The Impact of Pro-Inflammatory Cytokines on the Clinical Manifestations and Disease Progression of Spondyloarthritis: a Narrative Review
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Spondyloarthritis (SpA) is a group of inflammatory joint and spine diseases with various clinical manifestations. The classification and diagnosis of SpA are determined based on observations of the sacroiliac joints, hip joints, enthesitis, or the presence of human leukocyte antigen B27 (HLA-B*27). The main clinical manifestations of SpA are inflammatory pain, stiffness, and swelling of the joints and spine. Although the pathogenesis of SpA is not fully understood, genetic and environmental factors can lead to inflammation by producing pro-inflammatory cytokines such as TNF-α and the IL-23/IL-17 axis, which cause dysregulation of immune cells and stromal cells. This review aims to find out the impact of pro-inflammatory cytokines on the clinical manifestations and disease progression of Spondyloarthritis. Pro-inflammatory cytokines, such as TNF-α, IL-17, and IL-23 have an important role in the pathogenesis and progression of Spondyloarthritis. IL-17A stimulates the expression of RANKL and inhibits Wnt signaling, thereby suppressing osteoblast activity, promoting osteoclast differentiation and bone resorption in axSpA and PsA. IL-17 also trigger arthritis, spondylitis, and conjunctivitis in ReA. Increased expression of IL-17, IL-23, and TNF-α due to microbiota activity provides immune cell recruitment and mucosal injury, thus maintaining chronic inflammation in IBD. Pro-inflammatory cytokines have an impact on clinical manifestations of spondyloarthritis by stimulating an inflammatory response in the joints, leading to pain, and influencing disease progression by causing bone and joint tissue destruction. They also contribute to the formation of scar tissue around the joints, reducing mobility and causing significant stiffness in the spine
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Alvarez-Navarro, C., & de Castro, J. A. L. (2014). ERAP1 structure, function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases. Molecular Immunology, 57(1), 12–21.
Bakland, G., & Nossent, H. C. (2013). Epidemiology of spondyloarthritis: a review. Current Rheumatology Reports, 15(9), 351.
Bekaryssova, D., Yessirkepov, M., Zimba, O., Gasparyan, A. Y., & Ahmed, S. (2022). Reactive arthritis before and after the onset of the COVID-19 pandemic. Clinical Rheumatology, 41(6), 1641–1652.
Bittar, M., Yong, W. C., Magrey, M., & Khan, M. A. (2021). Worldwide differences in clinical phenotype of axial spondyloarthritis. Current Rheumatology Reports, 23(10), 76.
Bowness, P. (2015). HLA-B27. Annual Review of Immunology, 33(1), 29–48.
Coates, L. C., Kavanaugh, A., Mease, P. J., Soriano, E. R., Laura Acosta‐Felquer, M., Armstrong, A. W., Bautista‐Molano, W., Boehncke, W., Campbell, W., & Cauli, A. (2016). Group for research and assessment of psoriasis and psoriatic arthritis 2015 treatment recommendations for psoriatic arthritis. Arthritis & Rheumatology, 68(5), 1060–1071.
Croes, M., Öner, F. C., van Neerven, D., Sabir, E., Kruyt, M. C., Blokhuis, T. J., Dhert, W. J. A., & Alblas, J. (2016). Proinflammatory T cells and IL-17 stimulate osteoblast differentiation. Bone, 84, 262–270.
Cuthbert, R. J., Watad, A., Fragkakis, E. M., Dunsmuir, R., Loughenbury, P., Khan, A., Millner, P. A., Davison, A., Marzo-Ortega, H., & Newton, D. (2019). Evidence that tissue resident human enthesis γδT-cells can produce IL-17A independently of IL-23R transcript expression. Annals of the Rheumatic Diseases, 78(11), 1559–1565.
Davydova, A., Kurochkina, Y., Goncharova, V., Vorobyeva, M., & Korolev, M. (2023). The interleukine-17 cytokine family: role in development and progression of spondyloarthritis, current and potential therapeutic inhibitors. Biomedicines, 11(5), 1328.
Deodhar, A., Helliwell, P. S., Boehncke, W.-H., Kollmeier, A. P., Hsia, E. C., Subramanian, R. A., Xu, X. L., Sheng, S., Agarwal, P., & Zhou, B. (2020). Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial. The Lancet, 395(10230), 1115–1125.
Felice, C., Dal Buono, A., Gabbiadini, R., Rattazzi, M., & Armuzzi, A. (2023). Cytokines in spondyloarthritis and inflammatory bowel diseases: from pathogenesis to therapeutic implications. International Journal of Molecular Sciences, 24(4), 3957.
Furst, D. E., & Louie, J. S. (2019). Targeting inflammatory pathways in axial spondyloarthritis. Arthritis Research & Therapy, 21(1), 135.
