Skip to main content
SpringerLink
Log in

Immunological Basis of Inflammatory Arthritides

  • Chapter
  • First Online:
Book cover Absolute Rheumatology Review

Abstract

In this chapter, we present the immunological basis of inflammatory arthritides, with a focus on the etiology and pathogenesis of rheumatoid arthritis (RA) and spondyloarthritides (SpA). In genetically predisposed individuals, the initial immunologic events in the pathogenesis of seropositive RA occur in the lungs, where smoking (“first hit”) triggers citrullination of lung proteins and asymptomatic production of ACPA (preclinical RA). Not well-characterized “second hits” trigger a series of immunological events (e.g., changes in the effector functions and antigen specificities of ACPA, cytokine/chemokine production, and activation of resident synovial and endothelial cells) resulting in the onset of early RA. Then, synovial cytokine networks and immune complexes induce perpetuation of synovial inflammation (established RA) with pannus formation, bone and cartilage destruction, systemic osteoporosis, and extra-articular comorbidities (premature atherosclerosis and cardiovascular events). All SpA endotypes display strong polygenic heritability, with HLA-B27 conferring the highest risk. Type 3 inflammation (IL-23/IL-17 pathway) is central in SpA pathogenesis, with IL-17 and IL-23 playing tissue/organ-specific roles. In SpA pathogenesis, there is a mechanistic link between repeated mechano-inflammation in the entheses and events occurring in the gut (gut-joint axis), such as epithelial barrier disruption, dysbiosis, intestinal inflammation, and arthritogenic priming of the immune system.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Landre-Beauvais AJ. The first description of rheumatoid arthritis. Unabridged text of the doctoral dissertation presented in 1800. Joint Bone Spine. 2001;68:130–43.

    Article  CAS  PubMed  Google Scholar 

  2. Entezami P, Fox DA, Clapham PJ, Chung KC. Historical perspective on the etiology of rheumatoid arthritis. Hand Clin. 2011;27:1–10. https://doi.org/10.1016/j.hcl.2010.09.006.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Winchester R. A golden anniversary: recognition that rheumatoid arthritis sera contain autoantibodies specific for determinants on native IgG molecules. J Immunol. 2007;178:1227–8.

    Article  CAS  PubMed  Google Scholar 

  4. Tan EM, Smolen JS. Historical observations contributing insights on etiopathogenesis of rheumatoid arthritis and role of rheumatoid factor. J Exp Med. 2016;213:1937–50. https://doi.org/10.1084/jem.20160792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Franklin EC, Holman HR, Muller-Eberhard HJ, Kunkel HG. An unusual protein component of high molecular weight in the serum of certain patients with rheumatoid arthritis. J Exp Med. 1957;105:425–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nienhuis RL, Mandema EA. New serum factor in patients with rheumatoid arthritis; the antiperinuclear factor. Ann Rheum Dis. 1964;23:302–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sebbag M, et al. The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1995;95:2672–9. https://doi.org/10.1172/jci117969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Young BJ, Mallya RK, Leslie RD, Clark CJ, Hamblin TJ. Anti-keratin antibodies in rheumatoid arthritis. Br Med J. 1979;2:97–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998;101:273–81. https://doi.org/10.1172/jci1316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Girbal-Neuhauser E, et al. The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J Immunol. 1999;162:585–94.

    CAS  PubMed  Google Scholar 

  11. Malmstrom V, Catrina AI, Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat Rev Immunol. 2017;17:60–75. https://doi.org/10.1038/nri.2016.124.

    Article  CAS  PubMed  Google Scholar 

  12. Shi J, et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci U S A. 2011;108:17372–7. https://doi.org/10.1073/pnas.1114465108.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Juarez M, et al. Identification of novel antiacetylated vimentin antibodies in patients with early inflammatory arthritis. Ann Rheum Dis. 2016;75:1099–107. https://doi.org/10.1136/annrheumdis-2014-206785.

    Article  CAS  PubMed  Google Scholar 

  14. Trouw LA, Rispens T, Toes REM. Beyond citrullination: other post-translational protein modifications in rheumatoid arthritis. Nat Rev Rheumatol. 2017;13:331–9. https://doi.org/10.1038/nrrheum.2017.15.

    Article  CAS  PubMed  Google Scholar 

  15. Nielen MM, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50:380–6. https://doi.org/10.1002/art.20018.

    Article  PubMed  Google Scholar 

  16. Catrina AI, Ytterberg AJ, Reynisdottir G, Malmstrom V, Klareskog L. Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10:645–53. https://doi.org/10.1038/nrrheum.2014.115.

    Article  CAS  PubMed  Google Scholar 

  17. Catrina AI, Joshua V, Klareskog L, Malmstrom V. Mechanisms involved in triggering rheumatoid arthritis. Immunol Rev. 2016;269:162–74. https://doi.org/10.1111/imr.12379.

    Article  CAS  PubMed  Google Scholar 

  18. Catrina AI, Svensson CI, Malmstrom V, Schett G, Klareskog L. Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis. Nat Rev Rheumatol. 2017;13:79–86. https://doi.org/10.1038/nrrheum.2016.200.

    Article  CAS  PubMed  Google Scholar 

  19. Van de Wiele T, Van Praet JT, Marzorati M, Drennan MB, Elewaut D. How the microbiota shapes rheumatic diseases. Nat Rev Rheumatol. 2016;12:398–411. https://doi.org/10.1038/nrrheum.2016.85.

    Article  CAS  PubMed  Google Scholar 

  20. Astorga GP, Williams RC Jr. Altered reactivity in mixed lymphocyte culture of lymphocytes from patients with rheumatoid arthritis. Arthritis Rheum. 1969;12:547–54.

    Article  CAS  PubMed  Google Scholar 

  21. McMichael AJ, Sasazuki T, McDevitt HO, Payne RO. Increased frequency of HLA-Cw3 and HLA-Dw4 in rheumatoid arthritis. Arthritis Rheum. 1977;20:1037–42.

    Article  CAS  PubMed  Google Scholar 

  22. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med. 1978;298:869–71. https://doi.org/10.1056/nejm197804202981602.

    Article  CAS  PubMed  Google Scholar 

  23. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30:1205–13.

