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Beyond the TNF-α Inhibitors: New and Emerging Targeted Therapies for Patients with Axial Spondyloarthritis and their Relation to Pathophysiology

  • Susanne Juhl Pedersen
  • Walter P. Maksymowych
Leading Article

Abstract

Axial spondyloarthritis (axSpA) is a complex disease that affects the joints and entheses of axial and peripheral joints, and is associated with inflammation in extra-articular sites such as the gut. Improved knowledge on genetics and immunology has improved treatment options with the availability of treatments targeting tumor necrosis factor-α (TNF-α) and interleukin (IL)-17. However, these agents do not provide clinical benefit for about 40% of patients, and additional therapeutic options are necessary. Theories on pathogenesis includes misfolding of HLA-B*27 during its assembly leading to endoplasmic reticulum stress and autophagy/unfolded protein response (UPR). HLA-B*27 may express free heavy chain on the cell surface, which activates innate immune receptors on T, natural killer, and myeloid cells with pro-inflammatory effects. Activation of UPR genes is associated with increased TNF-α, interleukin-23 (IL-23), IL-17, interferon-γ expression, and expansion of T helper (Th)-17 cells. Certain genotypes of endoplasmic reticulum aminopeptidase (ERAP) 1 and 2 are associated with ankylosing spondylitis (AS) and functionally interact with the HLA-B27 peptidome. Innate immune cells type 3, which express RORγt, regulate expression of IL-17 and IL-22 in T cells. Stimulation of gamma-delta T cells with IL-23 also induces IL-17. Mucosa-associated invariant T cells residing in the gut mucosa express IL-17 in AS patients after stimulation with IL-7. Prostaglandin E2 induces IL-17A independent of IL-23 via IL-1β and IL-6. The pathogenic role of gut inflammation, zonulin and microbiota, which has a different composition in AS patients, remains to be elucidated. This article also includes a comprehensive review on the mechanism of action and efficacy of the biological treatments currently approved for axSpA (TNF-α inhibitors and IL-17 inhibitors) and future targets for treatment (other IL-17 family member (s), Janus kinase, IL-23, and phosphodiesterase 4).

Notes

Compliance with Ethical Standards

Conflicts of Interest

Walter P. Maksymowych has \received consulting honoraria from Abbvie, Eli-Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB; grants from Abbvie, Janssen, Novartis, and Pfizer; and holds a position as Chief Medical Officer in Canadian Research Education (CaRE) Arthritis. Susanne Juhl Pedersen has received research grants/honoraria/speaker fee from Abbvie, BMS, MSD, Pfizer, and Novartis.

Funding

No financial support was received for the preparation of this manuscript.

References

  1. 1.
    Taurog JD, Chhabra A, Colbert RA. Ankylosing spondylitis and axial spondyloarthritis. N Engl J Med. 2016;374(26):2563–74.PubMedCrossRefGoogle Scholar
  2. 2.
    Wright V. Seronegative polyarthritis: a unified concept. Arthritis Rheumatol. 1978;21(6):619–33.CrossRefGoogle Scholar
  3. 3.
    Calin A, Porta J, Fries JF, et al. Clinical history as a screening test for ankylosing spondylitis. Jama. 1977;237(24):2613–4.PubMedCrossRefGoogle Scholar
  4. 4.
    McGonagle D, Khan MA, Marzo-Ortega H, et al. Enthesitis in spondyloarthropathy. Curr Opin Rheumatol. 1999;11(4):244–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Maksymowych WP, Mallon C, Morrow S, Shojania K, Olszynski WP, Wong RL, et al. Development and validation of the spondyloarthritis research consortium of Canada (SPARCC) enthesitis index. Ann Rheum Dis. 2009;68(6):948–53.PubMedCrossRefGoogle Scholar
  6. 6.
    Mander M, Simpson JM, McLellan A, et al. Studies with an enthesis index as a method of clinical assessment in ankylosing spondylitis. Ann Rheum Dis. 1987;46(3):197–202.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    van Tubergen A. The changing clinical picture and epidemiology of spondyloarthritis. Nat Rev Rheumatol. 2015;11(2):110–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Mau W, Zeidler H, Mau R, et al. Clinical features and prognosis of patients with possible ankylosing spondylitis. Results of a 10-year followup. J Rheumatol. 1988;15(7):1109–14.PubMedGoogle Scholar
  9. 9.
    Sampaio-Barros PD, Bortoluzzo AB, Conde RA, et al. Undifferentiated spondyloarthritis: a longterm followup. J Rheumatol. 2010;37(6):1195–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Eder L, Thavaneswaran A, Chandran V, Gladman DD. Gender difference in disease expression, radiographic damage and disability among patients with psoriatic arthritis. Ann Rheum Dis. 2013;72(4):578–82.PubMedCrossRefGoogle Scholar
  11. 11.
    van der Horst-Bruinsma IE, Zack DJ, Szumski A, et al. Female patients with ankylosing spondylitis: analysis of the impact of gender across treatment studies. Ann Rheum Dis. 2013;72(7):1221–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Rudwaleit M, Landewe R, van der Heijde D, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal. Ann Rheum Dis. 2009;68(6):770–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Rudwaleit M, van der Heijde D, Landewe R, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. 2009;68(6):777–83.PubMedCrossRefGoogle Scholar
  14. 14.
    van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis. Rheumatol. 1984;27(4):361–8.Google Scholar
  15. 15.
