Differences between Treatment Guidelines in IBD Dig Dis 2013;31:357–359 DOI: 10.1159/000354694
Differences between Treatment Guidelines – Germany Klaus R. Herrlinger Innere Medizin, Asklepios Klinik Nord, Betriebsteil Heidelberg, Hamburg, Germany
This work focusses on three controversial topics in IBD, i.e. the role of mesalamine in Crohn’s disease (CD), the early use of anti-TNF therapy in CD (top-down) and the choice between calcineurin inhibitors and infliximab in severe steroid-refractory ulcerative colitis. In the following the concerning statements of the German consensus conferences [1, 2] will be discussed on the basis of the existing evidence.
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0357$38.00/0 E-Mail [email protected] www.karger.com/ddi
Role of Mesalamine in Crohn’s Disease
Mesalamine has been used in both remission induction and remission maintenance of CD. Results for remission induction are conflicting. Whereas the first trial by Singleton et al. [3] showed a significant decrease of the CDAI of 51 points when comparing mesalamine and placebo, two latter trials that never were completely published showed different results. Taking these three trials together, a meta-analysis calculated a benefit for mesalamine over placebo of only 18 points which is significant but rather not clinically relevant [4]. Therefore the German consensus does not recommend mesalamine for mild to moderate ileocecal CD. The concerning statement is as follows: Patients with ileocecal and/or rightsided colonic Crohn’s disease and mild inflammatory activity should be given budesonide initially. In case of contraindications against steroids or if the patient wishes so, a therapy with mesalazine or symptomatic treatment can be initiated. Nevertheless, in Germany, mesalamine is widely used in CD. A regional survey among gastroenterologists revealed the surprising result that 20% of patients treated in private practices receive mesalamine as monotherapy. Even in hospitals, 7.8% of patients receive mesalamine as Klaus R. Herrlinger Innere Medizin, Asklepios Klinik Nord, Betriebsteil Heidelberg Tangstedter Landstrasse 400 DE–22417 Hamburg (Germany) E-Mail k.herrlinger @ asklepios.com
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/30/2015 3:35:17 AM
Abstract When looking at different treatment guidelines the topics most debated for Crohn’s disease are the following: (a) the use of mesalamine for remission induction and maintenance in mild to moderate Crohn’s disease; (b) the early use of antiTNF antibodies in Crohn’s disease with or without classical immunomodulators for remission induction, and (c) remission induction in steroid-refractory disease with anti-TNF antibodies or calcineurin inhibitors. The topics mentioned above will be discussed with regard to the statements of the German Gastroenterology Association (DGVS) on the basis of the underlying evidence. © 2013 S. Karger AG, Basel
Early Use of Anti-TNF Antibodies in Crohn’s Disease
After the results of the SONIC trial [9] had been launched, the ECCO consensus conference decided to substantially change the treatment algorithms with regard to an earlier use of immunosuppression and especially the use of anti-TNF antibodies [10]. The German consensus is less liberate and reserves the anti-TNF antibodies for special refractory situations: Crohn’s disease with moderate to severe disease activity and refractory to systemic steroids should be treated with anti-TNF with/ without azathioprine. In case of insufficient efficacy of azathioprine/6-mercaptopurine, these agents should be used in combination with an anti-TNF antibody. An early use of anti-TNF antibodies is restricted to clinical situations with a high risk of complications: In certain high-risk situations an early therapy with antiTNF antibodies can be appropriate. These rather conservative statements are based on two principal considerations. On the one hand, there is a substantial proportion of patients with CD who will never require azathioprine or anti-TNF antibodies in their life. In the step-up versus top-down trial [11], only 60% of patients in the step-up arm received azathioprine and 20% infliximab only, respectively. This means that an unselec358
Dig Dis 2013;31:357–359 DOI: 10.1159/000354694
tive early use of these agents results in a significant and avoidable overtreatment of a substantial proportion of patients. The second consideration is that due to the limited treatment options in CD, the most effective (and aggressive) treatment options should be reserved for the severe and refractory cases. Otherwise no treatment options are left once (aggressive) first-line therapy has failed or the patient relapses early.
