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Syndesmophyte Growth in Ankylosing Spondylitis: from Laboratory to Bedside

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Abstract

Purpose of Review

This study aims to review recent studies on risk factors for syndesmophyte growth in ankylosing spondylitis (AS) and on treatment effects.

Recent Findings

New genetic studies, including a genome-wide association study, provided only limited evidence of specific genetic associations with radiographic severity. Measures of inflammation, including vertebral osteitis and C-reactive protein level, were strongly associated with radiographic progression, while studies of adipokines had mixed results. Mesenchymal stem cells from HLA-B27 positive AS patients were found to promote vertebral ossification via a pathway of B27 misfolding, retinoic acid receptor-β activation, and increased bone alkaline phosphatase. Low vertebral trabecular bone density is associated with syndesmophyte growth, with reciprocal effects when bridged. Several observational studies suggested radiographic severity was reduced by treatment with tumor necrosis factor inhibitors, particularly when longer than 2 years.

Summary

Syndesmophyte development in AS is the result of a complex, incompletely understood, interplay of inflammatory and mechanical factors.

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References

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  1. Jang JH, Ward MM, Rucker AN, Reveille JD, Davis JC Jr, Weisman MH, et al. Ankylosing spondylitis: patterns of radiographic involvement–a re-examination of accepted principles in a cohort of 769 patients. Radiology. 2011;258(1):192–8. https://doi.org/10.1148/radiol.10100426.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Tan S, Yao L, Ward MM. Thoracic syndesmophytes commonly occur in the absence of lumbar syndesmophytes in ankylosing spondylitis: a computed tomography study. J Rheumatol. 2017;44(12):1828–32. https://doi.org/10.3899/jrheum.170340.

    Article  CAS  PubMed  Google Scholar 

  3. Wanders AJ, Landewé RB, Spoorenberg A, Dougados M, van der Linden S, Mielants H, et al. What is the most appropriate radiologic scoring method for ankylosing spondylitis? A comparison of the available methods based on the Outcome Measures in Rheumatology Clinical Trials filter. Arthritis Rheum. 2004;50(8):2622–32. https://doi.org/10.1002/art.20446.

    Article  PubMed  Google Scholar 

  4. Poddubnyy D, Sieper J. Radiographic progression in ankylosing spondylitis/axial spondyloarthritis: how fast and how clinically meaningful? Curr Opin Rheumatol. 2012;24(4):363–9. https://doi.org/10.1097/BOR.0b013e328352b7bd.

    Article  PubMed  Google Scholar 

  5. Wang R, Bathon JM, Ward MM. Nonsteroidal antiinflammatory drugs as potential disease-modifying medications in axial spondyloarthritis. Arthritis Rheumatol. 2020;72(4):518–28. https://doi.org/10.1002/art.41164.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Cortes A, Maksymowych WP, Wordsworth BP, Inman RD, Danoy P, Rahman P, et al. Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis. Ann Rheum Dis. 2015;74(7):1387–93. https://doi.org/10.1136/annrheumdis-2013-204835.

    Article  CAS  PubMed  Google Scholar 

  7. Coates LC, Baraliakos X, Blanco FJ, Blanco-Morales EA, Braun J, Chandran V, et al. The phenotype of axial spondyloarthritis: is it dependent on HLA-B27 status? Arthritis Care Res. 2021;73(6):856–60. https://doi.org/10.1002/acr.24174.

    Article  CAS  Google Scholar 

  8. Zhou X, Wang J, Zou H, Ward MM, Weisman MH, Espitia MG, et al. MICA, a gene contributing strong susceptibility to ankylosing spondylitis. Ann Rheum Dis. 2014;73(8):1552–7. https://doi.org/10.1136/annrheumdis-2013-203352.

    Article  CAS  PubMed  Google Scholar 

  9. Wang CM, Tan KP, Jan Wu YJ, Lin JC, Zheng JW, Yu AL, et al. MICA*019 allele and soluble MICA as biomarkers for ankylosing spondylitis in Taiwanese. J Pers Med. 2021;11(6):564. https://doi.org/10.3390/jpm11060564.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wang CM, Jan Wu YJ, Lin JC, Huang LY, Wu J, Chen JY. Genetic effects of B3GNT2 on ankylosing spondylitis susceptibility and clinical manifestations in Taiwanese. J Formos Med Assoc. 2022;121(7):1283–94. https://doi.org/10.1016/j.jfma.2021.09.010.

