Optimization of Treatment Based on JAK-STAT Signaling Pathway: Comparison of the Efficacy of Iguratimod Combined Therapy and Biological Agents in the Reconstruction of Immune Function in RA Patients
Abstract
Rheumatoid arthritis (RA) involves aberrant JAK-STAT signaling. Adalimumab suppresses inflammation but offers limited immune reconstitution.
This retrospective study compared iguratimod+adalimumab versus adalimumab monotherapy in restoring immune function in RA patients.
A total of 112 RA patients treated between March 2022 and March 2025 were included and divided into a control group (adalimumab) and a study group (iguratimod + adalimumab). Clinical data of patients were collected before and after 24 weeks of treatment, including laboratory indicators [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP); T-lymphocyte subpopulations (CD4+, CD8+, CD4+ /CD8+ ratio)]; phosphorylated signal transducer and activator of transcription 3 (P-STAT3) levels; bone metabolism indicators osteocalcin N-terminal intermediate molecule (N-MID), total type I collagen amino-terminal prolongation peptide (T-P1NP), β-cross-linked C-telopeptide of type I collagen (β‑CTX); pain assessment; American College of Rheumatology 50% improvement criteria (ACR50) response rate; Fugl-Meyer Motor Function Assessment Scale (FMAS) score of upper and lower limbs; and incidence of adverse reactions. After treatment, serum TNF-α, IL-6, CRP levels, CD8+ T lymphocytes, β‑CTX, P-STAT3 levels, and pain assessment of patients in both groups were lower than those before treatment, and the study group was significantly lower; CD4+ T lymphocytes in the 2 groups, CD4+ /CD8+ ratio, N-MID, T-P1NP, limb function score upper and lower limb FMAS score, and ACR50 response rate after treatment were markedly higher in the study group.
In conclusion, iguratimod combined with adalimumab synergistically inhibits the JAK-STAT pathway, significantly improving immune reconstitution and inflammation control in RA, with superior efficacy to adalimumab alone.
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2. Di Matteo A, Bathon JM, Emery P. Rheumatoid arthritis. Lancet. 2023;402(10416):2019-2033.
3. Doumat G, Aksamit TR, Kanj AN. Bronchiectasis: a clinical review of inflammation. Respir Med. 2025;244:108179.
4. Zou W, Fang Y, Xu D, Zhu Y. Increasing global burden of rheumatoid arthritis: an epidemiological analysis from 1990 to 2019. Arch Med Sci. 2023.
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6. Kim M, Choe YH, Lee SI. Lessons from the success and failure of targeted drugs for rheumatoid arthritis: perspectives for effective basic and translational research. Immune Netw. 2022;22(1).
7. Ren J. Advances in combination therapy for gastric cancer: integrating targeted agents and immunotherapy. Adv Clin Pharmacol Ther. 2024;1(1):1-15.
8. Xue C, Yao Q, Gu X, Shi Q, Yuan X, Chu Q, et al. Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer. Signal Transduct Target Ther. 2023;8(1).
9. Wang MJ, Zhang HL, Chen F, Guo XJ, Liu QG, Hou J. The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases. Exp Hematol Oncol. 2024;13(1).
10. MacMullan MA, Wang P, Graham NA. Phospho-proteomics reveals that RSK signaling is required for proliferation of natural killer cells stimulated with IL-2 or IL-15. Cytokine. 2022;157:155958.
11. Moosic KB, Olson TL, Freijat M, Khalique S, Hamele CE, Shemo B, et al. Activating STAT3 mutations in CD8+ T-cells correlate to serological positivity in rheumatoid arthritis. Front Immunol. 2024;15.
12. Hu L, Liu R, Zhang L. Advance in bone destruction participated by JAK/STAT in rheumatoid arthritis and therapeutic effect of JAK/STAT inhibitors. Int Immunopharmacol. 2022;111:109095.