Calcineurin Inhibitors or Infliximab in Severe Steroid-Refractory Ulcerative Colitis
To avoid proctocolectomy in severe steroid-refractory ulcerative colitis, treatment options include the calcineurin inhibitors cyclosporine and tacrolimus as well as the anti-TNF antibody infliximab. All three treatment options seem to be similarly effective. Cyclosporine has been used in very severe ulcerative colitis and was able to avoid proctocolectomy in 80% of patients [12], although uncontrolled similar data exist on the efficacy of tacrolimus in severe steroid-refractory colitis [13]. Infliximab has also been used in severe colitis and revealed convincing results as well [14]. In this trial, infliximab seemed less effective in the very severe fulminant ulcerative colitis. Nevertheless, in direct comparison, cyclosporine and infliximab were equally effective [15]. Therefore, the German consensus statement does not favor one of these agents and is as follows: In case of insufficient response to systemic steroids, cyclosporine A, infliximab or tacrolimus should be used. Surgery should always be considered an alternative. When discussing this difficult clinical situation the option of sequential therapy has to be considered. After failure of a calcineurin inhibitor, infliximab still is an option for about 25% of patients [16]. Similar results exist for the use of cyclosporine after infliximab failure. One major concern when using these agents sequentially is the risk of opportunistic infections. The proportion of infectious complications reaches up to 10% of patients with single fatal outcomes [17, 18]. The half-life of substances should therefore be taken into consideration. This favors initial use of calcineurin inhibitors due to their short half-life in comparison with infliximab where serum levels may be detectable for several weeks. Taken together, mesalamine may be an option in remission induction in mild CD and in remission maintenance after surgically induced remission in uncomplicated cases. The German consensus favors an accelerated step-up in CD rather than a top-down strategy. Finally, Herrlinger
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/30/2015 3:35:17 AM
monotherapy [5]. Recently, a controlled trial comparing the ‘gold standard’ for remission induction budesonide with mesalamine showed both treatments to be equally effective in mild to moderate ileocecal CD [6]. Having in mind that there obviously is a collective of patients with a mild course of CD, the results described above justify a role for mesalamine in remission induction in mild cases. The data on mesalamine in remission maintenance of CD are less convincing. Due to a recent meta-analysis, neither sulfasalazine nor mesalamine were effective in preventing relapse in quiescent CD [7]. This is in line with the German consensus where mesalamine is not mentioned for this situation. In contrast, mesalamine seems to have a modest effect in remission maintenance after surgically induced remission. The number of patients needed to treat to prevent one relapse is ten [8]. The German consensus statement is as follows: Mesalazine may be given for postoperative remission maintenance. This seems to be reasonable in uncomplicated cases after first presentation with a singular stenosis without fistulae or abscesses. In complicated cases or after repeated resections, azathioprine should be used instead due to its better efficacy in direct comparison.
calcineurin inhibitors and infliximab seem to be equally effective in steroid-refractory ulcerative colitis. If having in mind the sequential use of these agents, calcineurin inhibitors should be used as first-line therapy due to their shorter half-life in comparison to infliximab.
Disclosure Statement The author has no conflicts of interest to disclose.
References
Differences between Treatment Guidelines – Germany
7 Ford AC, Kane SV, Khan KJ, Achkar JP, Talley NJ, Marshall JK, Moayyedi P: Efficacy of 5-aminosalicylates in Crohn’s disease: systematic review and meta-analysis. Am J Gastroenterol 2011;106:617–629. 8 Ford AC, Khan KJ, Talley NJ, Moayyedi P: 5-aminosalicylates prevent relapse of Crohn’s disease after surgically induced remission: systematic review and meta-analysis. Am J Gastroenterol 2011;106:413–420. 9 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; SONIC Study Group: Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010; 362: 1383–1395. 10 Dignass A, Van Assche G, Lindsay JO, Lémann M, Söderholm J, Colombel JF, Danese S, D’Hoore A, Gassull M, Gomollón F, Hommes DW, Michetti P, O’Morain C, Oresland T, Windsor A, Stange EF, Travis SP; European Crohn’s and Colitis Organisation (ECCO): The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: current management. J Crohns Colitis 2010;4:28–62. 11 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, Ochsenkühn T, van Bodegraven AA, Van Hootegem PP, Lambrecht GL, Mana F, Rutgeerts P, Feagan BG, Hommes D; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club: Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008;371:660–667. 12 Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841–1845.
