Immunsuppressiva in der Therapie chronisch entzündlicher Darmerkrankungen

W. Reinisch; C. Dejaco; P. Knoflach; W. Petritsch; H. Vogelsang; H. Tilg

doi:10.1055/s-2004-813500

Zeitschrift für Gastroenterologie, Table of Contents

Z Gastroenterol 2004; 42(9): 1033-1045
DOI: 10.1055/s-2004-813500

Leitlinien

Immunsuppressiva in der Therapie chronisch entzündlicher Darmerkrankungen

Konsensus der Arbeitsgruppe Chronisch Entzündliche Darmerkrankungen der ÖGGHImmunosuppressive Therapy for Inflammatory Bowel Disease: Consensus by the Austrian Working Group on IBDW. Reinisch¹ , C. Dejaco¹ , P. Knoflach² , W. Petritsch³ , H. Vogelsang¹ , H. Tilg⁴

¹Univ.-Klinik f. Innere Medizin IV, Abteilung Gastroenterologie und Hepatologie, AKH Wien
²AKH Wels, I. Interne Abteilung, Wels
³Med. Univ.-Klinik Graz, Klinische Abteilung f. Gastroenterologie und Hepatologie, Graz
⁴BKH Hall i. T., Akademisches Lehrkrankenhaus der Universität Innsbruck, Hall i. T.

Abstract

Zusammenfassung

Eine Therapie mit Azathioprin (AZA) oder 6-Mercaptopurin (6-MP) stellt heute in der Behandlung des Morbus Crohn die erste Wahl einer immunsuppressiven Therapie dar. Indikation ist oft der zweite steroidbedürftige Krankheitsschub innerhalb eines Jahres. Die optimale Dosierung beträgt bei den meisten Patienten 2,5 mg/kg KG und das Eintreten der vollen Wirkung ist manchmal erst nach 6 - 7 Monaten zu erwarten. Intramuskulär appliziertes Methotrexat (MTX) gilt als Mittel zweiter Wahl und die Wirksamkeit ist auf den Morbus Crohn beschränkt. Der Eintritt der Wirkung erfolgt früher als unter Therapie mit AZA. Studien zur Wirksamkeit oraler MTX-Gabe liegen zur zeit nicht vor. Cyclosporin A ist das Mittel der Wahl bei steroidrefraktärer schwerer akuter Colitis ulcerosa, wenn keine OP sinnvoll erscheint. Wahrscheinlich ist eine Dosierung von 2 mg/kg intravenös ausreichend. Bei Ansprechen ist eine Rezidivprophylaxe mit AZA umgehend einzuleiten. Weitere Einsatzgebiete für Cyclosporin A sind schwere extraintestinale Manifestationen chronisch entzündlicher Darmerkrankungen (CED). Zu anderen Immunsuppressiva wie Mycophenolat liegen keine ausreichend kontrollierten Daten vor bzw. ist das Toxizitätsprofil ungünstig (6-Thioguanin). Das Malignomrisiko unter immunsuppressiver Therapie bei CED dürfte nur unwesentlich gesteigert sein. Vor allem AZA und 6-MP können mit relativ hoher Sicherheit für Kind und Mutter in der Schwangerschaft gegeben werden, wenn auch die Indikation stets individuell in Abhängigkeit von der Krankheitsaktivität und dem zu erwartenden Krankheitsverlauf zu stellen ist.

Abstract

Azathioprine (AZA) or 6-mercaptopurine (6-MP) are the immunosuppressive drugs of choice in the treatment of inflammatory bowel disorders (IBD). Optimal dosage for AZA is around 2.5 mg/kg body weight and induction of remission by these drugs may take 6 - 7 months. Intramuscularly applied Methotrexate (MTX) is the second choice, while its efficacy starts earlier than that of AZA; studies assessing oral low-dose MTX treatment are lacking. Cyclosporin is the standard treatment in case of steroid-refractory severe ulcerative colitis. This drug may also be used in patients with severe extraintestinal manifestations of IBD. Regarding other immunosuppressive drugs such as mycophenolic acid or 6-thioguanine respective controlled clinical study data are not available. The risk of malignancy using immunosuppressive drugs such as AZA is low and furthermore, especially AZA and 6-MP can be used rather safely during pregnancy.

