Performance of tacrolimus in hospitalized patients with steroid-refractory acute severe ulcerative colitis
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摘要
BACKGROUND Acute severe ulcerative colitis unresponsive to systemic steroid treatment is a lifethreatening medical condition requiring hospitalization and often colectomy.Despite the increasing choice of medical therapy options for ulcerative colitis, the condition remains a great challenge in the field of inflammatory bowel diseases(IBD). The performance of the calcineurin inhibitor tacrolimus in this clinical setting is insufficiently elucidated.AIM To evaluate the short and long-term outcomes of tacrolimus therapy in adult inpatients with steroid-refractory acute severe ulcerative colitis.METHODS We conducted a retrospective monocentric study enrolling 22 patients at a tertiary care center for the treatment of IBD. All patients who were admitted to one of the wards of the Department of Gastroenterology and Hepatology of the Heidelberg University Hospital with acute severe ulcerative colitis between 2007 and 2018, and who received oral or intravenous tacrolimus for steroid-refractory disease were included. Baseline characteristics and data on the disease courses were retrieved from entirely computerized patient charts. The primary study endpoint was clinical response to tacrolimus therapy, resulting in discharge from the hospital. Secondary study endpoints were colectomy rate and time to colectomy, achievement of clinical remission under tacrolimus therapy, and the occurrence of side effects.RESULTSIn the majority of the 22 included patients(68.2%), tacrolimus therapy was initiated intravenously and subsequently converted to oral administration. The treatment duration was 128 ± 28.5 d(mean ± SEM), and the patients were followed up for 705 ± 110 d after treatment initiation. Among all patients, 86.4%were discharged from the hospital under continued oral tacrolimus therapy. In36.4% of the patients, the administration of tacrolimus resulted in clinical remission at some point during the treatment. Thirty-two percent of the patients underwent colectomy between 5 and 194 d after the initiation of tacrolimus treatment(mean: 97.4 ± 20.8 d). Colectomy-free survival rates at 1, 3, 6 and 12 mo after the initiation of tacrolimus therapy were 90.9%, 86.4%, 77.3% and 68.2%,respectively. The safety profile of tacrolimus was overall favorable. Only two patients discontinued the treatment due to side effects.CONCLUSION The short-term outcome of tacrolimus in steroid-refractory acute severe ulcerative colitis was beneficial, and side effects were rare. In all, tacrolimus therapy appears to be a viable option for short-term treatment of steroidrefractory acute severe ulcerative colitis besides ciclosporin and anti-tumor necrosis factor α treatment.
BACKGROUND Acute severe ulcerative colitis unresponsive to systemic steroid treatment is a lifethreatening medical condition requiring hospitalization and often colectomy.Despite the increasing choice of medical therapy options for ulcerative colitis, the condition remains a great challenge in the field of inflammatory bowel diseases(IBD). The performance of the calcineurin inhibitor tacrolimus in this clinical setting is insufficiently elucidated.AIM To evaluate the short and long-term outcomes of tacrolimus therapy in adult inpatients with steroid-refractory acute severe ulcerative colitis.METHODS We conducted a retrospective monocentric study enrolling 22 patients at a tertiary care center for the treatment of IBD. All patients who were admitted to one of the wards of the Department of Gastroenterology and Hepatology of the Heidelberg University Hospital with acute severe ulcerative colitis between 2007 and 2018, and who received oral or intravenous tacrolimus for steroid-refractory disease were included. Baseline characteristics and data on the disease courses were retrieved from entirely computerized patient charts. The primary study endpoint was clinical response to tacrolimus therapy, resulting in discharge from the hospital. Secondary study endpoints were colectomy rate and time to colectomy, achievement of clinical remission under tacrolimus therapy, and the occurrence of side effects.RESULTSIn the majority of the 22 included patients(68.2%), tacrolimus therapy was initiated intravenously and subsequently converted to oral administration. The treatment duration was 128 ± 28.5 d(mean ± SEM), and the patients were followed up for 705 ± 110 d after treatment initiation. Among all patients, 86.4%were discharged from the hospital under continued oral tacrolimus therapy. In36.4% of the patients, the administration of tacrolimus resulted in clinical remission at some point during the treatment. Thirty-two percent of the patients underwent colectomy between 5 and 194 d after the initiation of tacrolimus treatment(mean: 97.4 ± 20.8 d). Colectomy-free survival rates at 1, 3, 6 and 12 mo after the initiation of tacrolimus therapy were 90.9%, 86.4%, 77.3% and 68.2%,respectively. The safety profile of tacrolimus was overall favorable. Only two patients discontinued the treatment due to side effects.CONCLUSION The short-term outcome of tacrolimus in steroid-refractory acute severe ulcerative colitis was beneficial, and side effects were rare. In all, tacrolimus therapy appears to be a viable option for short-term treatment of steroidrefractory acute severe ulcerative colitis besides ciclosporin and anti-tumor necrosis factor α treatment.