Dig Dis 2013;31:357–359 DOI: 10.1159/000354694
13 Schmidt KJ, Herrlinger KR, Emmrich J, Barthel D, Koc H, Lehnert H, Stange EF, Fellermann K, Büning J: Short-term efficacy of tacrolimus in steroid-refractory ulcerative colitis – experience in 130 patients. Aliment Pharmacol Ther 2013;37:129–136. 14 Järnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlén P, Grännö C, Vilien M, Ström M, Danielsson A, Verbaan H, Hellström PM, Magnuson A, Curman B: Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005;128:1805–1811. 15 Laharie D, Bourreille A, Branche J, Allez M, Bouhnik Y, Filippi J, Zerbib F, Savoye G, Nachury M, Moreau J, Delchier JC, Cosnes J, Ricart E, Dewit O, Lopez-Sanroman A, Dupas JL, Carbonnel F, Bommelaer G, Coffin B, Roblin X, Van Assche G, Esteve M, Färkkilä M, Gisbert JP, Marteau P, Nahon S, de Vos M, Franchimont D, Mary JY, Colombel JF, Lémann M; Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives: Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet 2012; 380: 1909–1915. 16 Herrlinger KR, Barthel DN, Schmidt KJ, Büning J, Barthel CS, Wehkamp J, Stange EF, Fellermann K: Infliximab as rescue medication for patients with severe ulcerative/indeterminate colitis refractory to tacrolimus. Aliment Pharmacol Ther 2010;31:1036–1041. 17 Chaparro M, Burgueño P, Iglesias E, Panés J, Muñoz F, Bastida G, Castro L, Jiménez C, Mendoza JL, Barreiro-de Acosta M, Senent SG, Gomollón F, Calvet X, García-Planella E, Gómez M, Hernández V, Hinojosa J, Mañosa M, Nyssen OP, Gisbert JP: Infliximab salvage therapy after failure of ciclosporin in corticosteroid-refractory ulcerative colitis: a multicentre study. Aliment Pharmacol Ther. 2012; 35:275–283. 18 Maser EA, Deconda D, Lichtiger S, Ullman T, Present DH, Kornbluth A: Cyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis. Clin Gastroenterol Hepatol 2008; 6: 1112–1116.
359
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/30/2015 3:35:17 AM
1 Hoffmann JC, Preiss JC, Autschbach F, Buhr HJ, Häuser W, Herrlinger K, Höhne W, Koletzko S, Krieglstein CF, Kruis W, Matthes H, Moser G, Reinshagen M, Rogler G, Schreiber S, Schreyer AG, Sido B, Siegmund B, Stallmach A, Bokemeyer B, Stange EF, Zeitz M: Clinical practice guideline on diagnosis and treatment of Crohn’s disease (in German). Z Gastroenterol 2008;46:1094–1146. 2 Dignass A, Preiss JC, Aust DE, Autschbach F, Ballauff A, Barretton G, Bokemeyer B, Fichtner-Feigl S, Hagel S, Herrlinger KR, Jantschek G, Kroesen A, Kruis W, Kucharzik T, Langhorst J, Reinshagen M, Rogler G, Schleiermacher D, Schmidt C, Schreiber S, Schulze H, Stange E, Zeitz M, Hoffmann JC, Stallmach A: Updated German guideline on diagnosis and treatment of ulcerative colitis, 2011 (in German). Z Gastroenterol 2011;49:1276–1341. 3 Singleton JW, Hanauer SB, Gitnick GL, Peppercorn MA, Robinson MG, Wruble LD, Krawitt EL: Mesalamine capsules for the treatment of active Crohn’s disease: results of a 16-week trial. Pentasa Crohn’s Disease Study Group. Gastroenterology 1993; 104: 1293–1301. 4 Hanauer SB, Strömberg U: Oral Pentasa in the treatment of active Crohn’s disease: a metaanalysis of double-blind, placebo-controlled trials. Clin Gastroenterol Hepatol 2004; 2: 379–388. 5 Blumenstein I, Bock H, Weber C, Rambow A, Tacke W, Kihn R, Pfaff R, Orlemann S, Schaeffer R, Schröder O, Dignass A, Hartmann F, Stein J: Health care and cost of medication for inflammatory bowel disease in the Rhein-Main region, Germany: a multicenter, prospective, internet-based study. Inflamm Bowel Dis 2008;14:53–60. 6 Tromm A, Bunganič I, Tomsová E, Tulassay Z, Lukáš M, Kykal J, Bátovský M, Fixa B, Gabalec L, Safadi R, Kramm HJ, Altorjay I, Löhr H, Koutroubakis I, Bar-Meir S, Stimac D, Schäffeler E, Glasmacher C, Dilger K, Mohrbacher R, Greinwald R; International Budenofalk Study Group: Budesonide 9 mg is at least as effective as mesalamine 4.5 g in patients with mildly to moderately active Crohn’s disease. Gastroenterology 2011; 140: 425–434.