13. Wang Y, Gao Z, Liu Z, Liu G, Qu X, Chen J, et al. A randomized, double-blind, single-dose, two-way, parallel phase I clinical study comparing the pharmacokinetics and safety of adalimumab injecta and Humira® in healthy Chinese male volunteers. Expert Opin Biol Ther. 2021;22(2):225-4.
14. Galli Sanchez AP, Aidar Fernandes TE, Martelli Palomino G. The JAK-STAT pathway and the JAK inhibitors. J Clin Res Dermatol. 2020;7(5):1-6.
15. Nozaki Y. Iguratimod: novel molecular insights and a new csDMARD for rheumatoid arthritis, from Japan to the world. Life. 2021;11(5):457.
16. Chen X, Wang W, Xue J. Efficacy and safety of iguratimod combined with celecoxib in active axial spondyloarthritis: a randomized, double-blind, placebo-controlled study. Scand J Rheumatol. 2024;53(6):420-427.
17. Hu CJ, Zhang L, Zhou S, Jiang N, Zhao JL, Wang Q, et al. Effectiveness of iguratimod as monotherapy or combined therapy in patients with rheumatoid arthritis: a systematic review and meta-analysis of RCTs. J Orthop Surg Res. 2021;16(1).
18. Kong R, Gao J, Ji L, Peng Y, Zhang J, Zhao D. Iguratimod ameliorates rheumatoid arthritis progression through regulating miR-146a mediated IRAK1 expression and TRAF6/JNK1 pathway: an in vivo and in vitro study. Clin Exp Rheumatol. 2021;39(2):289-303.
19. Fehmina Nida FN, Maria Fathima MF, Bayyasirivennela B, Haritha PH, Sandhya RS, Swathi DB. Study of effectiveness iguratimod as a monotherapy in patients with rheumatoid arthritis. Int J Pharm Res Appl. 2025;10(1):600-5.
20. Lyu T, Jiang H, Zeng L, Liu S, He C, Luo C, et al. Iguratimod suppresses Tfh cell differentiation in primary Sjögren’s syndrome patients through inhibiting Akt/mTOR/STAT3 signaling. Arthritis Res Ther. 2023;25(1):152.
21. Wen HY, Wang J, Zhang SX, Luo J, Zhao XC, Zhang C, et al. Low-dose sirolimus immunoregulation therapy in patients with active rheumatoid arthritis: a 24-week follow-up of the randomized, open-label, parallel-controlled trial. J Immunol Res. 2019;2019:7684352.
22. Hall C, Pleasance J, Hickman O, Kirkham B, Panayi GS, Eggleton P, et al. The biologic IRL201805 alters immune tolerance leading to prolonged pharmacodynamics and efficacy in rheumatoid arthritis patients. Int J Mol Sci. 2024;25(8).
23. Zhang M, Ma Z, Suguro R, Zhu M, Chen EX, Dong X, et al. Assessment of clinical analgesic levels and serum biomarkers in patients with rheumatoid arthritis: a randomized controlled trial comparing the efficacy of diclofenac and methotrexate combined therapy with extracorporeal shockwave therapy. Pain Res Manag. 2024;2024:6687987.
24. Savvides CS, James EA, Buckner JH. Rheumatoid arthritis—the role of T cells in this complex systemic autoimmune disease. Curr Opin Immunol. 2025;94:102555.
25. Hu M, Zhou Y, Yao Z, Tang Y, Zhang Y, Liao J, et al. T cell dysregulation in rheumatoid arthritis: recent advances and natural product interventions. Int Immunopharmacol. 2025;153:114499.
26. Chen X, Ghanizada M, Mallajosyula V, Sola E, Capasso R, Kathuria KR, et al. Differential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses. Nat Immunol. 2025;26(2):230-9.
27. Emori T, Kasahara M, Sugahara S, Hashimoto M, Ito H, Narumiya S, et al. Role of JAK-STAT signaling in the pathogenic behavior of fibroblast-like synoviocytes in rheumatoid arthritis: effect of the novel JAK inhibitor peficitinib. Eur J Pharmacol. 2020;882:173238.
