Medical Treatment of Ulcerative Colitis

Ulcerative colitis is a chronic inflammatory disease of the colon with an increasing incidence worldwide. The medical management of this disease continues to expand as drugs to induce and maintain remission are sought to avoid the need for colectomy. This article will review the standard of care for the treatment of mild, moderate, and severe ulcerative colitis. The efficacy, optimal usage, and adverse events profile of agents such as 5-aminosalicylates, corticosteroids, azathioprine, and cyclosporine will be discussed and an algorithm for their use will be developed. Alternative and experimental therapies such as monoclonal antibodies, probiotics, and heparin will also be addressed.

Ulcerative colitis - medical therapy - cyclosporine

REFERENCES

• 1 Andres P G, Friedman L S. Epidemiology and the natural course of inflammatory bowel disease.  Gastroenterol Clin North Am. 1999;  28 255-281
• 2 Halfvarson J, Bodin L, Tysk C, Lindberg E, Jarnerot G. Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics.  Gastroenterology. 2003;  124 1767-1773
• 3 Harries A D, Baird A, Rhodes J. Non-smoking: a feature of ulcerative colitis.  Br Med J (Clin Res Ed). 1982;  284 706
• 4 Andersson R E, Olaison G, Tysk C, Ekbom A. Appendectomy and protection against ulcerative colitis.  N Engl J Med. 2001;  344 808-814
• 5 Moum B, Vatn M H, Ekbom A et al.. Incidence of inflammatory bowel disease in southeastern Norway: evaluation of methods after 1 year of registration. Southeastern Norway IBD Study Group of Gastroenterologists.  Digestion. 1995;  56 377-381
• 6 Langholz E, Munkholm P, Davidsen M, Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years.  Gastroenterology. 1994;  107 3-11
• 7 Langholz E, Munkholm P, Davidsen M, Nielsen O H, Binder V. Changes in extent of ulcerative colitis: a study on the course and prognostic factors.  Scand J Gastroenterol. 1996;  31 260-266
• 8 Truelove S C, Witts L. Cortisone in ulcerative colitis: final report on a therapeutic trial.  BMJ. 1955;  2 1041-1048
• 9 Marshall J K, Irvine E J. Rectal aminosalicylate therapy for distal ulcerative colitis: a meta-analysis.  Aliment Pharmacol Ther. 1995;  9 293-300
• 10 D'Arienzo A, Panarese A, D'Armiento F P et al.. 5-aminosalicylic acid suppositories in the maintenance of remission in idiopathic proctitis or proctosigmoiditis: a double-blind placebo-controlled clinical trial.  Am J Gastroenterol. 1990;  85 1079-1082
• 11 Campieri M, De Franchis R, Bianchi Porro G, Ranzi T, Brunetti G, Barbara L. Mesalazine (5-aminosalicylic acid) suppositories in the treatment of ulcerative proctitis or distal proctosigmoiditis. A randomized controlled trial.  Scand J Gastroenterol. 1990;  25 663-668
• 12 Sutherland L R, Martin F, Greer S et al.. 5-aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.  Gastroenterology. 1987;  92 1894-1898
• 13 d'Albasio G, Trallori G, Ghetti A et al.. Intermittent therapy with high-dose 5-aminosalicylic acid enemas for maintaining remission in ulcerative proctosigmoiditis.  Dis Colon Rectum. 1990;  33 394-397
• 14 Svartz N. Salazopyrine, a new sulfanilamide preparation.  Acta Med Scand. 1942;  110 557
• 15 Dick A P, Grayson M, Carpenter R G, Petrie A. Controlled trial of sulphasalazine in the treatment of ulcerative colitis.  Gut. 1964;  50 437-442
• 16 Baron J H, Connell A, Lennard-Jones J E, Jones F A. Sulphasalzine and salicylazosulphadimidine in ulcerative colitis.  Lancet. 1962;  1 1094-1096
• 17 Misiewicz J J, Lennard-Jones J E, Connell A M, Baron J H, Avery Jones F. Controlled trial of sulphasalazine in maintenance therapy for ulcerative colitis.  Lancet. 1965;  1 185-188
