Advanced axial spondyloarthritis: delayed diagnosis and identiftcation of potential predictors of disease progression

This review summarizes literature data on advanced axial spondyloarthritis (axSpA). In addition to the characteristic radiological manifestations, patients with advanced axSpA are characterized by sagittal imbalance and contracture-related deformities of the spine, which can potentially lead to disability, loss of working capacity and a decrease in the quality of life. Delayed diagnosis remains one of the reasons for advanced stage development. Despite the introduction of the ASAS criteria in 2009, diagnosis is delayed for several years worldwide. In this regard, attempts are being made to identify factors for delayed diagnosis, for example, female gender, young age of the disease onset, HLA-B27 negativity, presence of psoriasis, uveitis, etc., but there is still no unequivocal opinion on this issue. It is important to note that the subject of discussion is early diagnosis and early treatment; well-designed long-term studies are required to prove their positive impact on patients with axSpA. Based on the data on the importance of preserving working capacity and functional status in people of working and childbearing age suffering from axSpA, there is a question about the advisability of studying predictors of the formation of the advanced stage of the disease and, consequently, unfavorable functional outcomes. According to the literature, the most suitable candidates would be sclerostin, Dickkopf-1 (Dkk-1) and visfatin. The development of parameters associated with the possibility of using potential markers is required to formulate tactics for the management of patients with progression of spondyloarthritis into a disabling condition.

1. Khan M.A. Update on spondyloarthropathies. Ann. Intern. Med. 2002;136(12):896-907. DOI: 10.7326/0003-4819-136-12-200206180-00011.

2. Rudwaleit M., van der Heijde D., Landewé R. et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann. Rheum. Dis. 2009;68(6):777-783. DOI: 10.1136/ard.2009.108233.

3. Rudwaleit M., van der Heijde D., Landewé R. et al. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann. Rheum. Dis. 2011;70(1):25-31. DOI: 10.1136/ard.2010.133645.

4. Shostak N.A., Pravdyuk N.G. Spondyloarthritis: aspects of pathogenesis and diagnostics. Clinician. 2019;13(3-4):10-14. DOI: 10.17650/1818-8338-2019-13-3-4-10-14. (In Russ.)

5. Rudwaleit M. New approaches to diagnosis and classification of axial and peripheral spondyloarthritis. Curr. Opin. Rheumatol. 2010;22(4):375-380. DOI: 10.1097/BOR.0b013e32833ac5cc.

6. Clunie G., Horwood N. Loss and gain of bone in spondyloarthritis: what drives these opposing clinical features? Ther. Adv. Musculoskelet. Dis. 2020;12:1759720X20969260. DOI: 10.1177/1759720x20969260.

7. Stolwijk C., Boonen A., van Tubergen A., Reveille J.D. Epidemiology of spondyloarthritis. Rheum. Dis. Clin. North Am. 2012;38(3):441-476. DOI: 10.1016/j.rdc.2012.09.003.

8. Ramiro S., van der Heijde D., van Tubergen A. et al. Higher disease activity leads to more structural damage in the spine in ankylosing spondylitis: 12-YEAR longitudinal data from the OASIS cohort. Ann. Rheum. Dis. 2014;73(8):1455-1461. DOI: 10.1136/annrheumdis-2014-205178.

9. Strand V., Rao A.C., Shillington A.C. et al. Prevalence of axial spondyloarthritis in United States rheumatology practices: Assessment of SpondyloArthritis International Society criteria versus rheumatology expert clinical diagnosis. Arthritis Care Res. (Hoboken). 2013;65(8):1299-1306. DOI: 10.1002/acr.21994.

10. Costantino F., Talpin A., Said-Nahal R. et al. Prevalence of spondyloarthritis in reference to HLA-B27 in the French population: Results of the GAZEL cohort. Ann. Rheum. Dis. 2015;74(4):689-693. DOI: 10.1136/annrheumdis-2013-204436.

11. Bakland G., Alsing R., Singh K. et al. Assessment of SpondyloArthritis International Society criteria for axial spondyloarthritis in chronic back pain patients with a high prevalence of HLA-B27. Arthritis Care Res. (Hoboken). 2013;65(3):448-453. DOI: 10.1002/acr.21804.

12. Lila A.M., Dubinina T.V., Dreval R.O. et al. Medical and social significance and calculation of the economic burden of axial spondyloarthritis in the Russian Federation. Modern Rheumatology Journal. 2022;16(1):20-25. DOI: 10.14412/1996-7012-2022-1-20-25. (In Russ.)