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References

Referenzen

1 Meuwissen S G. et al . IOIBD questionnaire on the clinical use of azathioprine, 6-mercaptopurine, cyclosporin A and methotrexate in the treatment of inflammatory bowel diseases. Eur J Gastroenterol Hepatol. 2000; 12 13-18
2 Anstey A. et al . Azathioprine - Clinical Pharmacology and current indications in autoimmune disorders. Bio Drugs. 1998; 9 33-47
3 Aarbakke J, Janka-Schaub G, Elion G B. Thiopurine biology and pharmacology. Trends Pharmacol Sci. 1997; 18 3-7
4 Tiede I, Fritz G, Strand S. et al . CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4 + T lymphocytes. J Clin Invest. 2003; 111 1133-1145
5 Schwab M, Klotz U. Pharmacokinetic considerations in the treatment of inflammatory bowel disease. Clin Pharmacokinet. 2001; 40 723-751
6 Lowry P W, Franklin C L, Weaver A L. et al . Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide. Gut. 2001; 49 656-664
7 Dewit O, Vanheuverzwyn R, Desager J P. et al . Interaction between azathioprine and aminosalicylates: an in vivo study in patients with Crohn’s disease. Aliment Pharmacol Ther. 2002; 16 79-85
8 Sandborn W, Sutherland L, Pearson D. et al .Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease (Cochrane Review). In: The Cochrane Library, Issue 4. Oxford: Update Software; 2003
9 Pearson D C, May G R, Fick G. et al .Azathioprine for maintenance of remission in Crohn’s disease (Cochrane Review). In: The Cochrane Library, Issue 4. Oxford: Update Software; 2003
10 Present D H, Korelitz B I, Wisch N. et al . Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med. 1980; 302 981-987
11 Korelitz B I, Adler D J, Mendelsohn R A. et al . Long-term experience with 6-mercaptopurine in the treatment of Crohn’s disease. Am J Gastroenterol. 1993; 88 1198-1205
12 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
13 Lewis J D, Schwartz J S, Lichtenstein G R. Azathioprine for maintenance of remission in Crohn’s disease: benefits outweigh the risk of lymphoma. Gastroenterology. 2000; 118 1018-1024
14 Markowitz J, Grancher K, Kohn N. et al . A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology. 2000; 119 895-902
15 D’Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn’s (ileo-) colitis with azathioprine. Gastrointest Endosc. 1999; 50 667-671
16 D’Haens G, Geboes K, Ponette E. et al . Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn’s disease. Gastroenterology. 1997; 112 1475-1481
17 Cuillerier E, Lemann M, Bouhnik Y. et al . Azathioprine for prevention of postoperative recurrence in Crohn’s disease: a retrospective study. Eur J Gastroenterol Hepatol. 2001; 13 1291-1296
18 Nos P, Hinojosa J, Aguilera V. et al . Azathioprine and 5-ASA in the prevention of postoperative recurrence of Crohn’s disease. Gastroenterol Hepatol. 2000; 23 374-378
19 Korelitz B, Hanauer S, Rutgeerts P. et al . Post-operative prophylaxis with 6-MP, 5-ASA or placebo in Crohn’s disease: a 2 year multicenter trial. Gastroenterology. 1998; 114 G4141
20 Cosnes J, Larmurier I, Beaugerie L. et al . Do immunosuppressants have any impact on the need for surgery in Crohn’s disease?. Gastroenterology. 2003; 124 A-10
21 Lecomte T, Contou J F, Beugerie L. et al . Predictive factors of response of perianal Crohn’s disease to azathioprine or 6-mercaptopurine. Dis Colon Rectum. 2003; 46 1469-1475
22 Dejaco C, Harrer M, Waldhoer T. et al . Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn’s disease. Aliment Pharmacol Ther. 2003; 18 1113-1120
23 Baert F, Noman M, Vermeire S. et al . Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003; 348 601-608
24 Hanauer S B, Feagan B G, Lichtenstein G R. et al . Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002; 359 1541-1549
25 Parsi M A, Achkar J P, Richardson S. et al . Predictors of response to infliximab in patients with Crohn’s disease. Gastroenterology. 2002; 123 707-713
