J Rheum Dis.  2023 Oct;30(4):220-233. 10.4078/jrd.2023.0041.

Updates on ankylosing spondylitis: pathogenesis and therapeutic agents

• Kim SH
• Lee SH

• KMID: 2546238
• DOI: http://doi.org/10.4078/jrd.2023.0041

Abstract

Ankylosing spondylitis (AS) is an autoinflammatory disease that manifests with the unique feature of enthesitis. Gut microbiota, HLA-B*27, and biomechanical stress mutually influence and interact resulting in setting off a flame of inflammation. In the HLAB*27 positive group, dysbiosis in the gut environment disrupts the barrier to exogenous bacteria or viruses. Additionally, biomechanical stress induces inflammation through enthesial resident or gut-origin immune cells. On this basis, innate and adaptive immunity can propagate inflammation and lead to chronic disease. Finally, bone homeostasis is regulated by cytokines, by which the inflamed region is substituted into new bone. Agents that block cytokines are constantly being developed to provide diverse therapeutic options for preventing the progression of inflammation. In addition, some antibodies have been shown to distinguish disease selectively, which support the involvement of autoimmune immunity in AS. In this review, we critically analyze the complexity and uniqueness of the pathogenesis with updates on the findings of immunity and provide new information about biologics and biomarkers.

Keyword

Biological products; Hereditary autoinflammatory diseases; Gastrointestinal microbiome; Enthesopathy; Adaptive immunity

Figure

• 

  Fig. 1 Pathogenesis of ankylosing spondylitis. Gut microbiome produces short-chain fatty acids, tryptophan metabolites, and amino acids. Also, Paneth cells are source of IL-23 in the terminal ileum. HLA-B*27 provides arthritogenic peptide to TCR, and misfolded HLA-B*27 and accumulated protein induce UPR resulting in production of IL-23. Mechanical stress in enthesis induce DAMPs and IL-1β. As a result, produced IL-23 plays a pivotal role in initiating ankylosing spondylitis. Immune cells are involved to progress the disease by inducing IL-17, IL-22, and TNF-α. Bone remodeling is activated, as a result, new bone formation and bone resorption are promoted through cytokines. TCR: T-cell receptor, UPR: unfolded protein response, DAMPs: danger-associated molecular pattern, IL: interleukin, TNF: tumor necrosis factor, NK: natural killer, ERAP: endoplasmic reticulum aminopeptidases.

Reference

1. Generali E, Bose T, Selmi C, Voncken JW, Damoiseaux JGMC. 2018; Nature versus nurture in the spectrum of rheumatic diseases: classification of spondyloarthritis as autoimmune or autoinflammatory. Autoimmun Rev. 17:935–41. DOI: 10.1016/j.autrev.2018.04.002. PMID: 30005857.

2. Mauro D, Thomas R, Guggino G, Lories R, Brown MA, Ciccia F. 2021; Ankylosing spondylitis: an autoimmune or autoinflammatory disease? Nat Rev Rheumatol. 17:387–404. DOI: 10.1038/s41584-021-00625-y. PMID: 34113018.

3. Xiong Y, Cai M, Xu Y, Dong P, Chen H, He W, et al. 2022; Joint together: the etiology and pathogenesis of ankylosing spondylitis. Front Immunol. 13:996103. DOI: 10.3389/fimmu.2022.996103. PMID: 36325352. PMCID: PMC9619093.

4. Schett G, Lories RJ, D'Agostino MA, Elewaut D, Kirkham B, Soriano ER, et al. 2017; Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol. 13:731–41. DOI: 10.1038/nrrheum.2017.188. PMID: 29158573.

5. Baraliakos X, Heldmann F, Callhoff J, Listing J, Appelboom T, Brandt J, et al. 2014; Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography. Ann Rheum Dis. 73:1819–25. DOI: 10.1136/annrheumdis-2013-203425. PMID: 23852807.

6. Machado PM, Baraliakos X, van der Heijde D, Braun J, Landewé R. 2016; 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. 75:1486–93. DOI: 10.1136/annrheumdis-2015-208011. PMID: 26462728.

7. El-Zayadi AA, Jones EA, Churchman SM, Baboolal TG, Cuthbert RJ, El-Jawhari JJ, et al. 2017; Interleukin-22 drives the proliferation, migration and osteogenic differentiation of mesenchymal stem cells: a novel cytokine that could contribute to new bone formation in spondyloarthropathies. Rheumatology (Oxford). 56:488–93. DOI: 10.1093/rheumatology/kew384. PMID: 27940584.

8. Fan Y, Pedersen O. 2021; Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 19:55–71. DOI: 10.1038/s41579-020-0433-9. PMID: 32887946.

9. Valdes AM, Walter J, Segal E, Spector TD. 2018; Role of the gut microbiota in nutrition and health. BMJ. 361:k2179. DOI: 10.1136/bmj.k2179. PMID: 29899036. PMCID: PMC6000740.

10. Song ZY, Yuan D, Zhang SX. 2022; Role of the microbiome and its metabolites in ankylosing spondylitis. Front Immunol. 13:1010572. DOI: 10.3389/fimmu.2022.1010572. PMID: 36311749. PMCID: PMC9608452.

11. Ewing C, Ebringer R, Tribbick G, Geysen HM. 1990; Antibody activity in ankylosing spondylitis sera to two sites on HLA B27.1 at the MHC groove region (within sequence 65-85), and to a Klebsiella pneumoniae nitrogenase reductase peptide (within sequence 181-199). J Exp Med. 171:1635–47. DOI: 10.1084/jem.171.5.1635. PMID: 2185331. PMCID: PMC2187896.

12. Goodall JC, Wu C, Zhang Y, McNeill L, Ellis L, Saudek V, et al. 2010; Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc Natl Acad Sci U S A. 107:17698–703. DOI: 10.1073/pnas.1011736107. PMID: 20876114. PMCID: PMC2955096.

13. Long F, Wang T, Li Q, Xiong Y, Zeng Y. 2022; Association between Klebsiella pneumoniae and ankylosing spondylitis: a systematic review and meta-analysis. Int J Rheum Dis. 25:422–32. DOI: 10.1111/1756-185X.14283. PMID: 35019225.

14. Schwimmbeck PL, Oldstone MB. 1988; Molecular mimicry between human leukocyte antigen B27 and Klebsiella. Consequences for spondyloarthropathies. Am J Med. 85(6A):51–3. DOI: 10.1016/0002-9343(88)90385-3. PMID: 2462350.

