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Takahashi T, Shiga H, Tarasawa K, Shimoyama Y, Naito T, Moroi R, Kuroha M, Kakuta Y, Fushimi K, Fujimori K, Kinouchi Y, Masamune A. Comparative Effectiveness of Tacrolimus and Infliximab in Hospitalized Patients With Ulcerative Colitis. Clin Transl Gastroenterol 2024; 15:e00642. [PMID: 37753937 PMCID: PMC10810604 DOI: 10.14309/ctg.0000000000000642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 09/15/2023] [Indexed: 09/28/2023] Open
Abstract
INTRODUCTION Cyclosporine or infliximab (IFX) have been used to avoid surgery in patients with severe refractory ulcerative colitis (UC). Tacrolimus (Tac) is occasionally used as an alternative to cyclosporine; however, the comparative efficacy of Tac and IFX has not been reported. We aimed to compare the effectiveness of Tac and IFX in hospitalized patients with UC. METHODS In a propensity score-matched cohort derived from a large nationwide database, 4-year effectiveness was compared between patients initiated on Tac and those initiated on IFX. The primary outcome was the colectomy rate during the index hospitalization. We also analyzed the cumulative medication discontinuation, UC-related rehospitalization, and colectomy rates after discharge. RESULTS Among 29,239 hospitalized patients, 4,565 were extracted for eligibility, of whom 2,170 were treated with Tac and the remaining 2,395 with IFX. After propensity score matching, 1,787 patients were selected for each group. During the index hospitalization, excluding patients who switched to another molecular-targeted agent, the colectomy rate was higher in the Tac group than in the IFX group (7.8% vs 4.2%, P < 0.01). Among patients discharged without colectomy, the cumulative medication discontinuation (28.4% vs 17.1%, P < 0.01) and rehospitalization (22.4% vs 15.4%, P < 0.01) rates were higher in the Tac group than in the IFX group; however, there was no difference in the cumulative colectomy rate (3.3% vs 2.7%). DISCUSSION Although Tac and IFX were effective for avoiding surgery in hospitalized patients with UC, IFX was more effective than Tac. IFX also had higher long-term effectiveness. Future prospective studies comparing the efficacy of Tac and IFX are warranted.
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Affiliation(s)
- Takahiro Takahashi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hisashi Shiga
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kunio Tarasawa
- Department of Health Administration and Policy, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yusuke Shimoyama
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takeo Naito
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Rintaro Moroi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masatake Kuroha
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoichi Kakuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kiyohide Fushimi
- Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School of Medicine, Bunkyo-ku, Japan
| | - Kenji Fujimori
- Department of Health Administration and Policy, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshitaka Kinouchi
- Health Administration Center, Center for the Advancement of Higher Education, Tohoku University, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Takatsu N, Hisabe T, Kishi M, Takeda T, Yasukawa S, Koga A, Kinjo K, Hirai F, Ueki T, Yao K. Thiopurine naivety at tacrolimus induction is a predictor of long-term remission in patients with intractable ulcerative colitis who responded to tacrolimus. J Gastroenterol Hepatol 2023; 38:52-60. [PMID: 36128954 DOI: 10.1111/jgh.16006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 08/21/2022] [Accepted: 09/07/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND The short-term efficacy of tacrolimus (Tac) for steroid-dependent and steroid-resistant refractory ulcerative colitis (UC) has been demonstrated; however, its long-term outcomes have not been well documented. Thus, this study aimed to clarify the long-term outcomes of patients who achieved Tac-induced remission and identify its predictors. METHODS This study included patients with moderate-to-severe active UC who started receiving Tac at our hospital between July 2004 and December 2016. Short-term treatment response was assessed using the Lichtiger index 3 months after starting Tac, and responding patients were further followed up to assess long-term outcomes. The primary endpoint was the relapse-free survival after Tac-induced remission, and the secondary endpoint was the identification of factors associated with relapse after Tac-induced remission. RESULTS The cumulative relapse-free survival rate at 10 years after Tac-induced remission was 33.2%. Multivariate analysis revealed that being thiopurine naïve at Tac induction was associated with the absence of relapse (hazard ratio: 0.45; 95% confidence interval: 0.22-0.92). CONCLUSIONS Approximately one-third of patients who achieved Tac-induced remission maintained long-term remission. Being thiopurine naïve at Tac induction was a predictor of the absence of relapse.