    Article  CAS  PubMed  Google Scholar 

  11. Wang CM, Tsai SC, Lin JC, Wu YJ, Wu J, Chen JY. Association of genetic variants of RANK, RANKL, and OPG with ankylosing spondylitis clinical features in Taiwanese. Mediators Inflamm. 2019;2019:8029863. https://doi.org/10.1155/2019/8029863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hoppe B, Schwedler C, Haibel H, Verba M, Proft F, Protopopov M, et al. Predictive value of C-reactive protein for radiographic spinal progression in axial spondyloarthritis in dependence on genetic determinants of fibrin clot formation and fibrinolysis. RMD Open. 2021;7(2):e001751. https://doi.org/10.1136/rmdopen-2021-001751.

    Article  PubMed  PubMed Central  Google Scholar 

  13. • Nam B, Jo S, Bang SY, Park Y, Shin JH, Park YS, et al. Clinical and genetic factors associated with radiographic damage in patients with ankylosing spondylitis. Ann Rheum Dis. 2022;82(4):527–32. This article reports a genome-wide association study of markers of spine damage.

  14. Machado PM, Baraliakos X, van der Heijde D, Braun J, Landewé R. MRI vertebral corner inflammation followed by fat deposition is the strongest contributor to the development of new bone at the same vertebral corner: a multilevel longitudinal analysis in patients with ankylosing spondylitis. Ann Rheum Dis. 2016;75(8):1486–93. https://doi.org/10.1136/annrheumdis-2015-208011.

    Article  PubMed  Google Scholar 

  15. • Stal R, Baraliakos X, van der Heijde D, van Gaalen F, Ramiro S, van den Berg R, et al. Role of vertebral corner inflammation and fat deposition on MRI on syndesmophyte development detected on whole spine low-dose CT scan in radiographic axial spondyloarthritis. RMD Open. 2022;8(2):e002250. https://doi.org/10.1136/rmdopen-2022-002250. Vertebral inflammation predicts new syndesmophytes at the same location.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kang KY, Jung JY, Lee SK, Min HK, Hong YS, Park SH, et al. Trabecular bone score value is associated with new bone formation independently of fat metaplasia on spinal magnetic resonance imaging in patients with ankylosing spondylitis. Scand J Rheumatol. 2020;49(4):292–300. https://doi.org/10.1080/03009742.2019.1704053.

    Article  CAS  PubMed  Google Scholar 

  17. Kim JG, Jung JY, Lee J, Kwok SK, Ju JH, Park SH, et al. Can whole spine magnetic resonance imaging predict radiographic progression and inflammatory activity in axial spondyloarthritis? Joint Bone Spine. 2022;89(4):105352. https://doi.org/10.1016/j.jbspin.2022.105352.

    Article  PubMed  Google Scholar 

  18. San Koo B, Oh JS, Park SY, Shin JH, Nam B, Lee S, et al. Relationship between inflammation and radiographic progression in patients with ankylosing spondylitis attaining a BASDAI of less than 4 during tumor necrosis factor inhibitor treatment. J Rheumatol. 2022;49(12):1328–34. https://doi.org/10.3899/jrheum.220157.

    Article  CAS  Google Scholar 

  19. Lee TH, Koo BS, Nam B, Kim YJ, Son D, Lee S, et al. Age-stratified trends in the progression of spinal radiographic damage in patients with ankylosing spondylitis: a longitudinal study. Ther Adv Musculoskelet Dis. 2022;14:1759720X221100301. https://doi.org/10.1177/1759720X221100301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Konsta M, Sakellariou GT, Rusman T, Sfikakis PP, Iliopoulos A, van der Horst-Bruinsma IE. Long-term effect of TNF inhibitors on radiographic progression in ankylosing spondylitis is associated with time-averaged CRP levels. Joint Bone Spine. 2021;88(3):105111. https://doi.org/10.1016/j.jbspin.2020.105111.