28. Samarpita S, Rasool M. Cyanidin restores Th17/Treg balance and inhibits T follicular helper cell differentiation via modulation of ROCK2 signaling in an experimental model of rheumatoid arthritis. Int Immunopharmacol. 2021;101:108359.
29. 36. Yang XY, Wang Y, Zhang L, Pang SL, Li XJ, Wang PP, et al. SAR317461 inhibit JAK2/STAT3 phosphorylation for enhanced anti-leukemia activity. Indian J Hematol Blood Transfus. 2025.
30. Wei W, Wang J, Huang P, Gou S, Yu D, Zong L. Tumor necrosis factor-α induces proliferation and reduces apoptosis of colorectal cancer cells through STAT3 activation. Immunogenetics. 2023;75(2):161-9.
31. Yari S, Kikuta J, Shigyo H, Miyamoto Y, Okuzaki D, Furusawa Y, et al. JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors. Inflamm Regen. 2023;43(1).
32. Simon LS, Taylor PC, Choy EH, Sebba A, Quebe A, Knopp KL, et al. The Jak/STAT pathway: a focus on pain in rheumatoid arthritis. Semin Arthritis Rheum. 2021;51(1):278-84.
33. Kiełbowski K, Plewa P, Bratborska AW, Bakinowska E, Pawlik A. JAK inhibitors in rheumatoid arthritis: immunomodulatory properties and clinical efficacy. Int J Mol Sci. 2024;25(15):8327.
34. Wajid H, Rahman F, Rana ZH, Azam R, Batool S, Hashmi Z. Efficacy of JAK-JANUS kinase inhibitors as mono therapy and in combination with methotrexate in active rheumatoid arthritis. Pak Armed Forces Med J. 2024;74.
35. Sakthiswary R, Shaharir S, Wahab AA, Rajeswaran VU. Comparison of IgG4 with inflammatory cytokines (IL-1, IL-6 and TNFα) in rheumatoid arthritis. Front Immunol. 2025.
36. Meng L, Duan P, Fu M, Zhang X, Kang Y, Yan M, et al. Research on the mechanism of iguratimod in inhibiting arthritis through NF‐κB: an experimental study based on network pharmacology. J Biochem Mol Toxicol. 2025;39(6).
37. Crispino N, Ciccia F. JAK/STAT pathway and nociceptive cytokine signalling in rheumatoid arthritis and psoriatic arthritis. Clin Exp Rheumatol. 2021;39(3):668-75.
38. Baldini C, Moriconi FR, Galimberti S, Libby P, De Caterina R. The JAK–STAT pathway: an emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms. Eur Heart J. 2021;42(42):4389-400.
2. Di Matteo A, Bathon JM, Emery P. Rheumatoid arthritis. Lancet. 2023;402(10416):2019-2033.
3. Doumat G, Aksamit TR, Kanj AN. Bronchiectasis: a clinical review of inflammation. Respir Med. 2025;244:108179.
4. Zou W, Fang Y, Xu D, Zhu Y. Increasing global burden of rheumatoid arthritis: an epidemiological analysis from 1990 to 2019. Arch Med Sci. 2023.
5. Wu D, Luo Y, Li T, Zhao X, Lv T, Fang G, et al. Systemic complications of rheumatoid arthritis: focus on pathogenesis and treatment. Front Immunol. 2022;13.
6. Kim M, Choe YH, Lee SI. Lessons from the success and failure of targeted drugs for rheumatoid arthritis: perspectives for effective basic and translational research. Immune Netw. 2022;22(1).
7. Ren J. Advances in combination therapy for gastric cancer: integrating targeted agents and immunotherapy. Adv Clin Pharmacol Ther. 2024;1(1):1-15.
8. Xue C, Yao Q, Gu X, Shi Q, Yuan X, Chu Q, et al. Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer. Signal Transduct Target Ther. 2023;8(1).