13. Mease P., Deodhar A. Differentiating nonradiographic axial spondyloarthritis from its mimics: a narrative review. BMC Musculoskelet. Disord. 2022;23(1):240. DOI: 10.1186/s12891-022-05073-7.

14. Alexander M. (2023). Ankylosing spondylitis pathogenesis and pathophysiology. In Armas J.G. (ed.) Ankylosing spondylitis – Recent Concepts. DOI: 10.5772/intechopen.109164.

15. Sieper J., Rudwaleit M., Baraliakos X. et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann. Rheum. Dis. 2009;68 Suppl 2:II1-II44. DOI: 10.1136/ard.2008.104018.

16. Ankylosing spondylitis. Clinical recommendations /Association of Rheumatologists of Russia. 2018. URL: https://library.mededtech.ru/rest/documents/cr_175/ (accessed 03.06.2024).

17. Braun J., Sieper J. Ankylosing spondylitis. Lancet. 2007;369(9570):1379-1390. DOI: 10.1016/S0140-6736(07)60635-7.

18. Hu W., Yu J., Liu H. et al. Y shape osteotomy in ankylosing spondylitis, a prospective case series with minimum 2 year follow-up. PLoS One. 2016;11(12):E0167792. DOI: 10.1371/journal.pone.0167792.

19. Chang K.W., Chen Y.Y., Lin C.C. et al. Closing wedge osteotomy versus opening wedge osteotomy in ankylosing spondylitis with thoracolumbar kyphotic deformity. Spine (Phila Pa 1976). 2005;30(14):1584-1593. DOI: 10.1097/01.brs.0000170300.17082.49.

20. Shin J.K., Lee J.S., Goh T.S., Son S.M. Correlation between clinical outcome and spinopelvic parameters in ankylosing spondylitis. Eur. Spine J. 2014;23(1):242-247. DOI: 10.1007/s00586-013-2929-8.

21. Klassen A.F., Miller A., Fine S. Health-related quality of life in children and adolescents who have a diagnosis of attention-deficit/hyperactivity disorder. Pediatrics. 2004;114(5):E541-E547. DOI: 10.1542/peds.2004-0844.

22. Nikiphorou E., Ramiro S. Work disability in axial spondyloarthritis. Curr. Rheumatol. Rep. 2020;22(9):55. DOI: 10.1007/s11926-020-00932-5.

23. Volnukhin E.V., Galushko E.A., Bochkova A.G. et al. Clinical diversity of ankylosing spondylitis in the real practice of a rheumatologist in Russia (Part I). Rheumatology Science and Practice. 2012;50(2):44-49. DOI: 10.14412/1995-4484-2012-1272. (In Russ.)

24. Podryadnova M.V., Balabanova R.M., Urumova M.M., Erdes Sh.F. Correlation between clinical characteristics of ankylosing spondylitis and work capacity and productivity. Rheumatology Science and Practice. 2014;52(5):513-519. DOI: 10.14412/1995-4484-2014-513-519. (In Russ.)

25. Lila A.M., Dreval R.O., Shipitsyn V.V. Assessment of organization of medical care and drug provision for patients with rheumatic diseases, and the socioeconomic burden of these diseases in the Russian Federation. Modern Rheumatology Journal. 2018;12(3):112-119. DOI: 10.14412/1996-7012-2018-3-112-119. (In Russ.)

26. Yi E., Ahuja A., Rajput T. et al. Clinical, economic, and humanistic burden associated with delayed diagnosis of axial spondyloarthritis: a systematic review. Rheumatol. Ther. 2020;7(1):65-87. DOI: 10.1007/s40744-020-00194-8.

27. Feldtkeller E., Khan M.A., van der Heijde D. et al. Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol. Int. Rheumatol Int. 2003;23(2):61-66. DOI: 10.1007/s00296-002-0237-4.

28. Garrido-Cumbrera M., Navarro-Compán V., Bundy C. et al. Identifying parameters associated with delayed diagnosis in axial spondyloarthritis: data from the European map of axial spondyloarthritis. Rheumatology (Oxford). 2022;61(2):705-712. DOI: 10.1093/rheumatology/keab369.

29. Hay C.A., Packham J., Ryan S., Mallen C.D. et al. Diagnostic delay in axial spondyloarthritis: a systematic review. Clin. Rheumatol. 2022;41(7):1939-1950. DOI: 10.1007/s10067-022-06100-7.

