Approximately half of the children with ulcerative colitis (UC) have refractory, relapsing or steroid-dependent disease. UC in children is more extensive than in adults, presents more often with severe attacks and carries a more aggressive disease course. Therefore, although a step-up approach is usually recommended in UC, aggressive therapy will often be indicated in children since steroid dependency should never be tolerated. It is vital to ensure that in every resistant case, the symptoms are truly related to the inflammatory disease activity and not to other conditions such as poor adherence to treatment, infections, adverse reactions to drugs, irritable bowel syndrome, lactose intolerance, celiac disease and bacterial overgrowth. The clinician should be ready to escalate therapy in a timely manner but only after ensuring optimization of current treatments. Optimization may include, among others, appropriate dosage, utilization of assays that determine thiopurine, calcineurin inhibitors and anti-tumor necrosis factor levels, introduction of combination therapy when indicated (enemas and immunomodulators) and a long enough time for treatment to become effective. Colectomy is always a valid option and should be discussed before major treatment escalations. Experimental therapies can be considered when all else fails and the family prefers to avoid colectomy. The management of refractory and relapsing disease is particularly challenging in children, and this review summarizes the available evidence to guide treatment decisions in this setup.

1.
Van Limbergen J, Russell RK, Drummond HE, Aldhous MC, Round NK, Nimmo ER, et al: Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 2008;135:1114-1122.
2.
Turner D, Levine A, Escher JC, Griffiths AM, Russell RK, Dignass A, et al: Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines. J Pediatr Gastroenterol Nutr 2012;55:340-361.
3.
Gower-Rousseau C, Dauchet L, Vernier-Massouille G, Tilloy E, Brazier F, Merle V, et al: The natural history of pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol 2009;104:2080-2088.
4.
Aloi M, D'Arcangelo G, Pofi F, Vassallo F, Rizzo V, Nuti F, et al: Presenting features and disease course of pediatric ulcerative colitis. J Crohns Colitis 2013;7:e509-e515.
5.
Hyams J, Markowitz J, Lerer T, Griffiths A, Mack D, Bousvaros A, et al: The natural history of corticosteroid therapy for ulcerative colitis in children. Clin Gastroenterol Hepatol 2006;4:1118-1123.
6.
Turner D, Walsh CM, Benchimol EI, Mann EH, Thomas KE, Chow C, et al: Severe paediatric ulcerative colitis: incidence, outcomes and optimal timing for second-line therapy. Gut 2008;57:331-338.
7.
Dinesen LC, Walsh AJ, Protic MN, Heap G, Cummings F, Warren BF, et al: The pattern and outcome of acute severe colitis. J Crohns Colitis 2010;4:431-437.
8.
Turner D, Walsh CM, Steinhart AH, Griffiths AM: Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression. Clin Gastroenterol Hepatol 2007;5:103-110.
9.
Turner D, Griffiths AM: Acute severe ulcerative colitis in children: a systematic review. Inflamm Bowel Dis 2011;17:440-449.
10.
Hardy TL, Bulmer E: Ulcerative colitis: a survey of ninety-five cases. Br Med J 1933;2:812-815.
11.
Rice-Oxley JM, Truelove S: Complications of ulcerative colitis. Lancet 1950;255:607-611.
12.
De Ridder L, Turner D, Koletzko S, Levine A: Cancer and mortality in pediatric patients with IBD (abstract G-084). ESPGHAN Annu Meet, London, May 10, 2013.
13.
Randall J, Singh B, Warren BF, Travis SP, Mortensen NJ, George BD: Delayed surgery for acute severe colitis is associated with increased risk of postoperative complications. Br J Surg 2010;97:404-409.
14.
Soon IS, Wrobel I, deBruyn JC, Sauve R, Sigalet DL, Kaplan BS, et al: Postoperative complications following colectomy for ulcerative colitis in children. J Pediatr Gastroenterol Nutr 2012;54:763-768.
15.
Pakarinen MP, Natunen J, Ashorn M, Koivusalo A, Turunen P, Rintala RJ, et al: Long-term outcomes of restorative proctocolectomy in children with ulcerative colitis. Pediatrics 2009;123:1377-1382.
16.
Turner D, Travis SP, Griffiths AM, Ruemmele FM, Levine A, Benchimol EI, et al: Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. Am J Gastroenterol 2011;106:574-588.
17.
Meagher AP, Farouk R, Dozois RR, Kelly KA, Pemberton JH: J ileal pouch-anal anastomosis for chronic ulcerative colitis: complications and long-term outcome in 1310 patients. Br J Surg 1998;85:800-803.
18.
Hahnloser D, Pemberton JH, Wolff BG, Larson DR, Crownhart BS, Dozois RR: The effect of ageing on function and quality of life in ileal pouch patients: a single cohort experience of 409 patients with chronic ulcerative colitis. Ann Surg 2004;240:615-621; discussion 621-623.
