UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Pathogenesis of spondyloarthritis

Authors
David T Yu, MD
Astrid van Tubergen, MD, PhD
Section Editor
Joachim Sieper, MD
Deputy Editor
Paul L Romain, MD

INTRODUCTION

The term spondyloarthritis (SpA, formerly spondyloarthropathy) refers to a group of disorders that includes ankylosing spondylitis (AS), nonradiographic axial SpA (nr-axSpA), undifferentiated spondyloarthritis (USpA), reactive arthritis, and the arthritis and spondylitis that may accompany psoriasis and inflammatory bowel diseases (IBD). SpA can also be differentiated into axial and peripheral SpA, depending upon the predominant regions of involvement. Axial SpA includes both AS and nr-axSpA, based upon the presence or absence, respectively, of abnormalities of the sacroiliac joints on plain radiography.

This topic review will focus primarily on the pathogenesis of AS, regarding which the most is known. The pathogenesis of each of the other members of the SpA family, especially nr-axSpA, is probably closely related to that of AS [1]. The clinical manifestations, diagnosis, and treatment of AS are presented separately. (See "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Assessment and treatment of ankylosing spondylitis in adults".)

The clinical aspects of the other types of SpA are also presented in detail elsewhere, as is SpA in children. (See "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults" and "Reactive arthritis" and "Clinical manifestations and diagnosis of psoriatic arthritis" and "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases" and "Spondyloarthritis in children".)

OVERVIEW OF PATHOGENESIS

Several elements are important in the pathogenesis of spondyloarthritis (SpA), a group of diseases with diverse clinical manifestations, which involve several different structures. These elements include interactions in the context of a particular genetic background between the gut microbiome, innate lymphoid cells, and the anatomic structures that are disease targets. Those structures include, for axial SpA, the entheses along the axial skeleton, and for peripheral SpA, the peripheral joints. At the sites of pathology, the major mediators are tumor necrosis factor (TNF)-alpha and interleukin (IL)-17 and IL-17A. (See 'Proinflammatory mediators validated by clinical observations' below and 'The gut microbiome, gut mucosa, and IL-23' below.)

The largest single genetic contribution is from the gene for human leukocyte antigen (HLA)-B27, but the presence of HLA-B27 is not absolutely essential. Moreover, non-HLA genes and others are also involved. (See 'Genetic factors' below.)

