Skip to main content

Advertisement

SpringerLink
Log in

Ankylosing spondylitis risk factors: a systematic literature review

  • Review Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Radiographic axial spondyloarthritis (also known as ankylosing spondylitis [AS]) is a chronic immune-mediated arthritis characterized by inflammation of the axial skeleton, peripheral joints, and entheses. It is estimated that 1 in every 200 people are affected by AS, making it an important healthcare and socioeconomic issue. In this review, we aim to explore the current understanding of AS risk factors and provide a comprehensive update. Multiple search strings were used to identify articles of interest published in PubMed between January 1, 2013, and February 1, 2021. On the basis of the literature review and analysis, we present up-to-date information on the risk factors of developing AS and our viewpoints on disease onset and progression. Multiple genetic and nongenetic risk factors have been suggested in the onset of AS. HLA-B27 is known to have a strong association with the disease, but other genes have been implicated in disease development. Aside from genetics, other factors are thought to be involved; up to 70% of patients with AS have subclinical intestinal inflammation, suggesting that the origin of the disease may be in the gut. The exact mechanism by which AS onset begins is most likely complex and multifactorial.

Key Points

• It remains unclear how interactions between genes, microbes, mechanical stress, gender, and other environmental and lifestyle factors predispose patients to the development of ankylosing spondylitis (AS).

• The exact mechanisms of AS are complex and multifactorial which will require much future research

• Recognizing the risk factors, as well as understanding gene-environment interactions, may offer valuable insights into the etiology of AS and have important implications for diagnosis and treatment strategies

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

Not applicable.

References

  1. Ostergaard M, Lambert RG (2012) Imaging in ankylosing spondylitis. Ther Adv Musculoskelet Dis 4:301–311

    Article  PubMed  PubMed Central  Google Scholar 

  2. Rudwaleit M, van der Heijde D, Landewe R, Listing J, Akkoc N, Brandt J et al (2009) The development of Assessment of SpondyloArthritis International Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 68:777–783

    Article  PubMed  CAS  Google Scholar 

  3. Reveille JD, Witter JP, Weisman MH (2012) Prevalence of axial spondylarthritis in the United States: estimates from a cross-sectional survey. Arthritis Care Res (Hoboken) 64:905–910

    Article  Google Scholar 

  4. Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ (2014) Global prevalence of ankylosing spondylitis. Rheumatology (Oxford) 53:650–657

    Article  Google Scholar 

  5. Braun A, Saracbasi E, Grifka J, Schnitker J, Braun J (2011) Identifying patients with axial spondyloarthritis in primary care: how useful are items indicative of inflammatory back pain? Ann Rheum Dis 70:1782–1787

    Article  PubMed  CAS  Google Scholar 

  6. Dagfinrud H, Kjeken I, Mowinckel P, Hagen KB, Kvien TK (2005) Impact of functional impairment in ankylosing spondylitis: impairment, activity limitation, and participation restrictions. J Rheumatol 32:516–523

    PubMed  Google Scholar 

  7. Ellinghaus D, Jostins L, Spain SL, Cortes A, Bethune J, Han B et al (2016) Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet 48:510–518

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Costello ME, Ciccia F, Willner D, Warrington N, Robinson PC, Gardiner B et al (2015) Brief report: intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol 67:686–691

    Article  PubMed  Google Scholar 

  9. 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 Res 7:22

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Simone D, Al Mossawi MH, Bowness P (2018) Progress in our understanding of the pathogenesis of ankylosing spondylitis. Rheumatology (Oxford) 57(suppl 6):vi4–vi9

    Article  CAS  Google Scholar 

  11. Han R, Xia Q, Xu S, Fan D, Pan F (2018) Interleukin-23 receptor polymorphism (rs10889677 A/C) in ankylosing spondylitis: meta-analysis in Caucasian and Asian populations. Clin Chim Acta 477:53–59

    Article  PubMed  CAS  Google Scholar 

  12. Qian Y, Wang G, Xue F, Chen L, Wang Y, Tang L, Yang H (2017) Genetic association between TAP1 and TAP2 polymorphisms and ankylosing spondylitis: a systematic review and meta-analysis. Inflamm Res 66:653–661

    Article  PubMed  CAS  Google Scholar 

  13. Yang M, Zou Y, Bai Y, Li M (2015) The programmed cell death 1 gene polymorphisms (PD 1.3 G/A, PD 1.5 C/T and PD 1.9 C/T) and susceptibility to ankylosing spondylitis: a meta-analysis. J Orthop Sci 20:55–63

    Article  PubMed  Google Scholar 

  14. Zhang L, Zhang YJ, Chen J, Huang XL, Fang GS, Yang LJ, Duan Y, Wang J (2018) The association of HLA-B27 and Klebsiella pneumoniae in ankylosing spondylitis: a systematic review. Microb Pathog 117:49–54

    Article  PubMed  CAS  Google Scholar 

  15. Zhao S, Duffield SJ, Moots RJ, Goodson NJ (2014) Systematic review of association between vitamin D levels and susceptibility and disease activity of ankylosing spondylitis. Rheumatology (Oxford) 53:1595–1603