    Article  CAS  PubMed  Google Scholar 

  21. Rademacher J, Tietz LM, Le L, Hartl A, Hermann KG, Sieper J, et al. Added value of biomarkers compared with clinical parameters for the prediction of radiographic spinal progression in axial spondyloarthritis. Rheumatology (Oxford). 2019;58(9):1556–64. https://doi.org/10.1093/rheumatology/kez025.

    Article  CAS  PubMed  Google Scholar 

  22. Rademacher J, Siderius M, Gellert L, Wink FR, Verba M, Maas F, et al. Baseline serum biomarkers of inflammation, bone turnover and adipokines predict spinal radiographic progression in ankylosing spondylitis patients on TNF inhibitor therapy. Semin Arthritis Rheum. 2022;53:151974. https://doi.org/10.1016/j.semarthrit.2022.151974.

    Article  CAS  PubMed  Google Scholar 

  23. Deminger A, Klingberg E, Nurkkala M, Geijer M, Carlsten H, Jacobsson LT, et al. Elevated serum level of hepatocyte growth factor predicts development of new syndesmophytes in men with ankylosing spondylitis. Rheumatology (Oxford). 2021;60(4):1804–13. https://doi.org/10.1093/rheumatology/keaa460.

    Article  CAS  PubMed  Google Scholar 

  24. Tsui FW, Lin A, Sari I, Zhang Z, Pritzker KP, Tsui HW, et al. The role of LCN2 and LCN2-MMP9 in spondylitis radiographic development: gender and HLA-B27 status differences. Arthritis Res Ther. 2022;24(1):164. https://doi.org/10.1186/s13075-022-02854-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jo S, Lee EJ, Nam B, Kang J, Lee S, Youn J, et al. Effects of dihydrotestosterone on osteoblast activity in curdlan-administered SKG mice and osteoprogenitor cells in patients with ankylosing spondylitis. Arthritis Res Ther. 2020;22(1):121. https://doi.org/10.1186/s13075-020-02217-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Min HK, Lee J, Ju JH, Park SH, Kwok SK. Alcohol consumption as a predictor of the progression of spinal structural damage in axial spondyloarthritis: data from the Catholic Axial Spondyloarthritis COhort (CASCO). Arthritis Res Ther. 2019;21(1):187. https://doi.org/10.1186/s13075-019-1970-3.

    Article  PubMed  PubMed Central  Google Scholar 

  27. • Liu CH, Raj S, Chen CH, Hung KH, Chou CT, Chen IH, et al. HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis. J Clin Invest. 2019;129(12):5357–73. https://doi.org/10.1172/JCI125212. This study describes a novel pathway linking B27 with syndesmophyte development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ward MM, Reveille JD, Learch TJ, Davis JC Jr, Weisman MH. Occupational physical activities and long-term functional and radiographic outcomes in patients with ankylosing spondylitis. Arthritis Rheum. 2008;59(6):822–32. https://doi.org/10.1002/art.23704.

    Article  PubMed  PubMed Central  Google Scholar 

  29. • Tan S, Bagheri H, Lee D, Shafiei A, Keaveny TM, Yao L, et al. Vertebral bone mineral density, vertebral strength, and syndesmophyte growth in ankylosing spondylitis: the importance of bridging. Arthritis Rheumatol. 2022;74(8):1352–62. https://doi.org/10.1002/art.42120. This study identifies bridging as a major predictor of low vertebral bone density.

    Article  CAS  PubMed  Google Scholar 

  30. Lee SY, Song R, Yang HI, Chung SW, Lee YA, Hong SJ, et al. The bone bridge significantly affects the decrease in bone mineral density measured with quantitative computed tomography in ankylosing spondylitis. PLoS One. 2021;16(4):e0249578. https://doi.org/10.1371/journal.pone.0249578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fauny M, Morizot C, Allado E, Verhoeven F, Albuisson E, Semaan M, et al. Consequences of spinal ankylosis on bone trabecular fragility assessed on CT scans in patients with ankylosing spondylitis. A retrospective study. Joint Bone Spine. 2020;87(6):625–31. https://doi.org/10.1016/j.jbspin.2020.05.009.