26 Sands B, van Deventer S, Bernstein C. et al . Long-term treatment of fistulizing Crohn’s disease: Response to infliximab in the ACCENT II trial through 54 weeks. Gastroenterology. 2002; 122 A81-A82
27 Stack W A, Williams D, Stevenson M. et al . Immunosuppressive therapy for ulcerative colitis: results of a nation-wide survey among consultant physician members of the British Society of Gastroenterology. Aliment Pharmacol Ther. 1999; 13 569-575
28 Adler D J, Korelitz B I. The therapeutic efficacy of 6-mercaptopurine in refractory ulcerative colitis. Am J Gastroenterol. 1990; 85 717-722
29 George J, Present D H, Pou R. et al . The long-term outcome of ulcerative colitis treated with 6-mercaptopurine. Am J Gastroenterol. 1996; 91 1711-1714
30 Ardizzone S, Molteni P, Imbesi V. et al . Azathioprine in steroid-resistant and steroid-dependent ulcerative colitis. J Clin Gastroenterol. 1997; 25 330-333
31 Fraser A G, Orchard T R, Jewell D P. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut. 2002; 50 485-489
32 Khan Z H, Mayberry J F, Spiers N. et al . Retrospective case series analysis of patients with inflammatory bowel disease on azathioprine. A district general hospital experience. Digestion. 2000; 62 249-254
33 Jewell D P, Truelove S C. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Br Med J. 1974; 4 627-630
34 Rosenberg J L, Wall A J, Levin B. et al . A controlled trial of azathioprine in the management of chronic ulcerative colitis. Gastroenterology. 1975; 69 96-99
35 Kirk A P, Lennard-Jones J E. Controlled trial of azathioprine in chronic ulcerative colitis. Br Med J. 1982; 284 1291-1292
36 Sood A, Midha V, Sood N. et al . Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled, randomized trial. Indian J Gastroenterol. 2000; 19 14-16
37 Orth T, Peters M, Schlaak J F. et al . Mycophenolate mofetil versus azathioprine in patients with chronic active ulcerative colitis: a 12-month pilot study. Am J Gastroenterol. 2000; 95 1201-1207
38 Casson D H, Davies S E, Thomson M A. et al . Low-dose intravenous azathioprine may be effective in the management of acute fulminant colitis complicating inflammatory bowel disease. Aliment Pharmacol Ther. 1999; 13 891-895
39 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
40 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
41 Mate-Jimenez J, Hermida C, Cantero-Perona J. et al . 6-mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid-dependent inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2000; 12 1227-1233
42 Kim P S, Zlatanic J, Korelitz B I. et al . Optimum duration of treatment with 6-mercaptopurine for Crohn’s disease. Am J Gastroenterol. 1999; 94 3254-3257
43 Fernandez-Banares F, Bertran X, Esteve-Comas M. et al . Azathioprine is useful in maintaining long-term remission induced by intravenous cyclosporine in steroid-refractory severe ulcerative colitis. Am J Gastroenterol. 1996; 91 2498-2499
44 Van Gossum A, Schmit A, Adler M. et al . Short- and long-term efficacy of cyclosporin administration in patients with acute severe ulcerative colitis. Belgian IBD Group. Acta Gastroenterol Belg. 1997; 60 197-200
45 Cohen R D, Stein R, Hanauer S B. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol. 1999; 94 1587-1592
46 Actis G C, Bresso F, Astegiano M. et al . Safety and efficacy of azathioprine in the maintenance of ciclosporin-induced remission of ulcerative colitis. Aliment Pharmacol Ther. 2001; 15 1307-1311
47 Campbell S, Ghosh S. Combination immunomodulatory therapy with cyclosporine and azathioprine in corticosteroid-resistant severe ulcerative colitis: the Edinburgh experience of outcome. Dig Liver Dis. 2003; 35 546-551
48 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
49 Bouhnik Y, Lemann M, Mary J Y. et al . Long-term follow-up of patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Lancet. 1996; 347 215-219
50 Lemann M, Bouhnik Y, Colombel J F. et al . Randomized, double-blind, placebo-controlled, multicenter, azathioprine (AZA) withdrawal trial in Crohn’s disease (CD). Gastroenterology 122: 4: A23.