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Affiliation(s)
- Noritaka Takatsu
- Inflammatory bowel disease center, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Takashi Hisabe
- Inflammatory bowel disease center, Fukuoka University Chikushi Hospital, Fukuoka, Japan.,Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Masahiro Kishi
- Inflammatory bowel disease center, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Teruyuki Takeda
- Inflammatory bowel disease center, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Shigeyoshi Yasukawa
- Inflammatory bowel disease center, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Akihiro Koga
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Ken Kinjo
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Fumihito Hirai
- Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan
| | - Toshiharu Ueki
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Kenshi Yao
- Department of Endoscopy, Fukuoka University Chikushi Hospital, Fukuoka, Japan
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Efficacies of first and second tumor necrosis factor inhibitors in refractory ulcerative colitis patients in real-world practice. Indian J Gastroenterol 2020; 39:565-575. [PMID: 33106991 DOI: 10.1007/s12664-020-01092-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 09/08/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Switching tumor necrosis factor-α inhibitors is an important treatment option for refractory ulcerative colitis (UC) patients who fail the first anti-tumor necrosis factor-α therapy, although many questions about this option remain unanswered. METHODS The efficacy of the second anti-tumor necrosis factor-α therapy in refractory UC patients who failed the first anti-tumor necrosis factor-α therapy was examined using the Mayo score as a measure of disease activity at week 8. The efficacy of the first anti-tumor necrosis factor-α therapy before treatment and at weeks 8 and 52 was also evaluated in real-world practice. RESULTS There were no significant differences in remission induction and maintenance between infliximab and adalimumab as the first anti-tumor necrosis factor-α therapy in UC patients. Of 123 UC patients, 21 (17.1%) switched tumor necrosis factor-α inhibitors. Eight (38.1%), 4 (19.0%), 7 (33.3%), and 2 (9.5%) patients switched from infliximab to adalimumab, infliximab to golimumab, adalimumab to infliximab, and adalimumab to golimumab, respectively. Three (100%) with intolerance to the first anti-tumor necrosis factor-α therapy, 5 (41.7%) with loss of response to the first anti-tumor necrosis factor-α therapy, and 1 (20.0%) with no improvement with the first anti-tumor necrosis factor-α therapy had clinical remission at week 8. CONCLUSIONS Switching tumor necrosis factor-α inhibitors is more effective for refractory UC patients who are intolerant and lose response to the first anti-tumor necrosis factor-α therapy rather than for those showing no improvement with the first anti-tumor necrosis factor-α therapy. Patients with primary failure of anti-tumor necrosis factor-α therapy should be switched to another class of drug.
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Dong C, Metzger M, Holsbø E, Perduca V, Carbonnel F. Systematic review with meta-analysis: mortality in acute severe ulcerative colitis. Aliment Pharmacol Ther 2020; 51:8-33. [PMID: 31821584 DOI: 10.1111/apt.15592] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 11/07/2019] [Accepted: 11/05/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Acute severe ulcerative colitis (ASUC) is a life-threatening condition. Mortality in ASUC decreased in published series but there is uncertainty as to whether this also applies to the real-life setting. AIM To perform a systematic review and meta-analysis of mortality in ASUC in studies from referral centres and in population-based studies, separately and combined. A second aim was to identify risk factors of mortality in ASUC. METHODS We searched pubmed and embase from 1998 to 2016, to identify studies that reported 3-month or 12-month mortalities of acute UC in adult patients treated in referral centres, and in population-based studies. RESULTS Six population-based studies with 741 743 patients and 47 referral centre-based studies with 2556 patients were included. The pooled 3-month and 12-month mortalities were respectively 0.84% and 1.01%. Advanced age was significantly associated with both 3 month and 12 month mortalities (OR = 1.15 per year, 95% CI: 1.10-1.20 and OR = 1.19 per year, 95% CI: 1.15-1.23 respectively). The pooled 3-month and 12-month mortalities were 0.78% and 0.85% in studies with median age of less than 50 and 2.81% and 4.17% in studies with median age of 50 or more, respectively. After adjustment for age, 3-month and 12-month mortalities did not differ between population-based and referral centre-based studies. CONCLUSIONS Mortality in acute severe ulcerative colitis is approximately 1%; it is higher in older patients. Efforts should be made to improve the care of elderly patients with severe UC.
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Affiliation(s)
- Catherine Dong
- Hôpital de Bicêtre, Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris and Université Paris Saclay, Le Kremlin-Bicêtre, France
| | - Marie Metzger
- Inserm U1018, Centre for Research in Epidemiology and Population Health, Paris Saclay University, Villejuif, France
| | - Einar Holsbø
- Department of Computer Science, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Vittorio Perduca
- Inserm U1018, Centre for Research in Epidemiology and Population Health, Paris Saclay University, Villejuif, France.,MAP5 laboratory (UMR CNRS 8145), Université Paris Descartes, Université de Paris, Paris, France
| | - Franck Carbonnel
- Hôpital de Bicêtre, Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris and Université Paris Saclay, Le Kremlin-Bicêtre, France.,Inserm U1018, Centre for Research in Epidemiology and Population Health, Paris Saclay University, Villejuif, France
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Nishio M, Ishii Y, Hashimoto Y, Otake H, Ogashiwa T, Tsuda S, Yasuhara H, Saigusa Y, Kimura H, Maeda S, Kunisaki R. Short- and long-term efficacy of adalimumab salvage therapy after failure of calcineurin inhibitors in steroid-refractory ulcerative colitis. Scand J Gastroenterol 2019; 53:1236-1244. [PMID: 30353757 DOI: 10.1080/00365521.2018.1511825] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Calcineurin inhibitors are highly effective in patients with corticosteroid-refractory ulcerative colitis (UC). When therapy with calcineurin inhibitors fails, adalimumab can be considered to avoid colectomy. The efficacy and safety of this sequential alternative salvage therapy remain unknown. Therefore, the present study was performed to investigate the short- and long-term efficacy and safety of adalimumab after failure of calcineurin inhibitors in corticosteroid-refractory UC. MATERIALS AND METHODS Patients with a corticosteroid-refractory flare of UC who did not respond to calcineurin inhibitors and received continuing salvage therapy with adalimumab were included in this retrospective, observational, single-centre study. The cumulative rates of colectomy were calculated using the Kaplan-Meier method. Clinical remission and response were evaluated based on the Rachmilewitz index. The cumulative rates of colectomy were calculated. Predictive factors for clinical remission and colectomy were identified. In the safety evaluation, any adverse event occurring after the administration of adalimumab was considered. RESULTS Forty-one patients were enrolled; 78% had extensive colitis and 87% had moderate to severe colitis. Seventeen patients (41%) underwent colectomy during the follow-up period. At week 8, 26, and 52 after adalimumab injection, 27%, 39%, and 32% of patients achieved clinical remission, respectively. The adverse event rate was 17%, including one case of tuberculosis. CONCLUSIONS The efficacy of adalimumab for calcineurin inhibitor-refractory UC was examined for the first time. Treatment with adalimumab avoided the need for colectomy in two-thirds of patients with corticosteroid-refractory UC in whom calcineurin inhibitors had failed. However, attention is needed to avoid adverse events, especially infection.
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Affiliation(s)
- Masafumi Nishio
- a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan.,b Department of Gastroenterology , Yokohama City University Graduate School of Medicine , Yokohama , Japan
| | - Yoshito Ishii
- a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan
| | - Yu Hashimoto
- a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan
| | - Haruka Otake
- a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan
| | - Tsuyoshi Ogashiwa
- a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan
| | - Saya Tsuda
- a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan
| | - Hisae Yasuhara
- a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan
| | - Yusuke Saigusa
- c Department of Biostatistics , Yokohama City University Graduate School of Medicine , Yokohama , Japan
| | - Hideaki Kimura
- a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan
| | - Shin Maeda
- b Department of Gastroenterology , Yokohama City University Graduate School of Medicine , Yokohama , Japan
| | - Reiko Kunisaki
- a Inflammatory Bowel Disease Center , Yokohama City University Medical Center , Yokohama , Japan
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Suzuki T, Mizoshita T, Tanida S, Sugimura N, Katano T, Nishie H, Kataoka H. The efficacy of maintenance therapy after remission induction with tacrolimus in ulcerative colitis with and without previous tumor necrosis factor-α inhibitor. JGH OPEN 2019; 3:217-223. [PMID: 31276039 PMCID: PMC6586576 DOI: 10.1002/jgh3.12140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 12/16/2018] [Indexed: 01/08/2023]
Abstract
Background and Aim Tacrolimus (TAC) is an important therapeutic option for remission induction in patients with refractory ulcerative colitis (UC). However, there is little evidence available on long‐term outcomes and maintenance treatments after TAC therapy, especially in cases with previous tumor necrosis factor‐α (TNF‐α) inhibitor therapy. Methods Long‐term outcomes and remission induction after TAC treatment were retrospectively examined in refractory UC patients with and without previous TNF‐α inhibitor therapy. Results The mean disease activity index and the endoscopic activity index scores decreased significantly during the 12‐week treatment after TAC therapy in both groups, showing a significantly greater decrease in the group without TNF‐α inhibitor therapy than in the group with previous TNF‐α inhibitor therapy. One year or more after TAC therapy, TNF‐α inhibitor and/or azathioprine was used as maintenance therapy in most cases in the group without previous TNF‐α inhibitor treatment, while azathioprine was primarily used in the group with previous TNF‐α inhibitor treatment. Colectomy was performed in 45.5% (5/11) and 15.6% (7/45) of the groups with and without previous TNF‐α inhibitor therapy, respectively, and the group without previous TNF‐α inhibitor treatment had a better colectomy‐free rate than the group with previous TNF‐α inhibitor treatment after TAC therapy on Kaplan–Meier analysis. Conclusions TAC is effective for remission induction in refractory UC patients with and without previous TNF‐α inhibitor treatment. Maintenance medication after TAC therapy is an issue for the future, especially in UC cases with previous TNF‐α inhibitor treatment failure.
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Affiliation(s)
- Taketo Suzuki
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Tsutomu Mizoshita
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Satoshi Tanida
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Naomi Sugimura
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Takahito Katano
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Hirotada Nishie
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences Nagoya Japan
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Fernández-Salazar L, Muñoz F, Barrio J, Muñoz C, Pajares R, Rivero M, Prieto V, Legido J, Bouhmidi A, Herranz M, Fernández N, Sánchez-Ocaña R, Joao D, Santos F. Infliximab in ulcerative colitis: real-life analysis of factors predicting treatment discontinuation due to lack of response or colectomy: ECIA (ACAD Colitis and Infliximab Study). Scand J Gastroenterol 2016. [PMID: 26200929 DOI: 10.3109/00365521.2015.1070900] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To describe clinical practice with infliximab (IFX) in ulcerative colitis (UC); identification of predictive factors for IFX treatment discontinuation due to insufficient response and for colectomy. MATERIAL AND METHODS Retrospective, multicentric and observational study including every UC IFX-treated patient in 10 Spanish hospitals. Variables analyzed: epidemiological data; variables for poor prognosis; IFX prior treatments; characteristics of the IFX treatment; time from the UC diagnosis to induction with IFX; time from induction to colectomy or until data collection. Predictive and protective factors for IFX discontinuation due to lack of response and for colectomy were analyzed with binary logistic regression and Cox analysis. RESULTS Follow-up time from induction with IFX to the collection of data or colectomy: 36.7 ± 25.7 months. Prior treatment with immunomodulator medications (IMM): 79%; IFX + immunosuppressant therapy: 77%; discontinuation of IFX: 26%, colectomy 16%. Independent predictive or protective factors for IFX discontinuation: IMM resistance (OR: 2.9, p = 0.022, 95% CI: 1.2-7.2), prior use of leukocytapheresis (OR: 3.3, p = 0.024, 95% CI: 1.1-9.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95% CI: 0.1-0.9, and HR: 0.4, p = 0.006, 95% CI: 0.2-0.8) and corticosteroid use in induction (HR: 1.9, p = 0.049, 95% CI: 1.0-3.8). Independent predictive or protective factors for colectomy: Use of leukocytapheresis (OR: 3.0, p = 0.036, 95% CI: 1.1-8.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95% CI: 0.1-0.8, and HR: 0.3, p = 0.011, 95% CI: 0.1-0.8) and severe cortico-resistant flare-up (HR: 2.5, p = 0.032, 95% CI: 1.1-5.9). CONCLUSIONS Prior use of IMM and leukocytapheresis, the use of corticosteroids in induction and a severe cortico-resistant flare predict a worse response to IFX and the need for colectomy. Combination therapy is a protective factor for both.
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Affiliation(s)
| | - Fernando Muñoz
- b 2 Gastroenterology Unit, Complejo Asistencial Universitario , León, Spain
| | - Jesús Barrio
- c 3 Gastroenterology Unit, Hospital Universitario Río Hortega , Valladolid, Spain
| | - Concepción Muñoz
- d 4 Gastroenterology Unit, Hospital Virgen de la Salud , Toledo, Spain
| | - Ramón Pajares
- e 5 Gastroenterology Unit, Hospital Infanta Sofía, San Sebastián de los Reyes , Madrid, Spain
| | - Montserrat Rivero
- f 6 Gastroenterology Unit, Hospital Universitario Marqués de Valdecilla , Santander, Spain
| | - Vanessa Prieto
- g 7 Gastroenterology Unit, Complejo Asistencial Universitario , Salamanca, Spain
| | - Jesús Legido
- h 8 Gastroenterology Unit, Complejo Asistencial , Segovia, Spain
| | - Abdel Bouhmidi
- i 9 Gastroenterology Unit, Hospital Santa Bárbara de Puertollano , Ciudad Real, Spain
| | - Maite Herranz
- j 10 Gastroenterology Unit, Complejo Asistencial , Ávila, Spain
| | - Nereida Fernández
- b 2 Gastroenterology Unit, Complejo Asistencial Universitario , León, Spain
| | - Ramón Sánchez-Ocaña
- c 3 Gastroenterology Unit, Hospital Universitario Río Hortega , Valladolid, Spain
| | - Diana Joao
- b 2 Gastroenterology Unit, Complejo Asistencial Universitario , León, Spain
| | - Fernando Santos
- c 3 Gastroenterology Unit, Hospital Universitario Río Hortega , Valladolid, Spain
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Colectomy rates in patients with ulcerative colitis following treatment with infliximab or ciclosporin: a systematic literature review. Eur J Gastroenterol Hepatol 2016; 28:369-82. [PMID: 26825217 DOI: 10.1097/meg.0000000000000568] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This review aimed to compile all available published data on colectomy rates following treatment using infliximab or ciclosporin in adult ulcerative colitis patients and to analyse colectomy rates, timing to colectomy and postcolectomy mortality for each treatment. We systematically reviewed the literature after 1990 reporting colectomy rates in ulcerative colitis patients treated with infliximab or ciclosporin, excluding articles on paediatric patients, patients with indeterminate colitis or Crohn's disease and bowel surgery not related to ulcerative colitis. We presented weighted mean colectomy rates and mortality rates. Cox's regression was used to assess time to colectomy adjusting for colitis severity, patient age and sex. We tabulated 78 studies reporting on ciclosporin and/or infliximab and colectomy rates or postcolectomy mortality rates. Not all studies reported data in a standardized manner. Infliximab had a significantly lower colectomy rate than ciclosporin at 36 months when analysing all studies, studies directly comparing infliximab and ciclosporin and studies using severe colitis patients, but not at 3, 12 or 24 months. Severity and age were key indicators in the likelihood of undergoing colectomy after treatment. Postcolectomy mortality rates were less than 1.5% for both drugs. This review indicates that long-term colectomy rates following infliximab are significantly lower than ciclosporin in the longer term, and that postcolectomy mortality following infliximab and ciclosporin is very low. However, many key data items were missing from research articles, reducing our ability to establish with more confidence the actual impact of these two drugs on colectomy rates and postcolectomy mortality rates.
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Tanida S, Mizoshita T, Ozeki K, Katano T, Kataoka H, Kamiya T, Joh T. Advances in refractory ulcerative colitis treatment: A new therapeutic target, Annexin A2. World J Gastroenterol 2015; 21:8776-86. [PMID: 26269667 PMCID: PMC4528020 DOI: 10.3748/wjg.v21.i29.8776] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 05/08/2015] [Accepted: 07/08/2015] [Indexed: 02/07/2023] Open
Abstract
Medical treatment has progressed significantly over the past decade towards achieving and maintaining clinical remission in patients with refractory ulcerative colitis (UC). Proposed mediators of inflammation in UC include pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-2, and the cell-surface adhesive molecule integrin α4β7. Conventional therapeutics for active UC include 5-aminosalicylic acid, corticosteroids and purine analogues (azathioprine and 6-mercaptopurine). Patients who fail to respond to conventional therapy are treated with agents such as the calicineurin inhibitors cyclosporine and tacrolimus, the TNF-α inhibitors infliximab or adalimumab, or a neutralizing antibody (vedolizumab) directed against integrin α4β7. These therapeutic agents are of benefit for patients with refractory UC, but are not universally effective. Our recent research on TNF-α shedding demonstrated that inhibition of annexin (ANX) A2 may be a new therapeutic strategy for the prevention of TNF-α shedding during inflammatory bowel disease (IBD) inflammation. In this review, we provide an overview of therapeutic treatments that are effective and currently available for UC patients, as well as some that are likely to be available in the near future. We also propose the potential of ANX A2 as a new molecular target for IBD treatment.
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Systematic Review: Sequential Rescue Therapy in Severe Ulcerative Colitis: Do the Benefits Outweigh the Risks? Inflamm Bowel Dis 2015; 21:1683-94. [PMID: 25839775 DOI: 10.1097/mib.0000000000000350] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The options for medical management of acute severe steroid-refractory ulcerative colitis (UC) are limited. Recent guidelines recommend against use of sequential rescue therapy in the setting of failed medical management with initial salvage therapy. A systematic review was conducted to assess outcomes of sequential rescue therapy with infliximab (IFX) and calcineurin inhibitors like cyclosporine (CsA) or tacrolimus (Tac) in patients with steroid-refractory UC. METHODS A literature search identified studies that investigated treatment with IFX and CsA or Tac in acute severe UC. Outcomes of interest included short-term symptomatic response to treatment, rates of remission, adverse drug reactions, serious infections, mortality, and colectomy at 3 and 12 months. RESULTS Overall, ten studies with 314 participants were eligible for inclusion. After sequential treatment, patients achieved short-term treatment response in 62.4% (95% confidence interval [CI], 57.0%-67.8%) of cases and remission in 38.9% (95% CI, 33.5%-44.3%). Colectomy rates were 28.3% (95% CI, 21.7%-34.5%) at 3 months and 42.3% (95% CI, 36.0%-48.6%) at 12 months. Adverse events were encountered by 23.0% (95% CI, 17.7%-28.3%) of patients, including serious infections in 6.7% (95% CI, 3.6%-9.8%) and mortality in 1% (95% CI, 0%-2.1%). CONCLUSIONS The risk of sequential therapy in steroid-refractory UC seems lower than initially reported. Caution must be exercised however because of very low-quality evidence. In contrast to recent guidelines, the current analysis does not support a decision for or against use of sequential rescue therapy, which should only be performed at specialized referral centers familiar with the use of calcineurin inhibition.