• 18 Dissanayake A S, Truelove S C. A controlled therapeutic trial of long-term maintenance treatment of ulcerative colitis with sulphazalazine (Salazopyrin).  Gut. 1973;  14 923-926
• 19 Taffet S L, Das K M. Sulfasalazine. Adverse effects and desensitization.  Dig Dis Sci. 1983;  28 833-842
• 20 O'Morain C, Smethurst P, Dore C J, Levi A J. Reversible male infertility due to sulphasalazine: studies in man and rat.  Gut. 1984;  25 1078-1084
• 21 Das K M, Eastwood M A, McManus J P, Sircus W. The metabolism of salicylazosulphapyridine in ulcerative colitis. I. The relationship between metabolites and the response to treatment in inpatients.  Gut. 1973;  14 631-641
• 22 Klotz U, Maier K, Fischer C, Heinkel K. Therapeutic efficacy of sulfasalazine and its metabolites in patients with ulcerative colitis and Crohn's disease.  N Engl J Med. 1980;  303 1499-1502
• 23 Khan A K, Piris J, Truelove S C. An experiment to determine the active therapeutic moiety of sulphasalazine.  Lancet. 1977;  2 892-895
• 24 Hanauer S, Schwartz J, Robinson M et al.. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial Pentasa Study Group.  Am J Gastroenterol. 1993;  88 1188-1197
• 25 Sninsky C A, Cort D H, Shanahan F et al.. Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis. A multicenter study.  Ann Intern Med. 1991;  115 350-355
• 26 Schroeder K W, Tremaine W J, Ilstrup D M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.  N Engl J Med. 1987;  317 1625-1629
• 27 Safdi M, DeMicco M, Sninsky C 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
• 28 Rao S S, Dundas S A, Holdsworth C D, Cann P A, Palmer K R, Corbett C L. Olsalazine or sulphasalazine in first attacks of ulcerative colitis? A double-blind study.  Gut. 1989;  30 675-679
• 29 Willoughby C P, Cowan R E, Gould S R, Machell R J, Stewart J B. Double-blind comparison of olsalazine and sulphasalazine in active ulcerative colitis.  Scand J Gastroenterol Suppl. 1988;  148 40-44
• 30 Courtney M G, Nunes D P, Bergin C F et al.. Randomised comparison of olsalazine and mesalazine in prevention of relapses in ulcerative colitis.  Lancet. 1992;  339 1279-1281
• 31 Sandberg-Gertzen H, Jarnerot G, Kraaz W. Azodisal sodium in the treatment of ulcerative colitis. A study of tolerance and relapse-prevention properties.  Gastroenterology. 1986;  90 1024-1030
• 32 Meyers S, Sachar D B, Present D H, Janowitz H D. Olsalazine sodium in the treatment of ulcerative colitis among patients intolerant of sulfasalazine. A prospective, randomized, placebo-controlled, double-blind, dose-ranging clinical trial.  Gastroenterology. 1987;  93 1255-1262
• 33 Green J R, Lobo A J, Holdsworth C D et al.. Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis. The Abacus Investigator Group.  Gastroenterology. 1998;  114 15-22
• 34 Green J R, Mansfield J C, Gibson J A, Kerr G D, Thornton P C. A double-blind comparison of balsalazide, 6.75 g daily, and sulfasalazine, 3 g daily, in patients with newly diagnosed or relapsed active ulcerative colitis.  Aliment Pharmacol Ther. 2002;  16 61-68
• 35 Levine D S, Riff D S, Pruitt R et al.. A randomized, double blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis.  Am J Gastroenterol. 2002;  97 1398-1407
• 36 Pruitt R, Hanson J, Safdi M et al.. Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis.  Am J Gastroenterol. 2002;  97 3078-3086
• 37 Bitton A, Peppercorn M A, Hanrahan J P, Upton M P. Mesalamine-induced lung toxicity.  Am J Gastroenterol. 1996;  91 1039-1040