Gill, T., Asquith, M., Brooks, S. R., Rosenbaum, J. T., & Colbert, R. A. (2018). Effects of HLA–B27 on gut microbiota in experimental spondyloarthritis implicate an ecological model of dysbiosis. Arthritis & Rheumatology, 70(4), 555–565.
Gracey, E., Dumas, E., Yerushalmi, M., Qaiyum, Z., Inman, R. D., & Elewaut, D. (2019). The ties that bind: skin, gut and spondyloarthritis. Current Opinion in Rheumatology, 31(1), 62–69.
Hreggvidsdottir, H. S., Noordenbos, T., & Baeten, D. L. (2014). Inflammatory pathways in spondyloarthritis. Molecular Immunology, 57(1), 28–37.
Jethwa, H., & Bowness, P. (2016). The interleukin (IL)-23/IL-17 axis in ankylosing spondylitis: new advances and potentials for treatment. Clinical & Experimental Immunology, 183(1), 30–36.
Karmacharya, P., Duarte‐Garcia, A., Dubreuil, M., Murad, M. H., Shahukhal, R., Shrestha, P., Myasoedova, E., Crowson, C. S., Wright, K., & Davis III, J. M. (2020). Effect of therapy on radiographic progression in axial spondyloarthritis: a systematic review and meta‐analysis. Arthritis & Rheumatology, 72(5), 733–749.
Khan, Muhammad A. (2017). An update on the genetic polymorphism of HLA-B* 27 with 213 alleles encompassing 160 subtypes (and still counting). Current Rheumatology Reports, 19(2), 9.
Khan, Muhammad Asim. (2013). Polymorphism of HLA-B27: 105 subtypes currently known. Current Rheumatology Reports, 15(10), 362.
Khan, Muhammad Asim, Yong, S., & Wei, J. C. (2023). Ankylosing spondylitis: History, epidemiology, and HLA‐B27. International Journal of Rheumatic Diseases, 26(3).
Kiwalkar, S., Beier, S., & Deodhar, A. (2019). Ixekizumab for treating ankylosing spondylitis. Immunotherapy, 11(15), 1273–1282.
Kotyla, P. J., Islam, M. A., & Engelmann, M. (2020). Clinical aspects of Janus Kinase (JAK) inhibitors in the cardiovascular system in patients with rheumatoid arthritis. International Journal of Molecular Sciences, 21(19), 7390.
Lecuyer, E., Rakotobe, S., Lengline-Garnier, H., Lebreton, C., Picard, M., Juste, C., Fritzen, R., Eberl, G., McCoy, K. D., & Macpherson, A. J. (2014). Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses. Immunity, 40(4), 608–620.
Lim, G. R. S., Ng, C. H., Kwan, Y. H., & Fong, W. (2021). Prevalence and risk factors for falls in patients with spondyloarthritis: a systematic review. International Journal of Rheumatic Diseases, 24(5), 623–632.
McAllister, K., Goodson, N., Warburton, L., & Rogers, G. (2017). Spondyloarthritis: diagnosis and management: summary of NICE guidance. Bmj, 356.
Moz, S., Aita, A., Basso, D., Ramonda, R., Plebani, M., & Punzi, L. (2017). Spondyloarthritis: matrix metalloproteinasesas biomarkers of pathogenesis and response to tumor necrosis factor (TNF) inhibitors. International Journal of Molecular Sciences, 18(4), 830.
Navarro-Compán, V., Sepriano, A., Capelusnik, D., & Baraliakos, X. (2025). Axial spondyloarthritis. The Lancet, 405(10473), 159–172.
Nisa’, N., Rahmawati, L. D., & Prastayudha, C. (2022). HLA class I and discoveries of the HLA-K (pseudogene) related to disease severity and progression in patients with spondyloarthritis in Dr. Soetomo General Hospital, a tertiary health care center in Surabaya, Indonesia. F1000Research, 11, 1011.
Noto Llana, M., Sarnacki, S. H., Morales, A. L., Aya Castaneda, M. del R., Giacomodonato, M. N., Blanco, G., & Cerquetti, M. C. (2017). Activation of iNKT cells prevents Salmonella-Enterocolitis and Salmonella-induced reactive arthritis by downregulating IL-17-producing γδT cells. Frontiers in Cellular and Infection Microbiology, 7, 398.
Robinson, P. C., & Brown, M. A. (2014). Genetics of ankylosing spondylitis. Molecular Immunology, 57(1), 2–11.
Russell, T., Watad, A., Bridgewood, C., Rowe, H., Khan, A., Rao, A., Loughenbury, P., Millner, P., Dunsmuir, R., & Cuthbert, R. (2021). IL-17A and TNF modulate normal human spinal entheseal bone and soft tissue mesenchymal stem cell osteogenesis, adipogenesis, and stromal function. Cells, 10(2), 341.
Sakalyte, R., Bagdonaite, L., Stropuviene, S., Naktinyte, S., & Venalis, A. (2022). VEGF profile in early undifferentiated arthritis cohort. Medicina, 58(6), 833.