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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; 13:219-26. [PMID: 26130996 PMCID: PMC4479736 DOI: 10.5217/ir.2015.13.3.219] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 05/06/2014] [Accepted: 05/06/2014] [Indexed: 02/07/2023] Open
Abstract
Tacrolimus is a calcineurin inhibitor used for the treatment of corticosteroid-refractory ulcerative colitis (UC). Two randomized controlled trials and a number of retrospective studies have assessed the therapeutic effect of tacrolimus in UC patients. These studies showed that tacrolimus has excellent short-term efficacy in corticosteroid-refractory patients, with the rates of clinical response ranging from 61% to 96%. However, the long-term prognosis of patients treated with tacrolimus is disappointing, and almost 50% of patients eventually underwent colectomy in long-term follow-up. Tacrolimus can achieve mucosal healing in 40-50% of patients, and this is associated with a favorable long-term prognosis. Anti-tumor necrosis factor (TNF)-α antibodies are another therapeutic option in corticosteroid-refractory patients. A prospective head-to-head comparative study of tacrolimus and infliximab is currently being performed to determine which treatment is more effective in corticosteroid-refractory patients. Several retrospective studies have demonstrated that switching between tacrolimus and anti-TNF-α antibody therapy was effective in patients who were refractory to one of the treatments. Most adverse events of tacrolimus are mild; however, opportunistic infections, especially pneumocystis pneumonia, are the most important adverse events, and these should be carefully considered during treatment. Several issues on tacrolimus treatment in UC patients remain unsolved (e.g., use of tacrolimus as remission maintenance therapy). Further controlled studies are needed to optimize the use of tacrolimus for the treatment of UC.
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Affiliation(s)
- Katsuyoshi Matsuoka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Eiko Saito
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshimitsu Fujii
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kento Takenaka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Maiko Kimura
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masakazu Nagahori
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuo Ohtsuka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
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Minami N, Yoshino T, Matsuura M, Koshikawa Y, Yamada S, Toyonaga T, Madian A, Honzawa Y, Nakase H. Tacrolimus or infliximab for severe ulcerative colitis: short-term and long-term data from a retrospective observational study. BMJ Open Gastroenterol 2015; 2:e000021. [PMID: 26462273 PMCID: PMC4599165 DOI: 10.1136/bmjgast-2014-000021] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 12/13/2014] [Accepted: 12/26/2014] [Indexed: 12/18/2022] Open
Abstract
Objective Treatment of severe ulcerative colitis (UC) is challenging. Although the efficacy of tacrolimus (TAC) and infliximab (IFX) have been evaluated in patients with severe UC, the safety and efficacy levels of sequential therapies (TAC→IFX/IFX→TAC) in these patients remain unclear. The aim of this study was to assess short-term and long-term outcomes in patients with severe UC treated with TAC and IFX. Methods From October 2001 to February 2014, 29 patients with consecutive severe UC treated with TAC or IFX were retrospectively evaluated. Median follow-up duration was 27 months (range 0.5–118 months). The primary end point was short-term outcomes at 8 weeks after induction of TAC (TAC group, n=22) or IFX (IFX group, n=7). The secondary end point included long-term outcomes and colectomy-free survival. The clinical response was evaluated based on a partial Mayo score. Results The clinical remission (CR) rate at 8 weeks in the TAC and IFX groups was 63.6% and 71.4%, respectively. In 13 of the 29 patients (10 in the TAC group, 3 in the IFX group), sequential therapies were used in their clinical courses. In 9 of these 13 patients (6 in the TAC group, 3 in the IFX group), CR was achieved and maintained by sequential therapies. Overall cumulative colectomy-free survival was 79.3% at 118 months. Conclusions TAC and IFX had similar effects on remission induction in patients with severely active UC. Sequential therapies could rescue patients with UC who failed initial treatment with TAC or IFX. In clinical practice, sequential therapies might be deliberately performed.
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Affiliation(s)
- Naoki Minami
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Takuya Yoshino
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Minoru Matsuura
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Yorimitsu Koshikawa
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Satoshi Yamada
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Takahiko Toyonaga
- The Third Department of Internal Medicine , Kansai Medical University , Hirakata , Japan
| | - Ali Madian
- Department of Internal Medicine, Faculty of Medicine , Al-Azhar University , Cairo , Egypt
| | - Yusuke Honzawa
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology , Graduate School of Medicine, Kyoto University , Kyoto , Japan
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