19.
Pardi DS, Sandborn WJ: Systematic review: the management of pouchitis. Aliment Pharmacol Ther 2006;23:1087-1096.
20.
Cornish JA, Tan E, Teare J, Teoh TG, Rai R, Darzi AW, et al: The effect of restorative proctocolectomy on sexual function, urinary function, fertility, pregnancy and delivery: a systematic review. Dis Colon Rectum 2007;50:1128-1138.
21.
Waljee A, Waljee J, Morris AM, Higgins PD: Threefold increased risk of infertility: a meta-analysis of infertility after ileal pouch anal anastomosis in ulcerative colitis. Gut 2006;55:1575-1580.
22.
Tilney HS, Constantinides V, Ioannides AS, Tekkis PP, Darzi AW, Haddad MJ: Pouch-anal anastomosis vs straight ileoanal anastomosis in pediatric patients: a meta-analysis. J Pediatr Surg 2006;41:1799-1808.
23.
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.
24.
Manosa M, Lopez San Roman A, Garcia-Planella E, Bastida G, Hinojosa J, Gonzalez-Lama Y, et al: Infliximab rescue therapy after cyclosporin failure in steroid-refractory ulcerative colitis. Digestion 2009;80:30-35.
25.
Herrlinger KR, Barthel DN, Schmidt KJ, Buning J, Barthel CS, Wehkamp J, et al: Infliximab as rescue medication for patients with severe ulcerative/indeterminate colitis refractory to tacrolimus. Aliment Pharmacol Ther 2010;31:1036-1041.
26.
Leblanc S, Allez M, Seksik P, et al: Successive treatment with cyclosporine and infliximab in severe ulcerative colitis (UC). Am J Gastroenterol 2011;106:771-777.
27.
Chokshi RV, Hovis CE, Colditz GA, Early DS, Wang JS: Physician recommendations and patient adherence after inadequate bowel preparation on screening colonoscopy. Dig Dis Sci 2013;58:2151-2155.
28.
Reed-Knight B, Lewis JD, Blount RL: Behavioral functioning in youth with inflammatory bowel disease: perceived barriers as mediator of medication adherence. J Pediatr Psychol 2013;38:309-320.
29.
Sandborn WJ, Regula J, Feagan BG, Belousova E, Jojic N, Lukas M, et al: Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis. Gastroenterology 2009;137:1934-1943.
30.
Hanauer SB, Sandborn WJ, Dallaire C, Archambault A, Yacyshyn B, Yeh C, et al: Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared to 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: the ASCEND I trial. Can J Gastroenterol 2007;21:827-834.
31.
Hanauer SB, Sandborn WJ, Kornbluth A, Katz S, Safdi M, Woogen S, et al: Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial. Am J Gastroenterol 2005;100:2478-2485.
32.
Safdi M, DeMicco M, Sninsky C, Banks P, Wruble L, Deren J, et al: A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis. Am J Gastroenterol 1997;92:1867-1871.
33.
Rahhal RM, Bishop WP: Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2008;14:1678-1682.
34.
Van Assche G, D'Haens G, Noman M, Vermeire S, Hiele M, Asnong K, et al: Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology 2003;125:1025-1031.
35.
Ogata H, Matsui T, Nakamura M, Iida M, Takazoe M, Suzuki Y, et al: A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut 2006;55:1255-1262.
36.
Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al: Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010;362:1383-1395.
37.
Panaccione R, Ghosh S, Middleton S, et al: Infliximab, azathioprine or infliximab + azathioprine for treatment of moderate to severe ulcerative colitis. The UC SUCCESS trial. J Crohns Colitis 2011;5:13.
38.
Ben-Horin S, Kopylov U, Chowers Y: Optimizing anti-TNF treatments in inflammatory bowel disease. Autoimmun Rev 2014;13:24-30.
39.
Vande Casteele N, Gils A, Singh S, Ohrmund L, Hauenstein S, Rutgeerts P, et al: Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol 2013;108:962-971.
40.
Maser EA, Villela R, Silverberg MS, Greenberg GR: Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease. Clin Gastroenterol Hepatol 2006;4:1248-1254.
41.
Ben-Horin S, Waterman M, Kopylov U, Yavzori M, Picard O, Fudim E, et al: Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11:444-447.
42.
Yoon JY, Cheon JH, Park JJ, Hong SP, Kim TI, Kim WH: Clinical outcomes and factors for response prediction after the first course of corticosteroid therapy in patients with active ulcerative colitis. J Gastroenterol Hepatol 2011;26:1114-1122.
43.
Turner D, Griffiths AM, Veerman G, Johanns J, Damaraju L, Blank M, et al: Endoscopic and clinical variables that predict sustained remission in children with ulcerative colitis treated with infliximab. Clin Gastroenterol Hepatol 2013;11:1460-1465.
44.
