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Gut inflammation in the spondyloarthropathies

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Abstract

In this paper, the ample experimental, clinical, genetic, histopathologic, and immunologic evidence for an important role of the gut in the pathogenesis of spondylarthropathy (SpA) and for an overlap between SpA and Crohn’s disease is reviewed. These data suggest that SpA and Crohn’s disease should be scientifically and clinically considered as distinct phenotypes of common immune-mediated inflammatory disease pathways rather than as separate disease entities. Classification, diagnosis, and therapy based on pathophysiologic insights is likely to become superior to an approach based exclusively on signs and symptoms, as evidenced by the recent evolution in treatment of SpA by tumor necrosis factor-α blockade.

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References and Recommended Reading

  1. DeKeyser F, Elewaut D, De Vos M, et al.: Bowel inflammation and the spondyloarthropathies. Rheum Dis Clin North Am 1998, 24:785–813.

    Article  PubMed  Google Scholar 

  2. Mielants H, Veys EM, Cuvelier C, et al.: Gut inflammation in children with late onset pauciarticular juvenile chronic arthritis and evolution to adult spondylarthropathy: a prospective study. J Rheumatol 1993, 20:1567–1572.

    PubMed  CAS  Google Scholar 

  3. Schatteman L, Mielants H, Veys EM, et al.: Gut inflammation in psoriatic arthritis: A prospective ileocolonoscopic study. J Rheumatol 1995, 22:680–683.

    PubMed  CAS  Google Scholar 

  4. Banares AA, Jover JA, Fernandez-Gutierrez B, et al.: Bowel inflammation in anterior uveitis and spondylarthropathy. J Rheumatol 1995, 22:1112–1117.

    PubMed  CAS  Google Scholar 

  5. Cuvelier C, Barbatis C, Mielants H, et al.: Histopathology of intestinal inflammation related to reactive arthritis. Gut 1987, 28:394–401.

    Article  PubMed  CAS  Google Scholar 

  6. Mielants H, Veys EM, Cuvelier C, et al.: The evolution of spondyloarthropathies in relation to gut histology. Part II: histological aspects. J Rheumatol 1995, 22:2273–2278.

    PubMed  CAS  Google Scholar 

  7. De Vos M, Mielants H, Cuvelier C, et al.: Long-term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology 1996, 110:1696–1703.

    Article  Google Scholar 

  8. Demetter P, Van Huysse JA, De Keyser F, et al.: Increase in lymphoid follicles and leukocyte adhesion molecules emphasizes a role for the gut in spondyloarthropathy pathogenesis. J Pathol 2002, 198:517–522.

    Article  PubMed  CAS  Google Scholar 

  9. Demetter P, De Vos M, Van Huysse JA, et al.: Colon mucosa of both spondyloarthritis and Crohn’s disease patients is enriched with macrophages expressing the scavenger receptor CD163. Ann Rheum Dis 2005, 64:321–324.

    Article  PubMed  CAS  Google Scholar 

  10. Demetter P, De Vos M, Van Damme N, et al.: Focal upregulation of E-cadherin-catenin complex in inflamed bowel mucosa but reduced expression in ulcer-associated lineage. Am J Clin Pathol 2000, 114:364–370.

    PubMed  CAS  Google Scholar 

  11. Demetter P, Baeten D, De Keyser F, et al.: Subclinical gut inflammation in spondyloarthropathy patients is associated with upregulation of the E-cadherin/catenin complex. Ann Rheum Dis 2000, 59:211–216.

    Article  PubMed  CAS  Google Scholar 

  12. VanDamme N, De Keyser F, Demetter P, et al.: The proportion of Th1 cells, which prevail in gut mucosa, is decreased in inflammatory bowel syndrome. Clin Exp Immunol 2001, 125:383–390.

    Article  PubMed  Google Scholar 

  13. VanDamme N, De Vos M, Baeten D, et al.: Flow cytometric analysis of gut mucosal lymphocytes supports an impaired Th1 cytokine profile in spondyloarthropathy. Ann Rheum Dis 2001, 60:495–499.

    Article  PubMed  Google Scholar 

  14. Hoffman I, Demetter P, Peeters M, et al.: Anti-saccharomyces Cerevisiae antibodies are elevated in ankylosing spondylitis and undifferentiated spondyloarthropathy. Ann Rheum Dis 2003, 62:455–459. First study to demonstrate ASCA, a CD related serummarker, in SpA

    Article  PubMed  CAS  Google Scholar 

  15. Torok HP, Glas J, Gruber R, et al.: Inflammatory bowel diseasespecific autoantibodies in HLA-associated spondyloarthropathies: increased prevalence of AS pANCA. Digestion 2004, 70:49–54.