• 38 Iaquinto G, Sorrentini I, Petillo F E, Berardesca G. Pleuropericarditis in a patient with ulcerative colitis in longstanding 5-aminosalicylic acid therapy.  Ital J Gastroenterol. 1994;  26 145-147
• 39 Deltenre P, Berson A, Marcellin P, Degott C, Biour M, Pessayre D. Mesalazine (5-aminosalicylic acid) induced chronic hepatitis.  Gut. 1999;  44 886-888
• 40 Fernandez J, Sala M, Panes J, Feu F, Navarro S, Teres J. Acute pancreatitis after long-term 5-aminosalicylic acid therapy.  Am J Gastroenterol. 1997;  92 2302-2303
• 41 Brouillard M, Gheerbrant J D, Gheysens Y et al.. Chronic interstitial nephritis and mesalazine: 3 new cases? [in French].  Gastroenterol Clin Biol. 1998;  22 724-726
• 42 Hanauer S B, Verst-Brasch C, Regalli G. Renal safety of long-term mesalamine therapy in inflammatory bowel disease (IBD).  Gastroenterology. 1997;  112 A991
• 43 Marteau P, Nelet F, Le Lu M, Devaux C. Adverse events in patients treated with 5-aminosalicyclic acid: 1993-1994 pharmacovigilance report for Pentasa in France.  Aliment Pharmacol Ther. 1996;  10 949-956
• 43a Sturgeon J B, Bhatia P, Hermens D, Miner Jr P B. Exacerbation of chronic ulcerative colitis with mesalamine.  Gastroenterology. 1995;  108 1889-1893
• 44 Edwards F, Truelove S C. The course and prognosis of ulcerative colitis.  Gut. 1963;  41 299-315
• 45 Ekbom A, Helmick C G, Zack M, Holmberg L, Adami H O. Survival and causes of death in patients with inflammatory bowel disease: a population-based study.  Gastroenterology. 1992;  103 954-960
• 46 Faubion Jr W A, Loftus Jr E V, Harmsen W S, Zinsmeister A R, Sandborn W J. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study.  Gastroenterology. 2001;  121 255-260
• 47 Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn's disease.  Gut. 1994;  35 360-362
• 48 Honda M, Orii F, Ayabe T et al.. Expression of glucocorticoid receptor beta in lymphocytes of patients with glucocorticoid-resistant ulcerative colitis.  Gastroenterology. 2000;  118 859-866
• 49 Farrell R J, Murphy A, Long A et al.. High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy.  Gastroenterology. 2000;  118 279-288
• 50 Baron J H, Connell A M, Kanaghinis T G, Lennard-Jones J E, Jones A F. Out-patient treatment of ulcerative colitis. Comparison between three doses of oral prednisone.  BMJ. 1962;  5302 441-443
• 51 Powell-Tuck J, Bown R L, Lennard-Jones J E. A comparison of oral prednisolone given as single or multiple daily doses for active proctocolitis.  Scand J Gastroenterol. 1978;  13 833-837
• 52 Lennard-Jones J E, Misiewicz J J, Connell A M, Baron J H, Avery Jones F. Prednisone as maintenance treatment for ulcerative colitis in remission.  Lancet. 1965;  191 188-189
• 53 Watkinson G. Treatment of ulcerative colitis with topical hydrocortisone hemisuccinate sodium A controlled trial employing restricted sequential analysis.  BMJ. 1958;  1077-1082
• 54 Lennard-Jones J E, Baron J H, Connell A M et al.. A double blind controlled trial of prednisolone-21-phosphate suppositories in the treatment of idiopathic proctitis.  Gut. 1962;  3 207-210
• 55 Truelove S. Treatment of ulcerative colitis with local hydrocortisone hemisuccinate sodium. A report on a controlled therapeutic trial.  BMJ. 1958;  1072-1077
• 56 Lindgren S, Lofberg R, Bergholm L et al.. Effect of budesonide enema on remission and relapse rate in distal ulcerative colitis and proctitis.  Scand J Gastroenterol. 2002;  37 705-710
• 57 Cohen R D, Woseth D M, Thisted R A, Hanauer S B. A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis.  Am J Gastroenterol. 2000;  95 1263-1276