    Article  CAS  Google Scholar 

  16. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med 3:e123–e130

    PubMed  PubMed Central  Google Scholar 

  17. Jamalyaria F, Ward MM, Assassi S, Learch TJ, Lee M, Gensler LS, Brown MA, Diekman L, Tahanan A, Rahbar MH, Weisman MH, Reveille JD (2017) Ethnicity and disease severity in ankylosing spondylitis a cross-sectional analysis of three ethnic groups. Clin Rheumatol 36:2359–2364

    Article  PubMed  PubMed Central  Google Scholar 

  18. Reveille JD, Zhou X, Lee M, Weisman MH, Yi L, Gensler LS, Zou H, Ward MM, Ishimori ML, Learch TJ, He D, Rahbar MH, Wang J, Brown MA (2019) HLA class I and II alleles in susceptibility to ankylosing spondylitis. Ann Rheum Dis 78:66–73

    Article  PubMed  CAS  Google Scholar 

  19. Reveille JD, Hirsch R, Dillon CF, Carroll MD, Weisman MH (2009) The prevalence of HLA-B27 in the US: data from the US National Health and Nutrition Examination Survey. Arthritis Rheum 64:1407–1411

    Article  Google Scholar 

  20. Akkoc N, Khan MA (2005) Overestimation of the prevalence of ankylosing spondylitis in the Berlin study: comment on the article by Braun et al. Arthritis Rheum 52:4048–4049 author reply 4049–4050

    Article  PubMed  Google Scholar 

  21. Ziade NR (2017) HLA B27 antigen in Middle Eastern and Arab countries: systematic review of the strength of association with axial spondyloarthritis and methodological gaps. BMC Musculoskelet Disord 18:280

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bennett AN, McGonagle D, O'Connor P, Hensor EM, Sivera F, Coates LC et al (2008) Severity of baseline magnetic resonance imaging-evident sacroiliitis and HLA-B27 status in early inflammatory back pain predict radiographically evident ankylosing spondylitis at eight years. Arthritis Rheum 58:3413–3418

    Article  PubMed  CAS  Google Scholar 

  23. Galocha B, López de Castro JA (2010) Mutational analysis reveals a complex interplay of peptide binding and multiple biological features of HLA-B27. J Biol Chem 285:39180–39190

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Dashti N, Mahmoudi M, Aslani S, Jamshidi A (2018) HLA-B*27 subtypes and their implications in the pathogenesis of ankylosing spondylitis. Gene 670:15–21

    Article  PubMed  CAS  Google Scholar 

  25. Cortes A, Pulit SL, Leo PJ, Pointon JJ, Robinson PC, Weisman MH, Ward M, Gensler LS, Zhou X, Garchon HJ, Chiocchia G, Nossent J, Lie BA, Førre Ø, Tuomilehto J, Laiho K, Bradbury LA, Elewaut D, Burgos-Vargas R, Stebbings S, Appleton L, Farrah C, Lau J, Haroon N, Mulero J, Blanco FJ, Gonzalez-Gay MA, Lopez-Larrea C, Bowness P, Gaffney K, Gaston H, Gladman DD, Rahman P, Maksymowych WP, Crusius JBA, van der Horst-Bruinsma IE, Valle-Oñate R, Romero-Sánchez C, Hansen IM, Pimentel-Santos FM, Inman RD, Martin J, Breban M, Wordsworth BP, Reveille JD, Evans DM, de Bakker PIW, Brown MA (2015) Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nat Commun 6:7146

    Article  PubMed  Google Scholar 

  26. Van Gaalen FA (2012) Does HLA-B*2706 protect against ankylosing spondylitis? A meta-analysis. Int J Rheum Dis 15:8–12

    Article  PubMed  Google Scholar 

  27. Lin H, Gong YZ (2017) Association of HLA-B27 with ankylosing spondylitis and clinical features of the HLA-B27-associated ankylosing spondylitis: a meta-analysis. Rheumatol Int 37:1267–1280

    Article  PubMed  CAS  Google Scholar 

  28. Robinson PC, Claushuis TA, Cortes A, Martin TM, Evans DM, Leo P et al (2015) Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis. Arthritis Rheumatol 67:140–151

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Faham M, Carlton V, Moorhead M, Zheng J, Klinger M, Pepin F, Asbury T, Vignali M, Emerson RO, Robins HS, Ireland J, Baechler-Gillespie E, Inman RD (2017) Discovery of T cell receptor β motifs specific to HLA-B27-positive ankylosing spondylitis by deep repertoire sequence analysis. Arthritis Rheumatol 69:774–784

    Article  PubMed  CAS  Google Scholar 

  30. 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 72:428–434

    Article  PubMed  CAS  Google Scholar 

  31. Navid F, Holt V, Colbert RA (2021) The enigmatic role of HLA-B*27 in spondyloarthritis pathogenesis. Semin Immunopathol. https://doi.org/10.1007/s00281-021-00838-z

  32. Jeanty C, Sourisce A, Noteuil A, Jah N, Wielgosik A, Fert I, Breban M, André C (2014) HLA–B27 subtype oligomerization and intracellular accumulation patterns correlate with predisposition to spondyloarthritis. Arthritis Rheumatol 66:2113–2123