9. Wang MJ, Zhang HL, Chen F, Guo XJ, Liu QG, Hou J. The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases. Exp Hematol Oncol. 2024;13(1).
10. MacMullan MA, Wang P, Graham NA. Phospho-proteomics reveals that RSK signaling is required for proliferation of natural killer cells stimulated with IL-2 or IL-15. Cytokine. 2022;157:155958.
11. Moosic KB, Olson TL, Freijat M, Khalique S, Hamele CE, Shemo B, et al. Activating STAT3 mutations in CD8+ T-cells correlate to serological positivity in rheumatoid arthritis. Front Immunol. 2024;15.
12. Hu L, Liu R, Zhang L. Advance in bone destruction participated by JAK/STAT in rheumatoid arthritis and therapeutic effect of JAK/STAT inhibitors. Int Immunopharmacol. 2022;111:109095.
13. Wang Y, Gao Z, Liu Z, Liu G, Qu X, Chen J, et al. A randomized, double-blind, single-dose, two-way, parallel phase I clinical study comparing the pharmacokinetics and safety of adalimumab injecta and Humira® in healthy Chinese male volunteers. Expert Opin Biol Ther. 2021;22(2):225-4.
14. Galli Sanchez AP, Aidar Fernandes TE, Martelli Palomino G. The JAK-STAT pathway and the JAK inhibitors. J Clin Res Dermatol. 2020;7(5):1-6.
15. Nozaki Y. Iguratimod: novel molecular insights and a new csDMARD for rheumatoid arthritis, from Japan to the world. Life. 2021;11(5):457.
16. Chen X, Wang W, Xue J. Efficacy and safety of iguratimod combined with celecoxib in active axial spondyloarthritis: a randomized, double-blind, placebo-controlled study. Scand J Rheumatol. 2024;53(6):420-427.
17. Hu CJ, Zhang L, Zhou S, Jiang N, Zhao JL, Wang Q, et al. Effectiveness of iguratimod as monotherapy or combined therapy in patients with rheumatoid arthritis: a systematic review and meta-analysis of RCTs. J Orthop Surg Res. 2021;16(1).
18. Kong R, Gao J, Ji L, Peng Y, Zhang J, Zhao D. Iguratimod ameliorates rheumatoid arthritis progression through regulating miR-146a mediated IRAK1 expression and TRAF6/JNK1 pathway: an in vivo and in vitro study. Clin Exp Rheumatol. 2021;39(2):289-303.
19. Fehmina Nida FN, Maria Fathima MF, Bayyasirivennela B, Haritha PH, Sandhya RS, Swathi DB. Study of effectiveness iguratimod as a monotherapy in patients with rheumatoid arthritis. Int J Pharm Res Appl. 2025;10(1):600-5.
20. Lyu T, Jiang H, Zeng L, Liu S, He C, Luo C, et al. Iguratimod suppresses Tfh cell differentiation in primary Sjögren’s syndrome patients through inhibiting Akt/mTOR/STAT3 signaling. Arthritis Res Ther. 2023;25(1):152.
21. Wen HY, Wang J, Zhang SX, Luo J, Zhao XC, Zhang C, et al. Low-dose sirolimus immunoregulation therapy in patients with active rheumatoid arthritis: a 24-week follow-up of the randomized, open-label, parallel-controlled trial. J Immunol Res. 2019;2019:7684352.
22. Hall C, Pleasance J, Hickman O, Kirkham B, Panayi GS, Eggleton P, et al. The biologic IRL201805 alters immune tolerance leading to prolonged pharmacodynamics and efficacy in rheumatoid arthritis patients. Int J Mol Sci. 2024;25(8).
23. Zhang M, Ma Z, Suguro R, Zhu M, Chen EX, Dong X, et al. Assessment of clinical analgesic levels and serum biomarkers in patients with rheumatoid arthritis: a randomized controlled trial comparing the efficacy of diclofenac and methotrexate combined therapy with extracorporeal shockwave therapy. Pain Res Manag. 2024;2024:6687987.