• 58 Farmer R G, Schumacher O P. Treatment of ulcerative colitis with hydrocortisone enemas. Comparison of absorption and clinical response with hydrocortisone alcohol and hydrocortisone acetate.  Am J Gastroenterol. 1970;  54 229-236
• 59 Elliott P R, Powell-Tuck J, Gillespie P E et al.. Prednisolone absorption in acute colitis.  Gut. 1980;  21 49-51
• 60 Truelove S C, Jewell D P. Intensive intravenous regimen for severe attacks of ulcerative colitis.  Lancet. 1974;  1 1067-1070
• 61 Rizzello F, Gionchetti P, Venturi A, Campieri M. Medical treatment of severe ulcerative colitis.  Aliment Pharmacol Ther. 2003;  17(suppl 2) 7-10
• 62 Meyers S, Sachar D B, Goldberg J D, Janowitz H D. Corticotropin versus hydrocortisone in the intravenous treatment of ulcerative colitis. A prospective, randomized, double-blind clinical trial.  Gastroenterology. 1983;  85 351-357
• 63 Powell-Tuck J, Buckell N A, Lennard-Jones J E. A controlled comparison of corticotropin and hydrocortisone in the treatment of severe proctocolitis.  Scand J Gastroenterol. 1977;  12 971-975
• 64 Kaplan H P, Portnoy B, Binder H J, Amatruda T, Spiro H. A controlled evaluation of intravenous adrenocorticotropic hormone and hydrocortisone in the treatment of acute colitis.  Gastroenterology. 1975;  69 91-95
• 65 Talar-Williams C, Sneller M C. Complications of corticosteroid therapy.  Eur Arch Otorhinolaryngol. 1994;  251 131-136
• 66 Singleton J W, Law D H, Kelley Jr M L, Mekhjian H S, Sturdevant R A. National Cooperative Crohn's Disease Study: adverse reactions to study drugs.  Gastroenterology. 1979;  77 870-882
• 67 Kusunoki M, Moeslein G, Shoji Y et al.. Steroid complications in patients with ulcerative colitis.  Dis Colon Rectum. 1992;  35 1003-1009
• 68 Turunen U M, Farkkila M A, Hakala K et al.. Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study.  Gastroenterology. 1998;  115 1072-1078
• 69 Mantzaris G J, Archavlis E, Christoforidis P et al.. A prospective randomized controlled trial of oral ciprofloxacin in acute ulcerative colitis.  Am J Gastroenterol. 1997;  92 454-456
• 70 Mantzaris G J, Petraki K, Archavlis E 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
• 71 Burke D A, Axon A T, Clayden S A, Dixon M F, Johnston D, Lacey R W. The efficacy of tobramycin in the treatment of ulcerative colitis.  Aliment Pharmacol Ther. 1990;  4 123-129
• 72 Lobo A J, Burke D A, Sobala G M, Axon A T. Oral tobramycin in ulcerative colitis: effect on maintenance of remission.  Aliment Pharmacol Ther. 1993;  7 155-158
• 73 Mantzaris G J, 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
• 74 Dickinson R J, O'Connor H J, Pinder I, Hamilton I, Johnston D, Axon A T. Double blind controlled trial of oral vancomycin as adjunctive treatment in acute exacerbations of idiopathic colitis.  Gut. 1985;  26 1380-1384
• 75 Chapman R W, Selby W S, Jewell D P. Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis.  Gut. 1986;  27 1210-1212
• 76 Gionchetti P, Rizzello F, Ferrieri A 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
• 77 Gionchetti P, Rizzello F, Helwig U et al.. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial.  Gastroenterology. 2003;  124 1202-1209
• 78 Gionchetti P, Rizzello F, Venturi A et al.. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial.  Gastroenterology. 2000;  119 305-309
• 79 Rembacken B J, Snelling A M, Hawkey P M, Chalmers D M, Axon A T. Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial.  Lancet. 1999;  354 635-639
• 80 Kruis W, Schutz E, Fric P, Fixa B, Judmaier G, Stolte M. Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis.  Aliment Pharmacol Ther. 1997;  11 853-858