15. Asquith M, Sternes PR, Costello ME, Karstens L, Diamond S, Martin TM, et al. 2019; HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome. Arthritis Rheumatol. 71:1642–50. DOI: 10.1002/art.40917. PMID: 31038287.

16. Costello ME, Ciccia F, Willner D, Warrington N, Robinson PC, Gardiner B, et al. 2015; Brief report: intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol. 67:686–91. DOI: 10.1002/art.38967. PMID: 25417597.

17. Tito RY, Cypers H, Joossens M, Varkas G, Van Praet L, Glorieus E, et al. 2017; Brief report: Dialister as a microbial marker of disease activity in spondyloarthritis. Arthritis Rheumatol. 69:114–21. DOI: 10.1002/art.39802. PMID: 27390077.

18. Breban M, Tap J, Leboime A, Said-Nahal R, Langella P, Chiocchia G, et al. 2017; Faecal microbiota study reveals specific dysbiosis in spondyloarthritis. Ann Rheum Dis. 76:1614–22. DOI: 10.1136/annrheumdis-2016-211064. PMID: 28606969.

19. Zhou C, Zhao H, Xiao XY, Chen BD, Guo RJ, Wang Q, et al. 2020; Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis. J Autoimmun. 107:102360. DOI: 10.1016/j.jaut.2019.102360. PMID: 31806420.

20. Berland M, Meslier V, Berreira Ibraim S, Le Chatelier E, Pons N, Maziers N, et al. 2023; Both disease activity and HLA-B27 status are associated with gut microbiome dysbiosis in spondyloarthritis patients. Arthritis Rheumatol. 75:41–52. DOI: 10.1002/art.42289. PMID: 35818337. PMCID: PMC10099252.

21. Guggino G, Mauro D, Rizzo A, Alessandro R, Raimondo S, Bergot AS, et al. 2021; Inflammasome activation in ankylosing spondylitis is associated with gut dysbiosis. Arthritis Rheumatol. 73:1189–99. DOI: 10.1002/art.41644. PMID: 33452867.

22. Qaiyum Z, Gracey E, Yao Y, Inman RD. 2019; Integrin and transcriptomic profiles identify a distinctive synovial CD8+ T cell subpopulation in spondyloarthritis. Ann Rheum Dis. 78:1566–75. DOI: 10.1136/annrheumdis-2019-215349. PMID: 31471299.

23. Strauch UG, Mueller RC, Li XY, Cernadas M, Higgins JM, Binion DG, et al. 2001; Integrin alpha E(CD103)beta 7 mediates adhesion to intestinal microvascular endothelial cell lines via an E-cadherin-independent interaction. J Immunol. 166:3506–14. DOI: 10.4049/jimmunol.166.5.3506. PMID: 11207310.

24. Purwar R, Campbell J, Murphy G, Richards WG, Clark RA, Kupper TS. 2011; Resident memory T cells (T(RM)) are abundant in human lung: diversity, function, and antigen specificity. PLoS One. 6:e16245. DOI: 10.1371/journal.pone.0016245. PMID: 21298112. PMCID: PMC3027667.

25. Berlinberg AJ, Regner EH, Stahly A, Brar A, Reisz JA, Gerich ME, et al. 2021; Multi 'omics analysis of intestinal tissue in ankylosing spondylitis identifies alterations in the tryptophan metabolism pathway. Front Immunol. 12:587119. DOI: 10.3389/fimmu.2021.587119. PMID: 33746944. PMCID: PMC7966505.

26. Wei JC, Chou MC, Huang JY, Chang R, Hung YM. 2020; The association between Candida infection and ankylosing spondylitis: a population-based matched cohort study. Curr Med Res Opin. 36:2063–9. DOI: 10.1080/03007995.2020.1838460. PMID: 33066709.

27. Wei CY, Lin JY, Wang YT, Huang JY, Wei JC, Chiou JY. 2020; Risk of ankylosing spondylitis following human papillomavirus infection: a nationwide, population-based, cohort study. J Autoimmun. 113:102482. DOI: 10.1016/j.jaut.2020.102482. PMID: 32417193.

28. Segal Y, Calabrò M, Kanduc D, Shoenfeld Y. 2017; Human papilloma virus and lupus: the virus, the vaccine and the disease. Curr Opin Rheumatol. 29:331–42. DOI: 10.1097/BOR.0000000000000398. PMID: 28394823.

29. Damba JJ, Laskine M, Jin Y, Sinyavskaya L, Durand M. 2021; Incidence of autoimmune diseases in people living with HIV compared to a matched population: a cohort study. Clin Rheumatol. 40:2439–45. DOI: 10.1007/s10067-020-05500-x. PMID: 33230683.

30. Guiliano DB, North H, Panayoitou E, Campbell EC, McHugh K, Cooke FG, et al. 2017; Polymorphisms in the F pocket of HLA-B27 subtypes strongly affect assembly, chaperone interactions, and heavy-chain misfolding. Arthritis Rheumatol. 69:610–21. DOI: 10.1002/art.39948. PMID: 27723268.

31. Wang G, Kim TH, Li Z, Cortes A, Kim K, Bang SY, et al. 2020; MHC associations of ankylosing spondylitis in East Asians are complex and involve non-HLA-B27 HLA contributions. Arthritis Res Ther. 22:74. DOI: 10.1186/s13075-020-02148-5. PMID: 32272966. PMCID: PMC7146985.

32. Reveille JD, Zhou X, Lee M, Weisman MH, Yi L, Gensler LS, et al. 2019; HLA class I and II alleles in susceptibility to ankylosing spondylitis. Ann Rheum Dis. 78:66–73. DOI: 10.1136/annrheumdis-2018-213779. PMID: 30341055. PMCID: PMC6982366.

33. Reveille JD. 2006; The genetic basis of ankylosing spondylitis. Curr Opin Rheumatol. 18:332–41. DOI: 10.1097/01.bor.0000231899.81677.04. PMID: 16763451.

34. York IA, Chang SC, Saric T, Keys JA, Favreau JM, Goldberg AL, et al. 2002; The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8-9 residues. Nat Immunol. 3:1177–84. DOI: 10.1038/ni860. PMID: 12436110.