    Article  PubMed  CAS  Google Scholar 

  33. Jah N, Jobart-Malfait A, Ermoza K, Noteuil A, Chiocchia G, Breban M, André C (2020) HLA–B27 Subtypes Predisposing to Ankylosing Spondylitis Accumulate in an Endoplasmic Reticulum–Derived Compartment Apart From the Peptide‐Loading Complex. Arthritis Rheumatol 72:1534–1546

    Article  PubMed  CAS  Google Scholar 

  34. Lim Kam Sian TCC, Indumathy S, Halim H, Greule A, Cryle MJ, Bowness P, Rossjohn J, Gras S, Purcell AW, Schittenhelm RB (2019) Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation. J Biol Chem 294:20185–20195

    Article  PubMed  PubMed Central  Google Scholar 

  35. Sahlberg AS, Ruuska M, Colbert RA, Granfors K, Penttinen MA (2012) Altered PKR signalling and C / EBPβ expression is associated with HLA-B27 expression in monocytic cells. Scand J Immunol 75:184–192

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Boyle LH, Goodall JC, Opat SS, Gaston JS (2001) The recognition of HLA-B27 by human CD4(+) T lymphocytes. J Immunol 167:2619–2624

    Article  PubMed  CAS  Google Scholar 

  37. van Gaalen FA, Verduijn W, Roelen DL, Böhringer S, Huizinga TW, van der Heijde DM et al (2013) Epistasis between two HLA antigens defines a subset of individuals at a very high risk for ankylosing spondylitis. Ann Rheum Dis 72:974–978

    Article  PubMed  Google Scholar 

  38. Londono J, Santos AM, Peña P, Calvo E, Espinosa LR, Reveille JD et al (2015) Analysis of HLA-B15 and HLA-B27 in spondyloarthritis with peripheral and axial clinical patterns. BMJ Open 5:e009092

    Article  PubMed  PubMed Central  Google Scholar 

  39. López-Larrea C, Mijiyawa M, González S, Fernández-Morera JL, Blanco-Gelaz MA, Martínez-Borra J, López-Vázquez A (2002) Association of ankylosing spondylitis with HLA-B*1403 in a West African population. Arthritis Rheum 46:2968–2971

    Article  PubMed  CAS  Google Scholar 

  40. Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, Leo P et al (2013) Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 45:730–738

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Zhou X, Wang J, Zou H, Ward MM, Weisman MH, Espitia MG, Xiao X, Petersdorf E, Mignot E, Martin J, Gensler LS, Scheet P, Reveille JD (2014) MICA, a gene contributing strong susceptibility to ankylosing spondylitis. Ann Rheum Dis 73:1552–1557

    Article  PubMed  CAS  Google Scholar 

  42. Cortes A, Gladman D, Raychaudhuri S, Cui J, Wheeler L, Brown MA et al (2018) Imputation-based analysis of MICA alleles in the susceptibility to ankylosing spondylitis. Ann Rheum Dis 77:1691–1692

    Article  PubMed  CAS  Google Scholar 

  43. Wang CM, Wang SH, Jan Wu YJ, Lin JC, Wu J, Chen JY (2017) Human leukocyte antigen C*12:02:02 and killer immunoglobulin-like receptor 2DL5 are distinctly associated with ankylosing spondylitis in the Taiwanese. Int J Mol Sci 18:1775

    Article  PubMed Central  CAS  Google Scholar 

  44. Díaz-Peña R, Castro-Santos P, Aransay AM, Brüges-Armas J, Pimentel-Santos FM, López-Larrea C (2013) Genetic study confirms association of HLA-DPA1(∗)01:03 subtype with ankylosing spondylitis in HLA-B27-positive populations. Hum Immunol 74:764–767

    Article  PubMed  CAS  Google Scholar 

  45. Huang XF, Li Z, De Guzman E, Robinson P, Gensler L, Ward MM et al (2020) Genomewide association study of acute anterior uveitis indentifies new susceptibility loci. Invest Ophthalmol Vis Sci 61:3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Ma B, Yang B, Guo H, Wang Y, Zhang D, Zhang Y, Xiao Z (2013) The association between tumor necrosis factor alpha promoter polymorphisms and ankylosing spondylitis: a meta-analysis. Hum Immunol 74:1357–1362

    Article  PubMed  CAS  Google Scholar 

  47. Reveille JD, Sims AM, Danoy P, Evans DM, Leo P, Pointon JJ et al (2010) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42:123–127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Liu J, Pu W, Li Y, Ma Y, Zhu Q, Wan W, Yang C, Wang X, Chen X, Zhou X, Reveille JD, Jin L, Zou H, Wang J (2019) Genetic association of non-MHC region with ankylosing spondylitis in a Chinese population. Ann Rheum Dis 78:852–853

    Article  PubMed  Google Scholar 

  49. Lin Z, Bei JX, Shen M, Li Q, Liao Z, Zhang Y, Lv Q, Wei Q, Low HQ, Guo YM, Cao S, Yang M, Hu Z, Xu M, Wang X, Wei Y, Li L, Li C, Li T, Huang J, Pan Y, Jin O, Wu Y, Wu J, Guo Z, He P, Hu S, Wu H, Song H, Zhan F, Liu S, Gao G, Liu Z, Li Y, Xiao C, Li J, Ye Z, He W, Liu D, Shen L, Huang A, Wu H, Tao Y, Pan X, Yu B, Tai ES, Zeng YX, Ren EC, Shen Y, Liu J, Gu J (2011) A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nat Genet 44:73–77

