Crohn’s disease is a chronic inflammatory disease of diagnostic and therapeutic challenges. After proper diagnosis, treatment decisions must be made on precise clinical judgment. During the course of the disease there are variable clinical features, so each case must be managed individually. Physicians who care for patients with Crohn’s disease should be prepared for treatment options in different states of the disease and possible complications of both the disease and medications. This paper will focus on the management of Crohn’s disease. We aim to discuss current treatment options in different presentations of the disease and to provide algorithmic management strategy. 1. General Principles of Management Crohn’s disease can affect any area of the gastrointestinal tract. Transmural inflammation and segmental pattern are the classical features of the disease [1]. A treatment plan should be organized according to disease activity, behavior and localization of disease, and associated complications. Whatever treatment plan is chosen, it is most appropriate to individualize treatment according to clinical response and tolerance of the patient. It is certain that smoking is an independent risk factor for complications and has a direct influence on disease activity. All patients diagnosed with Crohn’s disease should be informed about the negative impact of smoking and strongly encouraged to cease smoking [2]. Nonsteroidal anti-inflammatory drug usage is known to be associated with mucosal damage in gastrointestinal tract. There is substantial evidence that exacerbation of inflammatory bowel disease occurs after nonsteroidal anti-inflammatory drug usage, although the available data is conflicting to make definitive conclusions. Regarding the mechanisms of relapse, the inhibition of prostaglandin synthesis appears to be the hallmark of the nonsteroidal anti-inflammatory drug effects [3–5]. The patients should be informed about the adverse effects of nonsteroidal anti-inflammatory drugs, and limited usage must be ensured. As a principle current treatment options are chosen sequentially from safer drugs with less adverse events to more potent and potentially more toxic drugs to induce clinical remission. In this “step-up” strategy, main purpose is to induce and maintain remission by safer and less expensive drugs by identifying patients who will benefit from conventional treatments. However, some authors recently suggested using a “top-down” strategy in which more potent treatment options are chosen early in the course of the disease, particularly in patients
References
[1]
G. R. Lichtenstein, S. B. Hanauer, W. J. Sandborn, and Practice Parameters Committee of American College of Gastroenterology, “Management of Crohn's disease in adults,” The American Journal of Gastroenterology, vol. 104, no. 2, pp. 465–483, 2009.
[2]
A. Dignass, G. van Assche, J. O. Lindsay et al., “The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management,” Journal of Crohn's and Colitis, vol. 4, no. 1, pp. 28–62, 2010.
[3]
K. Forrest, D. Symmons, and P. Foster, “Systematic review: is ingestion of paracetamol or non-steroidal anti-inflammatory drugs associated with exacerbations of inflammatory bowel disease?” Alimentary Pharmacology and Therapeutics, vol. 20, no. 10, pp. 1035–1043, 2004.
[4]
K. Takeuchi, S. Smale, P. Premchand et al., “Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease,” Clinical Gastroenterology and Hepatology, vol. 4, no. 2, pp. 196–202, 2006.
[5]
H. Kefalakes, T. J. Stylianides, G. Amanakis, and G. Kolios, “Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality?” European Journal of Clinical Pharmacology, vol. 65, no. 10, pp. 963–970, 2009.
[6]
G. D'Haens, F. Baert, G. van Assche et al., “Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial,” The Lancet, vol. 371, no. 9613, pp. 660–667, 2008.
[7]
J. F. Colombel, W. J. Sandborn, W. Reinisch et al., “Infliximab, azathioprine, or combination therapy for Crohn's disease,” The New England Journal of Medicine, vol. 362, no. 15, pp. 1383–1395, 2010.
[8]
L. Beaugerie, P. Seksik, I. Nion-Larmurier, J. Gendre, and J. Cosnes, “Predictors of crohn's disease,” Gastroenterology, vol. 130, no. 3, pp. 650–656, 2006.
[9]
R. F. Harvey and J. M. Bradshaw, “A simple index of Crohn's-disease activity,” The Lancet, vol. 1, no. 8167, p. 514, 1980.
[10]
G. van Assche, A. Dignass, J. Panes et al., “The second European evidence-based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis,” Journal of Crohn's and Colitis, vol. 4, no. 1, pp. 7–27, 2010.
[11]
C. H. Seow, E. I. Benchimol, A. M. Griffiths, A. R. Otley, and A. H. Steinhart, “Budesonide for induction of remission in Crohn's disease,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD000296, 2008.
[12]
S. B. Hanauer and U. Str？mberg, “Oral pentasa in the treatment of active Crohn's disease: a meta-analysis of double-blind, placebo-controlled trials,” Clinical Gastroenterology and Hepatology, vol. 2, no. 5, pp. 379–388, 2004.
[13]
A. C. Ford, S. V. Kane, K. J. Khan et al., “Efficacy of 5-aminosalicylates in crohn's disease: systematic review and meta-analysis,” The American Journal of Gastroenterology, vol. 106, no. 4, pp. 617–629, 2011.