    Article  PubMed  Google Scholar 

  16. Ogura Y, Bonen DK, Inohara N, et al.: A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001, 411:603–616. Original identification of the association between CD and NOD2 variants

    Article  PubMed  CAS  Google Scholar 

  17. Hugot JP, Chamaillard M, Zouali H, et al.: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001, 411:599–603. Original identification of the association between CD and NOD2 variants.

    Article  PubMed  CAS  Google Scholar 

  18. Laukens D, Peeters H, Marichal D, et al.: CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn’s disease. Ann Rheum Dis 2005, In press. The authors describe for the first time an association of NOD2/ CARD15 variants in patients with SpA, namely association with subclinical chronic gut inflammation.

  19. Hammer RE, Maika SD, Richardson JA, et al.: Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human b2m: an animal model of HLA-B27-associated human disorders. Cell 1990, 63:109–112.

    Article  Google Scholar 

  20. 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, 180:2359–2364.

    Article  PubMed  CAS  Google Scholar 

  21. Salmi M, Jalkanen S: Human leucocyte subpopulations from inflamed gut bind to joint vasculature using distinct sets of adhesion molecules. J Immunol 2001, 166:4650–4657.

    PubMed  CAS  Google Scholar 

  22. May E, Marker-Hermann E, Wittig BM, et al.: Identical T-cell expansions in the colon mucosa and the synovium of a patient with enterogenic spondyloarthropathy. Gastroenterology 2000, 119:1745–1755.

    Article  PubMed  CAS  Google Scholar 

  23. Yin Z, Siegert S, Neure L, et al.: The elevated ratio of interferon gamma-/interleukin-4-positive T-cells found in synovial fluid and synovial membrane of rheumatoid arthritis patients can be changed by interleukin-4 but not by interleukin-10 or transforming growth factor beta. Rheumatology 1999, 38:1058–1067.

    Article  PubMed  CAS  Google Scholar 

  24. Canete JD, Martinez SE, Farres J, et al.: Differential Th1/Th2 cytokine patterns in chronic arthritis: interferon gamma is highly expressed in synovium of rheumatoid arthritis compared with seronegative spondyloarthropathies. Ann Rheum Dis 2000, 59:263–268.

    Article  PubMed  CAS  Google Scholar 

  25. Seta N, Granfors K, Sahly H, et al.: Expression of host defense scavenger receptors in spondyloarthropathy. Arthritis Rheum 2001, 44:931–939.

    Article  PubMed  CAS  Google Scholar 

  26. Baeten D, Demetter P, Cuvelier CA, et al.: Macrophages expressing the scavenger receptor CD163: a link between immune alterations of the gut and synovial inflammation in spondyloarthropathy. J Pathol 2002, 196:343–350.

    Article  PubMed  CAS  Google Scholar 

  27. Baeten D, Moller HJ, Delanghe J, et al.: Association of CD163 positive macrophages and local production of CD163 with decreased lymphocyte activation in spondyloarthropathy synovitis. Arthritis Rheum 2004, 50:1611–1623.

    Article  PubMed  Google Scholar 

  28. Danning CL, Illei GG, Hitchon C, et al.: Macrophage-derived cytokine and nuclear factor kappaB p65 expression in synovial membrane and skin of patients with psoriatic arthritis. Arthritis Rheum 2000, 43:1244–1256.

    Article  PubMed  CAS  Google Scholar 

  29. Fiocchi C: Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 1998, 115:182–205.

    Article  PubMed  CAS  Google Scholar 

  30. vanDullemen HM, Van Deventer SJ, Hommes DW, et al.: Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995, 109:129–135.

    Article  PubMed  Google Scholar 

  31. Mielants H, Veys EM, Cuvelier C, et al.: Course of gut inflammation in spondylarthropathies and therapeutic consequences. Baillieres Clin Rheumatol 1996, 10:147–164.

    Article  PubMed  CAS  Google Scholar 

  32. Prajapati DN, Knox JF, Emmons J, et al.: Leflunomide treatment of Crohn’s disease patients intolerant to standard immunomodulator therapy. J Clin Gastroenterol 2003, 37:125–128.

    Article  PubMed  CAS  Google Scholar 

  33. Haibel H, Rudwaleit M, Braun J, et al.: Six months open-label trial of leflunomide in ankylosing spondylitis [abstract]. Ann Rheum Dis 2003, 62(Suppl 1):248.

    Google Scholar 

  34. Targan SR, Hanauer SB, van Deventer SJ, et al.: A shortterm study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997, 337:1029–1035.

    Article  PubMed  CAS  Google Scholar 

  35. Present DH, Rutgeerts P, Targan S, et al.: Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999, 340:1398–1405.

    Article  PubMed  CAS  Google Scholar 

  36. Rutgeerts P, D’Haens G, Targan S, et al.: Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999, 117:761–769.

    Article  PubMed  CAS  Google Scholar 

  37. Hanauer SB, Feagan BG, Lichtenstein GR, et al.: Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002, 359:1541–1549.

