In recent years, a change in the treatment goals for patients with Crohn's disease (CD) has come under intense discussion. Whereas 10 years ago treatment was initiated mainly in reaction to acute flares of the disease aimed to improve clinical symptoms, the focus now has changed to the prevention of damage to the intestinal wall. The prevention of structural damage by achievement of ‘mucosal healing', however, is associated with the more ‘aggressive' treatment and an earlier use of immunosuppressants and biologicals. The use of immunosuppressants and biologicals especially in patients with CD has decreased the rates of surgery and hospitalizations, indicating that there is a group of patients definitely profiting from such an early use of immunosuppressive treatment. In this group of patients, the benefits outweigh the disadvantages of immunosuppression: the increased risk of severe infections. However, it remains questionable whether this improvement can only be achieved by completely reversing established treatment strategies. The dispute has been condensed to the questions whether ‘top-down' (e.g. start with a combination of biological and immunosuppressant and ‘de-escalate' if possible) or ‘step-up' treatment (e.g. start with topical steroids, step up to systemic steroid, go to immunosuppression and biologicals if necessary) may be better. In general, in an upcoming era of individualized and personalized medicine, a ‘one-size-fits-all' approach does not appear to be desirable. CD patients definitely should not be undertreated (which is still frequently the case) or remain on steroid treatment (which is inappropriate); however, overtreatment (putting patients at risk of side effects without benefit) is against a fundamental principle of medicine: nihil nocere (do no harm).

Keywords:
Crohn’s disease, Biologicals, Top-down approach, Step-up approach, Immunosuppression, Mucosal healing
1.
Dignass A, Van Assche G, Lindsay JO, Lemann M, Soderholm J, Colombel JF, Danese S, D'Hoore A, Gassull M, Gomollon F, Hommes DW, Michetti P, O'Morain C, Oresland T, Windsor A, Stange EF, Travis SP: The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management. J Crohns Colitis 2010;4:28-62.
2.
Gordon M, Naidoo K, Thomas AG, Akobeng AK: Oral 5-aminosalicylic acid for maintenance of surgically-induced remission in Crohn's disease. Cochrane Database Syst Rev 2011;1:CD008414.
3.
Akobeng AK, Gardener E: Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's disease. Cochrane Database Syst Rev 2005;1:CD003715.
4.
Hanauer SB, Stromberg U: Oral pentasa in the treatment of active Crohn's disease: a meta-analysis of double-blind, placebo-controlled trials. Clin Gastroenterol Hepatol 2004;2:379-388.
5.
Dignass A, Marteau P: Mesalamine in the treatment of active Crohn's disease. Gastroenterology 2005;128:245-246.
6.
Solberg IC, Vatn MH, Hoie O, Stray N, Sauar J, Jahnsen J, Moum B, Lygren I: Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study. Clin Gastroenterol Hepatol 2007;5:1430-1438.
7.
Henriksen M, Jahnsen J, Lygren I, Aadland E, Schulz T, Vatn MH, Moum B: Clinical course in Crohn's disease: results of a five-year population-based follow-up study (the IBSEN study). Scand J Gastroenterol 2007;42:602-610.
8.
Seow CH, Benchimol EI, Griffiths AM, Otley AR, Steinhart AH: Budesonide for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2008;3:CD000296.
9.
Greenberg GR, Feagan BG, Martin F, Sutherland LR, Thomson AB, Williams CN, Nilsson LG, Persson T: Oral budesonide for active Crohn's disease. Canadian Inflammatory Bowel Disease Study Group. New Engl J Med 1994;331:836-841.
10.
Rutgeerts P, Lofberg R, Malchow H, Lamers C, Olaison G, Jewell D, Danielsson A, Goebell H, Thomsen OO, Lorenz-Meyer H, et al: A comparison of budesonide with prednisolone for active Crohn's disease. New Engl J Med 1994;331:842-845.
11.
Campieri M, Ferguson A, Doe W, Persson T, Nilsson LG: Oral budesonide is as effective as oral prednisolone in active Crohn's disease. The Global Budesonide Study Group. Gut 1997;41:209-214.
12.
Mantzaris GJ, Christidou A, Sfakianakis M, Roussos A, Koilakou S, Petraki K, Polyzou P: Azathioprine is superior to budesonide in achieving and maintaining mucosal healing and histologic remission in steroid-dependent Crohn's disease. Inflamm Bowel Dis 2009;15:375-382.
13.
Bar-Meir S, Chowers Y, Lavy A, Abramovitch D, Sternberg A, Leichtmann G, Reshef R, Odes S, Moshkovitz M, Bruck R, Eliakim R, Maoz E, Mittmann U: Budesonide versus prednisone in the treatment of active Crohn's disease. The Israeli Budesonide Study Group. Gastroenterology 1998;115:835-840.
14.
Caesar I, Gross V, Roth M, Andus T, Schmidt C, Raedsch R, Weber A, Gierend M, Ewe K, Scholmerich J: Treatment of active and postactive ileal and colonic Crohn's disease with oral pH-modified-release budesonide. German budesonide study group. Hepatogastroenterology 1997;44:445-451.