30. Lapshina S.A., Myasoutova L.I., Mukhina R.G., Salikhov I.G. Effectiveness of educational programs on early diagnosis of ankylosing spondylitis for primary care physicians in Kazan. Rheumatology Science and Practice. 2014;52(2):183-186. DOI: 10.14412/1995-4484-2014-183-186. (In Russ.)

31. Redeker I., Callhoff J., Hoffmann F., et al. Determinants of diagnostic delay in axial spondyloarthritis: an analysis based on linked claims and patient-reported survey data. Rheumatology (Oxford). 2019;58(9):1634-1638. DOI: 10.1093/rheumatology/kez090.

32. Rumyantseva D.G., Erdes Sh.F. Axial spondyloarthritis: a current look at the concept and evolution of the disease. Modern Rheumatology Journal. 2019;13(4):4-10. DOI: 10.14412/1996-7012-2019-4-4-10. (In Russ.)

33. Dubinina T.V., Erdes Sh.F. Reasons for late diagnosis of ankylosing spondylitis in clinical practice. Rheumatology Science and Practice. 2010;48(2):43-48. DOI: 10.14412/1995-4484-2010-1415. (In Russ.)

34. Barnett R., Ingram T., Sengupta R. Axial spondyloarthritis 10 years on: still looking for the lost tribe. Rheumatology (Oxford). 2020;59(SUPPL4):IV25-IV37. DOI: 10.1093/rheumatology/keaa472.

35. Mennini F.S., Viti R., Marcellusi A. et al. Economic evaluation of spondyloarthritis: economic impact of diagnostic delay in Italy. Clinicoecon. Outcomes Res. 2018;10:45-51. DOI: 10.2147/CEOR.S144209.

36. van Nies J.A.B., Krabben A., Schoones J.W. et al. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann. Rheum. Dis. 2014;73(5):861-870. DOI: 10.1136/annrheumdis-2012-203130.

37. Burgers L.E., Raza K., Van Der Helm-Van Mil A.H. Window of opportunity in rheumatoid arthritis-Definitions and supporting evidence: From old to new perspectives. RMD Open. 2019;5(1):E000870. DOI: 10.1136/rmdopen-2018-000870.

38. Benavent D., Capelusnik D., Ramiro S. et al. Looking through the window of opportunity in axial spondyloarthritis? Joint Bone Spine. 2023;90(6):105603. DOI: 10.1016/j.jbspin.2023.105603.

39. Capelusnik D., Benavent D., van der Heijde D. et al. Treating spondyloarthritis early: does it matter? Results from a systematic literature review. Rheumatology (Oxford). 2023;62(4):1398-1409. DOI: 10.1093/rheumatology/keac532.

40. Benavent D., Capelusnik D., van der Heijde D. et al. How is early spondyloarthritis defined in the literature? Results from a systematic review. Semin. Arthritis Rheum. 2022;55:152032. DOI: 10.1016/j.semarthrit.2022.152032.

41. Navarro-Compán V., Benavent D., Capelusnik D. et al. ASAS consensus definition of early axial spondyloarthritis. Ann. Rheum. Dis. 2023:ARD-2023-224232. DOI: 10.1136/ard-2023-224232.

42. Protopopov M., Poddubnyy D. Radiographic progression in non-radiographic axial spondyloarthritis. Expert Rev. Clin. Immunol. 2018;14(6):525-533. DOI: 10.1080/1744666X.2018.1477591.

43. Ramiro S., Nikiphorou E., Sepriano A. et al. ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update. Ann. Rheum. Dis. 2022;82(1):19-34. DOI: 10.1136/ard-2022-223296.

44. Milota T., Hurnakova J., Pavelka K. et al. Delayed treatment with a tumor necrosis factor alpha blocker associated with worse outcomes in patients with spondyloarthritis: data from the Czech National Registry ATTRA. Ther. Adv. Musculoskelet. Dis. 2022;14:1759720X221081649. DOI: 10.1177/1759720X221081649.

45. Ogdie A., Benjamin Nowell W., Reynolds R. et al. Real-world patient experience on the path to diagnosis of ankylosing spondylitis. Rheumatol. Ther. 2019;6(2):255-267. DOI: 10.1007/s40744-019-0153-7.

46. Dube C.E., Lapane K.L., Ferrucci K.A. et al. Personal experiences with diagnostic delay among axial spondyloarthritis patients: a qualitative study. Rheumatol. Ther. 2021;8(2):1015-1030. DOI: 10.1007/s40744-019-0153-7.