35. Tsui FW, Haroon N, Reveille JD, Rahman P, Chiu B, Tsui HW, et al. 2010; Association of an ERAP1 ERAP2 haplotype with familial ankylosing spondylitis. Ann Rheum Dis. 69:733–6. DOI: 10.1136/ard.2008.103804. PMID: 19433412.

36. Nakamura A, Boroojeni SF, Haroon N. 2021; Aberrant antigen processing and presentation: key pathogenic factors leading to immune activation in Ankylosing spondylitis. Semin Immunopathol. 43:245–53. DOI: 10.1007/s00281-020-00833-w. PMID: 33532928.

37. Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, et al. 2011; Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet. 43:761–7. Erratum in: Nat Genet 2011;43:919. DOI: 10.1038/ng0911-919a. PMID: 21743469. PMCID: PMC3640413.

38. Wei JC, Tsai WC, Lin HS, Tsai CY, Chou CT. 2004; HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients. Rheumatology (Oxford). 43:839–42. DOI: 10.1093/rheumatology/keh193. PMID: 15113995.

39. Robinson PC, Costello ME, Leo P, Bradbury LA, Hollis K, Cortes A, et al. 2015; ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients. Ann Rheum Dis. 74:1627–9. DOI: 10.1136/annrheumdis-2015-207416. PMID: 25917849. PMCID: PMC4498996.

40. Saveanu L, Carroll O, Lindo V, Del Val M, Lopez D, Lepelletier Y, et al. 2005; Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol. 6:689–97. DOI: 10.1038/ni1208. PMID: 15908954.

41. Martín-Esteban A, Sanz-Bravo A, Guasp P, Barnea E, Admon A, López de Castro JA. 2017; Separate effects of the ankylosing spondylitis associated ERAP1 and ERAP2 aminopeptidases determine the influence of their combined phenotype on the HLA-B*27 peptidome. J Autoimmun. 79:28–38. DOI: 10.1016/j.jaut.2016.12.008. PMID: 28063628.

42. Hanson AL, Cuddihy T, Haynes K, Loo D, Morton CJ, Oppermann U, et al. 2018; Genetic variants in ERAP1 and ERAP2 associated with immune-mediated diseases influence protein expression and the isoform profile. Arthritis Rheumatol. 70:255–65. DOI: 10.1002/art.40369. PMID: 29108111.

43. Gracey E, Burssens A, Cambré I, Schett G, Lories R, McInnes IB, et al. 2020; Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis. Nat Rev Rheumatol. 16:193–207. DOI: 10.1038/s41584-019-0364-x. PMID: 32080619. PMCID: PMC7815340.

44. Lavagnino M, Wall ME, Little D, Banes AJ, Guilak F, Arnoczky SP. 2015; Tendon mechanobiology: current knowledge and future research opportunities. J Orthop Res. 33:813–22. DOI: 10.1002/jor.22871. PMID: 25763779. PMCID: PMC4524513.

45. Maeda T, Sakabe T, Sunaga A, Sakai K, Rivera AL, Keene DR, et al. 2011; Conversion of mechanical force into TGF-β-mediated biochemical signals. Curr Biol. 21:933–41. DOI: 10.1016/j.cub.2011.04.007. PMID: 21600772. PMCID: PMC3118584.

46. Bergsbaken T, Fink SL, Cookson BT. 2009; Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 7:99–109. DOI: 10.1038/nrmicro2070. PMID: 19148178. PMCID: PMC2910423.

47. Akbar M, Gilchrist DS, Kitson SM, Nelis B, Crowe LAN, Garcia-Melchor E, et al. 2017; Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis. RMD Open. 3:e000456. DOI: 10.1136/rmdopen-2017-000456. PMID: 28879051. PMCID: PMC5574425.

48. Zhang K, Asai S, Yu B, Enomoto-Iwamoto M. 2015; IL-1β irreversibly inhibits tenogenic differentiation and alters metabolism in injured tendon-derived progenitor cells in vitro. Biochem Biophys Res Commun. 463:667–72. DOI: 10.1016/j.bbrc.2015.05.122. PMID: 26051275. PMCID: PMC4496264.

49. Tsuzaki M, Guyton G, Garrett W, Archambault JM, Herzog W, Almekinders L, et al. 2003; IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells. J Orthop Res. 21:256–64. DOI: 10.1016/S0736-0266(02)00141-9. PMID: 12568957.

50. Bridgewood C, Watad A, Russell T, Palmer TM, Marzo-Ortega H, Khan A, et al. 2019; Identification of myeloid cells in the human enthesis as the main source of local IL-23 production. Ann Rheum Dis. 78:929–33. DOI: 10.1136/annrheumdis-2018-214944. PMID: 31018959. PMCID: PMC6585277.

51. Cuthbert RJ, Watad A, Fragkakis EM, Dunsmuir R, Loughenbury P, Khan A, et al. 2019; Evidence that tissue resident human enthesis γδT-cells can produce IL-17A independently of IL-23R transcript expression. Ann Rheum Dis. 78:1559–65. DOI: 10.1136/annrheumdis-2019-215210. PMID: 31530557. PMCID: PMC6837256.

52. van Tok MN, Na S, Lao CR, Alvi M, Pots D, van de Sande MGH, et al. 2018; The initiation, but not the persistence, of experimental spondyloarthritis is dependent on interleukin-23 signaling. Front Immunol. 9:1550. DOI: 10.3389/fimmu.2018.01550. PMID: 30038617. PMCID: PMC6046377.

53. Tsukazaki H, Kaito T. 2020; The role of the IL-23/IL-17 pathway in the pathogenesis of spondyloarthritis. Int J Mol Sci. 21:6401. DOI: 10.3390/ijms21176401. PMID: 32899140. PMCID: PMC7504446.

54. Hamada S, Umemura M, Shiono T, Tanaka K, Yahagi A, Begum MD, et al. 2008; IL-17A produced by gammadelta T cells plays a critical role in innate immunity against listeria monocytogenes infection in the liver. J Immunol. 181:3456–63. DOI: 10.4049/jimmunol.181.5.3456. PMID: 18714018. PMCID: PMC2859669.

55. Wang X, Lin Z, Wei Q, Jiang Y, Gu J. 2009; Expression of IL-23 and IL-17 and effect of IL-23 on IL-17 production in ankylosing spondylitis. Rheumatol Int. 29:1343–7. DOI: 10.1007/s00296-009-0883-x. PMID: 19247658.