[14]
C. N. Bernstein, Z. Nugent, and J. F. Blanchard, “5-aminosalicylate is not chemoprophylactic for colorectal cancer in IBD: a population based study,” The American Journal of Gastroenterology, vol. 106, no. 4, pp. 731–736, 2011.
[15]
K. J. Khan, T. A. Ullman, A. C. Ford et al., “Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis,” The American Journal of Gastroenterology, vol. 106, no. 4, pp. 661–673, 2011.
[16]
D. C. Pearson, G. R. May, G. Fick, and L. R. Sutherland, “Azathioprine for maintaining remission of Crohn's disease,” Cochrane Database of Systematic Reviews, no. 2, Article ID CD000067, 2000.
[17]
A. G. Fraser, “Methotrexate: first-line or second-line immunomodulator?” European Journal of Gastroenterology and Hepatology, vol. 15, no. 3, pp. 225–231, 2003.
[18]
A. A. Alfadhli, J. W. McDonald, and B. G. Feagan, “Methotrexate for induction of remission in refractory Crohn's disease,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD003459, 2005.
[19]
J. M. Kremer, “Major side effects of low dose methotrexate,” in UpToDate, D. S. Basow, Ed., UpToDate, Waltham, Mass, USA, 2011.
[20]
H. S. Te, T. D. Schiano, S. F. Kuan, S. B. Hanauer, H. S. Conjeevaram, and A. L. Baker, “Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease,” The American Journal of Gastroenterology, vol. 95, no. 11, pp. 3150–3156, 2000.
[21]
L. Peyrin-Biroulet, P. Deltenre, N. de Suray, J. Branche, W. J. Sandborn, and J. Colombel, “Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials,” Clinical Gastroenterology and Hepatology, vol. 6, no. 6, pp. 644–653, 2008.
[22]
S. R. Targan, S. B. Hanauer, S. J. H. van Deventer et al., “A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's Disease,” The New England Journal of Medicine, vol. 337, no. 15, pp. 1029–1036, 1997.
[23]
S. B. Hanauer, B. G. Feagan, G. R. Lichtenstein et al., “Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial,” The Lancet, vol. 359, no. 9317, pp. 1541–1549, 2002.
[24]
S. B. Hanauer, W. J. Sandborn, P. Rutgeerts et al., “Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial,” Gastroenterology, vol. 130, no. 2, pp. 323–333, 2006.
[25]
J. Colombel, W. J. Sandborn, P. Rutgeerts et al., “Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial,” Gastroenterology, vol. 132, no. 1, pp. 52–65, 2007.
[26]
W. J. Sandborn, P. Rutgeerts, R. Enns et al., “Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial,” Annals of Internal Medicine, vol. 146, no. 12, pp. 829–838, 2007.
[27]
W. J. Sandborn, S. B. Hanauer, P. Rutgeerts et al., “Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial,” Gut, vol. 56, no. 9, pp. 1232–1239, 2007.
[28]
W. J. Sandborn, B. G. Feagan, S. Stoinov et al., “Certolizumab pegol for the treatment of Crohn's disease,” The New England Journal of Medicine, vol. 357, no. 3, pp. 228–238, 2007.
[29]
S. Schreiber, M. Khaliq-Kareemi, I. C. Lawrance et al., “Maintenance therapy with certolizumab pegol for Crohn's disease,” The New England Journal of Medicine, vol. 357, no. 3, pp. 239–250, 2007.
[30]
R. A. van Hogezand, A. M. Witte, R. A. Veenendaal, M. J. Wagtmans, and C. B. Lamers, “Proximal Crohn's disease: review of the clinicopathologic features and therapy,” Inflammatory Bowel Diseases, vol. 7, no. 4, pp. 328–337, 2001.
[31]
M. J. Wagtmans, H. W. Verspaget, C. B. H. W. Lamers, and R. A. van Hogezand, “Clinical aspects of Crohn's disease of the upper gastrointestinal tract: a comparison with distal Crohn's disease,” The American Journal of Gastroenterology, vol. 92, no. 9, pp. 1467–1471, 1997.
[32]
F. W. Nugent and M. A. Roy, “Duodenal Crohn's disease: an analysis of 89 cases,” The American Journal of Gastroenterology, vol. 84, no. 3, pp. 249–254, 1989.
[33]
N. J. Talley, M. T. Abreu, J. Achkar et al., “An evidence-based systematic review on medical therapies for inflammatory bowel disease,” The American Journal of Gastroenterology, vol. 106, no. 1, pp. S2–S25, 2011.
[34]
G. van Assche, A. Dignass, W. Reinisch et al., “The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: special situations,” Journal of Crohn's and Colitis, vol. 4, no. 1, pp. 63–101, 2010.
[35]
O. H. Nielsen, G. Rogler, D. Hahnloser, and O. ？. Thomsen, “Diagnosis and management of fistulizing Crohn's disease,” Nature Clinical Practice Gastroenterology and Hepatology, vol. 6, no. 2, pp. 92–106, 2009.
[36]
L. H. Bernstein, M. S. Frank, L. J. Brandt, and S. J. Boley, “Healing of perineal Crohn's disease with metronidazole,” Gastroenterology, vol. 79, no. 2, pp. 357–365, 1980.
