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Cytokine Network in Chronic Perianal Crohn’s Disease and Indeterminate Colitis After Colectomy

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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Antitumor necrosis factor alpha (anti-TNF-α) therapy in perianal Crohn’s disease (CD) is widely established but recent studies suggest that the underlying fistula tract and inflammation may persist. Treatment with a monoclonal antibody against interleukin (IL)-12 was reported to induce clinical responses and remissions in patients with active CD. The aim of our study was to analyze the cytokine network (TNF-α, IL-12, IL-1β, and IL-6) in 12 patients with chronic perianal CD and a Crohn’s disease activity index (CDAI) score <150 to exclude active intestinal disease, in 7 patients with indeterminate colitis (IC) after restorative proctocolectomy with perianal complications, in 7 patients with active intestinal CD without perianal manifestations, and in 19 healthy controls. Nonparametric Mann–Whitney U test and Spearman’s rank correlation test were used. Serum TNF-α levels were significantly higher in patients with IC than perianal CD patients and healthy controls. Serum TNF-α levels significantly correlated with perianal CDAI score and with the presence of anal fistulas. Serum IL-12 levels correlated with the presence of anal strictures and were similar in all groups. Serum IL-6 levels were significantly higher in the presence of perianal fistulas and lower in the presence of anal strictures. Our study confirmed that TNF-α plays a major role in the perianal and intestinal CD. Furthermore, the significantly higher TNF-α serum levels in patients with IC suggest the use of anti-TNF-α in such patients. On the contrary, according to our results the efficacy of anti-IL-12 antibodies appears doubtful in chronic perianal CD or IC without anal strictures. The role of IL-6 as a systemic mediator for active chronic inflammation was confirmed and a possible role for its monoclonal antibody was suggested.

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References

  1. Sangwan YP, Schoetz DJ Jr, Murray JJ, Roberts PL, Coller JA. Perianal Crohn’s disease. Results of local surgical treatment. Dis Colon Rectum 1996;39:529–535.

    Article  PubMed  CAS  Google Scholar 

  2. McClane SJ, Rombeau JL. Anorectal Crohn’s disease. Surg clin North Am 2001;81:169–183.

    Article  PubMed  CAS  Google Scholar 

  3. Williams DR, Coller JA, Corman ML, Nugent FW, Veidenheimer MC. Anal complications in Crohn’s disease. Dis Colon Rectum 1981;24:22–24.

    PubMed  CAS  Google Scholar 

  4. Keighley MR, Allan RN. Current status and influence of operation on perianal Crohn’s disease. Int J Colorectal Dis 1986;1:104–107.

    Article  PubMed  CAS  Google Scholar 

  5. Armuzzi A, Ahmad T, Ling KL, de Silva A, Cullen S, van heel D, Orchard TL, Welsh KI, Marshall KE, Jewel DP. Genotype–phenotype analysis of the Crohn’s disease susceptibility haplotype on chromosome 5q31. Gut 2003;52:1133–1139.

    Article  PubMed  CAS  Google Scholar 

  6. Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB. American Gastroenterological Association Clinical Practice Committee. AGA technical review on perianal Crohn’s disease. Gastroenterology 2003;125:1508–1530.

    Article  PubMed  Google Scholar 

  7. Plevy SE, Landers CJ, Prehn J, Carramanzana NM, Deem RL, Shealy D, Targan SR. A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease. J Immunol 1997;159:6276–6282.

    PubMed  CAS  Google Scholar 

  8. Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, De Woody KL, Schaible TF, Rutgeerts PJ. A short-term study of chimeric monoclonal antibody cA2 to tumour 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 

  9. Sandborn WJ, Feagan BG, Hanauer SB, Present DH, Sutherland LR, Kamm MA, Wolf DC, Baker JP, Hawkey C, Archaumbalt A, Bernstein CN, Novak C, Heath PK, Targan SR. CDP571 Crohn’s Disease Study Group. 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 

  10. Present DH, Rutgeerts P, Targan S, Hanauer S, Mayer L, von Hogezand RA, Podolsky DK, Sands BE, Braakman T, De Woody KL, Schaible TF, van Deventer SJ. 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 

  11. Farrell RJ, Shah SA, Lodhavia PJ, Alsahli M, Falchuk KR, Michetti P, Peppercorn MA. Clinical experience with infliximab therapy in 100 patients with Crohn’s disease. Am J Gastroenterol 2000;95:3490–3497.

    Article  PubMed  CAS  Google Scholar 

  12. van Bodegraven AA, Sloots CE, Felt-Bersma RJ, Meuwissen SG. Endosonographic evidence of persistence of Crohn’s disease-associated fistulas after infliximab treatment, irrespective of clinical response. Dis Colon Rectum 2002;45:39–45.

    Article  PubMed  Google Scholar 

  13. Van Assche G, Vanbeckevoort D, Bielen D, Coremans G, Aerden I, Noman M, D’Hoore A, Penninckx F, Marchal G, Cornillie F, Rutgeerts P. Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn’s disease. Am J Gastroenterol 2003;98:332–339.

    Article  PubMed  Google Scholar 

  14. Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present DH, Goodman N, Groden C, Hornung RL, Quezado M, Neurath MF, Salfeld J, Veldman GM, Schwertschlag U, Strober W. Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med 2004;351:2069–2079.

    Article  PubMed  CAS  Google Scholar 

  15. Irvine EJ. Usual therapy improves perianal Crohn’s disease as measured by a new disease activity index. McMaster IBD Study Group. J Clin Gastroenterol 1995;20:27–32.