• 81 Fedorak R, Gionchetti P, Campieri M, Madsen K, Isaacs K. VSL3 probiotic mixture induces remission in patients with active ulcerative colitis.  Gastroenterology. 2003;  124 A-377
• 82 Beaugerie L, Massot N, Carbonnel F, Cattan S, Gendre J P, Cosnes J. Impact of cessation of smoking on the course of ulcerative colitis.  Am J Gastroenterol. 2001;  96 2113-2116
• 83 Green J T, Richardson C, Marshall R W et al.. Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis.  Aliment Pharmacol Ther. 2000;  14 1429-1434
• 84 Sandborn W J. Nicotine therapy for ulcerative colitis: a review of rationale, mechanisms, pharmacology, and clinical results.  Am J Gastroenterol. 1999;  94 1161-1171
• 85 Pullan R D, Rhodes J, Ganesh S et al.. Transdermal nicotine for active ulcerative colitis.  N Engl J Med. 1994;  330 811-815
• 86 Sandborn W J, Tremaine W J, Offord K P et al.. Transdermal nicotine for mildly to moderately active ulcerative colitis. A randomized, double-blind, placebo-controlled trial.  Ann Intern Med. 1997;  126 364-371
• 87 Thomas G A, Rhodes J, Mani V et al.. Transdermal nicotine as maintenance therapy for ulcerative colitis.  N Engl J Med. 1995;  332 988-992
• 88 Guslandi M. Long-term effects of a single course of nicotine treatment in acute ulcerative colitis: remission maintenance in a 12-month follow-up study.  Int J Colorectal Dis. 1999;  14 261-262
• 89 Green J T, Thomas G A, Rhodes J et al.. Nicotine enemas for active ulcerative colitis-a pilot study.  Aliment Pharmacol Ther. 1997;  11 859-863
• 90 Sandborn W J, Tremaine W J, Leighton J A et al.. Nicotine tartrate liquid enemas for mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy: a pilot study.  Aliment Pharmacol Ther. 1997;  11 663-671
• 91 Bean R. The treatment of chronic ulcerative colitis with 6-mercaptopurine.  Med J Aust. 1962;  49 592-593
• 92 Jewell D P, Truelove S C. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial.  BMJ. 1974;  4 627-630
• 93 Kirk A P, Lennard-Jones J E. Controlled trial of azathioprine in chronic ulcerative colitis.  Br Med J (Clin Res Ed). 1982;  284 1291-1292
• 94 Hawthorne A B, Logan R F, Hawkey C J et al.. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.  BMJ. 1992;  305 20-22
• 95 Ardizzone S, Molteni P, Imbesi V, Bollani S, Bianchi Porro G, Molteni F. Azathioprine in steroid-resistant and steroid-dependent ulcerative colitis.  J Clin Gastroenterol. 1997;  25 330-333
• 96 Lobo A J, Foster P N, Burke D A, Johnston D, Axon A T. The role of azathioprine in the management of ulcerative colitis.  Dis Colon Rectum. 1990;  33 374-377
• 97 Steinhart A H, Baker J P, Brzezinski A, Prokipchuk E J. Azathioprine therapy in chronic ulcerative colitis.  J Clin Gastroenterol. 1990;  12 271-275
• 98 Korelitz B I, Adler D J, Mendelsohn R A, Sacknoff A L. Long-term experience with 6-mercaptopurine in the treatment of Crohn's disease.  Am J Gastroenterol. 1993;  88 1198-1205
• 99 George J, Present D H, Pou R, Bodian C, Rubin P H. The long-term outcome of ulcerative colitis treated with 6-mercaptopurine.  Am J Gastroenterol. 1996;  91 1711-1714
• 100 Pearson D C, May G R, Fick G H, Sutherland L R. Azathioprine and 6-mercaptopurine in Crohn's disease. A meta-analysis.  Ann Intern Med. 1995;  123 132-142
• 101 Mahadevan U, Tremaine W J, Johnson T et al.. Intravenous azathioprine in severe ulcerative colitis: a pilot study.  Am J Gastroenterol. 2000;  95 3463-3468
• 102 Black A J, McLeod H L, Capell H A et al.. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine.  Ann Intern Med. 1998;  129 716-718