    Rudwaleit M, Jurik AG, Hermann KG, et al. Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI group. Ann Rheum Dis. 2009;68(10):1520–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Lambert RG, Bakker PA, van der Heijde D, et al. Defining active sacroiliitis on MRI for classification of axial spondyloarthritis: update by the ASAS MRI working group. Ann Rheum Dis. 2016;75(11):1958–63.PubMedCrossRefGoogle Scholar
  17. 17.
    van der Heijde D, Ramiro S, Landewe R, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6):978–91.PubMedCrossRefGoogle Scholar
  18. 18.
    Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2016;68(2):282–98.PubMedCrossRefGoogle Scholar
  19. 19.
    Stolwijk C, Boonen A, van Tubergen A, et al. Epidemiology of spondyloarthritis. Rheum Dis Clin N Am. 2012;38(3):441–76.CrossRefGoogle Scholar
  20. 20.
    de Blecourt J, Polman A, de Blecourt-Meindersma T. Hereditary factors in rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis. 1961;20:215–20.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Brown MA, Kennedy LG, MacGregor AJ, et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheumatol. 1997;40(10):1823–8.CrossRefGoogle Scholar
  22. 22.
    Jarvinen P. Occurrence of ankylosing spondylitis in a nationwide series of twins. Arthritis Rheumatol. 1995;38(3):381–3.CrossRefGoogle Scholar
  23. 23.
    Pedersen OB, Svendsen AJ, Ejstrup L, et al. Ankylosing spondylitis in Danish and Norwegian twins: occurrence and the relative importance of genetic vs. environmental effectors in disease causation. Scand j Rheumatol. 2008;37(2):120–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Calin A, Marder A, Becks E, et al. Genetic differences between B27 positive patients with ankylosing spondylitis and B27 positive healthy controls. Arthritis Rheumatol. 1983;26(12):1460–4.CrossRefGoogle Scholar
  25. 25.
    van der Linden S, Valkenburg H, Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: a family and population study. Br J Rheumatol. 1983;22(4 Suppl 2):18–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Geirsson AJ, Kristjansson K, Gudbjornsson B. A strong familiality of ankylosing spondylitis through several generations. Ann Rheum Dis. 2010;69(7):1346–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Khan MA. An update on the genetic polymorphism of HLA-B*27 with 213 alleles encompassing 160 subtypes (and still counting). Curr Rheumatol Rep. 2017;19(2):9.PubMedCrossRefGoogle Scholar
  28. 28.
    Wei JC, Tsai WC, Lin HS, et al. HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients. Rheumatology (Oxford). 2004;43(7):839–42.PubMedCrossRefGoogle Scholar
  29. 29.
    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. Rheumatol. 1995;38(11):1672–7.Google Scholar
  30. 30.
    Cortes A, Pulit SL, Leo PJ, et al. Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nat Commun. 2015;6:7146.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Bowness P. HLA-B27. Annu Rev Immunol. 2015;33:29–48.PubMedCrossRefGoogle Scholar
  32. 32.
    Guiliano DB, North H, Panayoitou E, et al. Polymorphisms in the F pocket of HLA-B27 subtypes strongly affect assembly, chaperone interactions, and heavy-chain misfolding. Arthritis Rheumatol. 2017;69(3):610–21.PubMedCrossRefGoogle Scholar
  33. 33.
    Giles J, Shaw J, Piper C, et al. HLA-B27 homodimers and free H chains are stronger ligands for leukocyte Ig-like receptor B2 than classical HLA class I. J Immunol. 2012;188(12):6184–93.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Wong-Baeza I, Ridley A, Shaw J, 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(7):3216–24.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Chan AT, Kollnberger SD, Wedderburn LR, et al. Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis. Arthritis Rheumatol. 2005;52(11):3586–95.CrossRefGoogle Scholar
  36. 36.
    Shaw J, Kollnberger S. New perspectives on the ligands and function of the killer cell immunoglobulin-like receptor KIR3DL2 in health and disease. Front Immunol. 2012;3:339.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    DeLay ML, Turner MJ, Klenk EI, et al. HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheumatol. 2009;60(9):2633–43.CrossRefGoogle Scholar
  38. 38.
    Bowness P, Ridley A, Shaw J, et al. Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J Immunol. 2011;186(4):2672–80.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Cortes A, Hadler J, Pointon JP, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet. 2013;45(7):730–8.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Burton PR, Clayton DG, Cardon LR, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39(11):1329–37.PubMedCrossRefGoogle Scholar
  41. 41.
    Reveille JD, Sims AM, Danoy P, et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010;42(2):123–7.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    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(8):761–7.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    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(5):510–8.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Robinson PC, Leo PJ, Pointon JJ, et al. Exome-wide study of ankylosing spondylitis demonstrates additional shared genetic background with inflammatory bowel disease. NPJ Genom Med. 2016;1:16008.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    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(1):73–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Tsui FW, Haroon N, Reveille JD, et al. Association of an ERAP1 ERAP2 haplotype with familial ankylosing spondylitis. Ann Rheum Dis. 2010;69(4):733–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Chang SC, Momburg F, Bhutani N, et al. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc Natl Acad Sci USA. 2005;102(47):17107–12.PubMedCrossRefGoogle Scholar
  48. 48.