Santos, M. P. C., Gomes, C., & Torres, J. (2017). Familial and ethnic risk in inflammatory bowel disease. Annals of Gastroenterology, 31(1), 14.
Schett, G., Lories, R. J., D’Agostino, M.-A., Elewaut, D., Kirkham, B., Soriano, E. R., & McGonagle, D. (2017). Enthesitis: from pathophysiology to treatment. Nature Reviews Rheumatology, 13(12), 731–741.
Schett, G., McInnes, I. B., & Neurath, M. F. (2021). Reframing immune-mediated inflammatory diseases through signature cytokine hubs. New England Journal of Medicine, 385(7), 628–639.
Schwartz, D. M., Bonelli, M., Gadina, M., & O’shea, J. J. (2016). Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nature Reviews Rheumatology, 12(1), 25–36.
Sharip, A., & Kunz, J. (2020). Understanding the pathogenesis of spondyloarthritis. Biomolecules, 10(10), 1461.
Shaw, A. T., & Gravallese, E. M. (2016). Mediators of inflammation and bone remodeling in rheumatic disease. Seminars in Cell & Developmental Biology, 49, 2–10.
Sieper, J., & Poddubnyy, D. (2017). Axial spondyloarthritis. The Lancet, 390(10089), 73–84.
Stolwijk, C., van Onna, M., Boonen, A., & van Tubergen, A. (2016). Global prevalence of spondyloarthritis: a systematic review and meta‐regression analysis. Arthritis Care & Research, 68(9), 1320–1331.
Taams, L. S., Steel, K. J. A., Srenathan, U., Burns, L. A., & Kirkham, B. W. (2018). IL-17 in the immunopathogenesis of spondyloarthritis. Nature Reviews Rheumatology, 14(8), 453–466.
Taurog, J. D., Chhabra, A., & Colbert, R. A. (2016). Ankylosing spondylitis and axial spondyloarthritis. New England Journal of Medicine, 374(26), 2563–2574.
Tindell, A., Johnsson, H., & McInnes, I. B. (2017). Arthritis, Arthropathy, and Osteoporosis in Inflammatory Bowel Disease. In Crohn’s Disease and Ulcerative Colitis: From Epidemiology and Immunobiology to a Rational Diagnostic and Therapeutic Approach (pp. 571–583). Springer.
Van Der Heijde, D., Ramiro, S., Landewé, R., Baraliakos, X., Van den Bosch, F., Sepriano, A., Regel, A., Ciurea, A., Dagfinrud, H., & Dougados, M. (2017). 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Annals of the Rheumatic Diseases, 76(6), 978–991.
Walsh, J. A., & Magrey, M. (2021). Clinical manifestations and diagnosis of axial spondyloarthritis. JCR: Journal of Clinical Rheumatology, 27(8), e547–e560.
Wang, R., Bathon, J. M., & Ward, M. M. (2020). Nonsteroidal antiinflammatory drugs as potential disease‐modifying medications in axial spondyloarthritis. Arthritis & Rheumatology, 72(4), 518–528.
Watad, A., Bridgewood, C., Russell, T., Marzo-Ortega, H., Cuthbert, R., & McGonagle, D. (2018). The early phases of ankylosing spondylitis: emerging insights from clinical and basic science. Frontiers in Immunology, 9, 2668.
Watad, A., Rowe, H., Russell, T., Zhou, Q., Anderson, L. K., Khan, A., Dunsmuir, R., Loughenbury, P., Borse, V., & Rao, A. (2020). Normal human enthesis harbours conventional CD4+ and CD8+ T cells with regulatory features and inducible IL-17A and TNF expression. Annals of the Rheumatic Diseases, 79(8), 1044–1054.
Weinstein, J. E., & Pepple, K. L. (2018). Cytokines in uveitis. Current Opinion in Ophthalmology, 29(3), 267–274.
Xiong, Y., Cai, M., Xu, Y., Dong, P., Chen, H., He, W., & Zhang, J. (2022). Joint together: the etiology and pathogenesis of ankylosing spondylitis. Frontiers in Immunology, 13, 996103.
Yang, X., Garner, L. I., Zvyagin, I. V, Paley, M. A., Komech, E. A., Jude, K. M., Zhao, X., Fernandes, R. A., Hassman, L. M., & Paley, G. L. (2022). Autoimmunity-associated T cell receptors recognize HLA-B* 27-bound peptides. Nature, 612(7941), 771–777.
Zhang, L., Zhang, Y.-J., Chen, J., Huang, X.-L., Fang, G.-S., Yang, L.-J., Duan, Y., & Wang, J. (2018). The association of HLA-B27 and Klebsiella pneumoniae in ankylosing spondylitis: A systematic review. Microbial Pathogenesis, 117, 49–54.
Zhu, W., He, X., Cheng, K., Zhang, L., Chen, D., Wang, X., Qiu, G., Cao, X., & Weng, X. (2019). Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Research, 7(1), 22.