BACKGROUND Acute severe ulcerative colitis unresponsive to systemic steroid treatment is a lifethreatening medical condition requiring hospitalization and often colectomy.Despite the increasing choice of medical therapy options for ulcerative colitis, the condition remains a great challenge in the field of inflammatory bowel diseases(IBD). The performance of the calcineurin inhibitor tacrolimus in this clinical setting is insufficiently elucidated.AIM To evaluate the short and long-term outcomes of tacrolimus therapy in adult inpatients with steroid-refractory acute severe ulcerative colitis.METHODS We conducted a retrospective monocentric study enrolling 22 patients at a tertiary care center for the treatment of IBD. All patients who were admitted to one of the wards of the Department of Gastroenterology and Hepatology of the Heidelberg University Hospital with acute severe ulcerative colitis between 2007 and 2018, and who received oral or intravenous tacrolimus for steroid-refractory disease were included. Baseline characteristics and data on the disease courses were retrieved from entirely computerized patient charts. The primary study endpoint was clinical response to tacrolimus therapy, resulting in discharge from the hospital. Secondary study endpoints were colectomy rate and time to colectomy, achievement of clinical remission under tacrolimus therapy, and the occurrence of side effects.RESULTSIn the majority of the 22 included patients(68.2%), tacrolimus therapy was initiated intravenously and subsequently converted to oral administration. The treatment duration was 128 ± 28.5 d(mean ± SEM), and the patients were followed up for 705 ± 110 d after treatment initiation. Among all patients, 86.4%were discharged from the hospital under continued oral tacrolimus therapy. In36.4% of the patients, the administration of tacrolimus resulted in clinical remission at some point during the treatment. Thirty-two percent of the patients underwent colectomy between 5 and 194 d after the initiation of tacrolimus treatment(mean: 97.4 ± 20.8 d). Colectomy-free survival rates at 1, 3, 6 and 12 mo after the initiation of tacrolimus therapy were 90.9%, 86.4%, 77.3% and 68.2%,respectively. The safety profile of tacrolimus was overall favorable. Only two patients discontinued the treatment due to side effects.CONCLUSION The short-term outcome of tacrolimus in steroid-refractory acute severe ulcerative colitis was beneficial, and side effects were rare. In all, tacrolimus therapy appears to be a viable option for short-term treatment of steroidrefractory acute severe ulcerative colitis besides ciclosporin and anti-tumor necrosis factor α treatment.
引文
1 Ng SC,Shi HY,Hamidi N,Underwood FE,Tang W,Benchimol EI,Panaccione R,Ghosh S,Wu JCY,Chan FKL,Sung JJY,Kaplan GG.Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century:A systematic review of population-based studies.Lancet 2018;390:2769-2778[PMID:29050646 DOI:10.1016/S0140-6736(17)32448-0]
2 Edwards FC,Truelove SC.The course and prognosis of ulcerative colitis.Gut 1963;4:299-315[PMID:14084741 DOI:10.1136/gut.5.1.1]
3 Harbord M,Eliakim R,Bettenworth D,Karmiris K,Katsanos K,Kopylov U,Kucharzik T,Molnár T,Raine T,Sebastian S,de Sousa HT,Dignass A,Carbonnel F;European Crohn’s and Colitis Organisation[ECCO].Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis.Part 2:Current Management.J Crohns Colitis 2017;11:769-784[PMID:28513805 DOI:10.1093/ecco-jcc/jjx009]