    Martin-Esteban A, Guasp P, Barnea E, et al. Functional interaction of the ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 2 with the HLA-B*27 peptidome in human cells. Arthritis Rheumatol. 2016;68(10):2466–75.PubMedCrossRefGoogle Scholar
  49. 49.
    Strange A, Capon F, Spencer CC, et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet. 2010;42(11):985–90.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kirino Y, Bertsias G, Ishigatsubo Y, et al. Genome-wide association analysis identifies new susceptibility loci for Behcet’s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet. 2013;45(2):202–7.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Haroon N, Tsui FW, Uchanska-Ziegler B, et al. Endoplasmic reticulum aminopeptidase 1 (ERAP1) exhibits functionally significant interaction with HLA-B27 and relates to subtype specificity in ankylosing spondylitis. Ann Rheum Dis. 2012;71(4):589–95.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang Z, Ciccia F, Zeng F, et al. Brief report: functional interaction of endoplasmic reticulum aminopeptidase 2 and HLA-B27 activates the unfolded protein response. Arthritis Rheumatol. 2017;69(5):1009–15.PubMedCrossRefGoogle Scholar
  53. 53.
    Hanson AL, Cuddihy T, Haynes K, Loo D, Morton CJ, Oppermann U, et al. Genetic variants in ERAP1 and ERAP2 associated with immune-mediated diseases influence protein expression and the isoform profile. Arthritis Rheumatol. 2018;70(2):255–65.PubMedCrossRefGoogle Scholar
  54. 54.
    Edmunds L, Elswood J, Kennedy LG, et al. Primary ankylosing spondylitis, psoriatic and enteropathic spondyloarthropathy: a controlled analysis. J Rheumatol. 1991;18(5):696–8.PubMedGoogle Scholar
  55. 55.
    Mielants H, Veys EM, Cuvelier C, et al. Ileocolonoscopic findings in seronegative spondylarthropathies. Br J Rheumatol. 1988;27(Suppl 2):95–105.PubMedCrossRefGoogle Scholar
  56. 56.
    De Vos M, Mielants H, Cuvelier C, et al. Long-term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology. 1996;110(6):1696–703.PubMedCrossRefGoogle Scholar
  57. 57.
    Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Parkes M, Cortes A, van Heel DA, et al. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet. 2013;14(9):661–73.PubMedCrossRefGoogle Scholar
  59. 59.
    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(6):1123–32.PubMedCrossRefGoogle Scholar
  60. 60.
    Milia AF, Ibba-Manneschi L, Manetti M, et al. HLA-B27 transgenic rat: an animal model mimicking gut and joint involvement in human spondyloarthritides. Ann N Y Acad Sci. 2009;1173:570–4.PubMedCrossRefGoogle Scholar
  61. 61.
    Taurog JD, Richardson JA, Croft JT, et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med. 1994;180(6):2359–64.PubMedCrossRefGoogle Scholar
  62. 62.
    Costello ME, Ciccia F, Willner D, et al. Brief report: intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol. 2015;67(3):686–91.PubMedCrossRefGoogle Scholar
  63. 63.
    Tito RY, Cypers H, Joossens M, et al. Brief report: dialister as a microbial marker of disease activity in spondyloarthritis. Arthritis Rheumatol. 2017;69(1):114–21.PubMedCrossRefGoogle Scholar
  64. 64.
    Breban M, Tap J, Leboime A, et al. Faecal microbiota study reveals specific dysbiosis in spondyloarthritis. Ann Rheum Dis. 2017;76(9):1614–22.PubMedCrossRefGoogle Scholar
  65. 65.
    Spits H, Artis D, Colonna M, et al. Innate lymphoid cells - a proposal for uniform nomenclature. Nat Rev Immunol. 2013;13(2):145–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Cherrier M, Eberl G. The development of LTi cells. Curr Opin Immunol. 2012;24(2):178–83.PubMedCrossRefGoogle Scholar
  67. 67.
    Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126(6):1121–33.PubMedCrossRefGoogle Scholar
  68. 68.
    Kang J, Coles M. IL-7: the global builder of the innate lymphoid network and beyond, one niche at a time. Semin Immunol. 2012;24(3):190–7.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Ciccia F, Accardo-Palumbo A, Alessandro R, et al. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheumatol. 2012;64(6):1869–78.CrossRefGoogle Scholar
  70. 70.
    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(9):1739–47.PubMedCrossRefGoogle Scholar
  71. 71.
    Villanova F, Flutter B, Tosi I, et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J Investig Dermatol. 2014;134(4):984–91.PubMedCrossRefGoogle Scholar
  72. 72.
    Cuthbert RJ, Fragkakis EM, Dunsmuir R, et al. Brief report: group 3 innate lymphoid cells in human enthesis. Arthritis Rheumatol. 2017;69(9):1816–22.PubMedCrossRefGoogle Scholar
  73. 73.