    Article  PubMed  CAS  Google Scholar 

  50. Tang Y, Yang P, Wang F, Xu H, Zong SY (2018) Association of polymorphisms in ERAP1 and risk of ankylosing spondylitis in a Chinese population. Gene 646:8–11

    Article  PubMed  CAS  Google Scholar 

  51. Cinar M, Akar H, Yilmaz S, Simsek I, Karkucak M, Sagkan RI, Pekel A, Erdem H, Avci IY, Acikel C, Musabak U, Tunca Y, Pay S (2013) A polymorphism in ERAP1 is associated with susceptibility to ankylosing spondylitis in a Turkish population. Rheumatol Int 33:2851–2858

    Article  PubMed  CAS  Google Scholar 

  52. Wen YF, Wei JC, Hsu YW, Chiou HY, Wong HS, Wong RH et al (2014) rs10865331 associated with susceptibility and disease severity of ankylosing spondylitis in a Taiwanese population. PLoS One 9:e104525

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. 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 43:761–767

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A et al (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39:1329–1337

    Article  PubMed  CAS  Google Scholar 

  55. Seregin SS, Rastall DP, Evnouchidou I, Aylsworth CF, Quiroga D, Kamal RP et al (2013) Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens. Autoimmunity 46:497–508

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Robinson PC, Costello ME, Leo P, Bradbury LA, Hollis K, Cortes A, Lee S, Joo KB, Shim SC, Weisman M, Ward M, Zhou X, Garchon HJ, Chiocchia G, Nossent J, Lie BA, Førre Ø, Tuomilehto J, Laiho K, Jiang L, Liu Y, Wu X, Elewaut D, Burgos-Vargas R, Gensler LS, Stebbings S, Haroon N, Mulero J, Fernandez-Sueiro JL, Gonzalez-Gay MA, Lopez-Larrea C, Bowness P, Gafney K, Gaston JSH, Gladman DD, Rahman P, Maksymowych WP, Xu H, van der Horst-Bruinsma IE, Chou CT, Valle-Oñate R, Romero-Sánchez MC, Hansen IM, Pimentel-Santos FM, Inman RD, Martin J, Breban M, Evans D, Reveille JD, Kim TH, Wordsworth BP, Brown MA (2015) ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients. Ann Rheum Dis 74:1627–1629

    Article  PubMed  CAS  Google Scholar 

  57. Yuan Y, Ma Y, Zhang X, Han R, Hu X, Yang J, Wang M, Guan SY, Pan G, Xu SQ, Jiang S, Pan F (2019) Genetic polymorphisms of G protein-coupled receptor 65 gene are associated with ankylosing spondylitis in a Chinese Han population: a case-control study. Hum Immunol 80:146–150

    Article  PubMed  CAS  Google Scholar 

  58. Ruan WF, Xie JT, Jin Q, Wang WD, Ping AS (2018) The diagnostic and prognostic role of interleukin 12B and interleukin 6R gene polymorphism in patients with ankylosing spondylitis. J Clin Rheumatol 24:18–24

    Article  PubMed  Google Scholar 

  59. Wang NG, Wang DC, Tan BY, Wang F, Yuan ZN (2015) TNF-α and IL10 polymorphisms interaction increases the risk of ankylosing spondylitis in Chinese Han population. Int J Clin Exp Pathol 8:15204–15209

    PubMed  PubMed Central  Google Scholar 

  60. Zhang X, Li X, Han R, Chen M, Yuan Y, Hu X, Wang M, Li R, Yang X, Xia Q, Ma Y, Yang J, Tong J, Xu S, Xu J, Shuai Z, Pan F (2017) Copy number variations of the IL-22 gene are associated with ankylosing spondylitis: a case-control study in Chinese Han population. Hum Immunol 78:547–552

    Article  PubMed  CAS  Google Scholar 

  61. Xia Q, Wang M, Yang X, Li X, Zhang X, Xu S, Shuai Z, Xu J, Fan D, Ding C, Pan F (2017) Autophagy-related IRGM genes confer susceptibility to ankylosing spondylitis in a Chinese female population: a case-control study. Genes Immun 18:42–47

    Article  PubMed  CAS  Google Scholar 

  62. Yang X, Li M, Wang L, Hu Z, Zhang Y, Yang Q (2015) Association of KIF21B genetic polymorphisms with ankylosing spondylitis in a Chinese Han population of Shandong Province. Clin Rheumatol 34:1729–1736

    Article  PubMed  Google Scholar 

  63. Zhai Z, Wang Z, Wang L, Chen S, Ren H, Wang D (2018) Relationship between inducible NOS single-nucleotide polymorphisms and hypertension in Han Chinese. Herz 43:461–465

    Article  PubMed  CAS  Google Scholar 

  64. Lee YH, Bae SC, Kim JH, Song GG (2015) Meta-analysis of genetic polymorphisms in programmed cell death 1. Associations with rheumatoid arthritis, ankylosing spondylitis, and type 1 diabetes susceptibility. Z Rheumatol 74:230–239