56. Mei Y, Pan F, Gao J, Ge R, Duan Z, Zeng Z, et al. 2011; Increased serum IL-17 and IL-23 in the patient with ankylosing spondylitis. Clin Rheumatol. 30:269–73. DOI: 10.1007/s10067-010-1647-4. PMID: 21161669.

57. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. 2003; Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 278:1910–4. DOI: 10.1074/jbc.M207577200. PMID: 12417590.

58. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. 2000; Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 13:715–25. DOI: 10.1016/S1074-7613(00)00070-4. PMID: 11114383.

59. Ciccia F, Bombardieri M, Principato A, Giardina A, Tripodo C, Porcasi R, et al. 2009; Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum. 60:955–65. DOI: 10.1002/art.24389. PMID: 19333939.

60. Romand X, Liu X, Rahman MA, Bhuyan ZA, Douillard C, Kedia RA, et al. 2021; Mediation of interleukin-23 and tumor necrosis factor-driven reactive arthritis by Chlamydia-infected macrophages in SKG mice. Arthritis Rheumatol. 73:1200–10. DOI: 10.1002/art.41653. PMID: 33452873.

61. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. 2005; Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 6:1123–32. DOI: 10.1038/ni1254. PMID: 16200070.

62. Klasen C, Meyer A, Wittekind PS, Waqué I, Nabhani S, Kofler DM. 2019; Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis. Arthritis Res Ther. 21:159. DOI: 10.1186/s13075-019-1948-1. PMID: 31253169. PMCID: PMC6599260.

63. Schinocca C, Rizzo C, Fasano S, Grasso G, La Barbera L, Ciccia F, et al. 2021; Role of the IL-23/IL-17 pathway in rheumatic diseases: an overview. Front Immunol. 12:637829. DOI: 10.3389/fimmu.2021.637829. PMID: 33692806. PMCID: PMC7937623.

64. Baeten D, Adamopoulos IE. 2021; IL-23 inhibition in ankylosing spondylitis: where did it go wrong? Front Immunol. 11:623874. DOI: 10.3389/fimmu.2020.623874. PMID: 33679714. PMCID: PMC7935519.

65. Roark CL, Simonian PL, Fontenot AP, Born WK, O'Brien RL. 2008; gammadelta T cells: an important source of IL-17. Curr Opin Immunol. 20:353–7. DOI: 10.1016/j.coi.2008.03.006. PMID: 18439808. PMCID: PMC2601685.

66. Gracey E, Qaiyum Z, Almaghlouth I, Lawson D, Karki S, Avvaru N, et al. 2016; IL-7 primes IL-17 in mucosal-associated invariant T (MAIT) cells, which contribute to the Th17-axis in ankylosing spondylitis. Ann Rheum Dis. 75:2124–32. DOI: 10.1136/annrheumdis-2015-208902. PMID: 27165176.

67. Toussirot É, Laheurte C, Gaugler B, Gabriel D, Saas P. 2018; Increased IL-22- and IL-17A-producing mucosal-associated invariant T cells in the peripheral blood of patients with ankylosing spondylitis. Front Immunol. 9:1610. DOI: 10.3389/fimmu.2018.01610. PMID: 30057583. PMCID: PMC6053500.

68. Cuthbert RJ, Fragkakis EM, Dunsmuir R, Li Z, Coles M, Marzo-Ortega H, et al. 2017; Brief report: group 3 innate lymphoid cells in human enthesis. Arthritis Rheumatol. 69:1816–22. DOI: 10.1002/art.40150. PMID: 28511289.

69. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. 2005; A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 6:1133–41. DOI: 10.1038/ni1261. PMID: 16200068. PMCID: PMC1618871.

70. Wang C, Liao Q, Hu Y, Zhong D. 2015; T lymphocyte subset imbalances in patients contribute to ankylosing spondylitis. Exp Ther Med. 9:250–6. DOI: 10.3892/etm.2014.2046. PMID: 25452811. PMCID: PMC4247318.

71. Chowdhury AC, Chaurasia S, Mishra SK, Aggarwal A, Misra R. 2017; IL-17 and IFN-γ producing NK and γδ-T cells are preferentially expanded in synovial fluid of patients with reactive arthritis and undifferentiated spondyloarthritis. Clin Immunol. 183:207–12. DOI: 10.1016/j.clim.2017.03.016. PMID: 28390966.

72. Noordenbos T, Yeremenko N, Gofita I, van de Sande M, Tak PP, Caňete JD, et al. 2012; Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum. 64:99–109. DOI: 10.1002/art.33396. PMID: 21968742.

73. Rosine N, Rowe H, Koturan S, Yahia-Cherbal H, Leloup C, Watad A, et al. 2022; Characterization of blood mucosal-associated invariant T cells in patients with axial spondyloarthritis and of resident mucosal-associated invariant T cells from the axial entheses of non-axial spondyloarthritis control patients. Arthritis Rheumatol. 74:1786–95. DOI: 10.1002/art.42090. PMID: 35166073. PMCID: PMC9825958.

74. Venken K, Jacques P, Mortier C, Labadia ME, Decruy T, Coudenys J, et al. 2019; RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients. Nat Commun. 10:9. DOI: 10.1038/s41467-018-07911-6. PMID: 30602780. PMCID: PMC6315029.

75. Mortier C, Gracey E, Coudenys J, Manuello T, Decruy T, Maelegheer M, et al. 2023; Jan. 20. RORγt inhibition ameliorates IL-23 driven experimental Psoriatic Arthritis by predominantly modulating γδ-T cells. Rheumatology (Oxford). [Epub]. DOI:10.1093/rheumatology/kead022. DOI: 10.1093/rheumatology/kead022. PMID: 36661300.

76. Liu R, Lauridsen HM, Amezquita RA, Pierce RW, Jane-Wit D, Fang C, et al. 2016; IL-17 promotes neutrophil-mediated immunity by activating microvascular pericytes and not endothelium. J Immunol. 197:2400–8. DOI: 10.4049/jimmunol.1600138. PMID: 27534549. PMCID: PMC5010945.

77. Lubberts E. 2015; The IL-23-IL-17 axis in inflammatory arthritis. Nat Rev Rheumatol. 11:415–29. Erratum in: Nat Rev Rheumatol 2015;11:562. DOI: 10.1038/nrrheum.2015.53. PMID: 25907700.

