Background and Aims: In Crohn's disease (CD) patients still remain refractory to current regimens, including biologicals. Previous data from small single-center studies indicated cyclophosphamide pulse therapy (CPT) to be effective for induction of remission at least in steroid-refractory cases. The aim of the present study was to study the efficacy and safety of CPT in mainly tumor necrosis factor (TNF)-refractory complicated CD patients. Methods: Patients with refractory CD undergoing CPT were identified in 13 centers of the German IBD Study Group and retrospectively registered. In total, 41 patients (12 male, 29 female, median age 36 years, range 18-72 years) were included for analysis. Seventy-eight percent of these had previously been treated with thiopurines and 90% had previously received anti-TNF antibodies. Former steroid treatment was found throughout the cohort. Results: Patients received a median number of 5 (1-13) pulses every 28 (13-54) days in a period of 120 (12-411) days. A median dose of 766 (600-1,200) mg and a median cumulative dose of 4,500 (750-9,750) mg was given. A clinical response (reduction in the Harvey-Bradshaw Index [HBI] ≥2 points) was found in 68% of the patients and clinical remission (HBI <5 points) in 32%. Steroids could be reduced from 31 to 12 mg per day over all patients. Side effects were recorded in 71% (n = 29) of the patients. Three patients terminated CPT due to side effects. No patient died. Conclusion: Our data point to CPT as a therapeutic alternative for induction of remission in patients with severe refractory courses of CD including TNF antagonists. CPT might serve as bridging for maintenance treatment.

1.
Dias CC, Rodrigues PP, da Costa-Pereira A, Magro F: Clinical prognostic factors for disabling Crohn's disease: a systematic review and meta-analysis. World J Gastroenterol 2013;19:3866-3871.
2.
Rungoe C, Langholz E, Andersson M, Basit S, Nielsen NM, Wohlfahrt J, Jess T: Changes in medical treatment and surgery rates in inflammatory bowel disease: a nationwide cohort study 1979-2011. Gut 2014;63:1607-1616.
3.
Xu P, He Y, Chen B, Mao R, Tang R, Li M, Chen F, Wu Y, Zeng Z, Chen M: Clinical characteristics and risk factors of refractory Crohn's disease. Zhonghua Yi Xue Za Zhi 2014;94:2982-2987.
4.
Hanauer SB: Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: overview of randomized clinical studies. Rev Gastroenterol Disord 2004;4(suppl 3):S18-S24.
5.
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.
6.
Peyrin-Biroulet L, Deltenre P, de Suray N, Branche J, Sandborn WJ, Colombel JF: Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol 2008;6:644-653.
7.
Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, D'Haens G, Li J, Rosenfeld MR, Kent JD, Pollack PF: Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146:829-838.
8.
Stallmach A, Langbein C, Atreya R, Bruns T, Dignass A, Ende K, Hampe J, Hartmann F, Neurath MF, Maul J, Preiss JC, Schmel R, Siegmund B, Schulze H, Teich N, von Arnim U, Baumgart DC, Schmidt C: Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease - a prospective multicenter observational study. Aliment Pharmacol Ther 2016;44:1199-1212.
9.
Khorrami S, Ginard D, Marín-Jiménez I, Chaparro M, Sierra M, Aguas M, Sicilia B, García-Sánchez V, Suarez C, Villoria A, Taxonera C, Velasco-Guardado A, Martínez-González J, Gisbert JP: Ustekinumab for the treatment of refractory Crohn's disease: the Spanish experience in a large multicentre open-label cohort. Inflamm Bowel Dis 2016;22:1662-1669.
10.
Hawkey CJ, Allez M, Clark MM, Labopin M, Lindsay JO, Ricart E, Rogler G, Rovira M, Satsangi J, Danese S, Russell N, Gribben J, Johnson P, Larghero J, Thieblemont C, Ardizzone S, Dierickx D, Ibatici A, Littlewood T, Onida F, Schanz U, Vermeire S, Colombel JF, Jouet JP, Clark E, Saccardi R, Tyndall A, Travis S, Farge D: Autologous hematopoietic stem cell transplantation for refractory Crohn disease: a randomized clinical trial. JAMA 2015;314:2524-2534.
