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Adams A, Gupta V, Mohsen W, Chapman TP, Subhaharan D, Kakkadasam Ramaswamy P, Kumar S, Kedia S, McGregor CG, Ambrose T, George BD, Palmer R, Brain O, Walsh A, Ahuja V, Travis SPL, Satsangi J. Early management of acute severe UC in the biologics era: development and international validation of a prognostic clinical index to predict steroid response. Gut 2023; 72:433-442. [PMID: 36171080 DOI: 10.1136/gutjnl-2022-327533] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 08/27/2022] [Indexed: 12/08/2022]
Abstract
OBJECTIVES We aimed to determine whether changes in acute severe colitis (ASC) management have translated to improved outcomes and to develop a simple model predicting steroid non-response on admission. DESIGN Outcomes of 131 adult ASC admissions (117 patients) in Oxford, UK between 2015 and 2019 were compared with data from 1992 to 1993. All patients received standard treatment with intravenous corticosteroids and endoscopic disease activity scoring (Ulcerative Colitis Endoscopic Index of Severity (UCEIS)). Steroid non-response was defined as receiving medical rescue therapy or surgery. A predictive model developed in the Oxford cohort was validated in Australia and India (Gold Coast University Hospital 2015-2020, n=110; All India Institute of Medical Sciences, New Delhi 2018-2020, n=62). RESULTS In the 2015-2019 Oxford cohort, 15% required colectomy during admission vs 29% in 1992-1993 (p=0.033), while 71 (54%) patients received medical rescue therapy (27% ciclosporin, 27% anti-tumour necrosis factor, compared with 27% ciclosporin in 1992-1993 (p=0.0015). Admission C reactive protein (CRP) (false discovery rate, p=0.00066), albumin (0.0066) and UCEIS scores (0.015) predicted steroid non-response. A four-point model was developed involving CRP of ≥100 mg/L (one point), albumin of ≤25 g/L (one point), and UCEIS score of ≥4 (1 point) or ≥7 (2 points). Patients scoring 0, 1, 2, 3 and 4 in the validation cohorts had steroid response rates of 100, 75.0%, 54.9%, 18.2% and 0%, respectively. Scoring of ≥3 was 84% (95% CI 0.70 to 0.98) predictive of steroid failure (OR 11.9, 95% CI 10.8 to 13.0). Colectomy rates in the validation cohorts were were 8%-11%. CONCLUSIONS Emergency colectomy rates for ASC have halved in 25 years to 8%-15% worldwide. Patients who will not respond to corticosteroids are readily identified on admission and may be prioritised for early intensification of therapy.
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Affiliation(s)
- Alex Adams
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Vipin Gupta
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK.,Department of Gastroenterology, North Bristol NHS Trust, Bristol, UK
| | - Waled Mohsen
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK.,Digestive Diseases Unit, Gold Coast University Hospital, Southport, Queensland, Australia
| | - Thomas P Chapman
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK.,Department of Gastroenterology, St Richard's and Worthing Hospitals, University Hospitals Sussex NHS Foundation Trust, West Sussex, UK
| | - Deloshaan Subhaharan
- Digestive Diseases Unit, Gold Coast University Hospital, Southport, Queensland, Australia
| | | | - Sudheer Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Kedia
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Tim Ambrose
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Bruce D George
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Rebecca Palmer
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Oliver Brain
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Alissa Walsh
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Vineet Ahuja
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Simon P L Travis
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Jack Satsangi
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
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Damião AOMC, Azevedo MFCD, Carlos ADS, Wada MY, Silva TVM, Feitosa FDC. Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review. World J Gastroenterol 2019; 25:1142-1157. [PMID: 30863001 PMCID: PMC6406187 DOI: 10.3748/wjg.v25.i9.1142] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/28/2019] [Accepted: 02/16/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease (MS-IBD). This study hypothesized that as a standard of treatment and the primary alternative to biologics, conventional therapy should present robust effectiveness results in IBD outcomes.
AIM To investigate the effectiveness of conventional therapy for MS-IBD.