    Article  CAS  PubMed  Google Scholar 

  24. Raychaudhuri S, et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012;44:291–6. https://doi.org/10.1038/ng.1076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hill JA, et al. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1∗0401 MHC class II molecule. J Immunol. 2003;171:538–41.

    Article  CAS  PubMed  Google Scholar 

  26. Scally SW, et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med. 2013;210:2569–82. https://doi.org/10.1084/jem.20131241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Okada Y, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506:376–81. https://doi.org/10.1038/nature12873.

    Article  CAS  PubMed  Google Scholar 

  28. Viatte S, Plant D, Raychaudhuri S. Genetics and epigenetics of rheumatoid arthritis. Nat Rev Rheumatol. 2013;9:141–53. https://doi.org/10.1038/nrrheum.2012.237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Karlson EW, et al. Cumulative association of 22 genetic variants with seropositive rheumatoid arthritis risk. Ann Rheum Dis. 2010;69:1077–85. https://doi.org/10.1136/ard.2009.120170.

    Article  CAS  PubMed  Google Scholar 

  30. Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;46:183–96. https://doi.org/10.1016/j.immuni.2017.02.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Barturen G, Beretta L, Cervera R, Van Vollenhoven R, Alarcon-Riquelme ME. Moving towards a molecular taxonomy of autoimmune rheumatic diseases. Nat Rev Rheumatol. 2018;14:180. https://doi.org/10.1038/nrrheum.2018.23.

    Article  PubMed  Google Scholar 

  32. Padyukov L, et al. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann Rheum Dis. 2011;70:259–65. https://doi.org/10.1136/ard.2009.126821.

    Article  PubMed  Google Scholar 

  33. Viatte S, et al. Replication of associations of genetic loci outside the HLA region with susceptibility to anti-cyclic citrullinated peptide-negative rheumatoid arthritis. Arthritis Rheumatol. 2016;68:1603–13. https://doi.org/10.1002/art.39619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Okada Y, Eyre S, Suzuki A, Kochi Y, Yamamoto K. Genetics of rheumatoid arthritis: 2018 status. Ann Rheum Dis. 2018; https://doi.org/10.1136/annrheumdis-2018-213678.

    Article  PubMed  Google Scholar 

  35. Maurano MT, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science (New York, NY). 2012;337:1190–5. https://doi.org/10.1126/science.1222794.

    Article  CAS  Google Scholar 

  36. Chakravarty SD, Poulikakos PI, Ivashkiv LB, Salmon JE, Kalliolias GD. Kinase inhibitors: a new tool for the treatment of rheumatoid arthritis. Clin Immunol. 2013;148:66–78. https://doi.org/10.1016/j.clim.2013.04.007.

    Article  CAS  PubMed  Google Scholar 

  37. Frisell T, Saevarsdottir S, Askling J. Family history of rheumatoid arthritis: an old concept with new developments. Nat Rev Rheumatol. 2016;12:335–43. https://doi.org/10.1038/nrrheum.2016.52.

    Article  CAS  PubMed  Google Scholar 

  38. Alpizar-Rodriguez D, Finckh A. Environmental factors and hormones in the development of rheumatoid arthritis. Semin Immunopathol. 2017;39:461–8. https://doi.org/10.1007/s00281-017-0624-2.

    Article  CAS  PubMed  Google Scholar 

  39. Vessey MP, Villard-Mackintosh L, Yeates D. Oral contraceptives, cigarette smoking and other factors in relation to arthritis. Contraception. 1987;35:457–64.

    Article  CAS  PubMed  Google Scholar 

  40. Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 2004;50:3085–92. https://doi.org/10.1002/art.20553.

    Article  CAS  PubMed  Google Scholar 

  41. Kallberg H, et al. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet. 2007;80:867–75. https://doi.org/10.1086/516736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Linn-Rasker SP, et al. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis. 2006;65:366–71. https://doi.org/10.1136/ard.2005.041079.

    Article  CAS  PubMed  Google Scholar 

  43. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016;12:49–62. https://doi.org/10.1038/nrrheum.2015.169.

    Article  CAS  PubMed  Google Scholar 

  44. Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet. 1989;2:244–7.

    Article  CAS  PubMed  Google Scholar 

  45. Haworth C, et al. Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-alpha. Eur J Immunol. 1991;21:2575–9. https://doi.org/10.1002/eji.1830211039.

    Article  CAS  PubMed  Google Scholar 

  46. Elliott MJ, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 1993;36:1681–90.

    Article  CAS  PubMed  Google Scholar 

  47. Charles P, et al. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J Immunol. 1999;163:1521–8.

    CAS  PubMed  Google Scholar 

  48. Schett G, Elewaut D, McInnes IB, Dayer JM, Neurath MF. How cytokine networks fuel inflammation: toward a cytokine-based disease taxonomy. Nat Med. 2013;19:822–4. https://doi.org/10.1038/nm.3260.

    Article  CAS  PubMed  Google Scholar 

  49. Burmester GR, et al. A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2017;76:1020–30. https://doi.org/10.1136/annrheumdis-2016-210624.

    Article  CAS  PubMed  Google Scholar 

  50. Kalliolias GD, Liossis SN. The future of the IL-1 receptor antagonist anakinra: from rheumatoid arthritis to adult-onset Still’s disease and systemic-onset juvenile idiopathic arthritis. Expert Opin Investig Drugs. 2008;17:349–59. https://doi.org/10.1517/13543784.17.3.349.

    Article  CAS  PubMed  Google Scholar 

  51. Genovese MC, et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis. 2013;72:863–9. https://doi.org/10.1136/annrheumdis-2012-201601.

    Article  CAS  PubMed  Google Scholar 

  52. Smolen JS, et al. A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. Ann Rheum Dis. 2017;76:831–9. https://doi.org/10.1136/annrheumdis-2016-209831.

    Article  CAS  PubMed  Google Scholar 

  53. Shim JH, Stavre Z, Gravallese EM. Bone loss in rheumatoid arthritis: basic mechanisms and clinical implications. Calcif Tissue Int. 2018;102:533–46. https://doi.org/10.1007/s00223-017-0373-1.

    Article  CAS  PubMed  Google Scholar 

  54. Takayanagi H. New developments in osteoimmunology. Nat Rev Rheumatol. 2012;8:684–9. https://doi.org/10.1038/nrrheum.2012.167.