[37]
Y. Maeda, S. C. Ng, P. Durdey et al., “Randomized clinical trial of metronidazole ointment versus placebo in perianal Crohn's disease,” The British Journal of Surgery, vol. 97, no. 9, pp. 1340–1347, 2010.
[38]
P. J. Tozer, D. Burling, A. Gupta, R. K. S. Phillips, and A. L. Hart, “Review article: medical, surgical and radiological management of perianal Crohn's fistulas,” Alimentary Pharmacology and Therapeutics, vol. 33, no. 1, pp. 5–22, 2011.
[39]
K. T. Thia, U. Mahadevan, B. G. Feagan et al., “Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn's disease: a randomized, double-blind, placebo-controlled pilot study,” Inflammatory Bowel Diseases, vol. 15, no. 1, pp. 17–24, 2009.
[40]
R. L. West, C. J. van der Woude, B. E. Hansen et al., “Clinical and endosonographic effect of ciprofloxacin on the treatment of perianal fistulae in Crohn's disease with infliximab: a double-blind placebo-controlled study,” Alimentary Pharmacology and Therapeutics, vol. 20, no. 11-12, pp. 1329–1336, 2004.
[41]
C. Dejaco, M. Harrer, T. Waldhoer, W. Miehsler, H. Vogelsang, and W. Reinisch, “Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn's disease,” Alimentary Pharmacology and Therapeutics, vol. 18, no. 11-12, pp. 1113–1120, 2003.
[42]
D. H. Present, P. Rutgeerts, S. Targan et al., “Infliximab for the treatment of fistulas in patients with Crohn's disease,” The New England Journal of Medicine, vol. 340, no. 18, pp. 1398–1405, 1999.
[43]
B. E. Sands, F. H. Anderson, C. N. Bernstein et al., “Infliximab maintenance therapy for fistulizing Crohn's disease,” The New England Journal of Medicine, vol. 350, no. 9, pp. 876–885, 2004.
[44]
J. I. Fortea-Ormaechea, Y. González-Lama, B. Casis et al., “Adalimumab is effective in long-term real life clinical practice in both luminal and perianal Crohn's disease. The Madrid experience,” Gastroenterologia y Hepatologia, vol. 34, no. 7, pp. 443–448, 2011.
[45]
D. R. Topstad, R. Panaccione, J. A. Heine, D. R. E. Johnson, A. R. MacLean, and W. D. Buie, “Combined seton placement, infliximab infusion, and maintenance immunosuppressives improve healing rate in fistulizing anorectal Crohn's disease: a single center experience,” Diseases of the Colon and Rectum, vol. 46, no. 5, pp. 577–583, 2003.
[46]
S. Tanaka, K. Matsuo, T. Sasaki et al., “Clinical advantages of combined seton placement and infliximab maintenance therapy for perianal fistulizing Crohn's disease: when and how were the seton drains removed?” Hepato-Gastroenterology, vol. 57, no. 97, pp. 3–7, 2010.
[47]
C. Hassan, A. Zullo, V. de Francesco et al., “Systematic review: endoscopic dilatation in Crohn's disease,” Alimentary Pharmacology and Therapeutics, vol. 26, no. 11-12, pp. 1457–1464, 2007.
[48]
R. G. Rogers and V. L. Katz, “Course of Crohn's disease during pregnancy and its effect on pregnancy outcome: a retrospective review,” The American Journal of Perinatology, vol. 12, no. 4, pp. 262–264, 1995.
[49]
M. S. Cappell, V. J. Colon, and O. A. Sidhom, “A study at 10 medical centers of the safety and efficacy of 48 flexible sigmoidoscopies and 8 colonoscopies during pregnancy with follow-up of fetal outcome and with comparison to control groups,” Digestive Diseases and Sciences, vol. 41, no. 12, pp. 2353–2361, 1996.
[50]
R. O. Rajapakse, B. I. Korelitz, J. Zlatanic, P. J. Baiocco, and G. W. Gleim, “Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease,” The American Journal of Gastroenterology, vol. 95, no. 3, pp. 684–688, 2000.
[51]
C. Teruel, A. L. S. Román, F. Bermejo et al., “Outcomes of pregnancies fathered by inflammatory bowel disease patients exposed to thiopurines,” The American Journal of Gastroenterology, vol. 105, no. 9, pp. 2003–2008, 2010.
[52]
S. Ben-Horin and Y. Chowers, “Review article: loss of response to anti-TNF treatments in Crohn's disease,” Alimentary Pharmacology and Therapeutics, vol. 33, no. 9, pp. 987–995, 2011.
[53]
F. Baert, M. Noman, S. Vermeire et al., “Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease,” The New England Journal of Medicine, vol. 348, no. 7, pp. 601–608, 2003.
[54]
G. van Assche, C. Magdelaine-Beuzelin, G. D'Haens et al., “Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial,” Gastroenterology, vol. 134, no. 7, pp. 1861–1868, 2008.