• 103 Colombel J F, Ferrari N, Debuysere H et al.. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy.  Gastroenterology. 2000;  118 1025-1030
• 104 Snow J L, Gibson L E. A pharmacogenetic basis for the safe and effective use of azathioprine and other thiopurine drugs in dermatologic patients.  J Am Acad Dermatol. 1995;  32 114-116
• 105 Dubinsky M C, Lamothe S, Yang H Y et al.. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.  Gastroenterology. 2000;  118 705-713
• 106 Cuffari C, Theoret Y, Latour S, Seidman G. 6-mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity.  Gut. 1996;  39 401-406
• 107 Lowry P W, Franklin C L, Weaver A L et al.. Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease.  Gut. 2001;  49 665-670
• 108 Belaiche J, Desager J P, Horsmans Y, Louis E. Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn's disease.  Scand J Gastroenterol. 2001;  36 71-76
• 109 Sandborn W J, Tremaine W J, Wolf D C et al.. Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease North American Azathioprine Study Group.  Gastroenterology. 1999;  117 527-535
• 110 Present D H, Meltzer S J, Krumholz M P, Wolke A, Korelitz B I. 6-mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity.  Ann Intern Med. 1989;  111 641-649
• 111 Connell W R, Kamm M A, Dickson M, Balkwill A M, Ritchie J K, Lennard-Jones J E. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease.  Lancet. 1994;  343 1249-1252
• 112 Fraser A G, Orchard T R, Robinson E M, Jewell D P. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine.  Aliment Pharmacol Ther. 2002;  16 1225-1232
• 113 Dayharsh G A, Loftus Jr E V, Sandborn W J et al.. Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine.  Gastroenterology. 2002;  122 72-77
• 114 Feagan B G, Fedorak R N, Irvine E J et al.. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators.  N Engl J Med. 2000;  342 1627-1632
• 115 Feagan B G, Rochon J, Fedorak R N et al.. Methotrexate for the treatment of Crohn's disease. North American Crohn's Study Group Investigators.  N Engl J Med. 1995;  332 292-297
• 116 Egan L J, Tremaine W J, Mays D C, Lipsky J J, Sandborn W J. Clinical outcome and pharmacokinetics after addition of low-dose cyclosporine to methotrexate: a case study of five patients with treatment-resistant inflammatory bowel disease.  Inflamm Bowel Dis. 2000;  6 286-289
• 117 Baron T H, Truss C D, Elson C O. Low-dose oral methotrexate in refractory inflammatory bowel disease.  Dig Dis Sci. 1993;  38 1851-1856
• 118 Kozarek R A, Patterson D J, Gelfand M D, Botoman V A, Ball T J, Wilske K R. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease.  Ann Intern Med. 1989;  110 353-356
• 119 Oren R, Arber N, Odes S et al.. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial.  Gastroenterology. 1996;  110 1416-1421
• 120 Paoluzi O A, Pica R, Marcheggiano A et al.. Azathioprine or methotrexate in the treatment of patients with steroid-dependent or steroid-resistant ulcerative colitis: results of an open-label study on efficacy and tolerability in inducing and maintaining remission.  Aliment Pharmacol Ther. 2002;  16 1751-1759
• 121 Lichtiger S, Present D H, Kornbluth A et al.. Cyclosporine in severe ulcerative colitis refractory to steroid therapy.  N Engl J Med. 1994;  330 1841-1845
• 122 Svanoni F, Bonassi U, Bagnolo F et al.. Effectiveness of cyclosporoine A (CsA) in the treatment of active refractory ulcerative colitis.  Gastroenterology. 1998;  114 A1096
• 123 D'Haens G, Lemmens L, Geboes K et al.. Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis.  Gastroenterology. 2001;  120 1323-1329