    Article  CAS  PubMed  Google Scholar 

  55. Lacey DL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165–76.

    Article  CAS  PubMed  Google Scholar 

  56. Gravallese EM, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 2000;43:250–8. https://doi.org/10.1002/1529-0131(200002)43:2<250::Aid-anr3>3.0.Co;2-p.

    Article  CAS  PubMed  Google Scholar 

  57. Takayanagi H, et al. Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum. 2000;43:259–69. https://doi.org/10.1002/1529-0131(200002)43:2<259::Aid-anr4>3.0.Co;2-w.

    Article  CAS  PubMed  Google Scholar 

  58. Kotake S, et al. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum. 2001;44:1003–12. https://doi.org/10.1002/1529-0131(200105)44:5<1003::Aid-anr179>3.0.Co;2-#.

    Article  CAS  PubMed  Google Scholar 

  59. Gravallese EM, et al. Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol. 1998;152:943–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Cohen SB, et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum. 2008;58:1299–309. https://doi.org/10.1002/art.23417.

    Article  CAS  PubMed  Google Scholar 

  61. Kleyer A, et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis. 2014;73:854–60. https://doi.org/10.1136/annrheumdis-2012-202958.

    Article  PubMed  Google Scholar 

  62. Harre U, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest. 2012;122:1791–802. https://doi.org/10.1172/jci60975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Krishnamurthy A, et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann Rheum Dis. 2016;75:721–9. https://doi.org/10.1136/annrheumdis-2015-208093.

    Article  CAS  PubMed  Google Scholar 

  64. Wigerblad G, et al. Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Ann Rheum Dis. 2016;75:730–8. https://doi.org/10.1136/annrheumdis-2015-208094.

    Article  CAS  PubMed  Google Scholar 

  65. Negishi-Koga T, et al. Immune complexes regulate bone metabolism through FcRgamma signalling. Nat Commun. 2015;6:6637. https://doi.org/10.1038/ncomms7637.

    Article  CAS  PubMed  Google Scholar 

  66. Harre U, et al. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat Commun. 2015;6:6651. https://doi.org/10.1038/ncomms7651.

    Article  CAS  PubMed  Google Scholar 

  67. Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8:656–64. https://doi.org/10.1038/nrrheum.2012.153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Walsh NC, et al. Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis. J Bone Miner Res. 2009;24:1572–85. https://doi.org/10.1359/jbmr.090320.

    Article  CAS  PubMed  Google Scholar 

  69. Matzelle MM, et al. Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis Rheum. 2012;64:1540–50. https://doi.org/10.1002/art.33504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Baum R, Gravallese EM. Impact of inflammation on the osteoblast in rheumatic diseases. Curr Osteoporos Rep. 2014;12:9–16. https://doi.org/10.1007/s11914-013-0183-y.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Diarra D, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13:156–63. https://doi.org/10.1038/nm1538.

    Article  CAS  PubMed  Google Scholar 

  72. Wang SY, et al. Circulating Dickkopf-1 is correlated with bone erosion and inflammation in rheumatoid arthritis. J Rheumatol. 2011;38:821–7. https://doi.org/10.3899/jrheum.100089.

    Article  CAS  PubMed  Google Scholar 

  73. Heiland GR, et al. Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. Ann Rheum Dis. 2010;69:2152–9. https://doi.org/10.1136/ard.2010.132852.

    Article  CAS  PubMed  Google Scholar 

  74. Chen XX, et al. Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis. Ann Rheum Dis. 2013;72:1732–6. https://doi.org/10.1136/annrheumdis-2013-203345.

    Article  CAS  PubMed  Google Scholar 

  75. Lee DM, et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science (New York, NY). 2007;315:1006–10. https://doi.org/10.1126/science.1137306.

    Article  CAS  Google Scholar 

  76. Muller-Ladner U, et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol. 1996;149:1607–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Lefevre S, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med. 2009;15:1414–20. https://doi.org/10.1038/nm.2050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bucala R, Ritchlin C, Winchester R, Cerami A. Constitutive production of inflammatory and mitogenic cytokines by rheumatoid synovial fibroblasts. J Exp Med. 1991;173:569–74.

    Article  CAS  PubMed  Google Scholar 

  79. Lee A, et al. Tumor necrosis factor alpha induces sustained signaling and a prolonged and unremitting inflammatory response in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2013;65:928–38. https://doi.org/10.1002/art.37853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Nakano K, Whitaker JW, Boyle DL, Wang W, Firestein GS. DNA methylome signature in rheumatoid arthritis. Ann Rheum Dis. 2013;72:110–7. https://doi.org/10.1136/annrheumdis-2012-201526.

    Article  CAS  PubMed  Google Scholar 

  81. Ai R, et al. DNA Methylome signature in synoviocytes from patients with early rheumatoid arthritis compared to synoviocytes from patients with longstanding rheumatoid arthritis. Arthritis Rheumatol. 2015;67:1978–80. https://doi.org/10.1002/art.39123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Karouzakis E, Gay RE, Michel BA, Gay S, Neidhart M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2009;60:3613–22. https://doi.org/10.1002/art.25018.

    Article  CAS  PubMed  Google Scholar 

  83. Sohn C, et al. Prolonged tumor necrosis factor alpha primes fibroblast-like synoviocytes in a gene-specific manner by altering chromatin. Arthritis Rheumatol. 2015;67:86–95. https://doi.org/10.1002/art.38871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ai R, et al. Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat Commun. 2018;9:1921. https://doi.org/10.1038/s41467-018-04310-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Doody KM, Bottini N, Firestein GS. Epigenetic alterations in rheumatoid arthritis fibroblast-like synoviocytes. Epigenomics. 2017;9:479–92. https://doi.org/10.2217/epi-2016-0151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol. 2013;9:24–33. https://doi.org/10.1038/nrrheum.2012.190.

    Article  CAS  PubMed  Google Scholar 

  87. McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet. 2017;389:2328–37. https://doi.org/10.1016/s0140-6736(17)31472-1.

    Article  CAS  PubMed  Google Scholar 

  88. Feldmann M, Williams RO, Paleolog E. What have we learnt from targeted anti-TNF therapy? Ann Rheum Dis. 2010;69(Suppl 1):i97–9. https://doi.org/10.1136/ard.2009.117143.

