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Clin Colon Rectal Surg 2004; 17(1): 7-19
DOI: 10.1055/s-2004-823066
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Medical Treatment of Ulcerative Colitis

Uma Mahadevan1
  • 1Division of Gastroenterology, University of California, San Francisco, San Francisco, California
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Publication Date:
13 April 2004 (online)

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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.

KEYWORDS

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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 3 Harries A D, Baird A, Rhodes J. Non-smoking: a feature of ulcerative colitis.  Br Med J (Clin Res Ed). 1982;  284 706
    PubMedGoogle Scholar
  • 4 Andersson R E, Olaison G, Tysk C, Ekbom A. Appendectomy and protection against ulcerative colitis.  N Engl J Med. 2001;  344 808-814
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 8 Truelove S C, Witts L. Cortisone in ulcerative colitis: final report on a therapeutic trial.  BMJ. 1955;  2 1041-1048
    CrossrefPubMedGoogle Scholar
  • 9 Marshall J K, Irvine E J. Rectal aminosalicylate therapy for distal ulcerative colitis: a meta-analysis.  Aliment Pharmacol Ther. 1995;  9 293-300
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 14 Svartz N. Salazopyrine, a new sulfanilamide preparation.  Acta Med Scand. 1942;  110 557
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 16 Baron J H, Connell A, Lennard-Jones J E, Jones F A. Sulphasalzine and salicylazosulphadimidine in ulcerative colitis.  Lancet. 1962;  1 1094-1096
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 19 Taffet S L, Das K M. Sulfasalazine. Adverse effects and desensitization.  Dig Dis Sci. 1983;  28 833-842
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 23 Khan A K, Piris J, Truelove S C. An experiment to determine the active therapeutic moiety of sulphasalazine.  Lancet. 1977;  2 892-895
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 37 Bitton A, Peppercorn M A, Hanrahan J P, Upton M P. Mesalamine-induced lung toxicity.  Am J Gastroenterol. 1996;  91 1039-1040
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 43a Sturgeon J B, Bhatia P, Hermens D, Miner Jr P B. Exacerbation of chronic ulcerative colitis with mesalamine.  Gastroenterology. 1995;  108 1889-1893
    PubMedGoogle Scholar
  • 44 Edwards F, Truelove S C. The course and prognosis of ulcerative colitis.  Gut. 1963;  41 299-315
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 47 Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn's disease.  Gut. 1994;  35 360-362
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 53 Watkinson G. Treatment of ulcerative colitis with topical hydrocortisone hemisuccinate sodium A controlled trial employing restricted sequential analysis.  BMJ. 1958;  1077-1082
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 55 Truelove S. Treatment of ulcerative colitis with local hydrocortisone hemisuccinate sodium. A report on a controlled therapeutic trial.  BMJ. 1958;  1072-1077
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 59 Elliott P R, Powell-Tuck J, Gillespie P E et al.. Prednisolone absorption in acute colitis.  Gut. 1980;  21 49-51
    PubMedGoogle Scholar
  • 60 Truelove S C, Jewell D P. Intensive intravenous regimen for severe attacks of ulcerative colitis.  Lancet. 1974;  1 1067-1070
    PubMedGoogle Scholar
  • 61 Rizzello F, Gionchetti P, Venturi A, Campieri M. Medical treatment of severe ulcerative colitis.  Aliment Pharmacol Ther. 2003;  17(suppl 2) 7-10
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 65 Talar-Williams C, Sneller M C. Complications of corticosteroid therapy.  Eur Arch Otorhinolaryngol. 1994;  251 131-136
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 67 Kusunoki M, Moeslein G, Shoji Y et al.. Steroid complications in patients with ulcerative colitis.  Dis Colon Rectum. 1992;  35 1003-1009
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 85 Pullan R D, Rhodes J, Ganesh S et al.. Transdermal nicotine for active ulcerative colitis.  N Engl J Med. 1994;  330 811-815
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 91 Bean R. The treatment of chronic ulcerative colitis with 6-mercaptopurine.  Med J Aust. 1962;  49 592-593
    PubMedGoogle Scholar
  • 92 Jewell D P, Truelove S C. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial.  BMJ. 1974;  4 627-630
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 128 Sandborn W J. Cyclosporine in ulcerative colitis: state of the art.  Acta Gastroenterol Belg. 2001;  64 201-204
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 133 Sternthal M GJ, Kornbluth A. Toxicity associated with the use of cyclosporin in patients with inflammatory bowel disease.  Gastroenterology. 1996;  110 A1019
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 136 Matsuhashi N, Nakajima A, Watanabe K et al.. Tacrolimus in corticosteroid-resistant ulcerative colitis.  J Gastroenterol. 2000;  35 635-640
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 146 Dhillon A P, Anthony A, Sim R et al.. Mucosal capillary thrombi in rectal biopsies.  Histopathology. 1992;  21 127-133
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 153 Tuvlin J A, Kane S V. Novel therapies in the treatment of ulcerative colitis.  Expert Opin Investig Drugs. 2003;  12 483-490
    CrossrefPubMedGoogle Scholar
  • 154 Creed T, Hearing S, Probert C, Norman M, Dayan C. Basiliximab (IL-2 receptor antagonist) as a steroid sensitizing.  Gastroenterology. 2003;  124 A7
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 160 Sawada K, Kusugam K, Suzuki Y. Multicenter randomized double blind controlled trial for ulcerative colitis therapy with leukocytapheresis.  Gastroenterology. 2003;  124 A67
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 163 Yang Y X, Lichtenstein G R. Corticosteroids in Crohn's disease.  Am J Gastroenterol. 2002;  97 803-823
    CrossrefPubMedGoogle Scholar

Uma MahadevanM.D. 

UCSF/Mount Zion IBD Center

2330 Post Street #610

San Francisco, CA 94115

Email: umamah@itsa.ucsf.edu