78. Griffin GK, Newton G, Tarrio ML, Bu DX, Maganto-Garcia E, Azcutia V, et al. 2012; IL-17 and TNF-α sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation. J Immunol. 188:6287–99. DOI: 10.4049/jimmunol.1200385. PMID: 22566565. PMCID: PMC3370121.

79. Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. 2006; Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 203:2673–82. DOI: 10.1084/jem.20061775. PMID: 17088434. PMCID: PMC2118166.

80. Huang H, Kim HJ, Chang EJ, Lee ZH, Hwang SJ, Kim HM, et al. 2009; IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ. 16:1332–43. DOI: 10.1038/cdd.2009.74. PMID: 19543237.

81. Garcia KC, Gapin L, Adams JJ, Birnbaum ME, Scott-Browne JP, Kappler JW, et al. 2012; A closer look at TCR germline recognition. Immunity. 36:887–8. DOI: 10.1016/j.immuni.2012.05.018. PMID: 22705103. PMCID: PMC4237060.

82. Hanson AL, Nel HJ, Bradbury L, Phipps J, Thomas R, Lê Cao KA, et al. 2020; Altered repertoire diversity and disease-associated clonal expansions revealed by T cell receptor immunosequencing in ankylosing spondylitis patients. Arthritis Rheumatol. 72:1289–302. DOI: 10.1002/art.41252. PMID: 32162785.

83. Kok L, Masopust D, Schumacher TN. 2022; The precursors of CD8+ tissue resident memory T cells: from lymphoid organs to infected tissues. Nat Rev Immunol. 22:283–93. DOI: 10.1038/s41577-021-00590-3. PMID: 34480118. PMCID: PMC8415193.

84. Zheng M, Zhang X, Zhou Y, Tang J, Han Q, Zhang Y, et al. 2019; TCR repertoire and CDR3 motif analyses depict the role of αβ T cells in Ankylosing spondylitis. EBioMedicine. 47:414–26. DOI: 10.1016/j.ebiom.2019.07.032. PMID: 31477563. PMCID: PMC6796593.

85. Gracey E, Yao Y, Qaiyum Z, Lim M, Tang M, Inman RD. 2020; Altered cytotoxicity profile of CD8+ T cells in ankylosing spondylitis. Arthritis Rheumatol. 72:428–34. DOI: 10.1002/art.41129. PMID: 31599089.

86. Kucuksezer UC, Aktas Cetin E, Esen F, Tahrali I, Akdeniz N, Gelmez MY, et al. 2021; The role of natural killer cells in autoimmune diseases. Front Immunol. 12:622306. DOI: 10.3389/fimmu.2021.622306. PMID: 33717125. PMCID: PMC7947192.

87. Ren C, Li M, Zheng Y, Cai B, Du W, Zhang H, et al. 2022; Single-cell RNA-seq reveals altered NK cell subsets and reduced levels of cytotoxic molecules in patients with ankylosing spondylitis. J Cell Mol Med. 26:1071–82. DOI: 10.1111/jcmm.17159. PMID: 34994057. PMCID: PMC8831943.

88. Yang M, Zhou Y, Liu L, Wang S, Jiang J, Shang Q, et al. 2019; Decreased A20 expression on circulating CD56bright NK cells contributes to a worse disease status in patients with ankylosing spondylitis. Clin Exp Immunol. 198:1–10. DOI: 10.1111/cei.13341. PMID: 31206174. PMCID: PMC6718289.

89. Schulte-Wrede U, Sörensen T, Grün JR, Häupl T, Hirseland H, Steinbrich-Zöllner M, et al. 2018; An explorative study on deep profiling of peripheral leukocytes to identify predictors for responsiveness to anti-tumour necrosis factor alpha therapies in ankylosing spondylitis: natural killer cells in focus. Arthritis Res Ther. 20:191. DOI: 10.1186/s13075-018-1692-y. PMID: 30157966. PMCID: PMC6116509.

90. Jiang Y, Yang M, Zhang Y, Huang Y, Wu J, Xie Y, et al. 2021; Dynamics of adaptive immune cell and NK cell subsets in patients with ankylosing spondylitis after IL-17A inhibition by secukinumab. Front Pharmacol. 12:738316. DOI: 10.3389/fphar.2021.738316. PMID: 34721027. PMCID: PMC8551761.

91. Maksymowych WP, Wichuk S, Chiowchanwisawakit P, Lambert RG, Pedersen SJ. 2014; Fat metaplasia and backfill are key intermediaries in the development of sacroiliac joint ankylosis in patients with ankylosing spondylitis. Arthritis Rheumatol. 66:2958–67. DOI: 10.1002/art.38792. PMID: 25047851.

92. Baraliakos X, Boehm H, Bahrami R, Samir A, Schett G, Luber M, et al. 2019; What constitutes the fat signal detected by MRI in the spine of patients with ankylosing spondylitis? A prospective study based on biopsies obtained during planned spinal osteotomy to correct hyperkyphosis or spinal stenosis. Ann Rheum Dis. 78:1220–5. DOI: 10.1136/annrheumdis-2018-214983. PMID: 31122911.

93. Bleil J, Maier R, Hempfing A, Schlichting U, Appel H, Sieper J, et al. 2014; Histomorphologic and histomorphometric characteristics of zygapophyseal joint remodeling in ankylosing spondylitis. Arthritis Rheumatol. 66:1745–54. DOI: 10.1002/art.38404. PMID: 24574301.

94. Bleil J, Maier R, Hempfing A, Sieper J, Appel H, Syrbe U. 2016; Granulation tissue eroding the subchondral bone also promotes new bone formation in ankylosing spondylitis. Arthritis Rheumatol. 68:2456–65. DOI: 10.1002/art.39715. PMID: 27111225.

95. Rahman P, Inman RD, Gladman DD, Reeve JP, Peddle L, Maksymowych WP. 2008; Association of interleukin-23 receptor variants with ankylosing spondylitis. Arthritis Rheum. 58:1020–5. DOI: 10.1002/art.23389. PMID: 18383363.

96. Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, et al. 2012; IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 18:1069–76. DOI: 10.1038/nm.2817. PMID: 22772566.

97. Langrish CL, McKenzie BS, Wilson NJ, de Waal Malefyt R, Kastelein RA, Cua DJ. 2004; IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev. 202:96–105. DOI: 10.1111/j.0105-2896.2004.00214.x. PMID: 15546388.