4 Turner D,Walsh CM,Steinhart AH,Griffiths AM.Response to corticosteroids in severe ulcerative colitis:A systematic review of the literature and a meta-regression.Clin Gastroenterol Hepatol 2007;5:103-110[PMID:17142106 DOI:10.1016/j.cgh.2006.09.033]
5 Gustavsson A,Halfvarson J,Magnuson A,Sandberg-Gertzén H,Tysk C,J?rnerot G.Long-term colectomy rate after intensive intravenous corticosteroid therapy for ulcerative colitis prior to the immunosuppressive treatment era.Am J Gastroenterol 2007;102:2513-2519[PMID:17680849 DOI:10.1111/j.1572-0241.2007.01435.x]
6 Almawi WY,Melemedjian OK.Clinical and mechanistic differences between FK506(tacrolimus)and cyclosporin A.Nephrol Dial Transplant 2000;15:1916-1918[PMID:11096132 DOI:10.1093/ndt/15.12.1916]
7 Lichtiger S,Present DH,Kornbluth A,Gelernt I,Bauer J,Galler G,Michelassi F,Hanauer S.Cyclosporine in severe ulcerative colitis refractory to steroid therapy.N Engl J Med 1994;330:1841-1845[PMID:8196726 DOI:10.1056/NEJM199406303302601]
8 Kunz J,Hall MN.Cyclosporin A,FK506 and rapamycin:More than just immunosuppression.Trends Biochem Sci 1993;18:334-338[PMID:7694398 DOI:10.1016/0968-0004(93)90069-Y]
9 Ekberg H,Bernasconi C,N?ldeke J,Yussim A,Mj?rnstedt L,Erken U,Ketteler M,Navrátil P.Cyclosporine,tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study.Nephrol Dial Transplant 2010;25:2004-2010[PMID:20106825 DOI:10.1093/ndt/gfp778]
10 Ogata H,Matsui T,Nakamura M,Iida M,Takazoe M,Suzuki Y,Hibi T.A randomised dose finding study of oral tacrolimus(FK506)therapy in refractory ulcerative colitis.Gut 2006;55:1255-1262[PMID:16484504 DOI:10.1136/gut.2005.081794]
11 Ogata H,Kato J,Hirai F,Hida N,Matsui T,Matsumoto T,Koyanagi K,Hibi T.Double-blind,placebocontrolled trial of oral tacrolimus(FK506)in the management of hospitalized patients with steroidrefractory ulcerative colitis.Inflamm Bowel Dis 2012;18:803-808[PMID:21887732 DOI:10.1002/ibd.21853]
12 Yamamoto T,Shimoyama T,Umegae S,Matsumoto K.Tacrolimus vs.anti-tumour necrosis factor agents for moderately to severely active ulcerative colitis:A retrospective observational study.Aliment Pharmacol Ther 2016;43:705-716[PMID:26762838 DOI:10.1111/apt.13531]
13 Authors.;Collaborators:.Updated S3-Guideline Ulcerative Colitis.German Society for Digestive and Metabolic Diseases(DGVS).Z Gastroenterol 2019;57:162-241[PMID:30654406 DOI:10.1055/a-0824-0861]
14 Silverberg MS,Satsangi J,Ahmad T,Arnott ID,Bernstein CN,Brant SR,Caprilli R,Colombel JF,Gasche C,Geboes K,Jewell DP,Karban A,Loftus EV,Pe?a AS,Riddell RH,Sachar DB,Schreiber S,Steinhart AH,Targan SR,Vermeire S,Warren BF.Toward an integrated clinical,molecular and serological classification of inflammatory bowel disease:Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.Can J Gastroenterol 2005;19 Suppl A:5A-36A[PMID:16151544DOI:10.1155/2005/269076]
15 Truelove SC,Witts LJ.Cortisone in ulcerative colitis;preliminary report on a therapeutic trial.Br Med J1954;2:375-378
16 Schroeder KW,Tremaine WJ,Ilstrup DM.Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis.A randomized study.N Engl J Med 1987;317:1625-1629[PMID:3317057 DOI:10.1056/NEJM198712243172603]
17 Fellermann K,Ludwig D,Stahl M,David-Walek T,Stange EF.Steroid-unresponsive acute attacks of inflammatory bowel disease:Immunomodulation by tacrolimus(FK506).Am J Gastroenterol 1998;93:1860-1866[PMID:9772045 DOI:10.1111/j.1572-0241.1998.539_g.x]