    Article  PubMed  CAS  Google Scholar 

  38. Van DenBosch F, Kruithof E, De Vos M, et al.: Crohn’s disease associated with spondyloarthropathy: effect of TNF-alpha blockade with infliximab on articular symptoms. Lancet 2000, 356:1821–1822.

    Article  PubMed  Google Scholar 

  39. Van denBosch F, Kruithof E, Baeten D, et al.: Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor α (infliximab) versus placebo in active spondylarthropathy. Arthritis Rheum 2002, 46:755–765. First placebo-contolled study demonstrating the beneficial effect of TNF-blockers in spondylarthropathies

    Article  Google Scholar 

  40. Braun J, Brandt J, Listing J, et al.: Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002, 359:1187–1193. First placebo-contolled study demonstrating the beneficial effect of TNF-blockers in ankylosing spondylitis.

    Article  PubMed  CAS  Google Scholar 

  41. Hanauer SB, Lichtenstein GR, Mayer L, et al.: Extraintestinal manifestations of Crohn’s disease: response to infliximab (Remicade) in the ACCENT I trial through 30 weeks [abstract]. Am J Gastroenterol 2001, 96:A26.

    Article  Google Scholar 

  42. Generini S, Giacomelli R, Fedi R, et al.: Infliximab in spondyloarthropathy associated with Crohn’s disease: an open study on the efficacy of inducing and maintaining remission of musculoskeletal and gut manifestations. Ann Rheum Dis 2004, 63:1664–1669.

    Article  PubMed  CAS  Google Scholar 

  43. Gorman JD, Sack KE, Davis JC Jr, et al.: Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor _. N Engl J Med 2002, 346:1349–1356. First placebo-contolled study demonstrating the beneficial effect of a drug blocking soluble TNF in ankylosing spondylitis

    Article  PubMed  CAS  Google Scholar 

  44. Brandt J, Khariouzov A, Listing J, et al.: Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis. Arthritis Rheum 2003, 48:1667–1675.

    Article  PubMed  CAS  Google Scholar 

  45. Davis JC Jr., Van DerHeijde D, Braun J, et al.: Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis.: a randomized, controlled trial. Arthritis Rheum 2003, 48:3230–3236.

    Article  PubMed  CAS  Google Scholar 

  46. Sandborn WJ, Hanauer SB, Katz S, et al.: Etanercept for active Crohn’s disease: a randomised, double-blind placebocontrolled trial. Gastroenterology 2001, 121:1088–1094.

    Article  PubMed  CAS  Google Scholar 

  47. Marzo-Ortega H, McGonagle D, O’Connor P, et al.: Efficacy of etanercept for treatment of Crohn’s related spondyloarthritis but not colitis. Ann Rheum Dis 2003, 62:74–76.

    Article  PubMed  CAS  Google Scholar 

  48. Sandborn WJ, Feagan BG, Hanauer SB, et al.: An engineered human antibody to TNF (CDP571) for active Crohn’s disease: a randomized double-blind placebo-controlled trial. Gastroenterology 2001, 120:1330–1338.

    Article  PubMed  CAS  Google Scholar 

  49. Ghosh S, Goldin E, Gordon FH, et al.: Natalizumab for active Crohn’s disease. N Engl J Med 2003, 348:24–32. First study demonstrating the beneficial effect of a new biological other than a TNF-blocker in Chron’s disease.

    Article  PubMed  CAS  Google Scholar 

  50. Baeten D, VanDamme N, Van den Bosch F, et al.: Impaired Th1 cytokine production in spondyloarthropathy is restored by anti-TNF_. Ann Rheum Dis 2001, 60:750–755.

    Article  PubMed  CAS  Google Scholar 

  51. Baeten D, Kruithof E, Van denBosch E, et al.: Immunomodulatory effects of anti-tumor necrosis factor alpha therapy on synovium in spondyloarthropathy: histologic findings in eight patients from an open-label pilot study. Arthritis Rheum 2001, 44:186–195. First description of immunomodulatory effects of infliximab treatment on synovial membrane in patients with SpA.

    Article  PubMed  CAS  Google Scholar 

  52. Kruithof E, Baeten D, Van denBosch F, et al.: Histological evidence that infliximab treatment leads to downregulation of inflammation and tissue remodeling of the synovial membrane in spondyloarthropathy. Ann Rheum Dis 2005, 64:529–536.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Rheumatology, 0K12IB, Ghent University Hospital, De Pintelaan 185, 9000, Gent, Belgium

    Herman Mielants MD, PhD

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  1. Herman Mielants MD, PhD
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  2. Filip De Keyser MD, PhD
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  3. Dominique Baeten MD, PhD
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  4. Filip Van den Bosch MD, PhD
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Mielants, H., De Keyser, F., Baeten, D. et al. Gut inflammation in the spondyloarthropathies. Curr Rheumatol Rep 7, 188–194 (2005). https://doi.org/10.1007/s11926-996-0038-y

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