98. Veale DJ, McGonagle D, McInnes IB, Krueger JG, Ritchlin CT, Elewaut D, et al. 2019; The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis. Rheumatology (Oxford). 58:197–205. DOI: 10.1093/rheumatology/key070. PMID: 29618084. PMCID: PMC6343466.

99. Li CH, Xu LL, Jian LL, Yu RH, Zhao JX, Sun L, et al. 2018; Stattic inhibits RANKL-mediated osteoclastogenesis by suppressing activation of STAT3 and NF-κB pathways. Int Immunopharmacol. 58:136–44. DOI: 10.1016/j.intimp.2018.03.021. PMID: 29587202.

100. Jo S, Won EJ, Kim MJ, Lee YJ, Jin SH, Park PR, et al. 2021; STAT3 phosphorylation inhibition for treating inflammation and new bone formation in ankylosing spondylitis. Rheumatology (Oxford). 60:3923–35. DOI: 10.1093/rheumatology/keaa846. PMID: 33237331.

101. Russell T, Watad A, Bridgewood C, Rowe H, Khan A, Rao A, et al. 2021; IL-17A and TNF modulate normal human spinal entheseal bone and soft tissue mesenchymal stem cell osteogenesis, adipogenesis, and stromal function. Cells. 10:341. DOI: 10.3390/cells10020341. PMID: 33562025. PMCID: PMC7915379.

102. Kaaij MH, van Tok MN, Blijdorp IC, Ambarus CA, Stock M, Pots D, et al. 2020; Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis. J Exp Med. 217:e20200288. DOI: 10.1084/jem.20200288. PMID: 32662821. PMCID: PMC7537402.

103. Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, et al. 2003; MIF signal transduction initiated by binding to CD74. J Exp Med. 197:1467–76. DOI: 10.1084/jem.20030286. PMID: 12782713. PMCID: PMC2193907.

104. Kozaci LD, Sari I, Alacacioglu A, Akar S, Akkoc N. 2010; Evaluation of inflammation and oxidative stress in ankylosing spondylitis: a role for macrophage migration inhibitory factor. Mod Rheumatol. 20:34–9. DOI: 10.3109/s10165-009-0230-9. PMID: 19787418.

105. Ranganathan V, Ciccia F, Zeng F, Sari I, Guggino G, Muralitharan J, et al. 2017; Macrophage migration inhibitory factor induces inflammation and predicts spinal progression in ankylosing spondylitis. Arthritis Rheumatol. 69:1796–806. DOI: 10.1002/art.40175. PMID: 28597514.

106. Heiland GR, Appel H, Poddubnyy D, Zwerina J, Hueber A, Haibel H, et al. 2012; High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis. 71:572–4. DOI: 10.1136/annrheumdis-2011-200216. PMID: 22186710.

107. Uderhardt S, Diarra D, Katzenbeisser J, David JP, Zwerina J, Richards W, et al. 2010; Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints. Ann Rheum Dis. 69:592–7. DOI: 10.1136/ard.2008.102046. PMID: 19304568.

108. Aschermann S, Englbrecht M, Bergua A, Spriewald BM, Said-Nahal R, Breban M, et al. 2016; Presence of HLA-B27 is associated with changes of serum levels of mediators of the Wnt and hedgehog pathway. Joint Bone Spine. 83:43–6. DOI: 10.1016/j.jbspin.2015.03.019. PMID: 26494593.

109. Caparbo VF, Saad CGS, Moraes JC, de Brum-Fernandes AJ, Pereira RMR. 2018; Monocytes from male patients with ankylosing spondylitis display decreased osteoclastogenesis and decreased RANKL/OPG ratio. Osteoporos Int. 29:2565–73. DOI: 10.1007/s00198-018-4629-z. PMID: 30006885.

110. Wang CM, Tsai SC, Lin JC, Wu YJ, Wu J, Chen JY. 2019; Association of genetic variants of RANK, RANKL, and OPG with ankylosing spondylitis clinical features in Taiwanese. Mediators Inflamm. 2019:8029863. DOI: 10.1155/2019/8029863. PMID: 31015798. PMCID: PMC6446096.

111. Dar HY, Azam Z, Anupam R, Mondal RK, Srivastava RK. 2018; Osteoimmunology: the Nexus between bone and immune system. Front Biosci (Landmark Ed). 23:464–92. DOI: 10.2741/4600. PMID: 28930556.

112. Davis JC Jr, Van Der Heijde D, Braun J, Dougados M, Cush J, Clegg DO, et al. 2003; Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum. 48:3230–6. DOI: 10.1002/art.11325. PMID: 14613288.

113. van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Williamson P, et al. 2005; Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum. 52:582–91. DOI: 10.1002/art.20852. PMID: 15692973.

114. van der Heijde D, Kivitz A, Schiff MH, Sieper J, Dijkmans BA, Braun J, et al. 2006; Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 54:2136–46. DOI: 10.1002/art.21913. PMID: 16802350.

115. Inman RD, Davis JC Jr, Heijde D, Diekman L, Sieper J, Kim SI, et al. 2008; Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum. 58:3402–12. DOI: 10.1002/art.23969. PMID: 18975305.

116. Maxwell LJ, Zochling J, Boonen A, Singh JA, Veras MM, Tanjong Ghogomu E, et al. 2014; TNF-alpha inhibitors for ankylosing spondylitis. Cochrane Database Syst Rev. (4):CD005468. DOI: 10.1002/14651858.CD005468.pub2. PMID: 25887212.

117. Ward MM, Deodhar A, Gensler LS, Dubreuil M, Yu D, Khan MA, et al. 2019; 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 71:1599–613. DOI: 10.1002/art.41042. PMID: 31436036. PMCID: PMC6764882.

118. Ko JM, Gottlieb AB, Kerbleski JF. 2009; Induction and exacerbation of psoriasis with TNF-blockade therapy: a review and analysis of 127 cases. J Dermatolog Treat. 20:100–8. DOI: 10.1080/09546630802441234. PMID: 18923992.

119. Alivernini S, Pugliese D, Tolusso B, Bui L, Petricca L, Guidi L, et al. 2018; Paradoxical arthritis occurring during anti-TNF in patients with inflammatory bowel disease: histological and immunological features of a complex synovitis. RMD Open. 4:e000667. DOI: 10.1136/rmdopen-2018-000667. PMID: 29657833. PMCID: PMC5892785.