• 124 Van Assche G, D'Haens G, Noman M 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
• 125 Kornbluth A, Present D H, Lichtiger S, Hanauer S. Cyclosporin for severe ulcerative colitis: a user's guide.  Am J Gastroenterol. 1997;  92 1424-1428
• 126 Cohen R D, Stein R, Hanauer S B. Intravenous cyclosporin in ulcerative colitis: a five-year experience.  Am J Gastroenterol. 1999;  94 1587-1592
• 127 Domenech E, Garcia-Planella E, Bernal I et al.. Azathioprine without oral ciclosporin in the long-term maintenance of remission induced by intravenous ciclosporin in severe, steroid-refractory ulcerative colitis.  Aliment Pharmacol Ther. 2002;  16 2061-2065
• 128 Sandborn W J. Cyclosporine in ulcerative colitis: state of the art.  Acta Gastroenterol Belg. 2001;  64 201-204
• 129 Latteri M, Angeloni T G, Silveri N G, Manna R, Gasbarrini G, Navarra P. Pharmacokinetics of cyclosporin microemulsion in patients with inflammatory bowel disease.  Clin Pharmacokinet. 2001;  40 473-483
• 130 Actis G C, Aimo G, Priolo G, Moscato D, Rizzetto M, Pagni R. Efficacy and efficiency of oral microemulsion cyclosporin versus intravenous and soft gelatin capsule cyclosporin in the treatment of severe steroid-refractory ulcerative colitis: an open-label retrospective trial.  Inflamm Bowel Dis. 1998;  4 276-279
• 131 Navazo L, Salata H, Morales S et al.. Oral microemulsion cyclosporine in the treatment of steroid-refractory attacks of ulcerative and indeterminate colitis.  Scand J Gastroenterol. 2001;  36 610-614
• 132 Sood A, Midha V, Sood N. Oral cyclosporine in patients with active severe ulcerative colitis not responding to steroids.  Indian J Gastroenterol. 2002;  21 155-156
• 133 Sternthal M GJ, Kornbluth A. Toxicity associated with the use of cyclosporin in patients with inflammatory bowel disease.  Gastroenterology. 1996;  110 A1019
• 134 Bousvaros A, Kirschner B S, Werlin S L et al.. Oral tacrolimus treatment of severe colitis in children.  J Pediatr. 2000;  137 794-799
• 135 Baumgart D C, Wiedenmann B, Dignass A U. Rescue therapy with tacrolimus is effective in patients with severe and refractory inflammatory bowel disease.  Aliment Pharmacol Ther. 2003;  17 1273-1281
• 136 Matsuhashi N, Nakajima A, Watanabe K et al.. Tacrolimus in corticosteroid-resistant ulcerative colitis.  J Gastroenterol. 2000;  35 635-640
• 137 Pascu M, Muller A R, Wiedenmann B, Dignass A U. Rescue therapy with tacrolimus in a patient with toxic megacolon.  Int J Colorectal Dis. 2003;  18 271-275
• 138 Fellermann K, Tanko Z, Herrlinger K R et al.. Response of refractory colitis to intravenous or oral tacrolimus (FK506).  Inflamm Bowel Dis. 2002;  8 317-324
• 139 Hanauer S LG, Colombel J F et al.. Maintenance infliximab (Remicade) is safe, effective and steroid-sparing in Crohn's disease: preliminary results of the Accent I trial.  Gastroenterology. 2001;  120 A-21
• 140 Sands B E, Tremaine W J, Sandborn W J et al.. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study.  Inflamm Bowel Dis. 2001;  7 83-88
• 141 Chey W Y, Hussain A, Ryan C, Potter G D, Shah A. Infliximab for refractory ulcerative colitis.  Am J Gastroenterol. 2001;  96 2373-2381
• 142 Kaser A, Mairinger T, Vogel W, Tilg H. Infliximab in severe steroid-refractory ulcerative colitis: a pilot study.  Wien Klin Wochenschr. 2001;  113 930-933
• 143 Probert C, Hearing S D, Shreiber S, Kuhbacher T, Ghosh S, Forbes A. Infliximab in steroid-resistant ulcerative colitis: a randomized controlled trial.  Gastroenterology. 2002;  122 A-99