METHODS A systematic review with no time limit was conducted in July 2017 through the Cochrane Collaboration, MEDLINE, and LILACS databases. The inclusion criteria encompassed meta-analyses, systematic reviews, randomized clinical trials, observational and case-control studies concerning conventional therapy in adult patients with MS-IBD, including Crohn’s disease (CD) and ulcerative colitis (UC). Corticosteroids (prednisone, hydrocortisone, budesonide, prednisolone, dexamethasone), 5-aminosalicylic acid (5-ASA) derivatives (mesalazine and sulfasalazine) and immunosuppressants [azathioprine (AZA), methotrexate (MTX), mycophenolate, cyclosporine, tacrolimus, 6-mercaptopurine (6-MP)] were considered conventional therapy. The exclusion criteria were sample size below 50; narrative reviews; specific subpopulations (e.g., pregnant women, comorbidities); studies on postoperative IBD; and languages other than English, Spanish, French or Portuguese. The primary outcome measures were clinical remission (induction or maintenance), clinical response and mucosal healing. As secondary outcomes, fecal calprotectin, hospitalization, death, and surgeries were analyzed. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation criteria.
RESULTS The search strategy identified 1995 citations, of which 27 were considered eligible (7 meta-analyses, 20 individual studies). For induction of clinical remission, four meta-analyses were selected (AZA and 6-MP showed no advantage over placebo, MTX or 5-ASA in CD; MTX showed no statistically significant difference versus placebo, 6-MP, or 5-ASA in UC; tacrolimus was superior to placebo for UC in two meta-analyses). Only one meta-analysis evaluated clinical remission maintenance, showing no statistically significant difference between MTX and placebo, 5-ASA, or 6-MP in UC. AZA and 6-MP had no advantage over placebo in induction of clinical response in CD. Three meta-analyses showed the superiority of tacrolimus vs placebo for induction of clinical response in UC. The clinical response rates for cyclosporine were 41.7% in randomized controlled trials (RCTs) and 55.4% in non-RCTs for UC. For induction of mucosal healing, one meta-analysis showed a favorable rate with tacrolimus versus placebo for UC. For secondary outcomes, no meta-analyses specifically evaluated fecal calprotectin, hospitalization or death. Two meta-analyses were retrieved evaluating colectomy rates for tacrolimus and cyclosporine in UC. Most of the twenty individual studies retrieved contained a low or very low quality of evidence.
CONCLUSION High-quality evidence assessing conventional therapy in MS-IBD treatment is scarce, especially for remission maintenance, mucosal healing and fecal calprotectin.
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Affiliation(s)
| | | | - Alexandre de Sousa Carlos
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo 05403-000, Brazil
| | - Marcela Yumi Wada
- Department of Medical Affairs, Takeda Pharmaceuticals, São Paulo 04709-011, Brazil
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Saniabadi AR, Tanaka T, Yamamoto T, Kruis W, Sacco R. Granulomonocytapheresis as a cell-dependent treatment option for patients with inflammatory bowel disease: Concepts and clinical features for better therapeutic outcomes. J Clin Apher 2018; 34:51-60. [PMID: 30407662 DOI: 10.1002/jca.21670] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 05/25/2018] [Accepted: 10/02/2018] [Indexed: 12/11/2022]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are major phenotypes of the chronic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms. The chronic nature of IBD means that patients require life-long medications, and this may lead to drug dependency, loss of response together with adverse side effects as additional morbidity factors. The efficacy of antitumour necrosis factor (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation and perpetuation of IBD. However, cytokines are released by myeloid lineage leucocytes like the CD14+ CD16+ monocyte phenotype. Additionally in IBD, myeloid leucocytes are elevated with activation behavior, while lymphocytes are compromised. Therefore, patients' leucocytes appear logical targets of therapy. Adsorptive granulomonocytapheresis (GMA) with an Adacolumn uses carriers, which interact with the Fcγ receptor expressing leucocytes and deplete the elevated myeloid leucocytes, while the neutrophils, which re-enter the circulation via the Adacolumn outflow (≥40%) are phagocytosed by CD19 B-cells to become interleukin (IL)-10 producing Bregs or CD19high CD1Dhigh B-cells. IL-10 is an anti-inflammatory cytokine. GMA has been applied to treat patients with IBD. The efficacy outcomes have been impressive as well as disappointing, the clinical response to GMA defines the patients' disease course and severity at entry. Efficacy outcomes in patients with deep ulcers together with extensive loss of the mucosal tissue are not encouraging, while patients without these features respond well and attain a favorable long-term disease course. Accordingly, for responder patients, GMA fulfills a desire to be treated without drugs.