    Article  PubMed  Google Scholar 

  32. Jung JY, Kim MY, Hong YS, Park SH, Kang KY. Trabecular bone loss contributes to radiographic spinal progression in patients with axial spondyloarthritis. Semin Arthritis Rheum. 2020;50(5):827–33. https://doi.org/10.1016/j.semarthrit.2020.07.009.

    Article  PubMed  Google Scholar 

  33. Kim JW, Chung MK, Lee J, Kwok SK, Kim WU, Park SH, et al. Low bone mineral density of vertebral lateral projections can predict spinal radiographic damage in patients with ankylosing spondylitis. Clin Rheumatol. 2019;38(12):3567–74. https://doi.org/10.1007/s10067-019-04743-7.

    Article  PubMed  Google Scholar 

  34. Marques ML, Ramiro S, Machado PM, van der Heijde D, van Gaalen FA. No relationship between bone mineral density and syndesmophyte formation at the same level in the lumbar spine of patients with radiographic axial spondyloarthritis. RMD Open. 2020;6(3):e001391. https://doi.org/10.1136/rmdopen-2020-001391.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Chen CH, Chen HA, Liu CH, Liao HT, Chou CT, Chen CH. Association of obesity with inflammation, disease severity and cardiovascular risk factors among patients with ankylosing spondylitis. Int J Rheum Dis. 2020;23(9):1165–74. https://doi.org/10.1111/1756-185X.13912.

    Article  CAS  PubMed  Google Scholar 

  36. Atagündüz P, Kiraz S, Akar S, Küçükşahin O, Erden A, Aksoy A, et al. Clinical and laboratory factors associated with the bamboo spine in patients with axial spondyloarthritis: are there clues for the bamboo spine? Clin Exp Rheumatol. 2022. https://doi.org/10.55563/clinexprheumatol/eb1zpo.

    Article  PubMed  Google Scholar 

  37. Kong W, Jefferies C, Learch TJ, Gan X, Zhu F, Zhang N, et al. Risk factors for spinal structural damage in a Chinese cohort with ankylosing spondylitis. J Clin Rheumatol. 2022;28(1):e118–24. https://doi.org/10.1097/RHU.0000000000001658.

    Article  PubMed  Google Scholar 

  38. Wang CM, Hong WH, Ho HH, Chen JY, Tsai YL, Pei YC. Features of trunk muscle weakness in patients with ankylosing spondylitis: a cross-sectional study. Biomed J. 2019;42(2):124–30. https://doi.org/10.1016/j.bj.2019.01.001.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Stal R, Sepriano A, van Gaalen FA, Baraliakos X, van den Berg R, Reijnierse M, et al. Associations between syndesmophytes and facet joint ankylosis in radiographic axial spondyloarthritis patients on low-dose CT over 2 years. Rheumatology (Oxford). 2022;61(12):4722–30. https://doi.org/10.1093/rheumatology/keac176.

    Article  PubMed  Google Scholar 

  40. •• Chen S, Li Z, Chen D, Cui H, Wang J, Li Z, et al. Piezo1-mediated mechanotransduction promotes entheseal pathological new bone formation in ankylosing spondylitis. Ann Rheum Dis. 2023;82(4):533–45. This study identifies a molecular mediator for mechanical stress in enthesitis.

  41. Press release: The Nobel Prize in Physiology or Medicine 2021. Accessed March 7, 2023.

  42. Torgutalp M, Rios Rodriguez V, Dilbaryan A, Proft F, Protopopov M, Verba M, et al. Treatment with tumour necrosis factor inhibitors is associated with a time-shifted retardation of radiographic spinal progression in patients with axial spondyloarthritis. Ann Rheum Dis. 2022;81(9):1252–9. https://doi.org/10.1136/annrheumdis-2022-222324.