    Article  PubMed  CAS  Google Scholar 

  65. Liu X, Hu LH, Li YR, Chen FH, Ning Y, Yao QF (2011) Programmed cell death 1 gene polymorphisms is associated with ankylosing spondylitis in Chinese Han population. Rheumatol Int 31:209–213

    Article  PubMed  Google Scholar 

  66. Aita A, Basso D, Ramonda R, Moz S, Lorenzin M, Navaglia F, Zambon CF, Padoan A, Plebani M, Punzi L (2018) Genetics in TNF-TNFR pathway: A complex network causing spondyloarthritis and conditioning response to anti-TNFα therapy. PLoS One 13:e0194693

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Tsui FW, Tsui HW, Akram A, Haroon N, Inman RD (2014) The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis. Appl Clin Genet 7:105–115

    Article  PubMed  PubMed Central  Google Scholar 

  68. Wang M, Xin L, Cai G, Zhang X, Yang X, Li X, Xia Q, Wang L, Xu S, Xu J, Shuai Z, Ding C, Pan F (2017) Pathogenic variants screening in seventeen candidate genes on 2p15 for association with ankylosing spondylitis in a Han Chinese population. PLoS One 12:e0177080

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Lau MC, Keith P, Costello ME, Bradbury LA, Hollis KA, Thomas R, Thomas GP, Brown MA, Kenna TJ (2017) Genetic association of ankylosing spondylitis with TBX21 influences T-bet and pro-inflammatory cytokine expression in humans and SKG mice as a model of spondyloarthritis. Ann Rheum Dis 76:261–269

    Article  PubMed  CAS  Google Scholar 

  70. Brown MA, Wordsworth BP (2017) Genetics in ankylosing spondylitis - Current state of the art and translation into clinical outcomes. Best Pract Res Clin Rheumatol 31:763–776

    Article  PubMed  Google Scholar 

  71. Rath HC, Herfarth HH, Ikeda JS, Grenther WB, Hamm TE, Balish E et al (1996) Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. J Clin Invest 98:945–953

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Martínez A, Pacheco-Tena C, Vázquez-Mellado J, Burgos-Vargas R (2004) Relationship between disease activity and infection in patients with spondyloarthropathies. Ann Rheum Dis 63:1338–1340

    Article  PubMed  PubMed Central  Google Scholar 

  73. Rosenbaum JT, Davey MP (2011) Time for a gut check: evidence for the hypothesis that HLA-B27 predisposes to ankylosing spondylitis by altering the microbiome. Arthritis Rheum 63:3195–3198

    Article  PubMed  PubMed Central  Google Scholar 

  74. Asquith M, Sternes PR, Costello ME, Karstens L, Diamond S, Martin TM, Li Z, Marshall MS, Spector TD, Cao KA, Rosenbaum JT, Brown MA (2019) HLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influence the Gut Microbiome. Arthritis Rheumatol 71:1642–1650

    Article  PubMed  CAS  Google Scholar 

  75. Klingberg E, Magnusson MK, Strid H, Deminger A, Ståhl A, Sundin J et al (2019) A distinct gut microbiota composition in patients with ankylosing spondylitis is associated with increased levels of fecal calprotectin. Arthritis Res Ther 21:248

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Wen C, Zheng Z, Shao T, Liu L, Xie Z, Le Chatelier E et al (2017) Quantitative metagenomics reveals unique gut microbiome biomarkers in ankylosing spondylitis. Genome Biol. 18:142

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Yin J, Sternes PR, Wang M, Song J, Morrison M, Li T, Zhou L, Wu X, He F, Zhu J, Brown MA, Xu H (2020) Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy upon microbiome composition. Ann Rheum Dis 79:132–140

    Article  PubMed  CAS  Google Scholar 

  78. Breban M, Beaufrère M, Glatigny S (2019) The microbiome in spondyloarthritis. Best Pract Res Clin Rheumatol 33:101495

    Article  PubMed  Google Scholar 

  79. Rosenbaum JT, Asquith MJ (2016) The microbiome: a revolution in treatment for rheumatic diseases? Curr Rheumatol Rep 18:62

    Article  PubMed  CAS  Google Scholar 

  80. Montoya J, Matta NB, Suchon P, Guzian MC, Lambert NC, Mattei JP, Guis S, Breban M, Roudier J, Balandraud N (2016) Patients with ankylosing spondylitis have been breast fed less often than healthy controls: a case-control retrospective study. Ann Rheum Dis 75:879–882

    Article  PubMed  CAS  Google Scholar 

  81. Ebringer R, Cooke D, Cawdell DR, Cowling P, Ebringer A (1977) Ankylosing spondylitis: klebsiella and HL-A B27. Rheumatol Rehabil 16:190–196

    Article  PubMed  CAS  Google Scholar 

  82. Seager K, Bashir HV, Geczy AF, Edmonds J, de Vere-Tyndall A (1979) Evidence for a specific B27-associated cell surface marker on lymphocytes of patients with ankylosing spondylitis. Nature 277:68–70

    Article  PubMed  CAS  Google Scholar 

  83. Ebringer A (1983) The cross-tolerance hypothesis, HLA-B27 and ankylosing spondylitis. Br J Rheumatol 22(4 Suppl 2):53–66

    Article  PubMed  CAS  Google Scholar 

  84. Schwimmbeck PL, Yu DT, Oldstone MB (1987) Autoantibodies to HLA B27 in the sera of HLA B27 patients with ankylosing spondylitis and Reiter’s syndrome. Molecular mimicry with Klebsiella pneumoniae as potential mechanism of autoimmune disease. J Exp Med 166:173–181

    Article  PubMed  CAS  Google Scholar 

  85. Geczy AF, Alexander K, Bashir HV, Edmonds JP (1980) Characterization of a factor(s) present in Klebsiella culture filtrates that specifically modifies an HLA-B27-associated cell-surface component. J Exp Med 152(2 Pt 2):331 s–340 s

    CAS  Google Scholar 

  86. Puccetti A, Dolcino M, Tinazzi E, Moretta F, D'Angelo S, Olivieri I et al (2017) Antibodies directed against a peptide epitope of a Klebsiella pneumoniae-derived protein are present in ankylosing spondylitis. PLoS One 12:e0171073

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Rashid T, Wilson C, Ebringer A (2015) Raised incidence of ankylosing spondylitis among Inuit populations could be due to high HLA-B27 association and starch consumption. Rheumatol Int 35:945–951

    Article  PubMed  CAS  Google Scholar 

  88. Lindström U, Exarchou S, Lie E, Dehlin M, Forsblad-d'Elia H, Askling J et al (2016) Childhood hospitalisation with infections and later development of ankylosing spondylitis: a national case-control study. Arthritis Res Ther 18:240

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. McGonagle D, Stockwin L, Isaacs J, Emery P (2001) An enthesitis based model for the pathogenesis of spondyloarthropathy. additive effects of microbial adjuvant and biomechanical factors at disease sites. J Rheumatol 28:2155–2159

    PubMed  CAS  Google Scholar 

  90. Jacques P, Lambrecht S, Verheugen E, Pauwels E, Kollias G, Armaka M, Verhoye M, van der Linden A, Achten R, Lories RJ, Elewaut D (2014) Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Ann Rheum Dis 73:437–4454

    Article  PubMed  Google Scholar 

  91. Cuthbert RJ, Watad A, Evangelos M, Fragkakis EM, Dunsmuir R, Loughenbury P, Almas 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 78:1559–1565

    Article  PubMed  CAS  Google Scholar 

  92. Ward MM, Reveille JD, Learch TJ, Davis JC Jr, Weisman MH (2008) Occupational physical activities and long-term functional and radiographic outcomes in patients with ankylosing spondylitis. Arthritis Rheum 59:822–832

    Article  PubMed  PubMed Central  Google Scholar 

  93. Ramiro S, Landewé R, van Tubergen A, Boonen A, Stolwijk C, Dougados M, van den Bosch F, van der Heijde D (2015) Lifestyle factors may modify the effect of disease activity on radiographic progression in patients with ankylosing spondylitis: a longitudinal analysis. RMD Open 1:e000153

    Article  PubMed  PubMed Central  Google Scholar 

  94. Exarchou S, Lindstrom U, Askling J, Eriksson JK, Forsblad-d'Elia H, Neovius M et al (2015) The prevalence of clinically diagnosed ankylosing spondylitis and its clinical manifestations: a nationwide register study. Arthritis Res Ther 17:118

    Article  PubMed  PubMed Central  Google Scholar 

  95. Lee W, Reveille JD, Davis JC Jr, Learch TJ, Ward MM, Weisman MH (2007) Are there gender differences in severity of ankylosing spondylitis? Results from the PSOAS cohort. Ann Rheum Dis 66:633–638

    Article  PubMed  Google Scholar 

  96. Wang R, Gabriel SE, Ward MM (2016) Progression of nonradiographic axial spondyloarthritis to ankylosing spondylitis: a population-based cohort study. Arthritis Rheumatol 68:1415–1421

    Article  PubMed  PubMed Central  Google Scholar 

  97. Ortega Castro R, Font Ugalde P, Castro Villegas MC, Calvo Gutiérrez J, Muñoz Gomariz E, Zarco Montejo P, Almodóvar R, Mulero Mendoza J, Torre-Alonso JC, Gratacós Masmitjá J, Juanola Roura X, Ariza Ariza R, Fernández Dapica P, Linares Ferrando LF, Brito Brito ME, Cuende Quintana E, Vázquez Galeano C, Moreno Ramos MJ, Giménez Úbeda E, Rodríguez Lozano JC, Fernández Prada M, Queiro Silva R, Moreno Ruzafa E, Júdez Navarro E, Más AJ, Medrano le Quement C, Ornilla E, Montilla Morales C, Pujol Busquets M, Clavaguera Poch T, Fernández-Espartero MC, Carmona Ortell L, Collantes Estévez E (2013) Different clinical expression of patients with ankylosing spondylitis according to gender in relation to time since onset of disease. Data from REGISPONSER. Reumatol Clin 9:221–225

    Article  PubMed  Google Scholar 

  98. Park JS, Hong JY, Park YS, Han K, Suh SW (2018) Trends in the prevalence and incidence of ankylosing spondylitis in South Korea, 2010-2015 and estimated differences according to income status. Sci Rep 8:7694

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Jovaní V, Blasco-Blasco M, Ruiz-Cantero MT, Pascual E (2017) Understanding how the diagnostic delay of spondyloarthritis differs between women and men: a systematic review and metaanalysis. J Rheumatol 44:174–183

    Article  PubMed  Google Scholar 

  100. Landi M, Maldonado-Ficco H, Perez-Alamino R, Citera G, Arturi P et al (2016) Gender differences among patients with primary ankylosing spondylitis and spondylitis associated with psoriasis and inflammatory bowel disease in an iberoamerican spondyloarthritis cohort. Medicine (Baltimore) 95:e5652

    Article  CAS  Google Scholar 

  101. Webers C, Essers I, Ramiro S, Stolwijk C, Landewé R, van der Heijde D, van den Bosch F, Dougados M, van Tubergen A (2016) Gender-attributable differences in outcome of ankylosing spondylitis: long-term results from the outcome in Ankylosing Spondylitis International Study. Rheumatology (Oxford) 55:419–428

    Google Scholar 

  102. Gracey E, Yao Y, Green B, Qaiyum Z, Baglaenko Y, Lin A, Anton A, Ayearst R, Yip P, Inman RD (2016) Sexual dimorphism in the Th17 signature of ankylosing spondylitis. Arthritis Rheumatol 68:679–683

    Article  PubMed  CAS  Google Scholar 

  103. Lindström U, Forsblad-d'Elia H, Askling J, Kristensen LE, Lie E, Exarchou S et al (2016) Perinatal characteristics, older siblings, and risk of ankylosing spondylitis: a case-control study based on national registers. Arthritis Res Ther 18:16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Cai G, Wang L, Fan D, Xin L, Liu L, Hu Y, Ding N, Xu S, Xia G, Jin X, Xu J, Zou Y, Pan F (2015) Vitamin D in ankylosing spondylitis: review and meta-analysis. Clin Chim Acta 438:316–322

    Article  PubMed  CAS  Google Scholar 

  105. Videm V, Cortes A, Thomas R, Brown MA (2014) Current smoking is associated with incident ankylosing spondylitis -- the HUNT population-based Norwegian health study. J Rheumatol 41:2041–2048

    Article  PubMed  Google Scholar 

  106. Zhang H, Wan W, Liu J, Dai S, Zou Y, Qian Q, Ding Y, Xu X, Ji H, He H, Zhu Q, Yang C, Ye S, Jiang L, Tang J, Tong Q, He D, Zhao D, Li Y, Ma Y, Zhou J, Mei Z, Chen X, Yuan Z, Zhang J, Wang X, Yang Y, Jin L, Gao Y, Zhou X, Reveille JD, Zou H, Wang J (2018) Smoking quantity determines disease activity and function in Chinese patients with ankylosing spondylitis. Clin Rheumatol 37:1605–1616

    Article  PubMed  Google Scholar 

  107. Nikiphorou E, Ramiro S, Sepriano A, Ruyssen-Witrand A, Landewé RBM, van der Heijde D (2020) Do smoking and socioeconomic factors influence Imaging Outcomes in Axial Spondyloarthritis? Five-Year Data From the DESIR Cohort. Arthritis Rheumatol 72:1855–1862

    Article  PubMed  PubMed Central  Google Scholar 

  108. Lee J, Luria A, Rhodes C, Raghu H, Lingampalli N, Sharpe O, Rada B, Sohn DH, Robinson WH, Sokolove J (2017) Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis. Rheumatology (Oxford) 56:644–653

    CAS  Google Scholar 

  109. Ciccia F, Bombardieri M, Rizzo A, Principato A, Giardina AR, Raiata F, Peralta S, Ferrante A, Drago S, Cottone M, Pitzalis C, Triolo G (2010) Over-expression of Paneth cell-derived anti-microbial peptides in the gut of patients with ankylosing spondylitis and subclinical intestinal inflammation. Rheumatology (Oxford) 49:2076–2083

    Article  CAS  Google Scholar 

  110. Zambrano-Zaragoza JF, Agraz-Cibrian JM, González-Reyes C, Durán-Avelar MJ, Vibanco-Pérez N (2013) Ankylosing spondylitis: from cells to genes. Int J Inflam 2013:501653

    PubMed  PubMed Central  Google Scholar 

  111. Duan Z, Gui Y, Li C, Lin J, Gober HJ, Qin J, Li D, Wang L (2017) The immune dysfunction in ankylosing spondylitis patients. Biosci Trends 11:69–76

    Article  PubMed  CAS  Google Scholar 

  112. Ranganathan V, Ciccia F, Zeng F, Sari I, Guggino G, Muralitharan J, Gracey E, Haroon N (2017) Macrophage migration inhibitory factor induces inflammation and predicts spinal progression in ankylosing spondylitis. Arthritis Rheumatol 69:1796–1806

    Article  PubMed  CAS  Google Scholar 

  113. Brown MA, Kennedy LG, MacGregor AJ, Darke C, Duncan E, Shatford JL et al (1997) Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 40:1823–1828

    Article  PubMed  CAS  Google Scholar 

  114. EMBL-EBI. Allele Search Tool. 2020 [cited September 2020]; Available from: https://www.ebi.ac.uk/cgi-bin/ipd/imgt/hla/allele.cgi

  115. Martínez-González O, Cantero-Hinojosa J, Paule-Sastre P, Gómez-Magán JC, Salvatierra-Ríos D (1994) Intestinal permeability in patients with ankylosing spondylitis and their healthy relatives. Br J Rheumatol 33:644–647

    Article  PubMed  Google Scholar 

  116. Sharif K, Bridgewood C, Dubash S, McGonagle D (2020) Intestinal and enthesis innate immunity in early axial spondyloarthropathy. Rheumatology (Oxford) 59(Suppl4):iv67–iv78

    Article  CAS  Google Scholar 

  117. Mielants H, Veys EM, Cuvelier C, de Vos M (1988) Ileocolonoscopic findings in seronegative spondylarthropathies. Br J Rheumatol 27(Suppl 2):95–105

    Article  PubMed  Google Scholar 

  118. Klingberg E, Olerod G, Hammarsten O, Forsblad-d'Elia H (2016) The vitamin D status in ankylosing spondylitis in relation to intestinal inflammation, disease activity, and bone health: a cross-sectional study. Osteoporos Int 27:2027–2033

    Article  PubMed  CAS  Google Scholar 

  119. Ciccia F, Bombardieri M, Principato A, Giardina A, Tripodo C, Porcasi R, Peralta S, Franco V, Giardina E, Craxi A, Pitzalis C, Triolo G (2009) Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum 60:955–965

    Article  PubMed  CAS  Google Scholar 

  120. Warren RE, Brewerton DA (1980) Faecal carriage of klebsiella by patients with ankylosing spondylitis and rheumatoid arthritis. Ann Rheum Dis 39:37–44

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Stebbings S, Munro K, Simon MA, Tannock G, Highton J, Harmsen H, Welling G, Seksik P, Dore J, Grame G, Tilsala-Timisjarvi A (2002) Comparison of the faecal microflora of patients with ankylosing spondylitis and controls using molecular methods of analysis. Rheumatology (Oxford) 41:1395–1401

    Article  CAS  Google Scholar 

  122. de Vries DD, Dekker-Saeys AJ, Gyodi E, Bohm U, Ivanyi P (1992) Absence of autoantibodies to peptides shared by HLA-B27.5 and Klebsiella pneumoniae nitrogenase in serum samples from HLA-B27 positive patients with ankylosing spondylitis and Reiter’s syndrome. Ann Rheum Dis 51:783–789

    Article  PubMed  PubMed Central  Google Scholar 

  123. Mäki-Ikola O, Lehtinen K, Nissilä M, Granfors K (1994) IgM, IgA and IgG class serum antibodies against Klebsiella pneumoniae and Escherichia coli lipopolysaccharides in patients with ankylosing spondylitis. Br J Rheumatol 33:1025–1029

    Article  PubMed  Google Scholar 

  124. Kijlstra A, Luyendijk L, van der Gaag R, van Kregten E, Linssen A, Willers JM (1986) IgG and IgA immune response against klebsiella in HLA-B27-associated anterior uveitis. Br J Ophthalmol 70:85–88

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Trapani JA, McKenzie IF (1985) Klebsiella ‘modifying factor’: binding studies with HLA-B27+ and B27- lymphocytes. Ann Rheum Dis 44:169–175

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Ngo KY, Rochu D, D'Ambrosio AM, Muller JY, Lucotte G (1984) Klebsiella plasmid K21 is not involved in the aetiology of ankylosing spondylitis. Exp Clin Immunogenet 1:140–144

    PubMed  CAS  Google Scholar 

  127. Stone MA, Payne U, Schentag C, Rahman P, Pacheco-Tena C, Inman RD (2004) Comparative immune responses to candidate arthritogenic bacteria do not confirm a dominant role for Klebsiella pneumonia in the pathogenesis of familial ankylosing spondylitis. Rheumatology (Oxford) 43:148–155

    Article  CAS  Google Scholar 

  128. Sprenkels SH, Van Kregten E, Feltkamp TE (1996) IgA antibodies against Klebsiella and other Gram-negative bacteria in ankylosing spondylitis and acute anterior uveitis. Clin Rheumatol 15(Suppl 1):48–51

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Kheng Bekdache, PhD, of Health Interactions Inc, Hamilton, NJ, USA, and Shelley Maria Lindley, PhD, of SciMentum Ltd, London, UK, for providing medical writing support/editorial support.

Funding

Editorial support for this review article was sponsored by Novartis Pharmaceuticals Corporation. This review was funded by Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Rheumatology, McGovern Medical School at The University of Texas Health Science Center, 6431 Fannin, MSB 1.150, Houston, TX, 77030, USA

    Mark C. Hwang, Lauren Ridley & John D. Reveille

Authors
  1. Mark C. Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lauren Ridley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John D. Reveille
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.C. Hwang: Conceptualization, formal analysis, methodology, data curation, writing-original draft preparation; L. Ridley: Formal analysis, data curation; J.D. Reveille: Conceptualization, formal analysis, methodology, data curation, writing-original draft preparation, supervision.

Corresponding author

Correspondence to John D. Reveille.

Ethics declarations

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Disclosures

None.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

ESM 1

(DOCX 218 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hwang, M.C., Ridley, L. & Reveille, J.D. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol 40, 3079–3093 (2021). https://doi.org/10.1007/s10067-021-05679-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-021-05679-7

Keywords

Search

Navigation