51 Mantzaris G, Archavlis E, Christidou A. et al . Does the efficacy of azathioprine wane as time on treatment goes by?. Gastroenterology. 2003; 124 A377
52 Lennard L. TPMT in the treatment of Crohn’s disease with azathioprine. Gut. 2002; 51 143-146
53 Candy S, Wright J, Gerber M. et al . A controlled double blind study of azathioprine in the management of Crohn’s disease. Gut. 1995; 37 674-678
54 Colonna T, Korelitz B I. The role of leukopenia in the 6-mercaptopurine-induced remission of refractory Crohn’s disease. Am J Gastroenterol. 1994; 89 362-366
55 Campbell S, Ghosh S. Is neutropenia required for effective maintenance of remission during azathioprine therapy in inflammatory bowel disease?. Eur J Gastroenterol Hepatol. 2001; 13 1073-1076
56 Decaux G, Prospert F, Horsmans Y. et al . Relationship between red cell mean corpuscular volume and 6-thioguanine nucleotides in patients treated with azathioprine. J Lab Clin Med. 2000; 135 256-262
57 Thomas C W Jr, Lowry P W, Franklin C L. et al . Erythrocyte mean corpuscular volume as a surrogate marker for 6-thioguanine nucleotide concentration monitoring in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Inflamm Bowel Dis. 2003; 9 237-245
58 Pearson D C, May G R, Fick G H. et al . Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med. 1995; 123 132-142
59 Sandborn W J. Azathioprine: state of the art in inflammatory bowel disease. Scand J Gastroenterol Suppl. 1998; 225 92-99
60 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
61 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
62 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
63 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
64 Kaskas B A, Louis E, Hindorf U. et al . Safe treatment of thiopurine S-methyltransferase deficient Crohn’s disease patients with azathioprine. Gut. 2003; 52 140-142
65 Korelitz B I, Fuller S R, Warman J I. et al . Shingles during the course of treatment with 6-mercaptopurine for inflammatory bowel disease. Am J Gastroenterol. 1999; 94 424-426
66 Present D H, Meltzer S J, Krumholz M P. et al . 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989; 111 641-649
67 Warman J I, Korelitz B I, Fleisher M R. et al . Cumulative experience with short- and long-term toxicity to 6-mercaptopurine in the treatment of Crohn’s disease and ulcerative colitis. J Clin Gastroenterol. 2003; 37 220-225
68 Bowen D G, Selby W S. Use of 6-mercaptopurine in patients with inflammatory bowel disease previously intolerant of azathioprine. Dig Dis Sci. 2000; 45 1810-1813
69 Boulton-Jones J R, Pritchard K, Mahmoud A A. The use of 6-mercaptopurine in patients with inflammatory bowel disease after failure of azathioprine therapy. Aliment Pharmacol Ther. 2000; 14 1561-1565
70 McGovern D P, Travis S P, Duley J. et al . Azathioprine intolerance in patients with IBD may be imidazole-related and is independent of TPMT activity. Gastroenterology. 2002; 122 838-839
71 Lopez A J, Schwab M, Dejaco C. et al . The risk of re-induction after azthioprine (AZA)-induced pancreatitis is reduced under exposure to 6-thioguanine (6-TG) compared to 6-mercaptopurine (6-MP). Gut. 2003; 35 A171
72 Dubinsky M C, Yang H, Hassard P V. et al . 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology. 2002; 122 904-915
73 Kirschner B S. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology. 1998; 115 813-821
74 Russmann S, Zimmermann A, Krahenbuhl S. et al . Veno-occlusive disease, nodular regenerative hyperplasia and hepatocellular carcinoma after azathioprine treatment in a patient with ulcerative colitis. Eur J Gastroenterol Hepatol. 2001; 13 287-290
75 Schröder O, Stein J. Low dose methotrexate in inflammatory bowel disease: current status and future directions. Am J Gastroenterol. 2003; 98 530-537
76 Feagan B G, Rochon J, Fedorak R N. et al . Methotrexat for the treatment of Crohn’s disease. N Engl J Med. 1995; 332 292-297
77 Oren R, Moshkowitz M, Odes S. et al . Methotrexat in chronic active Crohn’s disease: A double-blind, randomized, Israeli multicenter trial. Am J Gastroenterol. 1997; 92 2203-2209