    Article  PubMed  CAS  Google Scholar 

  16. Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976;70:439–444.

    PubMed  CAS  Google Scholar 

  17. Winship DH, Summers RW, Singleton JW, Best WR, Becktel JM, Lenk LF, Kern F Jr. National Cooperative Crohn’s Disease Study: Study design and conduct of the study. Gastroenterology 1979,77:829–842.

    PubMed  CAS  Google Scholar 

  18. ICSH recommendations for measurement of erythrocyte sedimentation rate. International Council for Standardization in Haematology (Expert Panel on Blood Rheology). J Clin Pathol 1993;46:198–203.

    Google Scholar 

  19. Dominici R, Luraschi P, Franzini C. Measurement of C-reactive protein: two high sensitivity methods compared. J Clin Lab Anal 2004;18:280–284.

    Article  PubMed  CAS  Google Scholar 

  20. Brooks SP, Lampi BJ, Sarwar G, Botting HG. A comparison of methods for determining total body protein. Anal Biochem 1995;226:26–30.

    Article  PubMed  CAS  Google Scholar 

  21. Viscido A, Habib FI, Kohn A, Papi C, Marcheggiano A, Pimpo MT, Vernia P, Cadau G, Caprilli R. Infliximab in refractory pouchitis complicated by fistulae following ileo-anal pouch for ulcerative colitis. Aliment Pharmacol Ther 2003;17:1263–1271.

    Article  PubMed  CAS  Google Scholar 

  22. Orlando A, Colombo E, Kohn A, Biancone L, Rizzello F, Viscido A, Sostegni R, Benazzato L, Castiglione F, Papi C, Meucci G, Riegler G, Mocciaro F, Cassinotti A, Cosintino R, Geremia A, Morselli C, Angelucci E, Lavagna A, Rispo A, Bossa F, Scimeca D, Cottone M. Italian multicentric study group on infliximab. Infliximab in the treatment of Crohn’s disease: predictors of response in an Italian multicentric open study. Dig Liver Dis 2005;37:559–563.

    Article  CAS  Google Scholar 

  23. Hart AL, Al-Hassi HO, Rogby RJ, Bell SJ, Emmanuel AV, Knight SC, Kamm MA, Stagg AJ. Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Gastroenterology 2005;129:50–65.

    Article  PubMed  CAS  Google Scholar 

  24. Fuss IJ, Becker C, Yang Z, Groden C, Hornung RL, Heller F, Neurath MF, Strober W, Mannon PJ. Both IL-12p70 and IL-23 are synthesized during active Crohn’s disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm Bowel Dis 2006;12(1):9–15 Jan.

    Article  PubMed  Google Scholar 

  25. Nielsen OH, Kirman I, Rudiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol 2003;38:180–185.

    Article  PubMed  CAS  Google Scholar 

  26. Boggess KA, Price WA, Preisser JS, Moise KJ Jr, Offenbacher S. Insulin-like growth factor and interleukin-1beta levels and subsequent fetal size response to chronic Porphyromonas gingivalis exposure in the pregnant rabbit. Am J Obstet Gynecol 2005;193:1219–1223.

    Article  PubMed  CAS  Google Scholar 

  27. Aleksandra NA, Nederby NJ, Schmedes A, Brandslund I, Hey H. Saliva Interleukin-6 in patients with inflammatory bowel disease. Scand J Gastroenterol 2005;40:1444–1448.

    Article  Google Scholar 

  28. Mazlam MZ, Hodgson HJ. Interrelations between interleukin-6, interleukin-1beta, plasma C-reactive protein values, and in vitro C-reactive protein generation in patients with inflammatory bowel disease. Gut 1994;35:77–83.

    PubMed  CAS  Google Scholar 

  29. Vermeire S, Van Assche G, Rutgeerts P. C-reactive protein as a marker for inflammatory bowel disease. Inflamm Bowel Dis 2004;10:661–665.

    Article  PubMed  Google Scholar 

  30. Atreya R, Neurath MF. Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer. Clin Rev Allergy Immunol 2005;28:187–196.

    Article  PubMed  CAS  Google Scholar 

  31. Ito H, Takazoe M, Fukuda Y, Hibi T, Kusugami K, Andoh A, Matsumoto T, Yamamura T, Azuma J, Nishimoto N, Yoshizaki K, Shimoyama T, Kishimoto T. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology 2004;126:989–996.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Clinica Chirurgica 1^, Department of Surgical and Gastroenterological Sciences, University of Padua, Via Giustiniani, 2, Padova, 35100, Italy

    Cesare Ruffolo, Marco Scarpa, Teresa Filosa, Daniela Prando, Lino Polese, Michele Scopelliti, Fabio Pilon, Mauro Frego, Davide Francesco D’Amico & Imerio Angriman

  2. Medicina di Laboratorio, University of Padua, Padova, Italy

    Diego Faggian

  3. Department of Medical and Surgical Sciences, University of Padua, Padova, Italy

    Giovanna Romanato, AnnaMaria De Pellegrin & Elena Ossi

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  1. Cesare Ruffolo
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  2. Marco Scarpa
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  3. Diego Faggian
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Correspondence to Cesare Ruffolo.

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Ruffolo, C., Scarpa, M., Faggian, D. et al. Cytokine Network in Chronic Perianal Crohn’s Disease and Indeterminate Colitis After Colectomy. J Gastrointest Surg 11, 16–21 (2007). https://doi.org/10.1007/s11605-006-0021-y

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  • DOI: https://doi.org/10.1007/s11605-006-0021-y

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