    Forkel M, Mjosberg J. Dysregulation of group 3 innate lymphoid cells in the pathogenesis of inflammatory bowel disease. Curr Allergy Asthma Rep. 2016;16(10):73.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Paustian AMS, Paez-Cortez J, Bryant S, et al. Continuous IL-23 stimulation drives ILC3 depletion in the upper GI tract and in combination with TNFalpha, induces robust activation and a phenotypic switch of ILC3. PloS One. 2017;12(8):e0182841.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Cuvelier CA, De Wever N, Mielants H, et al. Expression of T cell receptors alpha beta and gamma delta in the ileal mucosa of patients with Crohn’s disease and with spondylarthropathy. Clin Exp Immunol. 1992;90(2):275–9.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Jansen DT, Hameetman M, van Bergen J, et al. IL-17-producing CD4+ T cells are increased in early, active axial spondyloarthritis including patients without imaging abnormalities. Rheumatology (Oxford). 2015;54(4):728–35.PubMedCrossRefGoogle Scholar
  77. 77.
    Kenna TJ, Davidson SI, Duan R, et al. Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive gamma/delta T cells in patients with active ankylosing spondylitis. Arthritis Rheumatol. 2012;64(5):1420–9.CrossRefGoogle Scholar
  78. 78.
    Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nat Rev Immunol. 2014;14(10):667–85.PubMedCrossRefGoogle Scholar
  79. 79.
    Gracey E, Qaiyum Z, Almaghlouth I, 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(12):2124–32.PubMedCrossRefGoogle Scholar
  80. 80.
    Hayashi E, Chiba A, Tada K, et al. Involvement of Mucosal-associated Invariant T cells in ankylosing spondylitis. J Rheumatol. 2016;43(9):1695–703.PubMedCrossRefGoogle Scholar
  81. 81.
    Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104(4):487–501.PubMedCrossRefGoogle Scholar
  82. 82.
    Braun J, Bollow M, Neure L, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheumatol. 1995;38(4):499–505.CrossRefGoogle Scholar
  83. 83.
    Crew MD, Effros RB, Walford RL, et al. Transgenic mice expressing a truncated Peromyscus leucopus TNF-alpha gene manifest an arthritis resembling ankylosing spondylitis. J Interferon Cytokine Res. 1998;18(4):219–25.PubMedCrossRefGoogle Scholar
  84. 84.
    Kontoyiannis D, Pasparakis M, Pizarro TT, et al. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity. 1999;10(3):387–98.PubMedCrossRefGoogle Scholar
  85. 85.
    Redlich K, Gortz B, Hayer S, et al. Overexpression of tumor necrosis factor causes bilateral sacroiliitis. Arthritis Rheumatol. 2004;50(3):1001–5.CrossRefGoogle Scholar
  86. 86.
    Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet. 2002;359(9313):1187–93.PubMedCrossRefGoogle Scholar
  87. 87.
    Van Den Bosch F, Kruithof E, Baeten D, et al. Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondylarthropathy. Arthritis Rheumatol. 2002;46(3):755–65.CrossRefGoogle Scholar
  88. 88.
    Jacques P, Lambrecht S, Verheugen E, 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(2):437–45.PubMedCrossRefGoogle Scholar
  89. 89.
    Wakefield D, Yates W, Amjadi S, et al. HLA-B27 Anterior Uveitis: Immunology and Immunopathology. Ocul Immunol Inflamm. 2016;24(4):450–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Ogawa E, Sato Y, Minagawa A, et al. Pathogenesis of psoriasis and development of treatment. J Dermatol. 2018;45(3):264–72.PubMedCrossRefGoogle Scholar
  91. 91.
    Lee SH, Kwon JE, Cho ML. Immunological pathogenesis of inflammatory bowel disease. Intest Res. 2018;16(1):26–42.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Veldhoen M. Interleukin 17 is a chief orchestrator of immunity. Nat Immunol. 2017;18(6):612–21.PubMedCrossRefGoogle Scholar
  93. 93.
    Appel H, Maier R, Wu P, Scheer R, Hempfing A, Kayser R, et al. Analysis of IL-17(+) cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res Ther. 2011;13(3):R95.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Liang Y, Pan HF, Ye DQ. Tc17 cells in immunity and systemic autoimmunity. Int Rev Immunol. 2015;34(4):318–31.PubMedCrossRefGoogle Scholar
  95. 95.
    Amatya N, Garg AV, Gaffen SL. IL-17 signaling: the yin and the yang. Trends Immunol. 2017;38(5):310–22.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Huang H, Kim HJ, Chang EJ, et al. IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ. 2009;16(10):1332–43.PubMedCrossRefGoogle Scholar
  97. 97.
    Ono T, Okamoto K, Nakashima T, et al. IL-17-producing gammadelta T cells enhance bone regeneration. Nat Commun. 2016;7:10928.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Goswami J, Hernandez-Santos N, Zuniga LA, et al. A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss. Eur J Immunol. 2009;39(10):2831–9.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13(5):715–25.PubMedCrossRefGoogle Scholar
  100. 100.