Differences between Treatment Guidelines – Germany Klaus R. Herrlinger Innere Medizin, Asklepios Klinik Nord, Betriebsteil Heidelberg, Hamburg, Germany
This work focusses on three controversial topics in IBD, i.e. the role of mesalamine in Crohn’s disease (CD), the early use of anti-TNF therapy in CD (top-down) and the choice between calcineurin inhibitors and infliximab in severe steroid-refractory ulcerative colitis. In the following the concerning statements of the German consensus conferences [1, 2] will be discussed on the basis of the existing evidence.
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0357$38.00/0 E-Mail [email protected] www.karger.com/ddi
Role of Mesalamine in Crohn’s Disease
Mesalamine has been used in both remission induction and remission maintenance of CD. Results for remission induction are conflicting. Whereas the first trial by Singleton et al. [3] showed a significant decrease of the CDAI of 51 points when comparing mesalamine and placebo, two latter trials that never were completely published showed different results. Taking these three trials together, a meta-analysis calculated a benefit for mesalamine over placebo of only 18 points which is significant but rather not clinically relevant [4]. Therefore the German consensus does not recommend mesalamine for mild to moderate ileocecal CD. The concerning statement is as follows: Patients with ileocecal and/or rightsided colonic Crohn’s disease and mild inflammatory activity should be given budesonide initially. In case of contraindications against steroids or if the patient wishes so, a therapy with mesalazine or symptomatic treatment can be initiated. Nevertheless, in Germany, mesalamine is widely used in CD. A regional survey among gastroenterologists revealed the surprising result that 20% of patients treated in private practices receive mesalamine as monotherapy. Even in hospitals, 7.8% of patients receive mesalamine as Klaus R. Herrlinger Innere Medizin, Asklepios Klinik Nord, Betriebsteil Heidelberg Tangstedter Landstrasse 400 DE–22417 Hamburg (Germany) E-Mail k.herrlinger @ asklepios.com
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/30/2015 3:35:17 AM
Abstract When looking at different treatment guidelines the topics most debated for Crohn’s disease are the following: (a) the use of mesalamine for remission induction and maintenance in mild to moderate Crohn’s disease; (b) the early use of antiTNF antibodies in Crohn’s disease with or without classical immunomodulators for remission induction, and (c) remission induction in steroid-refractory disease with anti-TNF antibodies or calcineurin inhibitors. The topics mentioned above will be discussed with regard to the statements of the German Gastroenterology Association (DGVS) on the basis of the underlying evidence. © 2013 S. Karger AG, Basel
Early Use of Anti-TNF Antibodies in Crohn’s Disease
After the results of the SONIC trial [9] had been launched, the ECCO consensus conference decided to substantially change the treatment algorithms with regard to an earlier use of immunosuppression and especially the use of anti-TNF antibodies [10]. The German consensus is less liberate and reserves the anti-TNF antibodies for special refractory situations: Crohn’s disease with moderate to severe disease activity and refractory to systemic steroids should be treated with anti-TNF with/ without azathioprine. In case of insufficient efficacy of azathioprine/6-mercaptopurine, these agents should be used in combination with an anti-TNF antibody. An early use of anti-TNF antibodies is restricted to clinical situations with a high risk of complications: In certain high-risk situations an early therapy with antiTNF antibodies can be appropriate. These rather conservative statements are based on two principal considerations. On the one hand, there is a substantial proportion of patients with CD who will never require azathioprine or anti-TNF antibodies in their life. In the step-up versus top-down trial [11], only 60% of patients in the step-up arm received azathioprine and 20% infliximab only, respectively. This means that an unselec358
Dig Dis 2013;31:357–359 DOI: 10.1159/000354694
tive early use of these agents results in a significant and avoidable overtreatment of a substantial proportion of patients. The second consideration is that due to the limited treatment options in CD, the most effective (and aggressive) treatment options should be reserved for the severe and refractory cases. Otherwise no treatment options are left once (aggressive) first-line therapy has failed or the patient relapses early.
