.
- Zheng SG, Wang J, Horwitz DA. Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6. J Immunol. 2008;180(11):7112-6.
- Taha HA, Hozayen WG, Okasha AM, Ahmed AE, Shata MAA, Abdel-Naem EA, et al. Investigating the Balance between Th17/Treg Cells in Rheumatoid Arthritis and its Association with Disease Activity. J Child Sci. 2019;09(01):e75-e83.
- Romano M, Fanelli G, Albany CJ, Giganti G, Lombardi G. Past, Present, and Future of Regulatory T Cell Therapy in Transplantation and Autoimmunity. Front Immunol. 2019;10:43.
- Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62-8.
- Shen H, Xia L, Lu J, Xiao W. Infliximab reduces the frequency of interleukin 17-producing cells and the amounts of interleukin 17 in patients with rheumatoid arthritis. J Investig Med. 2010;58(7):905-8.
- Daekh N, Mohammed KAS, Ali N. Polymorphism of HLA-B27 among Ankylosing Spondylitis Patients in Basrah, Iraq. Scientific Journal of Medical Research. 2020;04:12-6.
- Bodio C, Grossi C, Pregnolato F, Favalli EG, Biggioggero M, Marchesoni A, et al. Personalized medicine in rheumatoid arthritis: How immunogenicity impacts use of TNF inhibitors. Autoimmun Rev. 2020;19(5):102509.
- Levin AD, Wildenberg ME, van den Brink GR. Mechanism of Action of Anti-TNF Therapy in Inflammatory Bowel Disease. J Crohns Colitis. 2016;10(8):989-97.
- Talotta R, Berzi A, Atzeni F, Batticciotto A, Clerici M, Sarzi-Puttini P, et al. Paradoxical Expansion of Th1 and Th17 Lymphocytes in Rheumatoid Arthritis Following Infliximab Treatment: a Possible Explanation for a Lack of Clinical Response. J Clin Immunol. 2015;35(6):550-7.
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