    Tan ZY, Bealgey KW, Fang Y, et al. Interleukin-23: immunological roles and clinical implications. Int J Biochem Cell Biol. 2009;41(4):733–5.PubMedCrossRefGoogle Scholar
  101. 101.
    Becker C, Wirtz S, Blessing M, et al. Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J Clin Investig. 2003;112(5):693–706.PubMedCrossRefGoogle Scholar
  102. 102.
    Ciccia F, Bombardieri M, Principato A, et al. Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheumatol. 2009;60(4):955–65.CrossRefGoogle Scholar
  103. 103.
    Benham H, Rehaume LM, Hasnain SZ, et al. Interleukin-23 mediates the intestinal response to microbial beta-1,3-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis Rheumatol. 2014;66(7):1755–67.PubMedCrossRefGoogle Scholar
  104. 104.
    Awasthi A, Riol-Blanco L, Jager A, et al. Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells. J Immunol. 2009;182(10):5904–8.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Kenna TJ, Brown MA. The role of IL-17-secreting mast cells in inflammatory joint disease. Nat Rev Rheumatol. 2013;9(6):375–9.PubMedCrossRefGoogle Scholar
  106. 106.
    Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat med. 2012;18(7):1069–76.PubMedCrossRefGoogle Scholar
  107. 107.
    Reinhardt A, Yevsa T, Worbs T, et al. Interleukin-23-dependent gamma/delta T cells produce interleukin-17 and accumulate in the enthesis, aortic valve, and ciliary body in mice. Arthritis Rheumatol. 2016;68(10):2476–86.PubMedCrossRefGoogle Scholar
  108. 108.
    Koenders MI, Lubberts E, Oppers-Walgreen B, et al. Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. Am J Pathol. 2005;167(1):141–9.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Lubberts E, Joosten LA, Oppers B, et al. IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J Immunol. 2001;167(2):1004–13.PubMedCrossRefGoogle Scholar
  110. 110.
    Wang JH, Iosifidis MI, Fu FH. Biomechanical basis for tendinopathy. Clin Orthop Relat Res. 2006;443:320–32.PubMedCrossRefGoogle Scholar
  111. 111.
    Sakata D, Yao C, Narumiya S. Prostaglandin E2, an immunoactivator. J Pharmacol Sci. 2010;112(1):1–5.PubMedCrossRefGoogle Scholar
  112. 112.
    Paulissen SM, van Hamburg JP, Davelaar N, et al. Synovial fibroblasts directly induce Th17 pathogenicity via the cyclooxygenase/prostaglandin E2 pathway, independent of IL-23. J Immunol. 2013;191(3):1364–72.PubMedCrossRefGoogle Scholar
  113. 113.
    Samuels JS, Holland L, Lopez M, et al. Prostaglandin E2 and IL-23 interconnects STAT3 and RoRgamma pathways to initiate Th17 CD4(+) T-cell development during rheumatoid arthritis. Inflamm Res. 2018;67(7):589–96.PubMedCrossRefGoogle Scholar
  114. 114.
    Tracey D, Klareskog L, Sasso EH, et al. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):244–79.PubMedCrossRefGoogle Scholar
  115. 115.
    Maxwell LJ, Zochling J, Boonen A, et al. TNF-alpha inhibitors for ankylosing spondylitis. Cochrane Database Syst Rev. 2015;4:Cd005468.Google Scholar
  116. 116.
    Sepriano A, Regel A, van der Heijde D, et al. Efficacy and safety of biological and targeted-synthetic DMARDs: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis. RMD Open. 2017;3(1):e000396.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Corbett M, Soares M, Jhuti G, et al. Tumour necrosis factor-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation. Health Technol Assess. 2016;20(9):1–334, v–vi.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Park W, Hrycaj P, Jeka S, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 2013;72(10):1605–12.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Park W, Yoo DH, Jaworski J, et al. Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study. Arthritis Res Ther. 2016;18:25.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Park W, Yoo DH, Miranda P, et al. Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis. 2017;76(2):346–54.PubMedCrossRefGoogle Scholar
  121. 121.
    Sieper J, Koenig A, Baumgartner S, et al. Analysis of uveitis rates across all etanercept ankylosing spondylitis clinical trials. Ann Rheum Dis. 2010;69(1):226–9.PubMedCrossRefGoogle Scholar
  122. 122.
    Rudwaleit M, Rosenbaum JT, Landewe R, Marzo-Ortega H, Sieper J, van der Heijde D, et al. Observed incidence of uveitis following certolizumab pegol treatment in patients with axial spondyloarthritis. Arthritis Care Res (Hoboken). 2016;68(6):838–44.CrossRefGoogle Scholar
  123. 123.
    Lie E, Lindstrom U, Zverkova-Sandstrom T, et al. Tumour necrosis factor inhibitor treatment and occurrence of anterior uveitis in ankylosing spondylitis: results from the Swedish biologics register. Ann Rheum Dis. 2017;76(9):1515–21.PubMedCrossRefGoogle Scholar
  124. 124.
    Braun J, Baraliakos X, Listing J, et al. Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheumatol. 2005;52(8):2447–51.CrossRefGoogle Scholar
  125. 125.