120. Karmacharya P, Duarte-Garcia A, Dubreuil M, Murad MH, Shahukhal R, Shrestha P, et al. 2020; Effect of therapy on radiographic progression in axial spondyloarthritis: a systematic review and meta-analysis. Arthritis Rheumatol. 72:733–49. DOI: 10.1002/art.41206. PMID: 31960614. PMCID: PMC7218689.

121. Zhang JR, Liu XJ, Xu WD, Dai SM. 2016; Effects of tumor necrosis factor-α inhibitors on new bone formation in ankylosing spondylitis. Joint Bone Spine. 83:257–64. DOI: 10.1016/j.jbspin.2015.06.013. PMID: 26678001.

122. McGonagle D, Watad A, Sharif K, Bridgewood C. 2021; Why inhibition of IL-23 lacked efficacy in ankylosing spondylitis. Front Immunol. 12:614255. DOI: 10.3389/fimmu.2021.614255. PMID: 33815371. PMCID: PMC8017223.

123. Lee YH. 2022; Comparative efficacy and safety of Janus kinase inhibitors and secukinumab in patients with active ankylosing spondylitis: a systematic review and meta-analysis. Pharmacology. 107:537–44. DOI: 10.1159/000525627. PMID: 35817017. PMCID: PMC9811419.

124. Deodhar A, Gensler LS, Sieper J, Clark M, Calderon C, Wang Y, et al. 2019; Three multicenter, randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of ustekinumab in axial spondyloarthritis. Arthritis Rheumatol. 71:258–70. DOI: 10.1002/art.40728. PMID: 30225992.

125. Kavanaugh A, Puig L, Gottlieb AB, Ritchlin C, You Y, Li S, et al. 2016; Efficacy and safety of ustekinumab in psoriatic arthritis patients with peripheral arthritis and physician-reported spondylitis: post-hoc analyses from two phase III, multicentre, double-blind, placebo-controlled studies (PSUMMIT-1/PSUMMIT-2). Ann Rheum Dis. 75:1984–8. DOI: 10.1136/annrheumdis-2015-209068. PMID: 27098404.

126. Savage L, Goodfield M, Horton L, Watad A, Hensor E, Emery P, et al. 2019; Regression of peripheral subclinical enthesopathy in therapy-naive patients treated with ustekinumab for moderate-to-severe chronic plaque psoriasis: a fifty-two-week, prospective, open-label feasibility study. Arthritis Rheumatol. 71:626–31. DOI: 10.1002/art.40778. PMID: 30468001.

127. Deodhar A, Helliwell PS, Boehncke WH, Kollmeier AP, Hsia EC, Subramanian RA, et al. 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. Lancet. 395:1115–25. Erratum in: Lancet 2020;395:1114. DOI: 10.1016/S0140-6736(20)30265-8. PMID: 32178765.

128. Blair HA. 2019; Secukinumab: a review in ankylosing spondylitis. Drugs. 79:433–43. Erratum in: Drugs 2019;79:445. DOI: 10.1007/s40265-019-01075-3. PMID: 30793255. PMCID: PMC6422944.

129. Deodhar A, Blanco R, Dokoupilová E, Hall S, Kameda H, Kivitz AJ, et al. 2021; Improvement of signs and symptoms of nonradiographic axial spondyloarthritis in patients treated with secukinumab: primary results of a randomized, placebo-controlled phase III study. Arthritis Rheumatol. 73:110–20. DOI: 10.1002/art.41477. PMID: 32770640. PMCID: PMC7839589.

130. van Mens LJJ, van de Sande MGH, Menegatti S, Chen S, Blijdorp ICJ, de Jong HM, et al. 2018; Brief report: interleukin-17 blockade with secukinumab in peripheral spondyloarthritis impacts synovial immunopathology without compromising systemic immune responses. Arthritis Rheumatol. 70:1994–2002. DOI: 10.1002/art.40581. PMID: 29869838.

131. Mease PJ, Smolen JS, Behrens F, Nash P, Liu Leage S, Li L, et al. 2020; A head-to-head comparison of the efficacy and safety of ixekizumab and adalimumab in biological-naïve patients with active psoriatic arthritis: 24-week results of a randomised, open-label, blinded-assessor trial. Ann Rheum Dis. 79:123–31. DOI: 10.1136/annrheumdis-2019-215386. PMID: 31563894. PMCID: PMC6937408.

132. Chandran V, van der Heijde D, Fleischmann RM, Lespessailles E, Helliwell PS, Kameda H, et al. 2020; Ixekizumab treatment of biologic-naïve patients with active psoriatic arthritis: 3-year results from a phase III clinical trial (SPIRIT-P1). Rheumatology (Oxford). 59:2774–84. DOI: 10.1093/rheumatology/kez684. PMID: 32031665. PMCID: PMC7516094.

133. Hohenberger M, Cardwell LA, Oussedik E, Feldman SR. 2018; Interleukin-17 inhibition: role in psoriasis and inflammatory bowel disease. J Dermatolog Treat. 29:13–8. DOI: 10.1080/09546634.2017.1329511. PMID: 28521565.

134. Kammüller M, Tsai TF, Griffiths CE, Kapoor N, Kolattukudy PE, Brees D, et al. 2017; Inhibition of IL-17A by secukinumab shows no evidence of increased Mycobacterium tuberculosis infections. Clin Transl Immunology. 6:e152. DOI: 10.1038/cti.2017.34. PMID: 28868144. PMCID: PMC5579471.

135. Wei JC, Kim TH, Kishimoto M, Ogusu N, Jeong H, Kobayashi S. 2021; Efficacy and safety of brodalumab, an anti-IL17RA monoclonal antibody, in patients with axial spondyloarthritis: 16-week results from a randomised, placebo-controlled, phase 3 trial. Ann Rheum Dis. 80:1014–21. DOI: 10.1136/annrheumdis-2020-219406. PMID: 33827787. PMCID: PMC8292606.

136. Kim TH, Kishimoto M, Wei JC, Jeong H, Nozaki A, Kobayashi S. 2023; Brodalumab, an anti-interleukin-17 receptor A monoclonal antibody, in axial spondyloarthritis: 68-week results from a phase 3 study. Rheumatology (Oxford). 62:1851–9. DOI: 10.1093/rheumatology/keac522. PMID: 36130275. PMCID: PMC10152297.