• 144 Ochsenkuhn T, Sackmann M, Goeke B. Infliximab for acute severe uclerative colitis: a randomized pilot study in nonsteroid refractory patients.  Gastroenterology. 2003;  124 A62
• 145 Su C, Salzberg B A, Lewis J D et al.. Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis.  Am J Gastroenterol. 2002;  97 2577-2584
• 146 Dhillon A P, Anthony A, Sim R et al.. Mucosal capillary thrombi in rectal biopsies.  Histopathology. 1992;  21 127-133
• 147 Gaffney P R, Doyle C T, Gaffney A, Hogan J, Hayes D P, Annis P. Paradoxical response to heparin in 10 patients with ulcerative colitis.  Am J Gastroenterol. 1995;  90 220-223
• 148 Evans R C, Wong V S, Morris A I, Rhodes J M. Treatment of corticosteroid-resistant ulcerative colitis with heparin-a report of 16 cases.  Aliment Pharmacol Ther. 1997;  11 1037-1040
• 149 Panes J, Esteve M, Cabre E et al.. Comparison of heparin and steroids in the treatment of moderate and severe ulcerative colitis.  Gastroenterology. 2000;  119 903-908
• 150 Ang Y S, Mahmud N, White B et al.. Randomized comparison of unfractionated heparin with corticosteroids in severe active inflammatory bowel disease.  Aliment Pharmacol Ther. 2000;  14 1015-1022
• 151 Bloom S, Kiilerich S, Lassen M R, O'Morain C, Forbes A, Orm S. Randomized trial of tinzaparin, a low molecular weight heparin (LMWH), versus placebo in the treatment of mild to moderately active ulcerative colitis.  Gastroenterology. 2003;  124 A67
• 152 Korzenik J, Miner P, Stanton D et al.. Multicenter, randomized, double-blind, placebo-controlled trial of Deligoparin (ultra low molecular weight heparin) for active ulcerative colitis.  Gastroenterology. 2003;  124 A67
• 153 Tuvlin J A, Kane S V. Novel therapies in the treatment of ulcerative colitis.  Expert Opin Investig Drugs. 2003;  12 483-490
• 154 Creed T, Hearing S, Probert C, Norman M, Dayan C. Basiliximab (IL-2 receptor antagonist) as a steroid sensitizing.  Gastroenterology. 2003;  124 A7
• 155 Plevy S, Salzberg B A, Regueiro M et al.. A humanized anti-CD3 monoclonal antibody, visilizumab, for treatment of severe steroid-refractory ulcerative colitis: preliminary results of a phase I study.  Gastroenterology. 2003;  124 A7
• 156 Feagan B, Greenberg G, Wild G et al.. A randomized controlled trial of a humanized α4β7 antibody in ulcerative colitis.  Gastroenterology. 2003;  124:Abstract
• 157 Musch E, Raedler A, Andus T et al.. A phase II placebo-controlled, randomized, multicenter study to evaluate efficacy and safety of interferon beta-1a in patients with ulcerative colitis.  Gastroenterology. 2002;  122 A431
• 158 Sawada K, Ohnishi K, Fukui S et al.. Leukocytapheresis therapy, performed with leukocyte removal filter, for inflammatory bowel disease.  J Gastroenterol. 1995;  30 322-329
• 159 Sawada K, Muto T, Shimoyama T et al.. Multicenter randomized controlled trial for the treatment of ulcerative colitis with a leukocytapheresis column.  Curr Pharm Des. 2003;  9 307-321
• 160 Sawada K, Kusugam K, Suzuki Y. Multicenter randomized double blind controlled trial for ulcerative colitis therapy with leukocytapheresis.  Gastroenterology. 2003;  124 A67
• 161 Cottone M, Pietrosi G, Martorana G et al.. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn's colitis.  Am J Gastroenterol. 2001;  96 773-775
• 162 Mahadevan U, Loftus Jr E V, Tremaine W J et al.. Azathioprine or 6-mercaptopurine before colectomy for ulcerative colitis is not associated with increased postoperative complications.  Inflamm Bowel Dis. 2002;  8 311-316
• 163 Yang Y X, Lichtenstein G R. Corticosteroids in Crohn's disease.  Am J Gastroenterol. 2002;  97 803-823