    Article  CAS  PubMed  Google Scholar 

  89. Dakin SG, et al. Pathogenic stromal cells as therapeutic targets in joint inflammation. Nat Rev Rheumatol. 2018;14:714–26. https://doi.org/10.1038/s41584-018-0112-7.

    Article  PubMed  Google Scholar 

  90. Arend WP, Firestein GS. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat Rev Rheumatol. 2012;8:573–86. https://doi.org/10.1038/nrrheum.2012.134.

    Article  CAS  PubMed  Google Scholar 

  91. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–19. https://doi.org/10.1056/NEJMra1004965.

    Article  CAS  PubMed  Google Scholar 

  92. Smolen JS, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18001. https://doi.org/10.1038/nrdp.2018.1.

    Article  PubMed  Google Scholar 

  93. Noss EH, Brenner MB. The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis. Immunol Rev. 2008;223:252–70. https://doi.org/10.1111/j.1600-065X.2008.00648.x.

    Article  CAS  PubMed  Google Scholar 

  94. Matsumoto I, et al. How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat Immunol. 2002;3:360–5. https://doi.org/10.1038/ni772.

    Article  CAS  PubMed  Google Scholar 

  95. Schett G, Firestein GS. Mr outside and Mr inside: classic and alternative views on the pathogenesis of rheumatoid arthritis. Ann Rheum Dis. 2010;69:787–9. https://doi.org/10.1136/ard.2009.121657.

    Article  PubMed  Google Scholar 

  96. Murakami M, et al. Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells. J Exp Med. 2011;208:103–14. https://doi.org/10.1084/jem.20100900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Rombouts Y, et al. Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis. Ann Rheum Dis. 2015;74:234–41. https://doi.org/10.1136/annrheumdis-2013-203565.

    Article  CAS  PubMed  Google Scholar 

  98. Ioan-Facsinay A, et al. Marked differences in fine specificity and isotype usage of the anti-citrullinated protein antibody in health and disease. Arthritis Rheum. 2008;58:3000–8. https://doi.org/10.1002/art.23763.

    Article  PubMed  Google Scholar 

  99. Moll JM, Haslock I, Macrae IF, Wright V. Associations between ankylosing spondylitis, psoriatic arthritis, Reiter’s disease, the intestinal arthropathies, and Behcet’s syndrome. Medicine. 1974;53:343–64.

    Article  CAS  PubMed  Google Scholar 

  100. Taurog JD, Chhabra A, Colbert RA. Ankylosing spondylitis and axial spondyloarthritis. N Engl J Med. 2016;374:2563–74. https://doi.org/10.1056/NEJMra1406182.

    Article  PubMed  Google Scholar 

  101. Ritchlin CT, Colbert RA, Gladman D. Psoriatic arthritis. N Engl J Med. 2017;376:957–70. https://doi.org/10.1056/NEJMra1505557.

    Article  PubMed  Google Scholar 

  102. Peluso R, et al. Enteropathic spondyloarthritis: from diagnosis to treatment. Clin Dev Immunol. 2013;2013:631408. https://doi.org/10.1155/2013/631408.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Schmitt S, Reactive K. Arthritis. Infect Dis Clin N Am. 2017;31:265–77. https://doi.org/10.1016/j.idc.2017.01.002.

    Article  Google Scholar 

  104. Zochling J, Brandt J, Braun J. The current concept of spondyloarthritis with special emphasis on undifferentiated spondyloarthritis. Rheumatology (Oxford). 2005;44:1483–91. https://doi.org/10.1093/rheumatology/kei047.

    Article  CAS  Google Scholar 

  105. Gmuca S, Weiss PF. Juvenile spondyloarthritis. Curr Opin Rheumatol. 2015;27:364–72. https://doi.org/10.1097/bor.0000000000000185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bowness P. HLA-B27. Annu Rev Immunol. 2015;33:29–48. https://doi.org/10.1146/annurev-immunol-032414-112110.

    Article  CAS  PubMed  Google Scholar 

  107. Schett G, et al. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol. 2017;13:731–41. https://doi.org/10.1038/nrrheum.2017.188.

    Article  CAS  PubMed  Google Scholar 

  108. Gravallese EM, Schett G. Effects of the IL-23-IL-17 pathway on bone in spondyloarthritis. Nat Rev Rheumatol. 2018;14:631–40. https://doi.org/10.1038/s41584-018-0091-8.

    Article  CAS  PubMed  Google Scholar 

  109. Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017;390:73–84. https://doi.org/10.1016/s0140-6736(16)31591-4.

    Article  PubMed  Google Scholar 

  110. Sieper J, Braun J, Dougados M, Baeten D. Axial spondyloarthritis. Nat Rev Dis Primers. 2015;1:15013. https://doi.org/10.1038/nrdp.2015.13.

    Article  PubMed  Google Scholar 

  111. Gladman DD. Editorial: what is peripheral spondyloarthritis? Arthritis Rheumatol. 2015;67:865–8. https://doi.org/10.1002/art.39014.

    Article  PubMed  Google Scholar 

  112. Sieper J, van der Heijde D. Review: nonradiographic axial spondyloarthritis: new definition of an old disease? Arthritis Rheum. 2013;65:543–51. https://doi.org/10.1002/art.37803.

    Article  PubMed  Google Scholar 

  113. de BJ, Polman A, de B-M. Hereditary factors in rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis. 1961;20:215–20.

    Article  Google Scholar 

  114. Brewerton DA, et al. Ankylosing spondylitis and HL-A 27. Lancet. 1973;1:904–7.

    Article  CAS  PubMed  Google Scholar 

  115. Caffrey MF, James DC. Human lymphocyte antigen association in ankylosing spondylitis. Nature. 1973;242:121.

    Article  CAS  PubMed  Google Scholar 

  116. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med. 1973;288:704–6. https://doi.org/10.1056/nejm197304052881403.

    Article  CAS  PubMed  Google Scholar 

  117. Brown MA, et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum. 1997;40:1823–8. https://doi.org/10.1002/1529-0131(199710)40:10<1823::Aid-art15>3.0.Co;2-1.

    Article  CAS  PubMed  Google Scholar 

  118. Brown MA, Kenna T, Wordsworth BP. Genetics of ankylosing spondylitis--insights into pathogenesis. Nat Rev Rheumatol. 2016;12:81–91. https://doi.org/10.1038/nrrheum.2015.133.