18 Schmidt KJ,Müller N,Dignass A,Baumgart DC,Lehnert H,Stange EF,Herrlinger KR,Fellermann K,Büning J.Long-term Outcomes in Steroid-refractory Ulcerative Colitis Treated with Tacrolimus Alone or in Combination with Purine Analogues.J Crohns Colitis 2016;10:31-37[PMID:26419459 DOI:10.1093/ecco-jcc/jjv175]
19 Fung JJ,Eliasziw M,Todo S,Jain A,Demetris AJ,McMichael JP,Starzl TE,Meier P,Donner A.The Pittsburgh randomized trial of tacrolimus compared to cyclosporine for hepatic transplantation.J Am Coll Surg 1996;183:117-125[PMID:8696542 DOI:10.1006/jsre.1996.0331]
20 McAlister VC,Haddad E,Renouf E,Malthaner RA,Kjaer MS,Gluud LL.Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation:A meta-analysis.Am J Transplant 2006;6:1578-1585[PMID:16827858 DOI:10.1111/j.1600-6143.2006.01360.x]
21 Beckebaum S,Klein C,Varghese J,Sotiropoulos GC,Saner F,Schmitz K,Gerken G,Paul A,Cicinnati VR.Renal function and cardiovascular risk profile after conversion from ciclosporin to tacrolimus:Prospective study in 80 liver transplant recipients.Aliment Pharmacol Ther 2009;30:834-842[PMID:19624550 DOI:10.1111/j.1365-2036.2009.04099.x]
22 Komaki Y,Komaki F,Ido A,Sakuraba A.Efficacy and Safety of Tacrolimus Therapy for Active Ulcerative Colitis;A Systematic Review and Meta-analysis.J Crohns Colitis 2016;10:484-494[PMID:26645641 DOI:10.1093/ecco-jcc/jjv221]
23 Laharie D,Bourreille A,Branche J,Allez M,Bouhnik Y,Filippi J,Zerbib F,Savoye G,Vuitton L,Moreau J,Amiot A,Cosnes J,Ricart E,Dewit O,Lopez-Sanroman A,Fumery M,Carbonnel F,Bommelaer G,Coffin B,Roblin X,van Assche G,Esteve M,Farkkila M,Gisbert JP,Marteau P,Nahon S,de Vos M,Lambert J,Mary JY,Louis E;Groupe d'Etudes Thérapeutiques des Affections Inflammatoires Digestives.Long-term outcome of patients with steroid-refractory acute severe UC treated with ciclosporin or infliximab.Gut 2018;67:237-243[PMID:28053054 DOI:10.1136/gutjnl-2016-313060]
24 Matsuoka K,Saito E,Fujii T,Takenaka K,Kimura M,Nagahori M,Ohtsuka K,Watanabe M.Tacrolimus for the Treatment of Ulcerative Colitis.Intest Res 2015;13:219-226[PMID:26130996 DOI:10.5217/ir.2015.13.3.219]
25 Kawakami K,Inoue T,Murano M,Narabayashi K,Nouda S,Ishida K,Abe Y,Nogami K,Hida N,Yamagami H,Watanabe K,Umegaki E,Nakamura S,Arakawa T,Higuchi K.Effects of oral tacrolimus as a rapid induction therapy in ulcerative colitis.World J Gastroenterol 2015;21:1880-1886[PMID:25684955 DOI:10.3748/wjg.v21.i6.1880]
26 Pellet G,Stefanescu C,Carbonnel F,Peyrin-Biroulet L,Roblin X,Allimant C,Nachury M,Nancey S,Filippi J,Altwegg R,Brixi H,Fotsing G,de Rosamel L,Shili S,Laharie D;Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif.Efficacy and Safety of Induction Therapy With Calcineurin Inhibitors in Combination With Vedolizumab in Patients With Refractory Ulcerative Colitis.Clin Gastroenterol Hepatol 2019;17:494-501[PMID:30213584 DOI:10.1016/j.cgh.2018.08.081]
27 Ledder O,Turner D.Antibiotics in IBD:Still a Role in the Biological Era?Inflamm Bowel Dis 2018;24:1676-1688[PMID:29722812 DOI:10.1093/ibd/izy067]
28 Turner D,Levine A,Kolho KL,Shaoul R,Ledder O.Combination of oral antibiotics may be effective in severe pediatric ulcerative colitis:A preliminary report.J Crohns Colitis 2014;8:1464-1470[PMID:24958064 DOI:10.1016/j.crohns.2014.05.010]
2 Edwards FC,Truelove SC.The course and prognosis of ulcerative colitis.Gut 1963;4:299-315[PMID:14084741 DOI:10.1136/gut.5.1.1]