24. Savvides CS, James EA, Buckner JH. Rheumatoid arthritis—the role of T cells in this complex systemic autoimmune disease. Curr Opin Immunol. 2025;94:102555.
25. Hu M, Zhou Y, Yao Z, Tang Y, Zhang Y, Liao J, et al. T cell dysregulation in rheumatoid arthritis: recent advances and natural product interventions. Int Immunopharmacol. 2025;153:114499.
26. Chen X, Ghanizada M, Mallajosyula V, Sola E, Capasso R, Kathuria KR, et al. Differential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses. Nat Immunol. 2025;26(2):230-9.
27. Emori T, Kasahara M, Sugahara S, Hashimoto M, Ito H, Narumiya S, et al. Role of JAK-STAT signaling in the pathogenic behavior of fibroblast-like synoviocytes in rheumatoid arthritis: effect of the novel JAK inhibitor peficitinib. Eur J Pharmacol. 2020;882:173238.
28. Samarpita S, Rasool M. Cyanidin restores Th17/Treg balance and inhibits T follicular helper cell differentiation via modulation of ROCK2 signaling in an experimental model of rheumatoid arthritis. Int Immunopharmacol. 2021;101:108359.
29. 36. Yang XY, Wang Y, Zhang L, Pang SL, Li XJ, Wang PP, et al. SAR317461 inhibit JAK2/STAT3 phosphorylation for enhanced anti-leukemia activity. Indian J Hematol Blood Transfus. 2025.
30. Wei W, Wang J, Huang P, Gou S, Yu D, Zong L. Tumor necrosis factor-α induces proliferation and reduces apoptosis of colorectal cancer cells through STAT3 activation. Immunogenetics. 2023;75(2):161-9.
31. Yari S, Kikuta J, Shigyo H, Miyamoto Y, Okuzaki D, Furusawa Y, et al. JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors. Inflamm Regen. 2023;43(1).
32. Simon LS, Taylor PC, Choy EH, Sebba A, Quebe A, Knopp KL, et al. The Jak/STAT pathway: a focus on pain in rheumatoid arthritis. Semin Arthritis Rheum. 2021;51(1):278-84.
33. Kiełbowski K, Plewa P, Bratborska AW, Bakinowska E, Pawlik A. JAK inhibitors in rheumatoid arthritis: immunomodulatory properties and clinical efficacy. Int J Mol Sci. 2024;25(15):8327.
34. Wajid H, Rahman F, Rana ZH, Azam R, Batool S, Hashmi Z. Efficacy of JAK-JANUS kinase inhibitors as mono therapy and in combination with methotrexate in active rheumatoid arthritis. Pak Armed Forces Med J. 2024;74.
35. Sakthiswary R, Shaharir S, Wahab AA, Rajeswaran VU. Comparison of IgG4 with inflammatory cytokines (IL-1, IL-6 and TNFα) in rheumatoid arthritis. Front Immunol. 2025.
36. Meng L, Duan P, Fu M, Zhang X, Kang Y, Yan M, et al. Research on the mechanism of iguratimod in inhibiting arthritis through NF‐κB: an experimental study based on network pharmacology. J Biochem Mol Toxicol. 2025;39(6).
37. Crispino N, Ciccia F. JAK/STAT pathway and nociceptive cytokine signalling in rheumatoid arthritis and psoriatic arthritis. Clin Exp Rheumatol. 2021;39(3):668-75.
38. Baldini C, Moriconi FR, Galimberti S, Libby P, De Caterina R. The JAK–STAT pathway: an emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms. Eur Heart J. 2021;42(42):4389-400.
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How to Cite
1.
Zhang L, Shen H. Optimization of Treatment Based on JAK-STAT Signaling Pathway: Comparison of the Efficacy of Iguratimod Combined Therapy and Biological Agents in the Reconstruction of Immune Function in RA Patients. Iran J Allergy Asthma Immunol. 2026;:1-15.