    Braun J, Baraliakos X, Listing J, et al. Differences in the incidence of flares or new onset of inflammatory bowel diseases in patients with ankylosing spondylitis exposed to therapy with anti-tumor necrosis factor alpha agents. Arthritis Rheumatol. 2007;57(4):639–47.CrossRefGoogle Scholar
  126. 126.
    van der Heijde D, Kivitz A, Schiff MH, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2006;54(7):2136–46.CrossRefGoogle Scholar
  127. 127.
    Lambert RG, Salonen D, Rahman P, et al. Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. 2007;56(12):4005–14.CrossRefGoogle Scholar
  128. 128.
    Hu Z, Xu M, Li Q, et al. Adalimumab significantly reduces inflammation and serum DKK-1 level but increases fatty deposition in lumbar spine in active ankylosing spondylitis. Int J Rheum Dis. 2012;15(4):358–65.PubMedCrossRefGoogle Scholar
  129. 129.
    Huang F, Gu J, Zhu P, et al. Efficacy and safety of adalimumab in Chinese adults with active ankylosing spondylitis: results of a randomised, controlled trial. Ann Rheum Dis. 2014;73(3):587–94.PubMedCrossRefGoogle Scholar
  130. 130.
    Pedersen SJ, Poddubnyy D, Sorensen IJ, et al. Course of magnetic resonance imaging-detected inflammation and structural lesions in the sacroiliac joints of patients in the randomized, double-blind, placebo-controlled danish multicenter study of adalimumab in spondyloarthritis, as assessed by the Berlin and Spondyloarthritis Research Consortium of Canada Methods. Arthritis Rheumatol. 2016;68(2):418–29.PubMedCrossRefGoogle Scholar
  131. 131.
    Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med. 2002;346(18):1349–56.PubMedCrossRefGoogle Scholar
  132. 132.
    Davis JC Jr, Van Der Heijde D, Braun J, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheumatol. 2003;48(11):3230–6.CrossRefGoogle Scholar
  133. 133.
    Calin A, Dijkmans BA, Emery P, et al. Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis. 2004;63(12):1594–600.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    van der Heijde D, Da Silva JC, Dougados M, et al. Etanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitis. Ann Rheum Dis. 2006;65(12):1572–7.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Dijkmans B, Emery P, Hakala M, et al. Etanercept in the longterm treatment of patients with ankylosing spondylitis. J Rheumatol. 2009;36(6):1256–64.PubMedCrossRefGoogle Scholar
  136. 136.
    Dougados M, Braun J, Szanto S, et al. Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomised double-blind placebo-controlled study (SPINE). Ann Rheum Dis. 2011;70(5):799–804.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    van der Heijde D, Dijkmans B, Geusens P, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheumatol. 2005;52(2):582–91.CrossRefGoogle Scholar
  138. 138.
    Marzo-Ortega H, McGonagle D, Jarrett S, et al. Infliximab in combination with methotrexate in active ankylosing spondylitis: a clinical and imaging study. Ann Rheum Dis. 2005;64(11):1568–75.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Inman RD, Maksymowych WP. A double-blind, placebo-controlled trial of low dose infliximab in ankylosing spondylitis. J Rheumatol. 2010;37(6):1203–10.PubMedCrossRefGoogle Scholar
  140. 140.
    Inman RD, Davis JC Jr, Heijde D, et al. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheumatol. 2008;58(11):3402–12.CrossRefGoogle Scholar
  141. 141.
    Bao C, Huang F, Khan MA, et al. Safety and efficacy of golimumab in Chinese patients with active ankylosing spondylitis: 1-year results of a multicentre, randomized, double-blind, placebo-controlled phase III trial. Rheumatology (Oxford). 2014;53(9):1654–63.PubMedCrossRefGoogle Scholar
  142. 142.
    Tam LS, Shang Q, Kun EW, et al. The effects of golimumab on subclinical atherosclerosis and arterial stiffness in ankylosing spondylitis-a randomized, placebo-controlled pilot trial. Rheumatology (Oxford). 2014;53(6):1065–74.PubMedCrossRefGoogle Scholar
  143. 143.
    Landewe R, Braun J, Deodhar A, et al. Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study. Ann Rheum Dis. 2014;73(1):39–47.PubMedCrossRefGoogle Scholar
  144. 144.
    Haibel H, Rudwaleit M, Listing J, et al. Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week fifty-two. Arthritis Rheumatol. 2008;58(7):1981–91.CrossRefGoogle Scholar
  145. 145.
    Sieper J, van der Heijde D, Dougados M, et al. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis. 2013;72(6):815–22.PubMedCrossRefGoogle Scholar
  146. 146.
    Dougados M, van der Heijde D, Sieper J, et al. Symptomatic efficacy of etanercept and its effects on objective signs of inflammation in early nonradiographic axial spondyloarthritis: a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2014;66(8):2091–102.PubMedCrossRefGoogle Scholar
  147. 147.
    Barkham N, Keen HI, Coates LC, et al. Clinical and imaging efficacy of infliximab in HLA-B27-Positive patients with magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheumatol. 2009;60(4):946–54.CrossRefGoogle Scholar
  148. 148.