    Article  PubMed  Google Scholar 

  43. Sepriano A, Ramiro S, Wichuk S, Chiowchanwisawakit P, Paschke J, van der Heijde D, et al. Tumor necrosis factor inhibitors reduce spinal radiographic progression in patients with radiographic axial spondyloarthritis: a longitudinal analysis from the Alberta prospective cohort. Arthritis Rheumatol. 2021;73(7):1211–9. https://doi.org/10.1002/art.41667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sari I, Lee S, Tomlinson G, Johnson SR, Inman RD, Haroon N. Factors predictive of radiographic progression in ankylosing spondylitis. Arthritis Care Res. 2021;73(2):275–81. https://doi.org/10.1002/acr.24104.

    Article  CAS  Google Scholar 

  45. Pedersen SJ, Weber U, Said-Nahal R, Sørensen IJ, Loft AG, Kollerup G, et al. Structural progression rate decreases over time on serial radiography and magnetic resonance imaging of sacroiliac joints and spine in a five-year follow-up study of patients with ankylosing spondylitis treated with tumour necrosis factor inhibitor. Scand J Rheumatol. 2019;48(3):185–97. https://doi.org/10.1080/03009742.2018.1506822.

    Article  CAS  PubMed  Google Scholar 

  46. Koo BS, Oh JS, Park SY, Shin JH, Ahn GY, Lee S, et al. Tumour necrosis factor inhibitors slow radiographic progression in patients with ankylosing spondylitis: 18-year real-world evidence. Ann Rheum Dis. 2020;79(10):1327–32. https://doi.org/10.1136/annrheumdis-2019-216741.

    Article  CAS  PubMed  Google Scholar 

  47. Park JW, Kim MJ, Lee JS, Ha YJ, Park JK, Kang EH, et al. Impact of tumor necrosis factor inhibitor versus nonsteroidal antiinflammatory drug treatment on radiographic progression in early ankylosing spondylitis: its relationship to inflammation control during treatment. Arthritis Rheumatol. 2019;71(1):82–90. https://doi.org/10.1002/art.40661.

    Article  CAS  PubMed  Google Scholar 

  48. Llop M, Moreno M, Navarro-Compán V, Juanola X, de Miguel E, Almodóvar R, et al. Sustained low disease activity measured by ASDAS slow radiographic spinal progression in axial spondyloarthritis patients treated with TNF-inhibitors: data from REGISPONSERBIO. Arthritis Res Ther. 2022;24(1):30. https://doi.org/10.1186/s13075-021-02695-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Braun J, Baraliakos X, Deodhar A, Poddubnyy D, Emery P, Delicha EM, et al. Secukinumab shows sustained efficacy and low structural progression in ankylosing spondylitis: 4-year results from the MEASURE 1 study. Rheumatology (Oxford). 2019;58(5):859–68. https://doi.org/10.1093/rheumatology/key375.

    Article  CAS  PubMed  Google Scholar 

  50. van der Heijde D, Østergaard M, Reveille JD, Baraliakos X, Kronbergs A, Sandoval DM, et al. Spinal radiographic progression and predictors of progression in patients with radiographic axial spondyloarthritis receiving ixekizumab over 2 years. J Rheumatol. 2022;49(3):265–73. https://doi.org/10.3899/jrheum.210471.

    Article  CAS  PubMed  Google Scholar 

  51. Braun J, Haibel H, de Hooge M, Landewé R, Rudwaleit M, Fox T, et al. Spinal radiographic progression over 2 years in ankylosing spondylitis patients treated with secukinumab: a historical cohort comparison. Arthritis Res Ther. 2019;21(1):142. https://doi.org/10.1186/s13075-019-1911-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tan S, Yao J, Flynn JA, Yao L, Ward MM. Quantitative syndesmophyte measurement in ankylosing spondylitis using CT: longitudinal validity and sensitivity to change over 2 years. Ann Rheum Dis. 2015;74(2):437–43. https://doi.org/10.1136/annrheumdis-2013-203946.

    Article  PubMed  Google Scholar 

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Correspondence to Michael M. Ward.

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This work was supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases. Neither author has any conflicts of interest related to this work.

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All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki Declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines.

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Ward, M.M., Tan, S. Syndesmophyte Growth in Ankylosing Spondylitis: from Laboratory to Bedside. Curr Rheumatol Rep 25, 119–127 (2023). https://doi.org/10.1007/s11926-023-01104-x

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