11.
Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, FitzGerald JD, Karpouzas GA, Merrill JT, Wallace DJ, Yazdany J, Ramsey-Goldman R, Singh K, Khalighi M, Choi SI, Gogia M, Kafaja S, Kamgar M, Lau C, Martin WJ, Parikh S, Peng J, Rastogi A, Chen W, Grossman JM: American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012;64:797-808.
12.
Schmidt C, Wittig BM, Moser C, Zeitz M, Stallmach A: Cyclophosphamide pulse therapy followed by azathioprine or methotrexate induces long-term remission in patients with steroid-refractory Crohn's disease. Aliment Pharmacol Ther 2006;24:343-350.
13.
Schmidt KJ, Fellermann K, Wellhöner P, Weitz G, Homann N, Herrlinger K, Lehnert H, Ludwig D, Büning J: Clinical trial: cyclophosphamide pulse therapy - a promising therapeutic alternative in refractory Crohn's disease. Aliment Pharmacol Ther 2009;29:1230-1239.
14.
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.
15.
Matsumoto T, Motoya S, Watanabe K, Hisamatsu T, Nakase H, Yoshimura N, Ishida T, Kato S, Nakagawa T, Esaki M, Nagahori M, Matsui T, Naito Y, Kanai T, Suzuki Y, Nojima M, Watanabe M, Hibi T; DIAMOND study group: Adalimumab monotherapy and a combination with azathioprine for Crohn's disease: a prospective, randomized trial. J Crohns Colitis 2016;10:1259-1266.
16.
Gisbert JP, Marín AC, McNicholl AG, Chaparro M: Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed. Aliment Pharmacol Ther 2015;41:613-623.
17.
Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy R, D'Haens G, Ben-Horin S, Xu J, Rosario M, Fox I, Parikh A, Milch C, Hanauer S: Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology 2014;147:618-627.e3.
18.
Dulai PS, Singh S, Jiang X, Peerani F, Narula N, Chaudrey K, Whitehead D, Hudesman D, Lukin D, Swaminath A, Shmidt E, Wang S, Boland BS, Chang JT, Kane S, Siegel CA, Loftus EV, Sandborn WJ, Sands BE, Colombel JF: The real-world effectiveness and safety of vedolizumab for moderate-severe Crohn's disease: results from the US VICTORY Consortium. Am J Gastroenterol 2016;111:1147-1155.
19.
Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, Sands BE, Hanauer SB, Targan S, Rutgeerts P, Ghosh S, de Villiers WJ, Panaccione R, Greenberg G, Schreiber S, Lichtiger S, Feagan BG; CERTIFI Study Group: Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med 2012;367:1519-1528.
20.
Jauregui-Amezaga A, Rovira M, Marín P, Salas A, Pinó-Donnay S, Feu F, Elizalde JI, Fernández-Avilés F, Martínez C, Gutiérrez G, Rosiñol L, Carreras E, Urbano A, Lozano M, Cid J, Suárez-Lledó M, Mensa J, Rimola J, Rodríguez S, Masamunt MC, Comas D, Ruíz I, Ramírez-Morros A, Gallego M, Ordás I, Panés J, Ricart E: Improving safety of autologous haematopoietic stem cell transplantation in patients with Crohn's disease. Gut 2016;65:1456-1462.
21.
Stallmach A, Wittig BM, Moser C, Fischinger J, Duchmann R, Zeitz M: Safety and efficacy of intravenous pulse cyclophosphamide in acute steroid refractory inflammatory bowel disease. Gut 2003;52:377-382.
22.
Huong DL, Amoura Z, Duhaut P, Sbai A, Costedoat N, Wechsler B, Piette JC: Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients. J Rheumatol 2002;29:2571-2576.
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.