3 Harbord M,Eliakim R,Bettenworth D,Karmiris K,Katsanos K,Kopylov U,Kucharzik T,Molnár T,Raine T,Sebastian S,de Sousa HT,Dignass A,Carbonnel F;European Crohn’s and Colitis Organisation[ECCO].Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis.Part 2:Current Management.J Crohns Colitis 2017;11:769-784[PMID:28513805 DOI:10.1093/ecco-jcc/jjx009]
4 Turner D,Walsh CM,Steinhart AH,Griffiths AM.Response to corticosteroids in severe ulcerative colitis:A systematic review of the literature and a meta-regression.Clin Gastroenterol Hepatol 2007;5:103-110[PMID:17142106 DOI:10.1016/j.cgh.2006.09.033]
5 Gustavsson A,Halfvarson J,Magnuson A,Sandberg-Gertzén H,Tysk C,J?rnerot G.Long-term colectomy rate after intensive intravenous corticosteroid therapy for ulcerative colitis prior to the immunosuppressive treatment era.Am J Gastroenterol 2007;102:2513-2519[PMID:17680849 DOI:10.1111/j.1572-0241.2007.01435.x]
6 Almawi WY,Melemedjian OK.Clinical and mechanistic differences between FK506(tacrolimus)and cyclosporin A.Nephrol Dial Transplant 2000;15:1916-1918[PMID:11096132 DOI:10.1093/ndt/15.12.1916]
7 Lichtiger S,Present DH,Kornbluth A,Gelernt I,Bauer J,Galler G,Michelassi F,Hanauer S.Cyclosporine in severe ulcerative colitis refractory to steroid therapy.N Engl J Med 1994;330:1841-1845[PMID:8196726 DOI:10.1056/NEJM199406303302601]
8 Kunz J,Hall MN.Cyclosporin A,FK506 and rapamycin:More than just immunosuppression.Trends Biochem Sci 1993;18:334-338[PMID:7694398 DOI:10.1016/0968-0004(93)90069-Y]
9 Ekberg H,Bernasconi C,N?ldeke J,Yussim A,Mj?rnstedt L,Erken U,Ketteler M,Navrátil P.Cyclosporine,tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study.Nephrol Dial Transplant 2010;25:2004-2010[PMID:20106825 DOI:10.1093/ndt/gfp778]
10 Ogata H,Matsui T,Nakamura M,Iida M,Takazoe M,Suzuki Y,Hibi T.A randomised dose finding study of oral tacrolimus(FK506)therapy in refractory ulcerative colitis.Gut 2006;55:1255-1262[PMID:16484504 DOI:10.1136/gut.2005.081794]
11 Ogata H,Kato J,Hirai F,Hida N,Matsui T,Matsumoto T,Koyanagi K,Hibi T.Double-blind,placebocontrolled trial of oral tacrolimus(FK506)in the management of hospitalized patients with steroidrefractory ulcerative colitis.Inflamm Bowel Dis 2012;18:803-808[PMID:21887732 DOI:10.1002/ibd.21853]
12 Yamamoto T,Shimoyama T,Umegae S,Matsumoto K.Tacrolimus vs.anti-tumour necrosis factor agents for moderately to severely active ulcerative colitis:A retrospective observational study.Aliment Pharmacol Ther 2016;43:705-716[PMID:26762838 DOI:10.1111/apt.13531]
13 Authors.;Collaborators:.Updated S3-Guideline Ulcerative Colitis.German Society for Digestive and Metabolic Diseases(DGVS).Z Gastroenterol 2019;57:162-241[PMID:30654406 DOI:10.1055/a-0824-0861]
14 Silverberg MS,Satsangi J,Ahmad T,Arnott ID,Bernstein CN,Brant SR,Caprilli R,Colombel JF,Gasche C,Geboes K,Jewell DP,Karban A,Loftus EV,Pe?a AS,Riddell RH,Sachar DB,Schreiber S,Steinhart AH,Targan SR,Vermeire S,Warren BF.Toward an integrated clinical,molecular and serological classification of inflammatory bowel disease:Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.Can J Gastroenterol 2005;19 Suppl A:5A-36A[PMID:16151544DOI:10.1155/2005/269076]
15 Truelove SC,Witts LJ.Cortisone in ulcerative colitis;preliminary report on a therapeutic trial.Br Med J1954;2:375-378
16 Schroeder KW,Tremaine WJ,Ilstrup DM.Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis.A randomized study.N Engl J Med 1987;317:1625-1629[PMID:3317057 DOI:10.1056/NEJM198712243172603]
17 Fellermann K,Ludwig D,Stahl M,David-Walek T,Stange EF.Steroid-unresponsive acute attacks of inflammatory bowel disease:Immunomodulation by tacrolimus(FK506).Am J Gastroenterol 1998;93:1860-1866[PMID:9772045 DOI:10.1111/j.1572-0241.1998.539_g.x]
18 Schmidt KJ,Müller N,Dignass A,Baumgart DC,Lehnert H,Stange EF,Herrlinger KR,Fellermann K,Büning J.Long-term Outcomes in Steroid-refractory Ulcerative Colitis Treated with Tacrolimus Alone or in Combination with Purine Analogues.J Crohns Colitis 2016;10:31-37[PMID:26419459 DOI:10.1093/ecco-jcc/jjv175]
19 Fung JJ,Eliasziw M,Todo S,Jain A,Demetris AJ,McMichael JP,Starzl TE,Meier P,Donner A.The Pittsburgh randomized trial of tacrolimus compared to cyclosporine for hepatic transplantation.J Am Coll Surg 1996;183:117-125[PMID:8696542 DOI:10.1006/jsre.1996.0331]
20 McAlister VC,Haddad E,Renouf E,Malthaner RA,Kjaer MS,Gluud LL.Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation:A meta-analysis.Am J Transplant 2006;6:1578-1585[PMID:16827858 DOI:10.1111/j.1600-6143.2006.01360.x]
21 Beckebaum S,Klein C,Varghese J,Sotiropoulos GC,Saner F,Schmitz K,Gerken G,Paul A,Cicinnati VR.Renal function and cardiovascular risk profile after conversion from ciclosporin to tacrolimus:Prospective study in 80 liver transplant recipients.Aliment Pharmacol Ther 2009;30:834-842[PMID:19624550 DOI:10.1111/j.1365-2036.2009.04099.x]
22 Komaki Y,Komaki F,Ido A,Sakuraba A.Efficacy and Safety of Tacrolimus Therapy for Active Ulcerative Colitis;A Systematic Review and Meta-analysis.J Crohns Colitis 2016;10:484-494[PMID:26645641 DOI:10.1093/ecco-jcc/jjv221]
23 Laharie D,Bourreille A,Branche J,Allez M,Bouhnik Y,Filippi J,Zerbib F,Savoye G,Vuitton L,Moreau J,Amiot A,Cosnes J,Ricart E,Dewit O,Lopez-Sanroman A,Fumery M,Carbonnel F,Bommelaer G,Coffin B,Roblin X,van Assche G,Esteve M,Farkkila M,Gisbert JP,Marteau P,Nahon S,de Vos M,Lambert J,Mary JY,Louis E;Groupe d'Etudes Thérapeutiques des Affections Inflammatoires Digestives.Long-term outcome of patients with steroid-refractory acute severe UC treated with ciclosporin or infliximab.Gut 2018;67:237-243[PMID:28053054 DOI:10.1136/gutjnl-2016-313060]
24 Matsuoka K,Saito E,Fujii T,Takenaka K,Kimura M,Nagahori M,Ohtsuka K,Watanabe M.Tacrolimus for the Treatment of Ulcerative Colitis.Intest Res 2015;13:219-226[PMID:26130996 DOI:10.5217/ir.2015.13.3.219]
25 Kawakami K,Inoue T,Murano M,Narabayashi K,Nouda S,Ishida K,Abe Y,Nogami K,Hida N,Yamagami H,Watanabe K,Umegaki E,Nakamura S,Arakawa T,Higuchi K.Effects of oral tacrolimus as a rapid induction therapy in ulcerative colitis.World J Gastroenterol 2015;21:1880-1886[PMID:25684955 DOI:10.3748/wjg.v21.i6.1880]
26 Pellet G,Stefanescu C,Carbonnel F,Peyrin-Biroulet L,Roblin X,Allimant C,Nachury M,Nancey S,Filippi J,Altwegg R,Brixi H,Fotsing G,de Rosamel L,Shili S,Laharie D;Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif.Efficacy and Safety of Induction Therapy With Calcineurin Inhibitors in Combination With Vedolizumab in Patients With Refractory Ulcerative Colitis.Clin Gastroenterol Hepatol 2019;17:494-501[PMID:30213584 DOI:10.1016/j.cgh.2018.08.081]
27 Ledder O,Turner D.Antibiotics in IBD:Still a Role in the Biological Era?Inflamm Bowel Dis 2018;24:1676-1688[PMID:29722812 DOI:10.1093/ibd/izy067]
28 Turner D,Levine A,Kolho KL,Shaoul R,Ledder O.Combination of oral antibiotics may be effective in severe pediatric ulcerative colitis:A preliminary report.J Crohns Colitis 2014;8:1464-1470[PMID:24958064 DOI:10.1016/j.crohns.2014.05.010]
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