    Article  CAS  PubMed  Google Scholar 

  119. Costantino F, Breban M, Garchon HJ. Genetics and functional genomics of Spondyloarthritis. Front Immunol. 2018;9:2933. https://doi.org/10.3389/fimmu.2018.02933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Burton PR, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39:1329–37. https://doi.org/10.1038/ng.2007.17.

    Article  CAS  PubMed  Google Scholar 

  121. Reveille JD, et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010;42:123–7. https://doi.org/10.1038/ng.513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lin Z, et al. A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nat Genet. 2011;44:73–7. https://doi.org/10.1038/ng.1005.

    Article  CAS  PubMed  Google Scholar 

  123. Cortes A, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet. 2013;45:730–8. https://doi.org/10.1038/ng.2667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ellinghaus D, et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet. 2016;48:510–8. https://doi.org/10.1038/ng.3528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Danoy P, et al. Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn’s disease. PLoS Genet. 2010;6:e1001195. https://doi.org/10.1371/journal.pgen.1001195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Sarin R, Wu X, Abraham C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc Natl Acad Sci U S A. 2011;108:9560–5. https://doi.org/10.1073/pnas.1017854108.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Vecellio M, et al. The genetic association of RUNX3 with ankylosing spondylitis can be explained by allele-specific effects on IRF4 recruitment that alter gene expression. Ann Rheum Dis. 2016;75:1534–40. https://doi.org/10.1136/annrheumdis-2015-207490.

    Article  CAS  PubMed  Google Scholar 

  128. Jostins L, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–24. https://doi.org/10.1038/nature11582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Cortes A, et al. Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nat Commun. 2015;6:7146. https://doi.org/10.1038/ncomms8146.

    Article  PubMed  Google Scholar 

  130. Dashti N, Mahmoudi M, Aslani S, Jamshidi A. HLA-B∗27 subtypes and their implications in the pathogenesis of ankylosing spondylitis. Gene. 2018;670:15–21. https://doi.org/10.1016/j.gene.2018.05.092.

    Article  CAS  PubMed  Google Scholar 

  131. Schittenhelm RB, Sivaneswaran S, Lim Kam Sian TC, Croft NP, Purcell AW. Human leukocyte antigen (HLA) B27 allotype-specific binding and candidate arthritogenic peptides revealed through heuristic clustering of data-independent acquisition mass spectrometry (DIA-MS) data. Mol Cell Proteomics. 2016;15:1867–76. https://doi.org/10.1074/mcp.M115.056358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Lopez de Castro JA. How ERAP1 and ERAP2 shape the peptidomes of disease-associated MHC-I proteins. Front Immunol. 2018;9:2463. https://doi.org/10.3389/fimmu.2018.02463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Chang SC, Momburg F, Bhutani N, Goldberg AL. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc Natl Acad Sci U S A. 2005;102:17107–12. https://doi.org/10.1073/pnas.0500721102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Faham M, et al. Discovery of T cell receptor beta motifs specific to HLA-B27-positive ankylosing spondylitis by deep repertoire sequence analysis. Arthritis Rheumatol. 2017;69:774–84. https://doi.org/10.1002/art.40028.

    Article  CAS  PubMed  Google Scholar 

  135. May E, et al. CD8 alpha beta T cells are not essential to the pathogenesis of arthritis or colitis in HLA-B27 transgenic rats. J Immunol. 2003;170:1099–105.

    Article  CAS  PubMed  Google Scholar 

  136. Taurog JD, et al. Spondylarthritis in HLA-B27/human beta2-microglobulin-transgenic rats is not prevented by lack of CD8. Arthritis Rheum. 2009;60:1977–84. https://doi.org/10.1002/art.24599.

    Article  CAS  PubMed  Google Scholar 

  137. Khare SD, et al. Spontaneous inflammatory disease in HLA-B27 transgenic mice does not require transporter of antigenic peptides. Clin Immunol. 2001;98:364–9. https://doi.org/10.1006/clim.2000.4984.

    Article  CAS  PubMed  Google Scholar 

  138. Mear JP, 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;163:6665–70.

    CAS  PubMed  Google Scholar 

  139. Dangoria NS, et al. HLA-B27 misfolding is associated with aberrant intermolecular disulfide bond formation (dimerization) in the endoplasmic reticulum. J Biol Chem. 2002;277:23459–68. https://doi.org/10.1074/jbc.M110336200.

    Article  CAS  PubMed  Google Scholar 

  140. Turner MJ, Delay ML, Bai S, Klenk E, Colbert RA. HLA-B27 up-regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: implications for the pathogenesis of spondylarthritis-like disease. Arthritis Rheum. 2007;56:215–23. https://doi.org/10.1002/art.22295.

    Article  PubMed  Google Scholar 

  141. DeLay ML, et al. HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum. 2009;60:2633–43. https://doi.org/10.1002/art.24763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Guiliano DB, et al. Polymorphisms in the F pocket of HLA-B27 subtypes strongly affect assembly, chaperone interactions, and heavy-chain Misfolding. Arthritis Rheumatol. 2017;69:610–21. https://doi.org/10.1002/art.39948.

    Article  CAS  PubMed  Google Scholar 

  143. Zhang Z, et al. Brief report: functional interaction of endoplasmic reticulum Aminopeptidase 2 and HLA-B27 activates the unfolded protein response. Arthritis Rheumatol. 2017;69:1009–15. https://doi.org/10.1002/art.40033.

    Article  CAS  PubMed  Google Scholar 

  144. Ciccia F, et al. Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation. Ann Rheum Dis. 2014;73:1566–74. https://doi.org/10.1136/annrheumdis-2012-202925.

    Article  CAS  PubMed  Google Scholar 

  145. 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;162:5045–8.

    CAS  PubMed  Google Scholar 

  146. Kollnberger S, et al. HLA-B27 heavy chain homodimers are expressed in HLA-B27 transgenic rodent models of spondyloarthritis and are ligands for paired Ig-like receptors. J Immunol. 2004;173:1699–710.

    Article  CAS  PubMed  Google Scholar 

  147. Kollnberger S, et al. Cell-surface expression and immune receptor recognition of HLA-B27 homodimers. Arthritis Rheum. 2002;46:2972–82. https://doi.org/10.1002/art.10605.