    Sieper J, van der Heijde D, Dougados M, et al. A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2015;67(10):2702–12.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Baeten D, Baraliakos X, Braun J, et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382(9906):1705–13.PubMedCrossRefGoogle Scholar
  150. 150.
    Baeten D, Sieper J, Braun J, et al. Secukinumab, an Interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med. 2015;373(26):2534–48.PubMedCrossRefGoogle Scholar
  151. 151.
    Pavelka K, Kivitz A, Dokoupilova E, et al. Efficacy, safety, and tolerability of secukinumab in patients with active ankylosing spondylitis: a randomized, double-blind phase 3 study, MEASURE 3. Arthritis Res Ther. 2017;19(1):285.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    van der Heijde D, Deodhar A, Wei JC, et al. Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study. Ann Rheum Dis. 2017;76(8):1340–7.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    van der Heijde D, Dougados M, Davis J, et al. ASsessment in Ankylosing Spondylitis International Working Group/Spondylitis Association of America recommendations for conducting clinical trials in ankylosing spondylitis. Arthritis Rheumatol. 2005;52(2):386–94.CrossRefGoogle Scholar
  154. 154.
    European Medicines Agency. Cosentyx (secukinumab) Annex I summary of product characteristics. http://www.ema.europa.eu/. Accessed 20 Feb 2018.
  155. 155.
    US Food and Drug Administration (FDA). Siliq (Brodalumab). Center for drug evaluation and research application number: 761032Orig1s000 https://www.accessdata.fda.gov. Accessed 20 Feb 2018.
  156. 156.
    US Food and Drug Administration (FDA). Taltz (ixekizumab). Center for drug evaluation and reseach application number: 125521Orig1s000. Summary Review. https://www.accessdata.fda.gov Accessed 20 Feb 2018.
  157. 157.
    Glatt S, Helmer E, Haier B, et al. First-in-human randomized study of bimekizumab, a humanized monoclonal antibody and selective dual inhibitor of IL-17A and IL-17F, in mild psoriasis. Br J Clin Pharmacol. 2017;83(5):991–1001.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Glatt S, Baeten D, Baker T, et al. Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation. Ann Rheum Dis. 2018;77(4):523–32.PubMedCrossRefGoogle Scholar
  159. 159.
    Sieper J, Deodhar A, Marzo-Ortega H, et al. Secukinumab efficacy in anti-TNF-naive and anti-TNF-experienced subjects with active ankylosing spondylitis: results from the MEASURE 2 Study. Ann Rheum Dis. 2017;76(3):571–92.PubMedCrossRefGoogle Scholar
  160. 160.
    Braun J, Baraliakos X, Deodhar A, 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(6):1070–7.PubMedCrossRefGoogle Scholar
  161. 161.
    Marzo-Ortega H, Sieper J, Kivitz A, et al. Secukinumab and Sustained Improvement in Signs and Symptoms of Patients With Active Ankylosing Spondylitis Through Two Years: Results From a Phase III Study. Arthritis Care Res (Hoboken). 2017;69(7):1020–9.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Molnar C, Scherer A, Baraliakos X, 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(1):63–9.PubMedCrossRefGoogle Scholar
  163. 163.
    Haroon N, Inman RD, Learch TJ, et al. The impact of tumor necrosis factor alpha inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheumatol. 2013;65(10):2645–54.Google Scholar
  164. 164.
    van der Heijde D, Landewe R, Baraliakos X, et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheumatol. 2008;58(10):3063–70.CrossRefGoogle Scholar
  165. 165.
    van der Heijde D, Landewe R, Einstein S, et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheumatol. 2008;58(5):1324–31.CrossRefGoogle Scholar
  166. 166.
    van der Heijde D, Salonen D, Weissman BN, 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(4):R127.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Braun J, Baraliakos X, Hermann KG, et al. The effect of two golimumab doses on radiographic progression in ankylosing spondylitis: results through 4 years of the GO-RAISE trial. Ann Rheum Dis. 2014;73(6):1107–13.PubMedCrossRefGoogle Scholar
  168. 168.
    Baraliakos X, Haibel H, Listing J, et al. 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(4):710–5.PubMedCrossRefGoogle Scholar
  169. 169.
    Maas F, Spoorenberg A, Brouwer E, et al. Spinal radiographic progression in patients with ankylosing spondylitis treated with TNF-alpha blocking therapy: a prospective longitudinal observational cohort study. PloS One. 2015;10(4):e0122693.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    van der Heijde D, Baraliakos X, Hermann KA, et al. Limited radiographic progression and sustained reductions in MRI inflammation in patients with axial spondyloarthritis: 4-year imaging outcomes from the RAPID-axSpA phase III randomised trial. Ann Rheum Dis. 2018;77(5):699–705.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Poddubnyy D, Sieper J. Radiographic progression in ankylosing spondylitis/axial spondyloarthritis: how fast and how clinically meaningful? Curr Opin Rheumatol. 2012;24(4):363–9.PubMedCrossRefGoogle Scholar
  172. 172.
    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 Rheumatol. 2009;60(1):93–102.CrossRefGoogle Scholar
  173. 173.