Turner D, Mack D, Leleiko N, Walters TD, Uusoue K, Leach ST, et al: Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. Gastroenterology 2010;138:2282-2291.
45.
Kelley-Quon LI, Jen HC, Ziring DA, Gupta N, Kirschner BS, Ferry GD, et al: Predictors of proctocolectomy in children with ulcerative colitis. J Pediatr Gastroenterol Nutr 2012;55:534-540.
46.
Bessissow T, Lemmens B, Ferrante M, Bisschops R, Van Steen K, Geboes K, et al: Prognostic value of serologic and histologic markers on clinical relapse in ulcerative colitis patients with mucosal healing. Am J Gastroenterol 2012;107:1684-1692.
47.
Froslie KF, Jahnsen J, Moum BA, Vatn MH: Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412-422.
48.
Colombel JF, Rutgeerts P, Reinisch W, Esser D, Wang Y, Lang Y, et al: Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology 2011;141:1194-1201.
49.
Turner D, Leach ST, Mack D, Uusoue K, McLernon R, Hyams J, et al: Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison of predicting outcomes and monitoring response. Gut 2010;59:1207-1212.
50.
Levine A, Griffiths A, Markowitz J, Wilson DC, Turner D, Russell RK, et al: Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis 2011;17:1314-1321.
51.
Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D'Haens G, Wolf DC, et al: Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012;142:257-265.e3.
52.
Chapman RW, Selby WS, Jewell DP: Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut 1986;27:1210-1212.
53.
Mantzaris GJ, Petraki K, Archavlis E, Amberiadis P, Kourtessas D, Christidou A, et al: A prospective randomized controlled trial of intravenous ciprofloxacin as an adjunct to corticosteroids in acute, severe ulcerative colitis. Scand J Gastroenterol 2001;36:971-974.
54.
Mantzaris GJ, Hatzis A, Kontogiannis P, Triadaphyllou G: Intravenous tobramycin and metronidazole as an adjunct to corticosteroids in acute, severe ulcerative colitis. Am J Gastroenterol 1994;89:43-46.
55.
Burke DA, Axon AT, Clayden SA, Dixon MF, Johnston D, Lacey RW: The efficacy of tobramycin in the treatment of ulcerative colitis. Aliment Pharmacol Ther 1990;4:123-129.
56.
Dickinson RJ, O'Connor HJ, Pinder I, Hamilton I, Johnston D, Axon AT: Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis. Gut 1985;26:1380-1384.
57.
Gionchetti P, Rizzello F, Ferrieri A, Venturi A, Brignola C, Ferretti M, et al: Rifaximin in patients with moderate or severe ulcerative colitis refractory to steroid-treatment: a double-blind, placebo-controlled trial. Dig Dis Sci 1999;44:1220-1221.
58.
Ohkusa T, Nomura T, Terai T, Miwa H, Kobayashi O, Hojo M, et al: Effectiveness of antibiotic combination therapy in patients with active ulcerative colitis: a randomized, controlled pilot trial with long-term follow-up. Scand J Gastroenterol 2005;40:1334-1342.
59.
van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al: Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407-415.
60.
Anderson JL, Edney RJ, Whelan K: Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther 2012;36:503-516.
61.
Kunde S, Pham A, Bonczyk S, Crumb T, Duba M, Conrad H Jr, et al: Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr 2013;56:597-601.
62.
Romano C, Famiani A, Comito D, Rossi P, Raffa V, Fries W: Oral beclomethasone dipropionate in pediatric active ulcerative colitis: a comparison trial with mesalazine. J Pediatr Gastroenterol Nutr 2010;50:385-389.
63.
Yamamoto S, Nakase H, Matsuura M, Masuda S, Inui K, Chiba T: Tacrolimus therapy as an alternative to thiopurines for maintaining remission in patients with refractory ulcerative colitis. J Clin Gastroenterol 2011;45:526-530.
64.
Ziring DA, Wu SS, Mow WS, Martin MG, Mehra M, Ament ME: Oral tacrolimus for steroid-dependent and steroid-resistant ulcerative colitis in children. J Pediatr Gastroenterol Nutr 2007;45:306-311.
65.
Turner D, Shah PS, Steinhart AH, Zlotkin S, Griffiths AM: Maintenance of remission in inflammatory bowel disease using omega-3 fatty acids (fish oil): a systematic review and meta-analyses. Inflamm Bowel Dis 2011;17:336-345.
66.
Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, Andoh A, et al: Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006;4:1502-1506.
67.
Langmead L, Rampton DS: Review article: complementary and alternative therapies for inflammatory bowel disease. Aliment Pharmacol Ther 2006;23:341-349.
68.
Langmead L, Feakins RM, Goldthorpe S, Holt H, Tsironi E, De Silva A, et al: Randomized, double-blind, placebo-controlled trial of oral aloe vera gel for active ulcerative colitis. Aliment Pharmacol Ther 2004;19:739-747.
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