    Article  CAS  PubMed  Google Scholar 

  148. Wong-Baeza I, et al. KIR3DL2 binds to HLA-B27 dimers and free H chains more strongly than other HLA class I and promotes the expansion of T cells in ankylosing spondylitis. J Immunol. 2013;190:3216–24. https://doi.org/10.4049/jimmunol.1202926.

    Article  CAS  PubMed  Google Scholar 

  149. Cauli A, et al. The arthritis-associated HLA-B∗27:05 allele forms more cell surface B27 dimer and free heavy chain ligands for KIR3DL2 than HLA-B∗27:09. Rheumatology (Oxford). 2013;52:1952–62. https://doi.org/10.1093/rheumatology/ket219.

    Article  CAS  Google Scholar 

  150. Ridley A, et al. Activation-induced killer cell immunoglobulin-like receptor 3DL2 binding to HLA-B27 licenses pathogenic T cell differentiation in spondyloarthritis. Arthritis Rheumatol. 2016;68:901–14. https://doi.org/10.1002/art.39515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Mielants H, Veys EM, De Vos M, Cuvelier C. Increased intestinal permeability in ankylosing spondylitis. Gut. 1992;33:1150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Van Praet L, Jacques P, Van den Bosch F, Elewaut D. The transition of acute to chronic bowel inflammation in spondyloarthritis. Nat Rev Rheumatol. 2012;8:288–95. https://doi.org/10.1038/nrrheum.2012.42.

    Article  CAS  PubMed  Google Scholar 

  153. Taurog JD, et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med. 1994;180:2359–64.

    Article  CAS  PubMed  Google Scholar 

  154. Rehaume LM, et al. ZAP-70 genotype disrupts the relationship between microbiota and host, leading to spondyloarthritis and ileitis in SKG mice. Arthritis Rheumatol. 2014;66:2780–92. https://doi.org/10.1002/art.38773.

    Article  CAS  PubMed  Google Scholar 

  155. Costello ME, et al. Brief report: intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol. 2015;67:686–91. https://doi.org/10.1002/art.38967.

    Article  PubMed  Google Scholar 

  156. Breban M, et al. Faecal microbiota study reveals specific dysbiosis in spondyloarthritis. Ann Rheum Dis. 2017;76:1614–22. https://doi.org/10.1136/annrheumdis-2016-211064.

    Article  CAS  PubMed  Google Scholar 

  157. Lin P, et al. HLA-B27 and human beta2-microglobulin affect the gut microbiota of transgenic rats. PLoS One. 2014;9:e105684. https://doi.org/10.1371/journal.pone.0105684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Asquith M, et al. Intestinal metabolites are profoundly altered in the context of HLA-B27 expression and functionally modulate disease in a rat model of spondyloarthritis. Arthritis Rheumatol. 2017;69:1984–95. https://doi.org/10.1002/art.40183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ciccia F, Rizzo A, Triolo G. Subclinical gut inflammation in ankylosing spondylitis. Curr Opin Rheumatol. 2016;28:89–96. https://doi.org/10.1097/bor.0000000000000239.

    Article  CAS  PubMed  Google Scholar 

  160. Van Praet L, et al. Degree of bone marrow oedema in sacroiliac joints of patients with axial spondyloarthritis is linked to gut inflammation and male sex: results from the GIANT cohort. Ann Rheum Dis. 2014;73:1186–9. https://doi.org/10.1136/annrheumdis-2013-203854.

    Article  PubMed  Google Scholar 

  161. Van Praet L, et al. Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model. Ann Rheum Dis. 2013;72:414–7. https://doi.org/10.1136/annrheumdis-2012-202135.

    Article  PubMed  Google Scholar 

  162. Ciccia F, et al. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheum. 2012;64:1869–78. https://doi.org/10.1002/art.34355.

    Article  CAS  PubMed  Google Scholar 

  163. Ciccia F, et al. Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum. 2009;60:955–65. https://doi.org/10.1002/art.24389.

    Article  CAS  PubMed  Google Scholar 

  164. Ciccia F, 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;74:1739–47. https://doi.org/10.1136/annrheumdis-2014-206323.

    Article  CAS  PubMed  Google Scholar 

  165. Venken K, et al. RORgammat inhibition selectively targets IL-17 producing iNKT and gammadelta-T cells enriched in Spondyloarthritis patients. Nat Commun. 2019;10:9. https://doi.org/10.1038/s41467-018-07911-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Taams LS, Steel KJA, Srenathan U, Burns LA, Kirkham BW. IL-17 in the immunopathogenesis of spondyloarthritis. Nat Rev Rheumatol. 2018;14:453–66. https://doi.org/10.1038/s41584-018-0044-2.

    Article  CAS  PubMed  Google Scholar 

  167. Rizzo A, Guggino G, Ferrante A, Ciccia F. Role of subclinical gut inflammation in the pathogenesis of spondyloarthritis. Front Med. 2018;5:63. https://doi.org/10.3389/fmed.2018.00063.

    Article  Google Scholar 

  168. Gracey E, et al. IL-7 primes IL-17 in mucosal-associated invariant T (MAIT) cells, which contribute to the Th17-axis in ankylosing spondylitis. Ann Rheum Dis. 2016;75:2124–32. https://doi.org/10.1136/annrheumdis-2015-208902.

    Article  CAS  PubMed  Google Scholar 

  169. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Immunity. 2018;48:1104–17. https://doi.org/10.1016/j.immuni.2018.05.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Paulissen SM, et al. Synovial fibroblasts directly induce Th17 pathogenicity via the cyclooxygenase/prostaglandin E2 pathway, independent of IL-23. J Immunol. 2013;191:1364–72. https://doi.org/10.4049/jimmunol.1300274.

    Article  CAS  PubMed  Google Scholar 

  171. Hasegawa E, et al. IL-23-independent induction of IL-17 from gammadeltaT cells and innate lymphoid cells promotes experimental intraocular neovascularization. J Immunol. 2013;190:1778–87. https://doi.org/10.4049/jimmunol.1202495.

