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Therapy Insight: how the gut talks to the joints—inflammatory bowel disease and the spondyloarthropathies

Abstract

Axial and peripheral arthritis can occur in up to 30% of patients with inflammatory bowel disease. Likewise, the presence of gut inflammation in primary spondyloarthropathies is underappreciated, with subclinical gut inflammation documented in up to two-thirds of patients with this group of inflammatory disorders. Common genetic and immunologic mechanisms underlie the coincidence of inflammation in the joints and the intestine. New research highlights the critical role of innate and adaptive immune responses directed against components of the enteric microbial flora in driving gut and articular inflammation. Indeed, elucidation of genetic and serological immune markers will define clinically important subgroups of patients with these heterogeneous diseases. The treatment of inflammatory articular manifestations of inflammatory bowel disease is similar to the treatment of primary spondyloarthropathies. A notable exception is the use of NSAIDs, which can precipitate flares of inflammatory bowel disease and should be used with caution. Agents that target tumor necrosis factor have been a major advance in the treatment of both gut and joint inflammation in inflammatory bowel disease.

Key Points

  • The coincidence of multiple chronic inflammatory diseases is higher in patients with inflammatory bowel disorder (IBD) than in the general population

  • Arthritic manifestations are the most common inflammatory comorbidities in IBD

  • Asymptomatic gut inflammation is common in primary spondyloarthropathies and arthritic manifestations might predate a diagnosis of IBD by years

  • The coincidence of spondyloarthropathy and IBD suggests common genetic predispositions, environmental triggers, and immunologic mechanisms

  • Treatment of IBD-associated spondyloarthropathy is similar to the treatment of idiopathic spondyloarthropathy, except that NSAIDs should be used with caution and etanercept might not be efficacious in reducing symptoms of IBD compared with other tumor necrosis factor inhibitors

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References

  1. Greenstein AJ et al. (1976) The extra-intestinal complications of Crohn's disease and ulcerative colitis: a study of 700 patients. Medicine (Baltimore) 55: 401–412

    Article  CAS  Google Scholar 

  2. Loftus EV Jr (2004) Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 126: 1504–1517

    Article  Google Scholar 

  3. Cho JH and Abraham C (2007) Inflammatory bowel disease genetics: Nod2. Annu Rev Med 58: 401–416

    Article  CAS  Google Scholar 

  4. Rioux JD et al. (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39: 596–604

    Article  CAS  Google Scholar 

  5. Duerr RH et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314: 1461–1463

    Article  CAS  Google Scholar 

  6. Cargill M et al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80: 273–290

    Article  CAS  Google Scholar 

  7. Becker KG et al. (1998) Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc Natl Acad Sci USA 95: 9979–9984

    Article  CAS  Google Scholar 

  8. Bernstein CN et al. (2005) The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology 129: 827–836

    Article  Google Scholar 

  9. Weng X et al. (2007) Clustering of inflammatory bowel disease with immune mediated diseases among members of a northern California-managed care organization. Am J Gastroenterol 102: 1429–1435

    Article  Google Scholar 

  10. Fendler C et al. (2001) Frequency of triggering bacteria in patients with reactive arthritis and undifferentiated oligoarthritis and the relative importance of the tests used for diagnosis. Ann Rheum Dis 60: 337–343

    Article  CAS  Google Scholar 

  11. de Vlam K et al. (2000) Spondyloarthropathy is underestimated in inflammatory bowel disease: prevalence and HLA association. J Rheumatol 27: 2860–2865

    CAS  PubMed  Google Scholar 

  12. Palm O et al. (2002) Prevalence of ankylosing spondylitis and other spondyloarthropathies among patients with inflammatory bowel disease: a population study (the IBSEN study). J Rheumatol 29: 511–515

    PubMed  Google Scholar 

  13. Mielants H et al. (1996) Course of gut inflammation in spondylarthropathies and therapeutic consequences. Baillieres Clin Rheumatol 10: 147–164

    Article  CAS  Google Scholar 

  14. Orchard TR et al. (1998) Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut 42: 387–391

    Article  CAS  Google Scholar 

  15. Schorr-Lesnick B and Brandt LJ (1988) Selected rheumatologic and dermatologic manifestations of inflammatory bowel disease. Am J Gastroenterol 83: 216–223

    CAS  PubMed  Google Scholar 

  16. Dougados M et al. (1991) The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 34: 1218–1227

    Article  CAS  Google Scholar 

  17. Helliwell PS et al. (1998) Do the radiological changes of classic ankylosing spondylitis differ from the changes found in the spondylitis associated with inflammatory bowel disease, psoriasis, and reactive arthritis? Ann Rheum Dis 57: 135–140

    Article  CAS  Google Scholar 

  18. Dekker-Saeys BJ et al. (1978) Ankylosing spondylitis and inflammatory bowel disease. II. Prevalence of peripheral arthritis, sacroiliitis, and ankylosing spondylitis in patients suffering from inflammatory bowel disease. Ann Rheum Dis 37: 33–35

    Article  CAS  Google Scholar 

  19. Steer S et al. (2003) Low back pain, sacroiliitis, and the relationship with HLA-B27 in Crohn's disease. J Rheumatol 30: 518–522

    PubMed  Google Scholar 

  20. Brown MA et al. (1996) HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheum Dis 55: 268–270

    Article  CAS  Google Scholar 

  21. de Vos M et al. (2003) CARD15 mutations in patients with spondyloarthopathy are linked with disease progression and evolution in Crohn's disease. Gastroenterology 124 (Suppl): SA375

    Google Scholar 

  22. Leirisalo-Repo M et al. (1994) High frequency of silent inflammatory bowel disease in spondylarthropathy. Arthritis Rheum 37: 23–31

    Article  CAS  Google Scholar 

  23. Mielants H et al. (1995) The evolution of spondyloarthropathies in relation to gut histology. I. Clinical aspects. J Rheumatol 22: 2266–2272

    CAS  PubMed  Google Scholar 

  24. Simenon G et al. (1990) Macroscopic and microscopic gut lesions in seronegative spondyloarthropathies. J Rheumatol 17: 1491–1494

    CAS  PubMed  Google Scholar 

  25. Taurog JD et al. (1994) The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 180: 2359–2364

    Article  CAS  Google Scholar 

  26. Delamere JP et al. (1983) Jejuno-ileal bypass arthropathy: its clinical features and associations. Ann Rheum Dis 42: 553–557

    Article  CAS  Google Scholar 

  27. Hermann E et al. (1993) HLA-B27-restricted CD8 T cells derived from synovial fluids of patients with reactive arthritis and ankylosing spondylitis. Lancet 342: 646–650

    Article  CAS  Google Scholar 

  28. Elewaut D et al. (1998) Enrichment of T cells carrying beta7 integrins in inflamed synovial tissue from patients with early spondyloarthropathy, compared to rheumatoid arthritis. J Rheumatol 25: 1932–1937

    CAS  PubMed  Google Scholar 

  29. Vaile JH et al. (1999) Bowel permeability and CD45RO expression on circulating CD20+ B cells in patients with ankylosing spondylitis and their relatives. J Rheumatol 26: 128–135

    CAS  PubMed  Google Scholar 

  30. Munkholm P et al. (1994) Intestinal permeability in patients with Crohn's disease and ulcerative colitis and their first degree relatives. Gut 35: 68–72

    Article  CAS  Google Scholar 

  31. Devlin SM et al. (2007) NOD2 variants and antibody response to microbial antigens in Crohn's disease patients and their unaffected relatives. Gastroenterology 132: 576–586

    Article  CAS  Google Scholar 

  32. Dubinsky MC et al. (2006) Serum immune responses predict rapid disease progression among children with Crohn's disease: immune responses predict disease progression. Am J Gastroenterol 101: 360–367

    Article  Google Scholar 

  33. Seibold F et al. (1998) pANCA represents a cross-reactivity to enteric bacterial antigens. J Clin Immunol 18: 153–160

    Article  CAS  Google Scholar 

  34. Torok HP et al. (2004) Inflammatory bowel disease-specific autoantibodies in HLA-B27-associated spondyloarthropathies: increased prevalence of ASCA and pANCA. Digestion 70: 49–54

    Article  Google Scholar 

  35. Turkcapar N et al. (2006) The prevalence of extraintestinal manifestations and HLA association in patients with inflammatory bowel disease. Rheumatol Int 26: 663–668

    Article  Google Scholar 

  36. Hoffman IE et al. (2003) Anti-Saccharomyces cerevisiae IgA antibodies are raised in ankylosing spondylitis and undifferentiated spondyloarthropathy. Ann Rheum Dis 62: 455–459

    Article  CAS  Google Scholar 

  37. Crane AM et al. (2002) Role of NOD2 variants in spondylarthritis. Arthritis Rheum 46: 1629–1633

    Article  CAS  Google Scholar 

  38. Peeters H et al. (2004) Radiological sacroiliitis, a hallmark of spondylitis, is linked with CARD15 gene polymorphisms in patients with Crohn's disease. Ann Rheum Dis 63: 1131–1134

    Article  CAS  Google Scholar 

  39. Laukens D et al. (2005) CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn's disease. Ann Rheum Dis 64: 930–935

    Article  CAS  Google Scholar 

  40. Lichtenstein GR et al. (2006) American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 130: 940–987

    Article  CAS  Google Scholar 

  41. Altan L et al. (2001) Clinical investigation of methotrexate in the treatment of ankylosing spondylitis. Scand J Rheumatol 30: 255–259

    Article  CAS  Google Scholar 

  42. Chen J et al. Methotrexate for ankylosing spondylitis. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD004524. doi:10.1002/14651858.CD004524.pub3

  43. Norton KI et al. (1993) Atypical arthropathy associated with Crohn's disease. Am J Gastroenterol 88: 948–952

    CAS  PubMed  Google Scholar 

  44. Isdale A and Wright V (1989) Seronegative arthritis and the bowel. Baillieres Clin Rheumatol 3: 285–301

    Article  CAS  Google Scholar 

  45. Abi Karam G et al. (2003) Ileal pouchitis and arthritis. Semin Arthritis Rheum 33: 215

    Article  Google Scholar 

  46. Orchard TR and Jewell DP (1999) The importance of ileocaecal integrity in the arthritic complications of Crohn's disease. Inflamm Bowel Dis 5: 92–97

    Article  CAS  Google Scholar 

  47. Carter JD et al. (2004) Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydia-induced arthritis. A prospective, randomized 9-month comparison. J Rheumatol 31: 1973–1980

    CAS  PubMed  Google Scholar 

  48. Smieja M et al. (2001) Randomised, blinded, placebo controlled trial of doxycycline for chronic seronegative arthritis. Ann Rheum Dis 60: 1088–1094

    Article  CAS  Google Scholar 

  49. Gionchetti P et al. (2003) Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology 124: 1202–1209

    Article  Google Scholar 

  50. Karimi O et al. (2005) Probiotics (VSL#3) in arthralgia in patients with ulcerative colitis and Crohn's disease: a pilot study. Drugs Today (Barc) 41: 453–459

    Article  CAS  Google Scholar 

  51. Evans JM et al. (1997) Non-steroidal anti-inflammatory drugs are associated with emergency admission to hospital for colitis due to inflammatory bowel disease. Gut 40: 619–622

    Article  CAS  Google Scholar 

  52. Felder JB et al. (2000) Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study. Am J Gastroenterol 95: 1949–1954

    Article  CAS  Google Scholar 

  53. Matuk R et al. (2004) The spectrum of gastrointestinal toxicity and effect on disease activity of selective cyclooxygenase-2 inhibitors in patients with inflammatory bowel disease. Inflamm Bowel Dis 10: 352–356

    Article  Google Scholar 

  54. El Miedany Y et al. (2006) The gastrointestinal safety and effect on disease activity of etoricoxib, a selective Cox-2 inhibitor in inflammatory bowel diseases. Am J Gastroenterol 101: 311–317

    Article  CAS  Google Scholar 

  55. Braun J et al. (2006) First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis. Ann Rheum Dis 65: 316–320

    Article  CAS  Google Scholar 

  56. Chang JT and Lichtenstein GR (2006) Drug insight: antagonists of tumor-necrosis factor-alpha in the treatment of inflammatory bowel disease. Nat Clin Pract Gastroenterol Hepatol 3: 220–228

    Article  CAS  Google Scholar 

  57. Generini S et al. (2004) 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 63: 1664–1669

    Article  CAS  Google Scholar 

  58. Braun J et al. (2007) 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 Rheum 57: 639–647

    Article  CAS  Google Scholar 

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Correspondence to Scott Plevy.

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Competing interests

S Plevy is a consultant for, has received research support for clinical trials from, and has been a speaker at CME symposia supported in part by Abbott Laboratories, Centocor, UCB, and Elan Pharmaceuticals. C Meier declared no competing interests.

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Meier, C., Plevy, S. Therapy Insight: how the gut talks to the joints—inflammatory bowel disease and the spondyloarthropathies. Nat Rev Rheumatol 3, 667–674 (2007). https://doi.org/10.1038/ncprheum0625

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