Calcineurin Inhibitors or Infliximab in Severe Steroid-Refractory Ulcerative Colitis
To avoid proctocolectomy in severe steroid-refractory ulcerative colitis, treatment options include the calcineurin inhibitors cyclosporine and tacrolimus as well as the anti-TNF antibody infliximab. All three treatment options seem to be similarly effective. Cyclosporine has been used in very severe ulcerative colitis and was able to avoid proctocolectomy in 80% of patients [12], although uncontrolled similar data exist on the efficacy of tacrolimus in severe steroid-refractory colitis [13]. Infliximab has also been used in severe colitis and revealed convincing results as well [14]. In this trial, infliximab seemed less effective in the very severe fulminant ulcerative colitis. Nevertheless, in direct comparison, cyclosporine and infliximab were equally effective [15]. Therefore, the German consensus statement does not favor one of these agents and is as follows: In case of insufficient response to systemic steroids, cyclosporine A, infliximab or tacrolimus should be used. Surgery should always be considered an alternative. When discussing this difficult clinical situation the option of sequential therapy has to be considered. After failure of a calcineurin inhibitor, infliximab still is an option for about 25% of patients [16]. Similar results exist for the use of cyclosporine after infliximab failure. One major concern when using these agents sequentially is the risk of opportunistic infections. The proportion of infectious complications reaches up to 10% of patients with single fatal outcomes [17, 18]. The half-life of substances should therefore be taken into consideration. This favors initial use of calcineurin inhibitors due to their short half-life in comparison with infliximab where serum levels may be detectable for several weeks. Taken together, mesalamine may be an option in remission induction in mild CD and in remission maintenance after surgically induced remission in uncomplicated cases. The German consensus favors an accelerated step-up in CD rather than a top-down strategy. Finally, Herrlinger
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/30/2015 3:35:17 AM
monotherapy [5]. Recently, a controlled trial comparing the ‘gold standard’ for remission induction budesonide with mesalamine showed both treatments to be equally effective in mild to moderate ileocecal CD [6]. Having in mind that there obviously is a collective of patients with a mild course of CD, the results described above justify a role for mesalamine in remission induction in mild cases. The data on mesalamine in remission maintenance of CD are less convincing. Due to a recent meta-analysis, neither sulfasalazine nor mesalamine were effective in preventing relapse in quiescent CD [7]. This is in line with the German consensus where mesalamine is not mentioned for this situation. In contrast, mesalamine seems to have a modest effect in remission maintenance after surgically induced remission. The number of patients needed to treat to prevent one relapse is ten [8]. The German consensus statement is as follows: Mesalazine may be given for postoperative remission maintenance. This seems to be reasonable in uncomplicated cases after first presentation with a singular stenosis without fistulae or abscesses. In complicated cases or after repeated resections, azathioprine should be used instead due to its better efficacy in direct comparison.
calcineurin inhibitors and infliximab seem to be equally effective in steroid-refractory ulcerative colitis. If having in mind the sequential use of these agents, calcineurin inhibitors should be used as first-line therapy due to their shorter half-life in comparison to infliximab.
Disclosure Statement The author has no conflicts of interest to disclose.
References
Differences between Treatment Guidelines – Germany
7 Ford AC, Kane SV, Khan KJ, Achkar JP, Talley NJ, Marshall JK, Moayyedi P: Efficacy of 5-aminosalicylates in Crohn’s disease: systematic review and meta-analysis. Am J Gastroenterol 2011;106:617–629. 8 Ford AC, Khan KJ, Talley NJ, Moayyedi P: 5-aminosalicylates prevent relapse of Crohn’s disease after surgically induced remission: systematic review and meta-analysis. Am J Gastroenterol 2011;106:413–420. 9 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; SONIC Study Group: Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010; 362: 1383–1395. 10 Dignass A, Van Assche G, Lindsay JO, Lémann M, Söderholm J, Colombel JF, Danese S, D’Hoore A, Gassull M, Gomollón F, Hommes DW, Michetti P, O’Morain C, Oresland T, Windsor A, Stange EF, Travis SP; European Crohn’s and Colitis Organisation (ECCO): The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: current management. J Crohns Colitis 2010;4:28–62. 11 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, Ochsenkühn T, van Bodegraven AA, Van Hootegem PP, Lambrecht GL, Mana F, Rutgeerts P, Feagan BG, Hommes D; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club: Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008;371:660–667. 12 Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841–1845.