    Maksymowych WP, Morency N, Conner-Spady B, et al. Suppression of inflammation and effects on new bone formation in ankylosing spondylitis: evidence for a window of opportunity in disease modification. Ann Rheum Dis. 2013;72(1):23–8.PubMedCrossRefGoogle Scholar
  174. 174.
    Pedersen SJ, Chiowchanwisawakit P, Lambert RG, et al. Resolution of inflammation following treatment of ankylosing spondylitis is associated with new bone formation. J Rheumatol. 2011;38(7):1349–54.PubMedCrossRefGoogle Scholar
  175. 175.
    Chiowchanwisawakit P, Lambert RG, Conner-Spady B, et al. Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis. Arthritis Rheumatol. 2011;63(8):2215–25.CrossRefGoogle Scholar
  176. 176.
    Machado PM, Baraliakos X, van der Heijde D, et al. MRI vertebral corner inflammation followed by fat deposition is the strongest contributor to the development of new bone at the same vertebral corner: a multilevel longitudinal analysis in patients with ankylosing spondylitis. Ann Rheum Dis. 2016;75(8):1486–93.PubMedCrossRefGoogle Scholar
  177. 177.
    Maksymowych WP, Wichuk S, Chiowchanwisawakit P, et al. Fat metaplasia and backfill are key intermediaries in the development of sacroiliac joint ankylosis in patients with ankylosing spondylitis. Arthritis Rheumatol. 2014;66(11):2958–67.PubMedCrossRefGoogle Scholar
  178. 178.
    Maksymowych WP, Wichuk S, Chiowchanwisawakit P, et al. Fat metaplasia on MRI of the sacroiliac joints increases the propensity for disease progression in the spine of patients with spondyloarthritis. RMD Open. 2017;3(1):e000399.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004;117(Pt 8):1281–3.PubMedCrossRefGoogle Scholar
  180. 180.
    Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017;16(12):843–62.PubMedCrossRefGoogle Scholar
  181. 181.
    US Food and Drug Administration (FDA). Xeljanz (tofacitinib) Center for drug evaluation and reseach application number. 203214Orig1s000 medical reviews. https://www.accessdata.fda.gov Accessed 20 Feb 2018.
  182. 182.
    Maksymowych WP, Heijde DV, Baraliakos X, et al. Tofacitinib is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients. Rheumatology (Oxford). 2018;57(8):1390–9.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    European Medicines Agency. Stelara (ustekinumab) Annex I summary of product characteristics. http://www.ema.europa.eu/. Accessed 20 Feb 2018.
  184. 184.
    Poddubnyy D, Hermann KG, Callhoff J, et al. Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann Rheum Dis. 2014;73(5):817–23.PubMedCrossRefGoogle Scholar
  185. 185.
    Baeten D, Ostergaard M, Wei JC, 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(9):1295–302.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Raker VK, Becker C, Steinbrink K. The cAMP pathway as therapeutic target in autoimmune and inflammatory diseases. Front Immunol. 2016;7:123.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Schafer PH, Parton A, Capone L, et al. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal. 2014;26(9):2016–29.PubMedCrossRefGoogle Scholar
  188. 188.
    Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010;159(4):842–55.PubMedCrossRefGoogle Scholar
  189. 189.
    Pathan E, Abraham S, Van Rossen E, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing spondylitis. Ann Rheum Dis. 2013;72(9):1475–80.PubMedCrossRefGoogle Scholar
  190. 190.
    Haibel H, Rudwaleit M, Listing J, et al. Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann Rheum Dis. 2005;64(2):296–8.PubMedCrossRefGoogle Scholar
  191. 191.
    Tan AL, Marzo-Ortega H, O’Connor P, et al. Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study. Ann Rheum Dis. 2004;63(9):1041–5.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Sieper J, Braun J, Kay J, et al. Sarilumab for the treatment of ankylosing spondylitis: results of a phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann Rheum Dis. 2015;74(6):1051–7.PubMedCrossRefGoogle Scholar
  193. 193.
    Sieper J, Porter-Brown B, Thompson L, et al. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis. 2014;73(1):95–100.PubMedCrossRefGoogle Scholar
  194. 194.
    Lekpa FK, Farrenq V, Canoui-Poitrine F, et al. Lack of efficacy of abatacept in axial spondylarthropathies refractory to tumor-necrosis-factor inhibition. Jt Bone Spine. 2012;79(1):47–50.CrossRefGoogle Scholar
  195. 195.
    Do J, Kim D, Kim S, Valentin-Torres A, et al. Treg-specific IL-27Ralpha deletion uncovers a key role for IL-27 in Treg function to control autoimmunity. Proc Natl Acad Sci USA. 2017;114(38):10190–5.PubMedCrossRefGoogle Scholar
  196. 196.
    Meka RR, Venkatesha SH, Dudics S, Acharya B, Moudgil KD. IL-27-induced modulation of autoimmunity and its therapeutic potential. Autoimmun Rev. 2015;14(12):1131–41.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Susanne Juhl Pedersen
    • 1
  • Walter P. Maksymowych
    • 2
  1. 1.Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine DiseaseRigshospitaletGlostrupDenmark
  2. 2.Department of MedicineUniversity of AlbertaEdmontonCanada

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