47. Landewé R.B.M. Overdiagnosis and overtreatment in rheumatology: a little caution is in order. Ann. Rheum. Dis. 2018;77(10):1394-1396. DOI: 10.1136/annrheumdis-2018-213700.

48. Erdes Sh.F., Korotaeva T.V. Progression of axial spondyloarthritis. Modern Rheumatology Journal. 2021;15(3):7-14. DOI: 10.14412/1996-7012-2021-3-7-14. (In Russ.)

49. Rossini M., Viapiana O., Adami S. et al. Focal bone involvement in inflammatory arthritis: the role of IL17. Rheumatol Int. 2016;36(4):469-482. DOI: 10.1007/s00296-015-3387-x.

50. McGonagle D., Stockwin L., Isaaks J., Emery P. An enthesitis based model for the pathogenesis of spondyloarthropathy. Additive effects of microbial adjuvant and biomechanical factors at disease sites. J. Rheumatol. 2001;28(10):2155-2159.

51. Delgado-Calle J., Sato A.Y., Bellido T. Role and mechanism of action of sclerostin in bone. Bone. 2017;96:29-37. DOI: 10.1016/j.bone.2016.10.007.

52. Baron R., Rawadi G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148(6):2635-2643. DOI: 10.1210/en.2007-0270.

53. Omran A., Atanasova D., Landgren F., Magnusson P. Sclerostin: from molecule to clinical biomarker. Int. J. Mol. Sci. 2022;23(9):4751. DOI: 10.3390/ijms23094751.

54. Ito N., Prideaux M., Wijenayaka A.R. et al. Sclerostin directly stimulates osteocyte synthesis of fibroblast growth FACTOR-23. Calcif Tissue Int. 2021;109(1):66-76. DOI: 10.1007/s00223-021-00823-6.

55. Perrotta F.M., Ceccarelli F., Barbati C. et al. Serum sclerostin as a possible biomarker in ankylosing spondylitis: a case-control study. J. Immunol. Res. 2018;2018:9101964. DOI: 10.1155/2018/9101964.

56. Appel H., Ruiz-Heiland G., Listing J. et al. Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum. 2009;60(11):3257-3262. DOI:10.1002/art.24888.

57. Wu M., Chen M., Yang J. et al. Dickkopf-1 in ankylosing spondylitis: Review and meta-analysis. Clin. Chim. Acta. 2018;481:177-183. DOI: 10.1016/j.cca.2018.03.010.

58. Sakellariou G.T., Iliopoulos A., Konsta M. et al. Serum levels of DKK-1, sclerostin and VEGF in patients with ankylosing spondylitis and their association with smoking, and clinical, inflammatory and radiographic parameters. Joint Bone Spine. 2017;84(3):309-315. DOI: 10.1016/j.jbspin.2016.05.008.

59. Klingberg E., Nurkkala M., Carlsten H., Forsblad-d’Elia H. Biomarkers of bone metabolism in ankylosing spondylitis in relation to osteoproliferation and osteoporosis. J. Rheumatol. 2014;41(7):1349-1356. DOI: 10.3899/jrheum.131199.

60. Heiland G.R., Appel H., Poddubnyy D. et al. High level of functional Dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann. Rheum. Dis. 2012;71(4):572-574. DOI: 10.1136/annrheumdis-2011-200216.

61. Daoussis D., Kanellou A., Panagiotopoulos E., Papachristou D. DKK-1 is underexpressed in mesenchymal stem cells from patients with ankylosing spondylitis and further downregulated by IL-17. Int. J. Mol. Sci. 2022;23(12):6660. DOI: 10.3390/ijmS23126660.

62. Toussirot E. The Influence of adipokines on radiographic damage in inflammatory rheumatic diseases. Biomedicines. 2023;11(2):536. DOI: 10.3390/biomedicines11020536.

63. Moschen A.R., Geiger S., Gerner R., Tilg H. Pre-B cell colony enhancing factor/NAMPT/visfatin and its role in inflammation-related bone disease. Mutat Res. 2010;690(1-2):95-101. DOI: 10.1016/j.mrfmmm.2009.06.012.

64. Rademacher J., Siderius M., Gellert L. 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. DOI: 10.1016/j.semarthrit.2022.151974.

65. Syrbe U., Callhoff J., Conrad K. et al. Serum adipokine levels in patients with ankylosing spondylitis and their relationship to clinical parameters and radiographic spinal progression. Arthritis Rheumatol. 2015;67(3):678-685. DOI: 10.1002/art.38968.