78 Arora S, Katkov W, Cooley J. et al . Methotrexat in Crohn’s disease: Result of a randomized, double-blind, placebo-controlled trial. Hepatogastroenterology. 1999; 46 1724-1729
79 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. N Engl J Med. 2000; 342 1627-1632
80 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
81 Afadhli A AF, McDonald J WD, Feagan B G. Methotrexate for induction of remission in refractory Crohn’s disease (Cochrane Review). In: The Cochrane Library, Issue 1. Oxford; Update Software 2003
82 Stange E F, Schreiber S, Fölsch U R. et al . Diagnostik und Therapie des M. Crohn - Ergebnisse einer evidenzbasierten Konsensuskonferenz der Deutschen Gesellschaft für Verdauungs-und Stoffwechselerkrankungen. Z Gastroenterol. 2003; 41 19-20
83 Sandborn W J, Present D H, Isaacs K L. et al . Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology. 2003; 125 380-388
84 Sandborn W J. Cyclosporine in ulcerative colitis: state of the art. Acta Gastroenterol Belg. 2001; 64 201-204
85 Hawthorne A B. Ciclosporin and refractory colitis. Eur J Gastroenterol Hepatol. 2003; 15 239-244
86 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
87 Hogenauer C, Wenzl H H, Hinterleitner T A. et al . Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis. Aliment Pharmacol Ther. 2003; 18 415-423
88 Kornbluth A. Is there still an argument for cyclosporine in the treatment of inflammatory bowel disease? Pro argument. Inflamm Bowel Dis. 2003; 9 194-197
89 Fellermann K, Luhmann D, Stange E F. Is there still a role for cyclosporine in the treatment of inflammatory boewl disease? Con argument. Inflamm Bowel Dis. 2003; 9 198-201
90 Dubinsky M C, Hassard P V, Seidman E G. et al . An open-label pilot study using thioguanine as a therapeutic alternative in Crohn’s disease patients resistant to 6-mercaptopurine therapy. Inflamm Bowel Dis. 2001; 7 181-189
91 Herrlinger K R, Deibert P, Schwab M. et al . Remission maintenance by thioguanine in chronic active Crohn’s disease. Aliment Pharmacol Ther. 2003; 17 1459-1464
92 Derijks L J, de Jong D J, Gilissen L P. et al . 6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intolerant inflammatory bowel disease patients: a short-term safety assessment. Eur J Gastroenterol Hepatol. 2003; 15 63-67
93 Harrer M, Schwab M, Teml A. et al . Open prospective study on 6-thioguanine for Crohn’s disease intolerant or resistant to azathioprine and/or 6-mercaptopurine. Gastroenterology. 2003; 122 T1663
94 Dubinsky M C, Vasiliauskas E A, Singh H. et al . 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology. 2003; 125 298-303
95 Fickert P, Hinterleitner T A, Wenzl H H. et al . Mycophenolate mofetil in patients with Crohn’s disease. Am J Gastroenterol. 1998; 93 2529-2532
96 Neurath M F, Wanitschke R, Peters M. et al . Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease. Gut. 1999; 44 625-628
97 Miehsler W, Reinisch W, Moser G. et al . Is mycophenolate mofetil an effective alternative in azathioprine-intolerant patients with chronic active Crohn’s disease?. Am J Gastroenterol. 2001; 96 782-787
98 Orth T, Peters M, Schlaak J F. et al . Mycophenolate mofetil versus azathioprine in patients with chronic active ulcerative colitis: a 12-month pilot study. Am J Gastroenterol. 2000; 95 1201-1207
99 Vasiliauskas E A, Kam L Y, Abreu-Martin M T. et al . An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn’s disease. Gastroenterology. 1999; 117 1278-1287
100 Ehrenpreis E D, Kane S V, Cohen L B. et al . Thalidomide therapy for patients with refractory Crohn’s disease: an open-label trial. Gastroenterology. 1999; 117 1271-1277
101 Sabate J M, Villarejo J, Lemann M. et al . An open-label study of thalidomide for maintenance therapy in responders to infliximab in chronically active and fistulizing refractory Crohn’s disease. Aliment Pharmacol Ther. 2002; 16 1117-1124