Dig Dis 2013;31:357–359 DOI: 10.1159/000354694
13 Schmidt KJ, Herrlinger KR, Emmrich J, Barthel D, Koc H, Lehnert H, Stange EF, Fellermann K, Büning J: Short-term efficacy of tacrolimus in steroid-refractory ulcerative colitis – experience in 130 patients. Aliment Pharmacol Ther 2013;37:129–136. 14 Järnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlén P, Grännö C, Vilien M, Ström M, Danielsson A, Verbaan H, Hellström PM, Magnuson A, Curman B: Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005;128:1805–1811. 15 Laharie D, Bourreille A, Branche J, Allez M, Bouhnik Y, Filippi J, Zerbib F, Savoye G, Nachury M, Moreau J, Delchier JC, Cosnes J, Ricart E, Dewit O, Lopez-Sanroman A, Dupas JL, Carbonnel F, Bommelaer G, Coffin B, Roblin X, Van Assche G, Esteve M, Färkkilä M, Gisbert JP, Marteau P, Nahon S, de Vos M, Franchimont D, Mary JY, Colombel JF, Lémann M; Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives: Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet 2012; 380: 1909–1915. 16 Herrlinger KR, Barthel DN, Schmidt KJ, Büning J, Barthel CS, Wehkamp J, Stange EF, Fellermann K: Infliximab as rescue medication for patients with severe ulcerative/indeterminate colitis refractory to tacrolimus. Aliment Pharmacol Ther 2010;31:1036–1041. 17 Chaparro M, Burgueño P, Iglesias E, Panés J, Muñoz F, Bastida G, Castro L, Jiménez C, Mendoza JL, Barreiro-de Acosta M, Senent SG, Gomollón F, Calvet X, García-Planella E, Gómez M, Hernández V, Hinojosa J, Mañosa M, Nyssen OP, Gisbert JP: Infliximab salvage therapy after failure of ciclosporin in corticosteroid-refractory ulcerative colitis: a multicentre study. Aliment Pharmacol Ther. 2012; 35:275–283. 18 Maser EA, Deconda D, Lichtiger S, Ullman T, Present DH, Kornbluth A: Cyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis. Clin Gastroenterol Hepatol 2008; 6: 1112–1116.
359
Downloaded by: Stockholms Universitet 198.143.54.1 - 8/30/2015 3:35:17 AM
1 Hoffmann JC, Preiss JC, Autschbach F, Buhr HJ, Häuser W, Herrlinger K, Höhne W, Koletzko S, Krieglstein CF, Kruis W, Matthes H, Moser G, Reinshagen M, Rogler G, Schreiber S, Schreyer AG, Sido B, Siegmund B, Stallmach A, Bokemeyer B, Stange EF, Zeitz M: Clinical practice guideline on diagnosis and treatment of Crohn’s disease (in German). Z Gastroenterol 2008;46:1094–1146. 2 Dignass A, Preiss JC, Aust DE, Autschbach F, Ballauff A, Barretton G, Bokemeyer B, Fichtner-Feigl S, Hagel S, Herrlinger KR, Jantschek G, Kroesen A, Kruis W, Kucharzik T, Langhorst J, Reinshagen M, Rogler G, Schleiermacher D, Schmidt C, Schreiber S, Schulze H, Stange E, Zeitz M, Hoffmann JC, Stallmach A: Updated German guideline on diagnosis and treatment of ulcerative colitis, 2011 (in German). Z Gastroenterol 2011;49:1276–1341. 3 Singleton JW, Hanauer SB, Gitnick GL, Peppercorn MA, Robinson MG, Wruble LD, Krawitt EL: Mesalamine capsules for the treatment of active Crohn’s disease: results of a 16-week trial. Pentasa Crohn’s Disease Study Group. Gastroenterology 1993; 104: 1293–1301. 4 Hanauer SB, Strömberg U: Oral Pentasa in the treatment of active Crohn’s disease: a metaanalysis of double-blind, placebo-controlled trials. Clin Gastroenterol Hepatol 2004; 2: 379–388. 5 Blumenstein I, Bock H, Weber C, Rambow A, Tacke W, Kihn R, Pfaff R, Orlemann S, Schaeffer R, Schröder O, Dignass A, Hartmann F, Stein J: Health care and cost of medication for inflammatory bowel disease in the Rhein-Main region, Germany: a multicenter, prospective, internet-based study. Inflamm Bowel Dis 2008;14:53–60. 6 Tromm A, Bunganič I, Tomsová E, Tulassay Z, Lukáš M, Kykal J, Bátovský M, Fixa B, Gabalec L, Safadi R, Kramm HJ, Altorjay I, Löhr H, Koutroubakis I, Bar-Meir S, Stimac D, Schäffeler E, Glasmacher C, Dilger K, Mohrbacher R, Greinwald R; International Budenofalk Study Group: Budesonide 9 mg is at least as effective as mesalamine 4.5 g in patients with mildly to moderately active Crohn’s disease. Gastroenterology 2011; 140: 425–434.