137. van der Heijde D, Gensler LS, Deodhar A, Baraliakos X, Poddubnyy D, Kivitz A, et al. 2020; Dual neutralisation of interleukin-17A and interleukin-17F with bimekizumab in patients with active ankylosing spondylitis: results from a 48-week phase IIb, randomised, double-blind, placebo-controlled, dose-ranging study. Ann Rheum Dis. 79:595–604. Erratum in: Ann Rheum Dis 2021;80:e186. DOI: 10.1136/annrheumdis-2020-216980. PMID: 32253184. PMCID: PMC7213320.

138. Baraliakos X, Deodhar A, Dougados M, Gensler LS, Molto A, Ramiro S, et al. 2022; Safety and efficacy of bimekizumab in patients with active ankylosing spondylitis: three-year results from a phase IIb randomized controlled trial and its open-label extension study. Arthritis Rheumatol. 74:1943–58. DOI: 10.1002/art.42282. PMID: 35829672.

139. van der Heijde D, Baraliakos X, Sieper J, Deodhar A, Inman RD, Kameda H, et al. 2022; Efficacy and safety of upadacitinib for active ankylosing spondylitis refractory to biological therapy: a double-blind, randomised, placebo-controlled phase 3 trial. Ann Rheum Dis. 81:1515–23. DOI: 10.1136/ard-2022-222608. PMID: 35788492. PMCID: PMC9606523.

140. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. 2017; JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 16:843–62. Erratum in: Nat Rev Drug Discov 2017;17:78. DOI: 10.1038/nrd.2017.201. PMID: 29104284. PMCID: PMC6168198.

141. Deodhar A, Sliwinska-Stanczyk P, Xu H, Baraliakos X, Gensler LS, Fleishaker D, et al. 2021; Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 80:1004–13. DOI: 10.1136/annrheumdis-2020-219601. PMID: 33906853. PMCID: PMC8292568.

142. Taylor PC, Saurigny D, Vencovsky J, Takeuchi T, Nakamura T, Matsievskaia G, et al. 2019; Efficacy and safety of namilumab, a human monoclonal antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) ligand in patients with rheumatoid arthritis (RA) with either an inadequate response to background methotrexate therapy or an inadequate response or intolerance to an anti-TNF (tumour necrosis factor) biologic therapy: a randomized, controlled trial. Arthritis Res Ther. 21:101. DOI: 10.1186/s13075-019-1879-x. PMID: 30999929. PMCID: PMC6471864.

143. Perrotta FM, Scriffignano S, Ciccia F, Lubrano E. 2022; Therapeutic targets for ankylosing spondylitis - recent insights and future prospects. Open Access Rheumatol. 14:57–66. DOI: 10.2147/OARRR.S295033. PMID: 35469137. PMCID: PMC9034883.

144. Izana Bioscience Ltd. 2022. Mar. 8. Efficacy and safety of namilumab for moderate-to-severe axial spondyloarthritis (NAMASTE) [Internet]. ClinicalTrials.gov;Bethesda (MD): https://classic.clinicaltrials.gov/ct2/show/NCT03622658. cited 2023 Jul 13.

145. Sen R, Kim E, Napier RJ, Cheng E, Fernandez A, Manning ES, et al. 2023; Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as biomarkers in axial spondyloarthritis: observational studies from the Program to Understand the Longterm Outcomes in Spondyloarthritis registry. Arthritis Rheumatol. 75:232–41. DOI: 10.1002/art.42333. PMID: 36053919. PMCID: PMC9892177.

146. Wang J, Su J, Yuan Y, Jin X, Shen B, Lu G. 2021; The role of lymphocyte-monocyte ratio on axial spondyloarthritis diagnosis and sacroiliitis staging. BMC Musculoskelet Disord. 22:86. DOI: 10.1186/s12891-021-03973-8. PMID: 33453722. PMCID: PMC7811735.

147. Lee JH, Jung JH, Kim J, Baek WK, Rhee J, Kim TH, et al. 2020; Proteomic analysis of human synovial fluid reveals potential diagnostic biomarkers for ankylosing spondylitis. Clin Proteomics. 17:20. DOI: 10.1186/s12014-020-09281-y. PMID: 32518534. PMCID: PMC7269004.

148. Quaden D, Vandormael P, Ruytinx P, Geusens P, Corten K, Vanhoof J, et al. 2020; Antibodies against three novel peptides in early axial spondyloarthritis patients from two independent cohorts. Arthritis Rheumatol. 72:2094–105. DOI: 10.1002/art.41427. PMID: 32638516.

149. Do L, Granåsen G, Hellman U, Lejon K, Geijer M, Baraliakos X, et al. 2021; Anti-CD74 IgA autoantibodies in radiographic axial spondyloarthritis: a longitudinal Swedish study. Rheumatology (Oxford). 60:4085–93. DOI: 10.1093/rheumatology/keaa882. PMID: 33369649. PMCID: PMC8410007.

150. De Craemer AS, Witte T, Lobaton Ortega T, Hoorens A, De Vos M, Cuvelier C, et al. 2023; Anti-CD74 IgA antibodies show diagnostic potential for axial spondyloarthritis but are not associated with microscopic gut inflammation. Rheumatology (Oxford). 62:984–90. DOI: 10.1093/rheumatology/keac384. PMID: 35781486.

151. Abdelaziz MM, Gamal RM, Ismail NM, Lafy RA, Hetta HF. 2021; Diagnostic value of anti-CD74 antibodies in early and late axial spondyloarthritis and its relationship to disease activity. Rheumatology (Oxford). 60:263–8. DOI: 10.1093/rheumatology/keaa292. PMID: 32710117.

152. Baraliakos X, Baerlecken N, Witte T, Heldmann F, Braun J. 2014; High prevalence of anti-CD74 antibodies specific for the HLA class II-associated invariant chain peptide (CLIP) in patients with axial spondyloarthritis. Ann Rheum Dis. 73:1079–82. DOI: 10.1136/annrheumdis-2012-202177. PMID: 23644552.

153. Riechers E, Baerlecken N, Baraliakos X, Achilles-Mehr Bakhsh K, Aries P, Bannert B, et al. 2019; Sensitivity and specificity of autoantibodies against CD74 in nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 71:729–35. DOI: 10.1002/art.40777. PMID: 30418704.