                
To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Dec 13, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Baeten D, Breban M, Lories R, et al. Are spondylarthritides related but distinct conditions or a single disease with a heterogeneous phenotype? Arthritis Rheum 2013; 65:12.
  2. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 2011; 31:986.
  3. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 2016; 12:49.
  4. Raychaudhuri SP, Raychaudhuri SK. Mechanistic rationales for targeting interleukin-17A in spondyloarthritis. Arthritis Res Ther 2017; 19:51.
  5. Veldhoen M. Interleukin 17 is a chief orchestrator of immunity. Nat Immunol 2017; 18:612.
  6. Poddubnyy D, Sieper J. What is the best treatment target in axial spondyloarthritis: tumour necrosis factor α, interleukin 17, or both? Rheumatology (Oxford) 2017.
  7. Ranganathan V, Gracey E, Brown MA, et al. Pathogenesis of ankylosing spondylitis - recent advances and future directions. Nat Rev Rheumatol 2017; 13:359.
  8. Spadoni I, Zagato E, Bertocchi A, et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 2015; 350:830.
  9. Jethwa H, Abraham S. The evidence for microbiome manipulation in inflammatory arthritis. Rheumatology (Oxford) 2017; 56:1452.
  10. Cypers H, Van Praet L, Varkas G, Elewaut D. Relevance of the gut/joint axis for the management of spondyloarthritis in daily clinical practice. Curr Opin Rheumatol 2014; 26:371.
  11. Van Praet L, Van den Bosch F, Mielants H, Elewaut D. Mucosal inflammation in spondylarthritides: past, present, and future. Curr Rheumatol Rep 2011; 13:409.
  12. Danoy P, Pryce K, Hadler J, et al. Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease. PLoS Genet 2010; 6:e1001195.
  13. Vieira-Sousa E, van Duivenvoorde LM, Fonseca JE, et al. Review: animal models as a tool to dissect pivotal pathways driving spondyloarthritis. Arthritis Rheumatol 2015; 67:2813.
  14. Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human microbiome. Nutr Rev 2012; 70 Suppl 1:S38.
  15. Carding S, Verbeke K, Vipond DT, et al. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis 2015; 26:26191.
  16. Franzosa EA, Huang K, Meadow JF, et al. Identifying personal microbiomes using metagenomic codes. Proc Natl Acad Sci U S A 2015; 112:E2930.
  17. Tito RY, Cypers H, Joossens M, et al. Brief Report: Dialister as a Microbial Marker of Disease Activity in Spondyloarthritis. Arthritis Rheumatol 2017; 69:114.
  18. Costello ME, Ciccia F, Willner D, et al. Brief Report: Intestinal Dysbiosis in Ankylosing Spondylitis. Arthritis Rheumatol 2015; 67:686.
  19. Breban M, Tap J, Leboime A, et al. Faecal microbiota study reveals specific dysbiosis in spondyloarthritis. Ann Rheum Dis 2017; 76:1614.
  20. Ciccia F, Guggino G, Rizzo A, et al. Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis. Ann Rheum Dis 2017; 76:1123.
  21. Sonnenberg GF, Artis D. Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 2012; 37:601.
  22. Ciccia F, Guggino G, Rizzo A, et al. Type 3 innate lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial fluid and bone marrow of patients with ankylosing spondylitis. Ann Rheum Dis 2015; 74:1739.
  23. Cuthbert RJ, Fragkakis EM, Dunsmuir R, et al. Brief Report: Group 3 Innate Lymphoid Cells in Human Enthesis. Arthritis Rheumatol 2017; 69:1816.
  24. Ciccia F, Rizzo A, Triolo G. Subclinical gut inflammation in ankylosing spondylitis. Curr Opin Rheumatol 2016; 28:89.
  25. Sherlock JP, Buckley CD, Cua DJ. The critical role of interleukin-23 in spondyloarthropathy. Mol Immunol 2014; 57:38.
  26. Taurog JD. The mystery of HLA-B27: if it isn't one thing, it's another. Arthritis Rheum 2007; 56:2478.
  27. Brown MA, Kennedy LG, MacGregor AJ, et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 1997; 40:1823.
  28. Brown MA, Laval SH, Brophy S, Calin A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000; 59:883.
  29. Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HL-A 27. Lancet 1973; 1:904.
  30. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 1973; 288:704.
  31. Reveille JD. Genetics of spondyloarthritis--beyond the MHC. Nat Rev Rheumatol 2012; 8:296.
  32. Uchanska-Ziegler B, Ziegler A, Schmieder P. Structural and dynamic features of HLA-B27 subtypes. Curr Opin Rheumatol 2013; 25:411.
  33. Reveille JD. Recent studies on the genetic basis of ankylosing spondylitis. Curr Rheumatol Rep 2009; 11:340.
  34. International ImMunoGeneTics project IMGT/HLA Database. http://www.ebi.ac.uk/ipd/imgt/hla/ (Accessed on February 12, 2014).