    Article  CAS  PubMed  Google Scholar 

  172. Lee JS, et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity. 2015;43:727–38. https://doi.org/10.1016/j.immuni.2015.09.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. van Tok MN, et al. The initiation, but not the persistence, of experimental spondyloarthritis is dependent on interleukin-23 signaling. Front Immunol. 2018;9:1550. https://doi.org/10.3389/fimmu.2018.01550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Yao C, et al. Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion. Nat Med. 2009;15:633–40. https://doi.org/10.1038/nm.1968.

    Article  CAS  PubMed  Google Scholar 

  175. Esaki Y, et al. Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2010;107:12233–8. https://doi.org/10.1073/pnas.0915112107.

    Article  PubMed  PubMed Central  Google Scholar 

  176. Boniface K, et al. Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. J Exp Med. 2009;206:535–48. https://doi.org/10.1084/jem.20082293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Sherlock JP, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18:1069–76. https://doi.org/10.1038/nm.2817.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  179. Mei Y, et al. Increased serum IL-17 and IL-23 in the patient with ankylosing spondylitis. Clin Rheumatol. 2011;30:269–73. https://doi.org/10.1007/s10067-010-1647-4.

    Article  PubMed  Google Scholar 

  180. Taylan A, et al. Evaluation of the T helper 17 axis in ankylosing spondylitis. Rheumatol Int. 2012;32:2511–5. https://doi.org/10.1007/s00296-011-1995-7.

    Article  CAS  PubMed  Google Scholar 

  181. Toussirot E, Laheurte C, Gaugler B, Gabriel D, Saas P. Increased IL-22- and IL-17A-producing mucosal-associated invariant T cells in the peripheral blood of patients with ankylosing spondylitis. Front Immunol. 2018;9:1610. https://doi.org/10.3389/fimmu.2018.01610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Siebert S, Millar NL, McInnes IB. Why did IL-23p19 inhibition fail in AS: a tale of tissues, trials or translation? Ann Rheum Dis. 2018; https://doi.org/10.1136/annrheumdis-2018-213654.

    Article  PubMed  Google Scholar 

  183. Baeten D, et al. Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study. Ann Rheum Dis. 2018;77:1295–302. https://doi.org/10.1136/annrheumdis-2018-213328.

    Article  CAS  PubMed  Google Scholar 

  184. Deodhar A, et al. Three multicenter, randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of ustekinumab in axial spondyloarthritis. Arthritis Rheumatol. 2019;71:258–70. https://doi.org/10.1002/art.40728.

    Article  CAS  PubMed  Google Scholar 

  185. Targan SR, et al. A randomized, double-blind, placebo-controlled phase 2 study of brodalumab in patients with moderate-to-severe Crohn’s disease. Am J Gastroenterol. 2016;111:1599–607. https://doi.org/10.1038/ajg.2016.298.

    Article  CAS  PubMed  Google Scholar 

  186. Hueber W, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61:1693–700. https://doi.org/10.1136/gutjnl-2011-301668.

    Article  CAS  PubMed  Google Scholar 

  187. Langley RG, et al. Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med. 2014;371:326–38. https://doi.org/10.1056/NEJMoa1314258.

    Article  CAS  PubMed  Google Scholar 

  188. Griffiths CE, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386:541–51. https://doi.org/10.1016/s0140-6736(15)60125-8.

    Article  CAS  PubMed  Google Scholar 

  189. Gordon KB, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375:345–56. https://doi.org/10.1056/NEJMoa1512711.

    Article  CAS  PubMed  Google Scholar 

  190. Lebwohl M, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318–28. https://doi.org/10.1056/NEJMoa1503824.

    Article  CAS  PubMed  Google Scholar 

  191. Nash P, et al. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389:2317–27. https://doi.org/10.1016/s0140-6736(17)31429-0.

    Article  CAS  PubMed  Google Scholar 

  192. van der Heijde D, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392:2441–51. https://doi.org/10.1016/s0140-6736(18)31946-9.

    Article  CAS  PubMed  Google Scholar 

  193. Gordon KB, et al. A phase 2 trial of guselkumab versus adalimumab for plaque psoriasis. N Engl J Med. 2015;373:136–44. https://doi.org/10.1056/NEJMoa1501646.

    Article  CAS  PubMed  Google Scholar 

  194. Feagan BG, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2017;389:1699–709. https://doi.org/10.1016/s0140-6736(17)30570-6.

    Article  CAS  PubMed  Google Scholar 

  195. Deodhar A, et al. Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2018;391:2213–24. https://doi.org/10.1016/s0140-6736(18)30952-8.

    Article  CAS  PubMed  Google Scholar 

  196. Leonardi CL, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371:1665–74. https://doi.org/10.1016/s0140-6736(08)60725-4.

    Article  CAS  PubMed  Google Scholar 

  197. Davis JC Jr, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum. 2003;48:3230–6. https://doi.org/10.1002/art.11325.

    Article  CAS  PubMed  Google Scholar 

  198. Mease PJ, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet. 2000;356:385–90. https://doi.org/10.1016/s0140-6736(00)02530-7.

    Article  CAS  PubMed  Google Scholar 

  199. Farrell RJ. Crohn’s disease: not all anti-TNFs are the same! Inflamm Bowel Dis. 2002;8:232–3.

    Article  PubMed  Google Scholar 

  200. Sandborn WJ, et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2001;121:1088–94.

    Article  CAS  PubMed  Google Scholar 

  201. Foster CS, et al. Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate. Arch Ophthalmol. 2003;121:437–40. https://doi.org/10.1001/archopht.121.4.437.

    Article  CAS  PubMed  Google Scholar 

  202. McGonagle D, Lories RJ, Tan AL, Benjamin M. The concept of a “synovio-entheseal complex” and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond. Arthritis Rheum. 2007;56:2482–91. https://doi.org/10.1002/art.22758.

    Article  PubMed  Google Scholar 

  203. Jacques P, et al. Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Ann Rheum Dis. 2014;73:437–45. https://doi.org/10.1136/annrheumdis-2013-203643.

    Article  PubMed  Google Scholar 

  204. Cuthbert RJ, et al. Brief report: group 3 innate lymphoid cells in human enthesis. Arthritis Rheumatol. 2017;69:1816–22. https://doi.org/10.1002/art.40150.