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Affiliation(s)
| | - Tomotaka Tanaka
- Department of Gastroenterology, Akitsu Prefectural Hospital, Hiroshima, Japan
| | - Takayuki Yamamoto
- Inflammatory Bowel Disease Centre, Yokkaichi Hazu Medical Centre, Yokkaichi, Japan
| | - Wolfgang Kruis
- Evangelisches Krankenhaus Kalk, Cologen University, Cologne, Germany
| | - Rodolfo Sacco
- Department of Gastroenterology, Pisa University Hospital, Pisa, Italy
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Kho ZY, Lal SK. The Human Gut Microbiome - A Potential Controller of Wellness and Disease. Front Microbiol 2018; 9:1835. [PMID: 30154767 PMCID: PMC6102370 DOI: 10.3389/fmicb.2018.01835] [Citation(s) in RCA: 606] [Impact Index Per Article: 86.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 07/23/2018] [Indexed: 12/12/2022] Open
Abstract
Interest toward the human microbiome, particularly gut microbiome has flourished in recent decades owing to the rapidly advancing sequence-based screening and humanized gnotobiotic model in interrogating the dynamic operations of commensal microbiota. Although this field is still at a very preliminary stage, whereby the functional properties of the complex gut microbiome remain less understood, several promising findings have been documented and exhibit great potential toward revolutionizing disease etiology and medical treatments. In this review, the interactions between gut microbiota and the host have been focused on, to provide an overview of the role of gut microbiota and their unique metabolites in conferring host protection against invading pathogen, regulation of diverse host physiological functions including metabolism, development and homeostasis of immunity and the nervous system. We elaborate on how gut microbial imbalance (dysbiosis) may lead to dysfunction of host machineries, thereby contributing to pathogenesis and/or progression toward a broad spectrum of diseases. Some of the most notable diseases namely Clostridium difficile infection (infectious disease), inflammatory bowel disease (intestinal immune-mediated disease), celiac disease (multisystemic autoimmune disorder), obesity (metabolic disease), colorectal cancer, and autism spectrum disorder (neuropsychiatric disorder) have been discussed and delineated along with recent findings. Novel therapies derived from microbiome studies such as fecal microbiota transplantation, probiotic and prebiotics to target associated diseases have been reviewed to introduce the idea of how certain disease symptoms can be ameliorated through dysbiosis correction, thus revealing a new scientific approach toward disease treatment. Toward the end of this review, several research gaps and limitations have been described along with suggested future studies to overcome the current research lacunae. Despite the ongoing debate on whether gut microbiome plays a role in the above-mentioned diseases, we have in this review, gathered evidence showing a potentially far more complex link beyond the unidirectional cause-and-effect relationship between them.
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Affiliation(s)
- Zhi Y Kho
- School of Science, Tropical Medicine and Biology Platform, Monash University, Subang Jaya, Malaysia
| | - Sunil K Lal
- School of Science, Tropical Medicine and Biology Platform, Monash University, Subang Jaya, Malaysia
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Gisbert JP, Chaparro M. Acute severe ulcerative colitis: State of the art treatment. Best Pract Res Clin Gastroenterol 2018; 32-33:59-69. [PMID: 30060940 DOI: 10.1016/j.bpg.2018.05.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 05/03/2018] [Indexed: 01/31/2023]
Abstract
Acute severe ulcerative colitis (ASUC) is a potentially life-threatening condition. In the present review, we give a broad overview of the state of the art in the management of this condition. A systematic bibliographic search was performed in PubMed. Patient with ASUC should be hospitalized and managed by a multidisciplinary team (gastroenterologist plus surgeon). Intravenous corticosteroids remain the cornerstone of medical therapy. However, about 30% of patients do not respond. After failing 3-5 days of corticosteroids, patients should be considered for either rescue medical therapy or for colectomy. Cyclosporin and infliximab are similarly effective and safe. Cyclosporin should be mainly used as a "bridge" in thiopurine-naïve patients. More recently, infliximab has become the most widely used salvage therapy. Third-line salvage therapy with either cyclosporin or infliximab is efficacious in some patients but carries a significant risk of complications. Colectomy is appropriate in case of complications or medical rescue therapy failure.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
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Sacco R, Tanaka T, Yamamoto T, Bresci G, Saniabadi AR. Adacolumn leucocytapheresis for ulcerative colitis: clinical and endoscopic features of responders and unresponders. Expert Rev Gastroenterol Hepatol 2015; 9:327-33. [PMID: 25160857 DOI: 10.1586/17474124.2014.953060] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Cytokines such as TNF-α have a validated role in the immunopathogensis of ulcerative colitis (UC), and intercepting inflammatory cytokines is currently the best option for maximizing treatment efficacy. One of the major sources of inflammatory cytokines are myeloid linage leucocytes (granulocytes, monocytes), which are present in great numbers in the colonic tissue. Their selective depletion by adsorptive granulocyte, monocyte apheresis (GMA), should be therapeutic in patients with UC, although until now efficacy outcomes have been both encouraging and disappointing. The authors' view is that in patients with UC, there is an evolving scope for therapeutic opportunity based on taking away the sources of inflammatory cytokines, also considering the favorable safety profile of GMA.
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Affiliation(s)
- Rodolfo Sacco
- Department of Gastroenterology-Pisa University Hospital, Pisa, Italy
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Saniabadi AR, Tanaka T, Ohmori T, Sawada K, Yamamoto T, Hanai H. Treating inflammatory bowel disease by adsorptive leucocytapheresis: A desire to treat without drugs. World J Gastroenterol 2014; 20:9699-9715. [PMID: 25110409 PMCID: PMC4123360 DOI: 10.3748/wjg.v20.i29.9699] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/20/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis and Crohn’s disease are the major phenotypes of the idiopathic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms, impairing function and quality of life. Current medications are aimed at reducing the symptoms or suppressing exacerbations. However, patients require life-long medications, and this can lead to drug dependency, loss of response together with adverse side effects. Indeed, drug side effects become additional morbidity factor in many patients on long-term medications. Nonetheless, the efficacy of anti-tumour necrosis factors (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation of IBD. However, inflammatory cytokines are released by patients’ own cellular elements including myeloid lineage leucocytes, which in patients with IBD are elevated with activation behaviour and prolonged survival. Accordingly, these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn. Based on this background, recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries. Efficacy rates have been impressive as well as disappointing. In fact the clinical response to GMA seems to define the patients’ disease course, response to medications, duration of active disease, and severity at entry. The best responders have been first episode cases (up to 100%) followed by steroid naïve and patients with a short duration of active disease prior to GMA. Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA. It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD. Additionally, GMA is very much favoured by patients for its good safety profile. GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates. However, in patients with IBD, there is a scope for removing from the body the sources of pro-inflammatory cytokines and achieve disease remission. The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications, many patients should respond to GMA and avoid pharmacologics. This should fulfill the desire to treat without drugs.
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C Leitner G, Worel N, Vogelsang H. Selective Granulocyte and Monocyte Apheresis as a Non-Pharmacological Option for Patients with Inflammatory Bowel Disease. ACTA ACUST UNITED AC 2012; 39:246-252. [PMID: 22969694 DOI: 10.1159/000341801] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Accepted: 07/11/2012] [Indexed: 12/18/2022]
Abstract
Ulcerative colitis and Crohn's disease are the two most prevalent inflammatory bowel diseases. In both cases, the medically refractory and steroid-dependent type presents a therapeutic challenge. To help resolve this problem, a mainly Japanese team developed a new therapeutic option. There are two systems, both of which are able to selectively remove the main mediators of the disease, namely the activated pro-inflammatory cytokine-producing granulocytes and monocytes/macrophages, from the patient's blood circulation (GMA = granulocyte monocyte apheresis). One of the two systems is the Adacolumn( (®) ) (Immunoresearch Laboratories, Takasaki, Japan) consisting of the ADA-monitor and a single-use column, which contains approximately 35,000 cellulose acetate beads. The exact mode of action is not yet sufficiently understood, but however, a modulation of the immune system takes place. As a result, less pro-inflammatory cytokines are released. Furthermore, the production of anti-inflammatory interleukin-1 receptor antagonist is increased, and the apoptosis of granulocytes boosted. The decreased LECAM-1-expression on leukocytes impedes the leukotaxis to the inflamed tissue, and CD10-negative immature granulocytes appear in the peripheral blood. Another effect to be mentioned is the removal of the peripheral dendritic cells and the leachate of regulatory T cells (T-regs). The second system is the Cellsorba( (®) ) FX Filter (Asahi Medical, Tokyo, Japan). The range of efficiency, the indication, and the procedure are very similar to the Adacolumn. Solely the additional removal of lymphocytes can possibly limit the implementation since lymphopenia can increase the risk of autoimmune disease. Both systems provide a low-risk therapy with few adverse reactions. ASFA recommendations for GMA in inflammatory bowel disease are 2B due to the fact that not enough randomized double-blind studies are available to proof the efficacy of this treatment.
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Affiliation(s)
- Gerda C Leitner
- University Clinic for Blood Group Serology and Transfusion Medicine, Vienna, Austria
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Beddy D, Dozois EJ, Pemberton JH. Perioperative complications in inflammatory bowel disease. Inflamm Bowel Dis 2011; 17:1610-9. [PMID: 21674718 DOI: 10.1002/ibd.21504] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2010] [Accepted: 08/25/2010] [Indexed: 12/27/2022]
Abstract
Almost 50% of patients with inflammatory bowel disease (IBD) will undergo surgery for their disease at some stage of its clinical course. Complications seen following surgery may occur early or late in the postoperative period. Patient factors, including active inflammatory disease, malnutrition, and use of immunosuppressant medications, make these patients a challenging surgical group and at increased risk for surgical complications. The purpose of this review is to characterize the complications that are commonly seen following surgery in patients with IBD and to discuss the surgical and patient factors that may influence their development.
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Affiliation(s)
- David Beddy
- Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, Rochester, Minnesota, USA
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Leblanc S, Allez M, Seksik P, Flourié B, Peeters H, Dupas JL, Bouguen G, Peyrin-Biroulet L, Duclos B, Bourreille A, Dewit O, Bouhnik Y, Michetti P, Chaussade S, Saussure P, Mary JY, Colombel JF, Lémann M. Successive treatment with cyclosporine and infliximab in steroid-refractory ulcerative colitis. Am J Gastroenterol 2011; 106:771-7. [PMID: 21386832 DOI: 10.1038/ajg.2011.62] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Rescue therapy with either cyclosporine (CYS) or infliximab (IFX) is an effective option in patients with intravenous steroid-refractory attacks of ulcerative colitis (UC). In patients who fail, colectomy is usually recommended, but a second-line rescue therapy with IFX or CYS is an alternative. The aims of this study were to investigate the efficacy and tolerance of IFX and CYS as a second-line rescue therapy in steroid-refractory UC or indeterminate colitis (IC) unsuccessfully treated with CYS or IFX. METHODS This was a retrospective survey of patients seen during the period 2000-2008 in the GETAID centers. Inclusion criteria included a delay of <1 month between CYS withdrawal (when used first) and IFX, or a delay of <2 months between IFX (when used first) and CYS, and a follow-up of at least 3 months after inclusion. Time-to-colectomy, clinical response, and occurrence of serious adverse events were analyzed. RESULTS A total of 86 patients (median age 34 years; 49 males; 71 UC and 15 IC) were successively treated with CYS and IFX. The median (± s.e.) follow-up time was 22.6 (7.0) months. During the study period, 49 patients failed to respond to the second-line rescue therapy and underwent a colectomy. The probability of colectomy-free survival (± s.e.) was 61.3 ± 5.3% at 3 months and 41.3 ± 5.6 % at 12 months. A case of fatal pulmonary embolism occurred at 1 day after surgery in a 45-year-old man. Also, nine infectious complications were observed during the second-line rescue therapy. CONCLUSIONS In patients with intravenous steroid-refractory UC and who fail to respond to CYS or IFX, a second-line rescue therapy may be effective in carefully selected patients, avoiding colectomy within 2 months in two-thirds of them. The risk/benefit ratio should still be considered individually.
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Affiliation(s)
- S Leblanc
- Hôpital Saint-Louis, Université Paris-Diderot, Assistance Publique-Hôpitaux de Paris, Paris, France
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Walch A, Meshkat M, Vogelsang H, Novacek G, Dejaco C, Angelberger S, Mikulits A, Miehsler W, Gangl A, Reinisch W. Long-term outcome in patients with ulcerative colitis treated with intravenous cyclosporine A is determined by previous exposure to thiopurines. J Crohns Colitis 2010; 4:398-404. [PMID: 21122535 DOI: 10.1016/j.crohns.2010.01.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2009] [Revised: 01/02/2010] [Accepted: 01/02/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Rescue therapy with intravenous cyclosporine A (CsA) helps to avoid colectomy in a substantial proportion of patients with severe ulcerative colitis (UC) but the impact on long-term outcome remains unclear. Therefore, we aimed to define predictive factors for colectomy in patients treated with intravenous CsA for severely active UC. METHODS A retrospective, single-center study with a minimum follow-up of 18 months was performed. RESULTS A total of 64 patients were evaluable (median age 33 years [range 17-80 years], female 54.7%). Median intravenous CsA dose was 4 mg/kg/day (range 2-5mg/kg/day). After a median follow-up of 65 months (range 2-160 months), 19 patients (29.7%) underwent colectomy, 15 within 18 months. Of the various baseline parameters tested, only previous non-response to thiopurine treatment (p=0.006) was associated with an increased risk of colectomy. During 18 months follow-up, thiopurine-naïve patients receiving thiopurine maintenance therapy after intravenous CsA (32/64, 50.0%) underwent colectomy in 12.5% of cases. The colectomy rate was 27.3% among 22 patients previously non-responsive to thiopurines who continued treatment after intravenous CsA, compared to 50.0% in the 10 patients who discontinued thiopurines prior to intravenous CsA or who never received thiopurines (p=0.037). CONCLUSIONS The long-term colectomy rate after intravenous CsA in patients with severely active UC was relatively low in our series compared to the literature. Concomitant treatment with thiopurines was the only predictor for a reduced risk of colectomy.
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Affiliation(s)
- Andrea Walch
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University Vienna, Vienna, Austria
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Abstract
BACKGROUND Management of acute severe ulcerative colitis (UC) is a clinical challenge, with a mortality rate of approximately 1-2%. The traditional management with intravenous corticosteroids has been modified by introduction of ciclosporin and more recently, infliximab. AIM To provide a detailed and comprehensive review of the medical management of acute severe UC. METHODS PubMed and recent conference abstracts were searched for articles relating to treatment of acute severe UC. RESULTS Two-thirds of patients respond to intravenous steroids in the short term. In those who fail steroids, low-dose intravenous ciclosporin at 2 mg/kg/day is effective. Approximately 75% and 50% of patients treated with ciclosporin avoid colectomy in the short and long-terms, respectively. Long-term outcome of ciclosporin therapy is improved by introduction of azathioprine on discharge from hospital, together with oral ciclosporin as a bridging therapy. Controlled data show that infliximab is effective as rescue therapy for acute severe UC and the effect appears to be durable, although longer-term follow-up data are needed. CONCLUSIONS Both ciclosporin and infliximab have demonstrated efficacy as rescue medical therapies in patients with acute severe UC, but surgery needs to be considered if there is failure to improve or clinical deterioration.
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Stewart D, Chao A, Kodner I, Birnbaum E, Fleshman J, Dietz D. Subtotal colectomy for toxic and fulminant colitis in the era of immunosuppressive therapy. Colorectal Dis 2009; 11:184-90. [PMID: 18477020 DOI: 10.1111/j.1463-1318.2008.01579.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Prolonged use of immunosuppressive medication to avoid surgery is becoming more common in patients with inflammatory bowel disease, with severe or fulminant colitis. The effect of immunosuppression on postoperative outcomes was reviewed. METHOD Patients undergoing subtotal colectomy (STC) for fulminant or toxic colitis from 1992 to 2006 were studied to define the effect of immunosuppression (IS) on postoperative complications (POCs). Patient characteristics, diagnosis, operative indication, details of surgery, use of IS, and POC's were reviewed and univariate and multivariate analysis was performed. RESULTS Eighty-nine patients were studied (55 males). Seventy-two (91%) patients had fulminant colitis and 17 (20%) had toxic colitis. The preoperative diagnosis was ulcerative colitis in 74, indeterminate in 10, and Crohn's disease in five patients. Eighty-two (92%) patients were on some form of immunosuppression, and 14 had a perforation at surgery. Thirty-nine (43.8%) patients experienced a POC. There was no operative mortality. Univariate analysis identified perforation (P = 0.048) and length of surgery (P = 0.002) as predictive of POCs, while multivariate analysis failed to identify a predictor of complications. CONCLUSION There was no association between immunosuppression and postoperative complications. Complications in this setting are a result of the severity of the inflammatory bowel disease.