  35. Sorrentino R, Böckmann RA, Fiorillo MT. HLA-B27 and antigen presentation: at the crossroads between immune defense and autoimmunity. Mol Immunol 2014; 57:22.
  36. Wucherpfennig KW. Presentation of a self-peptide in two distinct conformations by a disease-associated HLA-B27 subtype. J Exp Med 2004; 199:151.
  37. D'Amato M, Fiorillo MT, Carcassi C, et al. Relevance of residue 116 of HLA-B27 in determining susceptibility to ankylosing spondylitis. Eur J Immunol 1995; 25:3199.
  38. Koh WH, Boey ML. Ankylosing spondylitis in Singapore: a study of 150 patients and a local update. Ann Acad Med Singapore 1998; 27:3.
  39. Madden DR, Gorga JC, Strominger JL, Wiley DC. The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation. Nature 1991; 353:321.
  40. Madden DR, Gorga JC, Strominger JL, Wiley DC. The three-dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC. Cell 1992; 70:1035.
  41. Yamaguchi A, Tsuchiya N, Mitsui H, et al. Association of HLA-B39 with HLA-B27-negative ankylosing spondylitis and pauciarticular juvenile rheumatoid arthritis in Japanese patients. Evidence for a role of the peptide-anchoring B pocket. Arthritis Rheum 1995; 38:1672.
  42. Bowness P. HLA-B27. Annu Rev Immunol 2015; 33:29.
  43. Ben Dror L, Barnea E, Beer I, et al. The HLA-B*2705 peptidome. Arthritis Rheum 2010; 62:420.
  44. López de Castro JA. The HLA-B27 peptidome: building on the cornerstone. Arthritis Rheum 2010; 62:316.
  45. Faham M, Carlton V, Moorhead M, et al. Discovery of T Cell Receptor β Motifs Specific to HLA-B27-Positive Ankylosing Spondylitis by Deep Repertoire Sequence Analysis. Arthritis Rheumatol 2017; 69:774.
  46. Allen RL, Bowness P, McMichael A. The role of HLA-B27 in spondyloarthritis. Immunogenetics 1999; 50:220.
  47. Allen RL, O'Callaghan CA, McMichael AJ, Bowness P. Cutting edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. J Immunol 1999; 162:5045.
  48. Shaw J, Hatano H, Kollnberger S. The biochemistry and immunology of non-canonical forms of HLA-B27. Mol Immunol 2014; 57:52.
  49. Colbert RA, DeLay ML, Layh-Schmitt G, Sowders DP. HLA-B27 misfolding and spondyloarthropathies. Prion 2009; 3:15.
  50. Mear JP, Schreiber KL, Münz C, et al. Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol 1999; 163:6665.
  51. Smith JA. The role of the unfolded protein response in axial spondyloarthritis. Clin Rheumatol 2016; 35:1425.
  52. Australo-Anglo-American Spondyloarthritis Consortium (TASC), Reveille JD, Sims AM, et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 2010; 42:123.
  53. Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium (TASC), Burton PR, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007; 39:1329.
  54. Evans DM, Spencer CC, Pointon JJ, et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 2011; 43:761.
  55. Lin Z, Bei JX, Shen M, et al. A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nat Genet 2011; 44:73.
  56. International Genetics of Ankylosing Spondylitis Consortium (IGAS), Cortes A, Hadler J, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 2013; 45:730.
  57. Brown MA, Kenna T, Wordsworth BP. Genetics of ankylosing spondylitis--insights into pathogenesis. Nat Rev Rheumatol 2016; 12:81.
  58. Brown MA, Edwards S, Hoyle E, et al. Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis. Hum Mol Genet 2000; 9:1563.
  59. Tsui HW, Inman RD, Paterson AD, et al. ANKH variants associated with ankylosing spondylitis: gender differences. Arthritis Res Ther 2005; 7:R513.
  60. Zhu X, Wang Y, Sun L, et al. A novel gene variation of TNFalpha associated with ankylosing spondylitis: a reconfirmed study. Ann Rheum Dis 2007; 66:1419.
  61. Ellinghaus D, Jostins L, Spain SL, et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet 2016; 48:510.
  62. Robinson PC, Brown MA. Genetics of ankylosing spondylitis. Mol Immunol 2014; 57:2.
  63. Kanaseki T, Blanchard N, Hammer GE, et al. ERAAP synergizes with MHC class I molecules to make the final cut in the antigenic peptide precursors in the endoplasmic reticulum. Immunity 2006; 25:795.
  64. Maksymowych WP, Chiowchanwisawakit P, Clare T, et al. Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: evidence of a relationship between inflammation and new bone formation. Arthritis Rheum 2009; 60:93.
  65. Poddubnyy D, Sieper J. Mechanism of New Bone Formation in Axial Spondyloarthritis. Curr Rheumatol Rep 2017; 19:55.
  66. Schett G, Lories RJ, D'Agostino MA, et al. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol 2017; 13:731.
  67. Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet 2017; 390:73.
  68. El-Zayadi AA, Jones EA, Churchman SM, et al. 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) 2017; 56:488.