102 Shimoyama T, Sawada K, Hiwatashi N. et al . Safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active ulcerative colitis: a multicenter study. J Clin Apheresis. 2001; 16 1-9
103 Hanauer S B, Present D H. The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol Disord. 2003; 3 81-92
104 Greenstein A J, Gennuso R, Sachar D B. et al . Extraintestinal cancers in inflammatory bowel disease. Cancer. 1985; 56 2914-2921
105 Asten P, Barrett J, Symmons D. Risk of developing certain malignancies is related to duration of immunosuppressive drug exposure in patients with rheumatic diseases. J Rheumatol. 1999; 26 1705-1714
106 Palli D, Trallori G, Bagnoli S. et al . Hodgkin’s disease risk is increased in patients with ulcerative colitis. Gastroenterology. 2000; 119 647-653
107 Lewis J D, Bilker W B, Brensinger C. et al . Inflammatory bowel disease is not associated with an increased risk of lymphoma. Gastroenterology. 2001; 121 1080-1087
108 Aithal G P, Mansfield J C. Review article: the risk of lymphoma associated with inflammatory bowel disease and immunosuppressive treatment. Aliment Pharmacol Ther. 2001; 15 1101-1108
109 Bebb J R, Logan R P. Review article: does the use of immunosuppressive therapy in inflammatory bowel disease increase the risk of developing lymphoma?. Aliment Pharmacol Ther. 2001; 15 1843-1849
110 Opelz G, Henderson R. Incidence of Non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet. 1993; 342 1514-1516
111 Connell W R, Kamm M A, Dickson M. et al . Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet. 1994; 343 1249-1252
112 Korelitz B I, Mirsky F J, Fleisher M R. et al . Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine. Am J Gastroenterol. 1999; 94 3248-3253
113 Fraser A G, Orchard T R, Robinson E M. et al . Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther. 2002; 16 1225-1232
114 Farrell R J, Ang Y, Kileen P. et al . Increased incidence of non-Hodgkin’s lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low. Gut. 2000; 47 514-519
115 Dayharsh G A, Loftus E V Jr, 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
116 Lewis J D, Schwartz J S, Lichtenstein G R. Azathioprine for maintenance of remission in Crohn’s disease: benefits outweigh the risk of lymphoma. Gastroenterology. 2000; 118 1018-1024
117 Nielsen O H, Andreasson B, Bondesen S. et al . Pregnancy in Crohn’s disease. Scand J Gastroenterol. 1984; 19 724-732
118 Nielsen O H, Andreasson B, Bondesen S. et al . Pregnancy in ulcerative colitis. Scand J Gastroenterol. 1983; 18 735-742
119 Alstead E M, Ritchie J K, Lennard-Jones J E. et al . Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology. 1990; 99 443-446
120 Alstead E M, Ritchie J K, Lennard-Jones J E. et al . Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology. 1990; 99 443-446
121 Francella A, Dyan A, Bodian C. et al . The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology. 2003; 124 9-17
122 Huynh L A, Min D I. Outcomes of pregnancy and the management of immunosuppressive agents to minimize fetal risks in organ transplant patients. Ann Pharmacother. 1994; 28 1355-1357
123 Bertschinger P, Himmelmann A, Risti B. et al . Cyclosporine treatment of severe ulcerative colitis during pregnancy. Am J Gastroenterol. 1995; 90 330
124 Armenti V T, Ahlswede K M, Ahlswede B A. et al . National transplantation Pregnancy Registry - outcomes of pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation. 1994; 57 502-506
125 Armenti V T, McGrory C H, Cater J R. et al . Pregnancy outcomes in female renal transplant recipients. Transplant Proc. 1998; 30 1732-1734
126 Data on file at Centocor Inc (Malvern, PA) .
127 Donnenfeld A E, Pastuszak A, Noah J S. et al . Methotrexate exposure prior to and during pregnancy. Teratology. 1994; 49 79-81
128 Kozlowski R D, Steinbrunner J V, MacKenzie A H. et al . Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med. 1990; 88 589-592
129 Petri M. Immunosuppressive drug use in pregnancy. Autoimmunity. 2003; 36 51-56

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