    Article  CAS  PubMed  Google Scholar 

  205. Ono T, et al. IL-17-producing gammadelta T cells enhance bone regeneration. Nat Commun. 2016;7:10928. https://doi.org/10.1038/ncomms10928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. van Tok MN, et al. Interleukin-17A inhibition diminishes inflammation and new bone formation in experimental spondyloarthritis. Arthritis Rheumatol. 2019;71:612–25. https://doi.org/10.1002/art.40770.

    Article  CAS  PubMed  Google Scholar 

  207. Croes M, et al. Proinflammatory T cells and IL-17 stimulate osteoblast differentiation. Bone. 2016;84:262–70. https://doi.org/10.1016/j.bone.2016.01.010.

    Article  CAS  PubMed  Google Scholar 

  208. El-Zayadi AA, 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;56:488–93. https://doi.org/10.1093/rheumatology/kew384.

    Article  CAS  Google Scholar 

  209. Yoshida K, et al. Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation. Proc Natl Acad Sci U S A. 2002;99:4580–5. https://doi.org/10.1073/pnas.062053399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Zhang X, et al. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest. 2002;109:1405–15. https://doi.org/10.1172/jci15681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Chen H, et al. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nat Commun. 2019;10:181. https://doi.org/10.1038/s41467-018-08097-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Maksymowych WP, Elewaut D, Schett G. Motion for debate: the development of ankylosis in ankylosing spondylitis is largely dependent on inflammation. Arthritis Rheum. 2012;64:1713–9. https://doi.org/10.1002/art.34442.

    Article  PubMed  Google Scholar 

  213. Deodhar A. Spondyloarthropathies: TNF inhibitors and structural damage in ankylosing spondylitis. Nat Rev Rheumatol. 2018;14:5–6. https://doi.org/10.1038/nrrheum.2017.197.

    Article  PubMed  Google Scholar 

  214. Sieper J, Poddubnyy D. Inflammation, new bone formation and treatment options in axial spondyloarthritis. Ann Rheum Dis. 2014;73:1439–41. https://doi.org/10.1136/annrheumdis-2014-205464.

    Article  CAS  PubMed  Google Scholar 

  215. Boersma JW. Retardation of ossification of the lumbar vertebral column in ankylosing spondylitis by means of phenylbutazone. Scand J Rheumatol. 1976;5:60–4.

    CAS  PubMed  Google Scholar 

  216. Wanders A, et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum. 2005;52:1756–65. https://doi.org/10.1002/art.21054.

    Article  CAS  PubMed  Google Scholar 

  217. Poddubnyy D, et al. Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort. Ann Rheum Dis. 2012;71:1616–22. https://doi.org/10.1136/annrheumdis-2011-201252.

    Article  CAS  PubMed  Google Scholar 

  218. Sieper J, et al. Effect of continuous versus on-demand treatment of ankylosing spondylitis with diclofenac over 2 years on radiographic progression of the spine: results from a randomised multicentre trial (ENRADAS). Ann Rheum Dis. 2016;75:1438–43. https://doi.org/10.1136/annrheumdis-2015-207897.

    Article  CAS  PubMed  Google Scholar 

  219. van der Heijde D, et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum. 2008;58:1324–31. https://doi.org/10.1002/art.23471.

    Article  CAS  PubMed  Google Scholar 

  220. van der Heijde D, et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum. 2008;58:3063–70. https://doi.org/10.1002/art.23901.

    Article  PubMed  Google Scholar 

  221. van der Heijde D, et al. Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res Ther. 2009;11:R127. https://doi.org/10.1186/ar2794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Haroon N, et al. The impact of tumor necrosis factor alpha inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum. 2013;65:2645–54. https://doi.org/10.1002/art.38070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Baraliakos X, Haibel H, Listing J, Sieper J, Braun J. Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis. Ann Rheum Dis. 2014;73:710–5. https://doi.org/10.1136/annrheumdis-2012-202698.

    Article  CAS  PubMed  Google Scholar 

  224. Maas F, et al. Reduction in spinal radiographic progression in ankylosing spondylitis patients receiving prolonged treatment with tumor necrosis factor inhibitors. Arthritis Care Res. 2017;69:1011–9. https://doi.org/10.1002/acr.23097.

    Article  CAS  Google Scholar 

  225. Molnar C, et al. TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort. Ann Rheum Dis. 2018;77:63–9. https://doi.org/10.1136/annrheumdis-2017-211544.

    Article  CAS  PubMed  Google Scholar 

  226. Braun J, et al. Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study. Ann Rheum Dis. 2017;76:1070–7. https://doi.org/10.1136/annrheumdis-2016-209730.

    Article  CAS  PubMed  Google Scholar 

  227. Kampylafka E, et al. Resolution of synovitis and arrest of catabolic and anabolic bone changes in patients with psoriatic arthritis by IL-17A blockade with secukinumab: results from the prospective PSARTROS study. Arthritis Res Ther. 2018;20:153. https://doi.org/10.1186/s13075-018-1653-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Ruiz-Heiland G, et al. Blockade of the hedgehog pathway inhibits osteophyte formation in arthritis. Ann Rheum Dis. 2012;71:400–7. https://doi.org/10.1136/ard.2010.148262.

    Article  CAS  PubMed  Google Scholar 

  229. Uderhardt S, et al. Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints. Ann Rheum Dis. 2010;69:592–7. https://doi.org/10.1136/ard.2008.102046.

    Article  CAS  PubMed  Google Scholar 

  230. Lories RJ, Derese I, Luyten FP. Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J Clin Invest. 2005;115:1571–9. https://doi.org/10.1172/jci23738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Arthritis & Tissue Degeneration Program, Hospital for Special Surgery, New York, NY, USA

    George D. Kalliolias

  2. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    George D. Kalliolias

  3. Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA

    George D. Kalliolias & Dimitris Skokos

Authors
  1. George D. Kalliolias
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dimitris Skokos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George D. Kalliolias .

Editor information

Editors and Affiliations

  1. New York University, New York, NY, USA

    Petros Efthimiou

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kalliolias, G.D., Skokos, D. (2020). Immunological Basis of Inflammatory Arthritides. In: Efthimiou, P. (eds) Absolute Rheumatology Review. Springer, Cham. https://doi.org/10.1007/978-3-030-23022-7_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-23022-7_1

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-23021-0

  • Online ISBN: 978-3-030-23022-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation