Skip to main content

Extraintestinal Manifestations of Inflammatory Bowel Disease: Epidemiology, Etiopathogenesis, and Management

Current Gastroenterology Reports volume 21, Article number: 31 (2019) Cite this article

Abstract

Purpose of Review

Extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) represent a complex array of disease processes with variable epidemiologic penetrance, genetic antecedents, and phenotypic presentations. The purpose of this review is to provide an overview of primary and secondary EIMs as well as salient treatment strategies utilized.

Recent Findings

While the genetic antecedents remain incompletely understood, the treatment armamentarium for EIMs has expanded with new pharmaceutical drug classes that effectively treat IBD.

Summary

EIMs are an increasingly recognized complication of IBD that require prompt recognition, multidisciplinary management, and a multifaceted therapeutic approach. This review highlights the complexities and ramifications of EIM management and offers therapeutic guidance.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Fiocchi C. Inflammatory bowel disease pathogenesis: where are we? J Gastroenterol Hepatol. 2015;30:12–8. https://doi.org/10.1111/jgh.12751.

    Article  PubMed  Google Scholar 

  2. Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590–605. https://doi.org/10.1016/S0140-6736(12)60026-9.

    Article  PubMed  Google Scholar 

  3. Ordás I, et al. Ulcerative colitis. Lancet. 2012. https://doi.org/10.1056/NEJMc1113995#SA1.

  4. Vavricka SR, Brun L, Ballabeni P, Pittet V, Vavricka BMP, Zeitz J, et al. Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort. Am J Gastroenterol. 2010;106:110–9. https://doi.org/10.1038/ajg.2010.343.

    Article  PubMed  Google Scholar 

  5. Bernstein CN, Blanchard JF, Rawsthorne P, Yu N. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. 2001.

  6. Ricart E, Panaccione R, Loftus EV, et al. Autoimmune disorders and extraintestinal manifestations in first-degree familial and sporadic inflammatory bowel disease: a case-control study. Inflamm Bowel Dis. 2004;10:207–14. https://doi.org/10.1097/00054725-200405000-00005.

    Article  PubMed  Google Scholar 

  7. Rankin GB, Watts HD, Melnyk CS, Kelley ML. National Cooperative Crohn’s Disease Study: extraintestinal manifestations and perianal complications. Gastroenterology. 1979;77(4 Pt 2):914–20.

    CAS  Article  Google Scholar 

  8. Greenstein AJ, Janowitz HD, Sachar DB. The extra-intestinal complications of crohn’s disease and ulcerative colitis: a study of 700 patients. Med (United States). 1976. https://doi.org/10.1097/00005792-197609000-00004.

    CAS  Article  Google Scholar 

  9. Veloso FT, Carvalho J, Magro F. Immune-related systemic manifestations of inflammatory bowel disease: a prospective study of 792 patients. J Clin Gastroenterol. 1996;23:29–34. https://doi.org/10.1097/00004836-199607000-00009.

    CAS  Article  PubMed  Google Scholar 

  10. •• Vavricka SR, Rogler G, Gantenbein C, et al. Chronological order of appearance of extraintestinal manifestations relative to the time of IBD diagnosis in the Swiss Inflammatory Bowel Disease Cohort. Inflamm Bowel Dis. 2015;21(8):1794–800. https://doi.org/10.1097/MIB.0000000000000429 This study provides insight on types of EIM, their preponderance in IBD cohorts, the order in which they typically manifest, and how they manifest (before or after) the diagnosis of IBD.

    Article  PubMed  Google Scholar 

  11. Mendoza JL, Lana R, Taxonera C, Alba C, Izquierdo S, Diaz-Rubio M. Extraintestinal manifestations in inflammatory bowel disease: differences between Crohn’s disease and ulcerative colitis. Med Clin (Barc). 2005;183:7842–50. https://doi.org/10.4049/jimmunol.0804379.

    CAS  Article  Google Scholar 

  12. Trikudanathan G, Venkatesh PGK, Navaneethan U. Diagnosis and therapeutic management of extra-intestinal manifestations of inflammatory bowel disease. Drugs. 2012;72:2333–49. https://doi.org/10.2165/11638120-000000000-00000.

    CAS  Article  PubMed  Google Scholar 

  13. Satsangi J, Grootscholten C, Holt H, Jewell DP. Clinical patterns of familial inflammatory bowel disease. Gut. 1996;38:738–41. https://doi.org/10.1136/gut.38.5.738.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Van Sommeren S, Janse M, Karjalainen J, et al. Extraintestinal manifestations and complications in inflammatory bowel disease: from shared genetics to shared biological pathways. Inflamm Bowel Dis. 2014;20:987–94. https://doi.org/10.1097/MIB.0000000000000032.

    Article  PubMed  Google Scholar 

  15. Orchard TR, Chua CN, Ahmad T, Cheng H, Welsh KI, Jewell DP. Uveitis and erythema nodosum in inflammatory bowel disease: clinical features and the role of HLA genes. Gastroenterology. 2002;123:714–8. https://doi.org/10.1053/gast.2002.35396.

    Article  PubMed  Google Scholar 

  16. Nguyen GC, Torres EA, Regueiro M, et al. Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic whites: characterization of a large North American cohort. Am J Gastroenterol. 2006;101:1012–23. https://doi.org/10.1111/j.1572-0241.2006.00504.x.

    Article  PubMed  Google Scholar 

  17. Levine J, Burakoff R. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Hepatol. 2011;347:417–29. https://doi.org/10.1056/NEJMra020831.

    Article  Google Scholar 

  18. Su C, Judge T, Lichtenstein G. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Clin North Am. 2002;31:307–27.

    Article  Google Scholar 

  19. Vavricka S, Schoepfer AM, Scharl M, Lakatos PL, Navarini A, Rogler G. Extraintestinal manifestations of inflammatory bowel disease. Inflamm Bowel Dis. 2015;21(8):1982–92.

    Article  Google Scholar 

  20. Hedin CRH, Vavricka SR, Stagg AJ, et al. Results of the sixth ECCO Scientific Workshop: the pathogenesis of inflammatory extraintestinal manifestations of inflammatory bowel disease: implications for research, diagnosis, and therapy. J Crohn’s Colitis. 2018. https://doi.org/10.1093/ecco-jcc/jjx180.110.

  21. Smale S, Natt RS, Orchard TR, Russell AS, Bjarnason I. Inflammatory bowel disease and spondylarthropathy. Arthritis Rheum. 2001;44:2728–36. https://doi.org/10.1002/1529-0131(200112)44:12<2728::AID-ART459>3.0.CO;2-8.

    CAS  Article  PubMed  Google Scholar 

  22. Orchard TR, Wordsworth BP, Jewell DP. Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut. 1998;42:387–91. https://doi.org/10.1136/gut.42.3.387.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Orchard TR, Thiyagaraja S, Welsh KI, Wordsworth BP, Gaston JSH, Jewell DP. Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease. Gastroenterology. 2000;118:274–8. https://doi.org/10.1016/S0016-5085(00)70209-5.

    CAS  Article  PubMed  Google Scholar 

  24. Farmer RG, Hawk WA, Turnbull RB. Clinical patterns in Crohn’s disease: a statistical study of 615 cases. Gastroenterology. 1975;68:627–35. https://doi.org/10.1016/S0016-5085(75)80270-8.

    CAS  Article  PubMed  Google Scholar 

  25. Yang BR, Choi NK, Kim MS, Chun J, Joo SH, Kim H, et al. Prevalence of extraintestinal manifestations in Korean inflammatory bowel disease patients. PLoS One. 2018;13:e0200363. https://doi.org/10.1371/journal.pone.0200363.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Rudwaleit M, Landewé 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;68:770–6. https://doi.org/10.1136/ard.2009.108217.

    CAS  Article  PubMed  Google Scholar 

  27. Rudwaleit M, Van Der Heijde D, Landewé 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;68:777–83. https://doi.org/10.1136/ard.2009.108233.

    CAS  Article  PubMed  Google Scholar 

  28. Rudwaleit M, Baeten D. Ankylosing spondylitis and bowel disease. Best Pract Res Clin Rheumatol. 2006;20:451–71. https://doi.org/10.1016/j.berh.2006.03.010.

    Article  PubMed  Google Scholar 

  29. Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: a Department of Veterans Affairs cooperative study. Arthritis Rheum. 1999;42:2325–9. https://doi.org/10.1002/1529-0131(199911)42:11<2325::AID-ANR10>3.0.CO;2-C.

    CAS  Article  PubMed  Google Scholar 

  30. Rijk MCM, Van Hogezand RA, Van Lier HJJ, Van Tongeren JHM. Sulphasalazine and prednisone compared with sulphasalazine for treating active Crohn disease: a double-blind, randomized, multicenter trial. Ann Intern Med. 1991;114:445–50. https://doi.org/10.7326/0003-4819-114-6-445.

    CAS  Article  PubMed  Google Scholar 

  31. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG clinical guideline: management of Crohn’s disease in adults. Am J Gastroenterol. 2018;113:481–517. https://doi.org/10.1038/ajg.2018.27.

    Article  PubMed  Google Scholar 

  32. Wang Y, Parker CE, Bhanji T, Feagan BG, Macdonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2016;10:CD000543. https://doi.org/10.1002/14651858.CD000543.pub4.

    Article  Google Scholar 

  33. Peyrin-Biroulet L, Van Assche G, Gómez-Ulloa D, et al. Systematic review of tumor necrosis factor antagonists in extraintestinal manifestations in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2017;15:25–36.e27. https://doi.org/10.1016/j.cgh.2016.06.025.

    CAS  Article  PubMed  Google Scholar 

  34. Felder JB, Korelitz BI, Rajapakse R, Schwarz S, Horatagis AP, Gleim G. Effects of nonsteroidal antiinflammatory drugs on inflammatory bowel disease: a case-control study. Am J Gastroenterol. 2000;95:1949–54. https://doi.org/10.1016/S0002-9270(00)01054-6.

    CAS  Article  PubMed  Google Scholar 

  35. El Miedany Y, Youssef S, Ahmed I, El Gaafary M. The gastrointestinal safety and effect on disease activity of etoricoxib, a selective Cox-2 inhibitor in inflammatory bowel diseases. Am J Gastroenterol. 2006;101:311–7. https://doi.org/10.1111/j.1572-0241.2006.00384.x.

    CAS  Article  PubMed  Google Scholar 

  36. Sandborn WJ, Stenson WF, Brynskov J, Lorenz RG, Steidle GM, Robbins JL, et al. Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study. Clin Gastroenterol Hepatol. 2006;4:203–11. https://doi.org/10.1016/j.cgh.2005.12.002.

    CAS  Article  PubMed  Google Scholar 

  37. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data Results of the first international workshop. Am J Ophthalmol. 2005;140:509–16. https://doi.org/10.1016/j.ajo.2005.03.057.

    Article  PubMed  Google Scholar 

  38. Van Der Heijde D, Ramiro S, Landewé R, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76:978–91. https://doi.org/10.1136/annrheumdis-2016-210770.

    Article  PubMed  Google Scholar 

  39. Chen J, Lin S, Liu C. Sulfasalazine for ankylosing spondylitis. Cochrane Database Syst Rev. 2014. https://doi.org/10.1002/14651858.CD004800.pub3.

  40. Ostendorf B, Specker C, Schneider M. Methotrexate lacks efficacy in the treatment of severe ankylosing spondylitis compared with rheumatoid and psoriatic arthritis. J Clin Rheumatol. 1998;4:129–36. https://doi.org/10.1097/00124743-199806000-00007.

    CAS  Article  PubMed  Google Scholar 

  41. Zochling J, Van Der Heijde D, Dougados M, Braun J. Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis. Ann Rheum Dis. 2006;65:423–32. https://doi.org/10.1136/ard.2005.041129.

    CAS  Article  PubMed  Google Scholar 

  42. Dubinsky MC, Cross RK, Sandborn WJ, et al. Extraintestinal manifestations in vedolizumab and anti-TNF-treated patients with inflammatory bowel disease. Inflammatory Bowel Diseases. 2018. https://doi.org/10.1093/ibd/izy065.

    Article  Google Scholar 

  43. Feagan BG, Sandborn WJ, Colombel JF, Byrne SO’, Khalid JM, Kempf C, et al. Incidence of arthritis/arthralgia in inflammatory bowel disease with long-term vedolizumab treatment: post hoc analyses of the GEMINI Trials. J Crohn’s Colitis. 2018;13:50–7. https://doi.org/10.1093/ecco-jcc/jjy125.

    Article  Google Scholar 

  44. Hagen JW, Swoger JM, Grandinetti LM. Cutaneous manifestations of Crohn disease. Dermatol Clin. 2015;33:417–31. https://doi.org/10.1016/j.det.2015.03.007.

    CAS  Article  PubMed  Google Scholar 

  45. Thrash B, Patel M, Shah KR, Boland CR, Menter A. Cutaneous manifestations of gastrointestinal disease: part II. J Am Acad Dermatol. 2013;68:211.e1–211.e33.

    Article  Google Scholar 

  46. Timani S, Mutasim DF. Skin manifestations of inflammatory bowel disease. Clin Dermatol. 2008;26:265–73.

    Article  Google Scholar 

  47. Greuter T, Navarini A, Vavricka SR. Skin manifestations of inflammatory bowel disease. Clin Rev Allergy Immunol. 2017;53:413–27. https://doi.org/10.1007/s12016-017-8617-4.

    CAS  Article  PubMed  Google Scholar 

  48. Brooklyn T, Dunnill G, Probert C. Diagnosis and treatment of pyoderma gangrenosum. BMJ. 2006;42:8547–51. https://doi.org/10.1021/es8016842.

    CAS  Article  Google Scholar 

  49. Kawakami T, Ohashi S, Kawa Y, Takahama H, Ito M, Soma Y, et al. Elevated serum granulocyte colony-stimulating factor levels in patients with active phase of sweet syndrome and patients with active Behçet disease: implication in neutrophil apoptosis dysfunction. Arch Dermatol. 2004;140:570–4. https://doi.org/10.1001/archderm.140.5.570.

    CAS  Article  PubMed  Google Scholar 

  50. Cohen PR. Sweet’s syndrome - a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34. https://doi.org/10.1186/1750-1172-2-34.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Cohen PR. Neutrophilic dermatoses: a review of current treatment options. Am J Clin Dermatol. 2009;10:301–12. https://doi.org/10.2165/11310730-000000000-00000.

    Article  PubMed  Google Scholar 

  52. Morgan AJ, Schwartz RA. Cutaneous polyarteritis nodosa: a comprehensive review. Int J Dermatol. 2010;49:750–6. https://doi.org/10.1111/j.1365-4632.2010.04522.x.

    Article  PubMed  Google Scholar 

  53. Daoud MS, Hutton KP, Gibson LE. Cutaneous periarteritis nodosa: a clinicopathological study of 79 cases. Br J Dermatol. 1997;136:706–13. https://doi.org/10.1111/j.1365-2133.1997.tb03656.x.

    CAS  Article  PubMed  Google Scholar 

  54. Siroy A, Wasman J. Metastatic Crohn disease: a rare cutaneous entity. Arch Pathol Lab Med. 2012;136:329–32. https://doi.org/10.5858/arpa.2010-0666-RS.

    Article  PubMed  Google Scholar 

  55. Hegarty AM, Barrett AW, Scully C. Pyostomatitis vegetans. Clin Exp Dermatol. 2004;29:1–7. https://doi.org/10.1111/j.1365-2230.2004.01438.x.

    CAS  Article  PubMed  Google Scholar 

  56. Lee FI, Bellary SV, Francis C. Increased occurrence of psoriasis in patients with Crohn’s disease and their relatives. Am J Gastroenterol. 1990;85:962–3. https://doi.org/10.1111/j.1572-0241.1990.tb06788.x.

    CAS  Article  PubMed  Google Scholar 

  57. Reddy H, Shipman AR, Wojnarowska F. Epidermolysis bullosa acquisita and inflammatory bowel disease: a review of the literature. Clin Exp Dermatol. 2013;38:225–30. https://doi.org/10.1111/ced.12114.

    CAS  Article  PubMed  Google Scholar 

  58. Brenner SM, Delany HM. Erythema multiforme and Crohn’s disease of the large intestine. Gastroenterology. 1972. https://doi.org/10.1016/S0016-5085(72)80157-4.

    CAS  Article  Google Scholar 

  59. Yates MV, Watkinson G, Kelman A. Further evidence for an association between psoriasis, Crohn’s disease and ulcerative colitis. Br J Dermatol. 1982;106(3):323–30. https://doi.org/10.1111/j.1365-2133.1982.tb01731.x.

    CAS  Article  PubMed  Google Scholar 

  60. Guerre-Schmidt AR, Pelletier F, Carbonnel F, Humbert PAF. Dermatosis-arthritis syndrome associated with Crohn’s disease in a teenager. Rev Med Interne. 2006. https://doi.org/10.1016/j.revmed.2006.07.017.

    Article  Google Scholar 

  61. Keyal U, Liu Y, Bhatta AK. Dermatologic manifestations of inflammatory bowel disease: a review. Discov Med. 2018;25:225–33.

    PubMed  Google Scholar 

  62. Kaplan RP, Callen JP. Dermatitis herpetiformis: autoimmune disease associations. Clin Dermatol. 1991;9:347–60. https://doi.org/10.1016/0738-081X(91)90026-H.

    CAS  Article  PubMed  Google Scholar 

  63. Cholongitis E, Pipili C, Ioannidou D. Dermatitis herpetiformis in a patient with ulcerative colitis. Inflamm Bowel Dis. 2008;14(4):581–2.

    Article  Google Scholar 

  64. Egeberg A, Mallbris L, Warren RB, Bachelez H, Gislason GH, Hansen PR, et al. Association between psoriasis and inflammatory bowel disease: a Danish nationwide cohort study. Br J Dermatol. 2016;175:487–92. https://doi.org/10.1111/bjd.14528.

    CAS  Article  PubMed  Google Scholar 

  65. Fu Y, Lee C, CC C. Association of psoriasis with Inflammatory bowel disease: a systematic review and meta-analysis. JAMA Dermatol. 2018;154(12):1417–23.

    Article  Google Scholar 

  66. Steinwurz F, Denadai R, Saad-Hossne R, Queiroz ML, Teixeira FV, Romiti R. Infliximab induced psoriasis in a cohort of children with inflammatory bowel disease: a 12 years follow-up study. United Eur Gastroenterol J. 2017;6:610–6. https://doi.org/10.1177/2050640617725676 LK - http://rd8hp6du2b.search.serialssolutions.com?sid=EMBASE&issn=20506414&id=doi:10.1177%2F2050640617725676&atitle=Infliximab+induced+psoriasis+in+a+cohort+of+children+with+inflammatory+bowel+disease%3A+A+12+years+follow-up+study&stitle=United+Eur.+Gastroenterol.+J.&title=United+European+Gastroenterology+Journal&volume=5&issue=5&spage=A540&epage=&aulast=Martinez-Vinson&aufirst=C.&auinit=C.&aufull=Martinez-Vinson+C.&coden=&isbn=&pages=A540-&date=2017&auinit1=C&auinitm=. Accessed 6 May 2019.

  67. Thomas K, Ormerod AD, Craig FE, et al. Clinical outcomes and response of patients applying topical therapy for pyoderma gangrenosum: a prospective cohort study. J Am Acad Dermatol. 2016;75:940–9. https://doi.org/10.1016/j.jaad.2016.06.016.

    Article  PubMed  Google Scholar 

  68. Craig F, Greenlaw N, Harrison E, et al. Clinical outcomes of patients receiving topical treatments for pyoderma gangrenosum: a prospective observational study. Br J Dermatol. 2014. https://doi.org/10.1111/bjd.12931.

  69. Ormerod AD, Thomas KS, Craig FE, Mitchell E, Greenlaw N, Norrie J, et al. Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial. BMJ. 2015;2015:350. https://doi.org/10.1136/bmj.h2958.

    Article  Google Scholar 

  70. Brooklyn TN, Dunnill MGS, Shetty A, Bowden JJ, Williams JD, Griffiths CE, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut. 2006;55:505–9. https://doi.org/10.1136/gut.2005.074815.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Regueiro M, Valentine J, Plevy S, Fleisher MR, Lichtenstein GR. Infliximab for treatment of pyoderma gangrenosum associated with inflammatory bowel disease. Am J Gastroenterol. 2003;98:1821–6. https://doi.org/10.1111/j.1572-0241.2003.07581.x.

    CAS  Article  PubMed  Google Scholar 

  72. Fonder MA, Cummins DL, Ehst BD, Anhalt GJ, Meyerle JH. Adalimumab therapy for recalcitrant pyoderma gangrenosum. J Burns Wounds. 2006;5:e8.

    PubMed  PubMed Central  Google Scholar 

  73. Greb JE, Gottlieb AB, Goldminz AM. High-dose ustekinumab for the treatment of severe, recalcitrant pyoderma gangrenosum. Dermatol Ther. 2016;29:482–3. https://doi.org/10.1111/dth.12387.

    Article  PubMed  Google Scholar 

  74. Goldminz AM, Botto NC, Gottlieb AB. Severely recalcitrant pyoderma gangrenosum successfully treated with ustekinumab. J Am Acad Dermatol. 2012;67:e237–8. https://doi.org/10.1016/j.jaad.2012.04.045.

    Article  PubMed  Google Scholar 

  75. Low ZM, Mar A. Treatment of severe recalcitrant pyoderma gangrenosum with ustekinumab. Australas J Dermatol. 2018;59:131–4. https://doi.org/10.1111/ajd.12744.

    Article  PubMed  Google Scholar 

  76. Marzano AV, Ishak RS, Saibeni S, Crosti C, Meroni PL, Cugno M. Autoinflammatory skin disorders in inflammatory bowel diseases, pyoderma gangrenosum and sweet’s syndrome: a comprehensive review and disease classification criteria. Clin Rev Allergy Immunol. 2013;45:202–10. https://doi.org/10.1007/s12016-012-8351-x.

    CAS  Article  PubMed  Google Scholar 

  77. Miller J, Yentzer BA, Clark A, Jorizzo JL, Feldman SR. Pyoderma gangrenosum: a review and update on new therapies. J Am Acad Dermatol. 2010;62:646–54. https://doi.org/10.1016/j.jaad.2009.05.030.

    CAS  Article  PubMed  Google Scholar 

  78. Alavi A, French LE, Davis MD, Brassard A, Kirsner RS. Pyoderma gangrenosum: an update on pathophysiology, diagnosis and treatment. Am J Clin Dermatol. 2017;18:355–72. https://doi.org/10.1007/s40257-017-0251-7.

    Article  PubMed  Google Scholar 

  79. Karamlou K, Gorn AH. Refractory sweet syndrome with autoimmune organizing pneumonia treated with monoclonal antibodies to tumor necrosis factor. J Clin Rheumatol. 2004;10:331–5. https://doi.org/10.1097/01.rhu.0000147053.60795.46.

    Article  PubMed  Google Scholar 

  80. Agarwal A, Barrow W, Angelica Selim M, Nicholas MW. Refractory subcutaneous sweet syndrome treated with adalimumab. JAMA Dermatol. 2016;152:842–4. https://doi.org/10.1001/jamadermatol.2016.0503.

    Article  PubMed  Google Scholar 

  81. Ribi C, Cohen P, Pagnoux C, Mahr A, Arène JP, Puéchal X, et al. Treatment of polyarteritis nodosa and microscopic polyangiitis without poor-prognosis factors a prospective randomized study of one hundred twenty-four patients. Arthritis Rheum. 2010;62:1186–97. https://doi.org/10.1002/art.27340.

    Article  PubMed  Google Scholar 

  82. Forbess L, Bannykh S. Polyarteritis nodosa. Rheum Dis Clin N Am. 2015;41(1):33–46.

    Article  Google Scholar 

  83. Kiuru M, Camp B, Adhami K, Jacob V, Magro C, Wildman H. Treatment of metastatic cutaneous crohn disease with certolizumab. Dermatol Online J. 2015.

  84. Zullow S, Lichtman MK, Larson A, Stier EA, Farraye FA. Case series: ustekinumab use in metastatic cutaneous Crohn’s disease. Am J Gastroenterol. 2017;112:S1085. https://doi.org/10.1038/ajg.2017.319.

    Article  Google Scholar 

  85. Cury DB, Alan C, Moss MD, Elias G, Nakao A. Adalimumab for cutaneous metastatic Crohn’s disease. Inflamm Bowel Dis. 2010;16:723–4. https://doi.org/10.1002/ibd.21082.

    Article  PubMed  Google Scholar 

  86. Escher JC, Stoof TJ, Van Deventer SJH, Van Furth AM. Successful treatment of metastatic Crohn disease with infliximab. J Pediatr Gastroenterol Nutr. 2002;34:420–3. https://doi.org/10.1097/00005176-200204000-00021.

    Article  PubMed  Google Scholar 

  87. Troncoso LL, Biancardi AL, De Moraes HV, Zaltman C. Ophthalmic manifestations in patients with inflammatory bowel disease: a review. World J Gastroenterol. 2017;23:5836–48. https://doi.org/10.3748/wjg.v23.i32.5836.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Thomas AS, Lin P. Ocular manifestations of inflammatory bowel disease. Curr Opin Ophthalmol. 2016;27:552–60. https://doi.org/10.1097/ICU.0000000000000310.

    Article  PubMed  Google Scholar 

  89. Mintz R, Feller E, Bahr RL, Shah SA. Ocular manifestations of inflammatory bowel disease. Inflamm Bowel Dis. 2004;10(2):135–9.

    Article  Google Scholar 

  90. Williams CPR, Browning AC, Sleep TJ, Webber SK, McGill JI. A randomised, double-blind trial of topical ketorolac vs artificial tears for the treatment of episcleritis. Eye. 2005;19:739–42. https://doi.org/10.1038/sj.eye.6701632.

    CAS  Article  PubMed  Google Scholar 

  91. Suhler EB, Smith JR, Wertheim MS, Lauer AK, Kurz DE, Pickard TD, et al. A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol. 2005;123:903–12. https://doi.org/10.1001/archopht.123.7.903.

    CAS  Article  PubMed  Google Scholar 

  92. Suhler EB, Lowder CY, Goldstein DA, Giles T, Lauer AK, Kurz PA, et al. Adalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trial. Br J Ophthalmol. 2013;97:481–6. https://doi.org/10.1136/bjophthalmol-2012-302292.

    Article  PubMed  Google Scholar 

  93. Borrás-Blasco J, Casterá D-E, Cortes X, Abad FJ, Rosique-Robles JD, Mallench LG. Effectiveness of infliximab, adalimumab and golimumab for non-infectious refractory uveitis in adults. Int J Clin Pharmacol Ther. 2015;53:377–90. https://doi.org/10.5414/CP202171.

    CAS  Article  PubMed  Google Scholar 

  94. •• Weismüller TJ, Trivedi PJ, Bergquist A, et al. Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis. Gastroenterology. 2017;152:1975–1984.e8. https://doi.org/10.1053/j.gastro.2017.02.038 This study provides new insight on IBD subtype, PSC phenotype and risk of liver transplantation and mortality.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Loftus EV, Harewood GC, Loftus CG, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut. 2005;54:91–6. https://doi.org/10.1136/gut.2004.046615.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. AASLD Practice Guidelines. Hepatology. 2010;409:234–50. https://doi.org/10.1016/j.virol.2010.10.018.

    CAS  Article  Google Scholar 

  97. Harbord M, Annese V, Vavricka SR, Allez M, Barreiro-de Acosta M, Boberg KM, et al. The first european evidence-based consensus on extra-intestinal manifestations in inflammatory bowel disease. J Crohn's Colitis. 2016;10:239–54. https://doi.org/10.1093/ecco-jcc/jjv213.

    Article  Google Scholar 

  98. Bajer L, Slavcev A, Macinga P, Sticova E, Brezina J, Roder M, et al. Risk of recurrence of primary sclerosing cholangitis after liver transplantation is associated with de novo inflammatory bowel disease. World J Gastroenterol. 2018;24(43):4939–49.

    CAS  Article  Google Scholar 

  99. Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology. 2005;129:827–36. https://doi.org/10.1053/j.gastro.2005.06.021.

    Article  PubMed  Google Scholar 

  100. Raj AA, Birring SS, Green R, Grant A, de Caestecker J, Pavord ID. Prevalence of inflammatory bowel disease in patients with airways disease. Respir Med. 2008;102:780–5. https://doi.org/10.1016/j.rmed.2007.08.014.

    CAS  Article  PubMed  Google Scholar 

  101. Ekbom A, Brandt L, Granath F, Löfdahl CG, Egesten A. Increased risk of both ulcerative colitis and Crohn’s disease in a population suffering from COPD. Lung. 2008;186:167–72. https://doi.org/10.1007/s00408-008-9080-z.

    Article  PubMed  Google Scholar 

  102. Vutcovici M, Brassard P, Bitton A. Inflammatory bowel disease and airway diseases. World J Gastroenterol. 2016;22:7735–41. https://doi.org/10.3748/wjg.v22.i34.7735.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Basseri B, Enayati P, Marchevsky A, Papadakis KA. Pulmonary manifestations of inflammatory bowel disease: case presentations and review. J Crohn's Colitis. 2010;4:390–7. https://doi.org/10.1016/j.crohns.2010.03.008.

    Article  Google Scholar 

  104. Alrashid AI, Brown RD, Mihalov ML, Sekosan M, Pastika BJ, Venu RP. Crohn’s disease involving the lung: resolution with infliximab. Dig Dis Sci. 2001;46:1736–9. https://doi.org/10.1023/A:1010665807294.

    CAS  Article  PubMed  Google Scholar 

  105. Corica D, Romano C. Renal involvement in inflammatory bowel diseases. J Crohn's Colitis. 2015;10:226–35. https://doi.org/10.1093/ecco-jcc/jjv138.

    Article  Google Scholar 

  106. Oikonomou K, Kapsoritakis A, Eleftheriadis T, Stefanidis I, Potamianos S. Renal manifestations and complications of inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:1034–45. https://doi.org/10.1002/ibd.21468.

    Article  PubMed  Google Scholar 

  107. Primas C, Novacek G, Schweiger K, Mayer A, Eser A, Papay P, et al. Renal insufficiency in IBD - prevalence and possible pathogenetic aspects. J Crohn's Colitis. 2013;7:e630–4. https://doi.org/10.1016/j.crohns.2013.05.001.

    Article  Google Scholar 

  108. Ambruzs J, Larsen C. Renal manifestations of inflammatory bowel disease. Rheum Dis Clin N Am. 2018;44(4):699–714.

    Article  Google Scholar 

  109. Kane S. Urogenital complications of Crohn’s disease. Am J Gastroenterol. 2006. https://doi.org/10.1111/j.1572-0241.2006.00976.x.

    Article  Google Scholar 

  110. Farraye FA, Melmed GY, Lichtenstein GR, Kane SV. ACG clinical guideline: preventive care in inflammatory bowel disease. Am J Gastroenterol. 2017;112:241–58. https://doi.org/10.1038/ajg.2016.537.

    Article  PubMed  Google Scholar 

  111. Bernstein CN, Leslie WD, Leboff MS. AGA technical review on osteoporosis in gastrointestinal diseases. Gastroenterology. 2003;124:795–841. https://doi.org/10.1053/gast.2003.50106.

    Article  PubMed  Google Scholar 

  112. Siris ES, Adler R, Bilezikian J, Bolognese M, Dawson-Hughes B, Favus MJ, et al. The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int. 2014;25:1439–43. https://doi.org/10.1007/s00198-014-2655-z.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. McConnell N, Campbell S, Gillanders I, Rolton H, Danesh B. Risk factors for developing renal stones in inflammatory bowel disease. BJU Int. 2002;89:835–41. https://doi.org/10.1046/j.1464-410X.2002.02739.x.

    CAS  Article  PubMed  Google Scholar 

  114. Parks JH, Worcester EM, Corey O’Connor R, Coe FL. Urine stone risk factors in nephrolithiasis patients with and without bowel disease. Kidney Int. 2003;63:255–65. https://doi.org/10.1046/j.1523-1755.2003.00725.x.

    Article  PubMed  Google Scholar 

  115. Kumar R, Ghoshal UC, Singh G, Mittal RD. Infrequency of colonization with Oxalobacter formigenes in inflammatory bowel disease: possible role in renal stone formation. J Gastroenterol Hepatol. 2004;19:1403–9. https://doi.org/10.1111/j.1440-1746.2004.03510.x.

    Article  PubMed  Google Scholar 

  116. Fagagnini S, Heinrich H, Rossel JB, Biedermann L, Frei P, Zeitz J, et al. Risk factors for gallstones and kidney stones in a cohort of patients with inflammatory bowel diseases. PLoS One. 2017;12:e0185193. https://doi.org/10.1371/journal.pone.0185193.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. Zhang F, Xu C, Shan G, Chen H, Xu G. Is gallstone disease associated with inflammatory bowel diseases? A meta-analysis. J Dig Dis. 2015;16(11):634–41.

    Article  Google Scholar 

  118. Ibrahim M, Sarvepalli S, Morris-Stiff G, et al. Gallstones: watch and wait, or intervene? Cleve Clin J Med. 2018. https://doi.org/10.3949/ccjm.85a.17035.

    Article  Google Scholar 

  119. Bernstein CN, Blanchard JF, Houston DS, Wajda A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb Haemost. 2001.

  120. Johannesdottir SA, Horváth-Puhó E, Dekkers OM, et al. Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study. JAMA Intern Med. 2013. https://doi.org/10.1001/jamainternmed.2013.122.

    CAS  Article  Google Scholar 

  121. Wallaert JB, De Martino RR, Marsicovetere PS, et al. Venous thromboembolism after surgery for inflammatory bowel disease: are there modifiable risk factors? Data from ACS NSQIP. Dis Colon Rectum. 2012;55:1138–44. https://doi.org/10.1097/DCR.0b013e3182698f60.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Koutroumpakis EI, Tsiolakidou G, Koutroubakis IE. Risk of venous thromboembolism in patients with inflammatory bowel disease. Semin Thromb Hemost. 2013;39:461–8. https://doi.org/10.1055/s-0033-1343886.

    CAS  Article  PubMed  Google Scholar 

  123. Papa A, Gerardi V, Marzo M, Felice C, Rapaccini GL, Gasbarrini A. Venous thromboembolism in patients with inflammatory bowel disease: focus on prevention and treatment. World J Gastroenterol. 2014;20:3173–9. https://doi.org/10.3748/wjg.v20.i12.3173.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet. 2010;375:657–63. https://doi.org/10.1016/S0140-6736(09)61963-2.

    Article  PubMed  Google Scholar 

  125. Murthy SK, Nguyen GC. Venous thromboembolism in inflammatory bowel disease: an epidemiological review. Am J Gastroenterol. 2011;106:713–8. https://doi.org/10.1038/ajg.2011.53.

    Article  PubMed  Google Scholar 

  126. Nguyen GC, Sam J. Rising prevalence of venous thromboembolism and its impact on mortality among hospitalized inflammatory bowel disease patients. Am J Gastroenterol. 2008;103:2272–80. https://doi.org/10.1111/j.1572-0241.2008.02052.x.

    Article  PubMed  Google Scholar 

  127. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315–52. https://doi.org/10.1016/j.chest.2015.11.026.

    Article  PubMed  Google Scholar 

  128. Bartholomew J. Update on the management of venous thromboembolism. Cleve Clin J Med. 2017;84(12):39–46.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Gastroenterology, Hepatology & Nutrition, Digestive Disease and Surgical Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, USA

    Ari Garber & Miguel Regueiro

Authors
  1. Ari Garber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miguel Regueiro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Miguel Regueiro.

Ethics declarations

Conflict of Interest

- AG: none. - MR: Miguel Regueiro serves as a consultant and advisory boards for Abbvie, Janssen, UCB, Takeda, Miraca, Pfizer, Celgene, Seres, and Amgen and receives research support from Abbvie, Janssen, Takeda, and Pfizer and unrestricted educational grants from Abbvie, Janssen, UCB, Pfizer, Takeda, Salix, and Shire.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Large Intestine

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Garber, A., Regueiro, M. Extraintestinal Manifestations of Inflammatory Bowel Disease: Epidemiology, Etiopathogenesis, and Management. Curr Gastroenterol Rep 21, 31 (2019). https://doi.org/10.1007/s11894-019-0698-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11894-019-0698-1

Keywords

  • Inflammatory bowel disease
  • Extraintestinal manifestations
  • EIMs
  • Epidemiologic penetrance
  • Genetic antecedents
  • And phenotypic presentations
  • Large intestine