15.
Almawi WY, Beyhum HN, Rahme AA, Rieder MJ: Regulation of cytokine and cytokine receptor expression by glucocorticoids. J Leukocyte Biol 1996;60:563-572.
16.
Herfarth H, Gross V, Andus T, Caesar I, Vogelsang H, Adler G, Malchow H, Petri A, Gierend M, Scholmerich J: Analysis of the therapeutic efficacy of different doses of budesonide in patients with active Crohn's ileocolitis depending on disease activity and localization. Intern J Colorectal Dis 2004;19:147-152.
17.
Modigliani R, Mary JY, Simon JF, Cortot A, Soule JC, Gendre JP, Rene E: Clinical, biological, and endoscopic picture of attacks of Crohn's disease. Evolution on prednisolone. Groupe d'etude therapeutique des affections inflammatoires digestives. Gastroenterology 1990;98:811-818.
18.
Benchimol EI, Seow CH, Steinhart AH, Griffiths AM: Traditional corticosteroids for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2008;2: CD006792.
19.
Pearson DC, May GR, Fick G, Sutherland LR: Azathioprine for maintaining remission of Crohn's disease. Cochrane Database Syst Rev 2000;2:CD000067.
20.
Fraser AG: Methotrexate: first-line or second-line immunomodulator? Eur J Gastroenterol Hepatol 2003;15:225-231.
21.
Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. New Engl J Med 1997;337:1029-1035.
22.
Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, Panaccione R, Wolf D, Pollack P: Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology 2006;130:323-333.
23.
Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, Bloomfield R, Schreiber S: Certolizumab pegol for the treatment of Crohn's disease. New Engl J Med 2007;357:228-238.
24.
Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh DG, Panaccione R, Wolf D, Kent JD, Bittle B, Li J, Pollack PF: Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial. Gut 2007;56:1232-1239.
25.
Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, Bernstein CN, Staun M, Thomsen OO, Innes A: A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. Gastroenterology 2005;129:807-818.
26.
Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P: Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359:1541-1549.
27.
Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, Schreiber S, Byczkowski D, Li J, Kent JD, Pollack PF: Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007;132:52-65.
28.
Sandborn WJ: Clinical perspectives in Crohn's disease. Moving forward with anti-TNF-alpha therapy: current needs and future treatments. Rev Gastroenterol Disord 2007;7(suppl 2):S23-S35.
29.
Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OO, Hanauer SB, McColm J, Bloomfield R, Sandborn WJ: Maintenance therapy with certolizumab pegol for Crohn's disease. New Engl J Med 2007;357:239-250.
30.
Molnar T, Farkas K, Nyari T, Szepes Z, Nagy F, Wittmann T: Frequency and predictors of loss of response to infliximab or adalimumab in Crohn's disease after one-year treatment period - a single center experience. J Gastrointestin Liver Dis 2012;21:265-269.
31.
Yanai H, Hanauer SB: Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol 2011;106:685-698.
32.
Billioud V, Sandborn WJ, Peyrin-Biroulet L: Loss of response and need for adalimumab dose intensification in Crohn's disease: a systematic review. Am J Gastroenterol 2011;106:674-684.
33.
Ben-Horin S, Chowers Y: Review article: loss of response to anti-TNF treatments in Crohn's disease. Aliment Pharmacol Ther 2011;33:987-995.
34.
Chao J, Mulani P: What is the rate of loss of response to infliximab therapy in Crohn's disease? Am J Gastroenterol 2009;104:2353-2354.
35.
Gisbert JP, Panes J: Loss of response and requirement of infliximab dose intensification in Crohn's disease: a review. Am J Gastroenterol 2009;104:760-767.
36.
Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P: Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol 2011;106:644-659.
37.
Faubion WA Jr, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Sandborn WJ: The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001;121:255-260.
38.
Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C: Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease. Cochrane Database Syst Rev 2000;2:CD000545.
39.
Sandborn WJ, Feagan BG, Lichtenstein GR: Medical management of mild to moderate Crohn's disease: evidence-based treatment algorithms for induction and maintenance of remission. Aliment Pharmacol Ther 2007;26:987-1003.
40.
Kirwan JR: Conceptual issues in scoring radiographic progression in rheumatoid arthritis. J Rheumatol 1999;26:720-725.
41.
Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D'Haens G, Diamond RH, Broussard DL, Tang KL, van der Woude CJ, Rutgeerts P: Infliximab, azathioprine, or combination therapy for Crohn's disease. New Engl J Med 2010;362:1383-1395.
42.
Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, Van Assche G, Hoffman I, Van Steen K, Vermeire S, Rutgeerts P: Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort. Gut 2009;58:492-500.
43.
Louis E, Belaiche J, Reenaers C: Anti-tumor necrosis factor nonresponders in Crohn's disease: therapeutic strategies. Dig Dis 2009;27:351-357.
44.
Allez M, Vermeire S, Mozziconacci N, Michetti P, Laharie D, Louis E, Bigard MA, Hebuterne X, Treton X, Kohn A, Marteau P, Cortot A, Nichita C, van Assche G, Rutgeerts P, Lemann M, Colombel JF: The efficacy and safety of a third anti-TNF monoclonal antibody in Crohn's disease after failure of two other anti-TNF antibodies. Aliment Pharmacol Ther 2010;31:92-101.
45.
Louis E, Mary JY, Vernier-Massouille G, Grimaud JC, Bouhnik Y, Laharie D, Dupas JL, Pillant H, Picon L, Veyrac M, Flamant M, Savoye G, Jian R, Devos M, Porcher R, Paintaud G, Piver E, Colombel JF, Lemann M: Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 2012;142:63-70.
46.
D'Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, De Vos M, van Deventer S, Stitt L, Donner A, Vermeire S, Van de Mierop FJ, Coche JC, van der Woude J, Ochsenkuhn T, van Bodegraven AA, Van Hootegem PP, Lambrecht GL, Mana F, Rutgeerts P, Feagan BG, Hommes D: Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 2008;371:660-667.
47.
Pariente B, Cosnes J, Danese S, Sandborn WJ, Lewin M, Fletcher JG, Chowers Y, D'Haens G, Feagan BG, Hibi T, Hommes DW, Irvine EJ, Kamm MA, Loftus EV Jr, Louis E, Michetti P, Munkholm P, Oresland T, Panes J, Peyrin-Biroulet L, Reinisch W, Sands BE, Schoelmerich J, Schreiber S, Tilg H, Travis S, van Assche G, Vecchi M, Mary JY, Colombel JF, Lemann M: Development of the Crohn's disease digestive damage score, the Lemann score. Inflam Bowel Dis 2011;17:1415-1422.
48.
Schreiber S, Reinisch W, Colombel JF, Sandborn WJ, Hommes DW, Robinson AM, Huang B, Lomax KG, Pollack PF: Subgroup analysis of the placebo-controlled charm trial: Increased remission rates through 3 years for adalimumab-treated patients with early Crohn's disease. J Crohns Colitis 2013;7:213-221.
49.
Baert F, Moortgat L, Van Assche G, Caenepeel P, Vergauwe P, De Vos M, Stokkers P, Hommes D, Rutgeerts P, Vermeire S, D'Haens G: Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. Gastroenterology 2010;138:463-468.
50.
Rutgeerts P, Van Assche G, Sandborn WJ, Wolf DC, Geboes K, Colombel JF, Reinisch W, Kumar A, Lazar A, Camez A, Lomax KG, Pollack PF, D'Haens G: Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the extend trial. Gastroenterology 2012;142:1102-1111.
51.
Rutgeerts P, Diamond RH, Bala M, Olson A, Lichtenstein GR, Bao W, Patel K, Wolf DC, Safdi M, Colombel JF, Lashner B, Hanauer SB: Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease. Gastrointest Endoscopy 2006;63:433-442.
52.
Rutgeerts P, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Hanauer SB: Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease. Gastroenterology 2004;126:402-413.
53.
Sandborn WJ: Mucosal healing in inflammatory bowel disease. Rev Gastroenterol Dis 2008;8:271-272.
54.
Markowitz J, Grancher K, Kohn N, Lesser M, Daum F: A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology 2000;119:895-902.
55.
Lichtenstein GR, Cuffari C, Kane SV, Hanauer S, Present DH: Maintaining remissions across the lifespan: a roundtable discussion with Crohn's disease experts. Inflamm Bowel Dis 2004;10(suppl 2):S11-S21.
56.
Lichtenstein GR, Hanauer SB, Kane SV, Present DH: Crohn's is not a 6-week disease: lifelong management of mild to moderate Crohn's disease. Inflamm Bowel Dis 2004;10(suppl 2):S2-S10.
57.
Caprilli R, Angelucci E, Cocco A: Early or late guided missile in the treatment of Crohn's disease? Dig Liver Dis 2005;37:973-979.
58.
Cosnes J, Bourrier A, Bouhnik Y, Laharie D, Nahon S, Bonnet J, Carbonnel F, Dupas J, Jean Marie R, Jouet P, Savoye G, Mary J, Colombel JF: Accelerated step-care therapy with early azathioprine (AZA) vs. conventional step-care therapy in Crohn's disease. A randomized study. Gastroenterology 2012;142 (suppl 1):161.
59.
Sorrentino D, Terrosu G, Paviotti A, Geraci M, Avellini C, Zoli G, Fries W, Danese S, Occhipinti P, Croatto T, Zarifi D: Early diagnosis and treatment of postoperative endoscopic recurrence of Crohn's disease: partial benefit by infliximab - a pilot study. Dig Dis Sci 2012;57:1341-1348.
60.
Regueiro M, Schraut W, Baidoo L, Kip KE, Sepulveda AR, Pesci M, Harrison J, Plevy SE: Infliximab prevents Crohn's disease recurrence after ileal resection. Gastroenterology 2009;136:441-450.
61.
Fasci Spurio F, Aratari A, Margagnoni G, Doddato MT, Papi C: Early treatment in Crohn's disease: do we have enough evidence to reverse the therapeutic pyramid? J Gastrointestin Liver Dis 2012;21:67-73.
© 2013 S. Karger AG, Basel
2013
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.