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Affiliation(s)
- D Stewart
- Department of Surgery, Section of Colon and Rectal Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA
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Yamamoto S, Nakase H, Mikami S, Inoue S, Yoshino T, Takeda Y, Kasahara K, Ueno S, Uza N, Kitamura H, Tamaki H, Matsuura M, Inui K, Chiba T. Long-term effect of tacrolimus therapy in patients with refractory ulcerative colitis. Aliment Pharmacol Ther 2008; 28:589-97. [PMID: 18549460 DOI: 10.1111/j.1365-2036.2008.03764.x] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Little is known about long-term outcome of tacrolimus therapy for ulcerative colitis. Aim To evaluate long-term efficacy and safety of tacrolimus in Japanese patients with refractory ulcerative colitis. METHODS Twenty-seven patients with UC refractory to conventional therapy were administered tacrolimus with trough whole-blood levels of 10-15 ng/mL to induce remission and 5-10 ng/mL to maintain remission. Median treatment duration was 11 months (1-39 months) and median follow-up duration was 17 months (2-65 months). Evaluation of the clinical response was based on a modified Truelove-Witts severity index (MTWSI). RESULTS Tacrolimus produced a clinical response in 21 patients (77.8%), and remission was achieved in 19 of these 21 (70.4%) within 30 days. Overall cumulative colectomy-free survival was estimated as 62.3% at 65 months. In 18 of 19 patients treated with corticosteroids at the initiation of tacrolimus therapy, corticosteroids were discontinued or tapered. Adverse events were tremor (25.9%), renal function impairment (18.5%), infectious disease (14.8%), hot flashes (11.1%), hyperkalaemia (7.4%), headache (7.4%), epigastralgia (7.4%) and nausea (3.7%). No mortality occurred. CONCLUSION Long-term administration of tacrolimus appears to be an effective and well-tolerated treatment for Japanese patients with refractory ulcerative colitis.
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Affiliation(s)
- S Yamamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto, Japan
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15
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Abstract
(Table is included in full-text article.)The development of biologicals such as infliximab to intercept TNF-alpha validates the current perception that certain cytokines are major factors in the immunopathogenesis of inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease. Furthermore, major sources of inflammatory cytokines include activated peripheral granulocytes and monocytes (GM), which in patients with IBD are elevated with increased survival time and are found in vast numbers within the inflamed intestinal mucosa. Hence, elevated GM should be appropriate targets of therapy in IBD. Accordingly, in recent years technologies such as the Adacolumn have been developed for selective depletion of elevated GM by extracorporeal adsorption (GMA). Published data show that GMA in patients with steroid-dependent or steroid-refractory IBD is associated with striking efficacy and tapering or discontinuation of steroids, whereas in steroid-naïve patients GMA spared patients from steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse significantly suppressed relapse, thus sparing the patients from the morbidity associated with active IBD. First ulcerative colitis episode, steroid naivety and short disease duration seem to be good predictors of response to GMA and on the basis of our experience, GMA seems to have an excellent safety profile.
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16
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Aceituno M, García-Planella E, Heredia C, Zabana Y, Feu F, Domènech E, Gassull MA, Panés J. Steroid-refractory ulcerative colitis: predictive factors of response to cyclosporine and validation in an independent cohort. Inflamm Bowel Dis 2008; 14:347-52. [PMID: 18050296 DOI: 10.1002/ibd.20322] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND One-third of patients with steroid-refractory ulcerative colitis (UC) do not respond to cyclosporine and require colectomy. Since alternative pharmacological treatments for this condition are available, it is pertinent to identify factors that predict response. The objective of this study was to determine predictive factors of response prior to cyclosporine administration, with validation in an independent cohort. METHODS The 2 cohorts of patients were identified from prospectively established databases. All patients had received 1 mg/kg/day prednisolone or equivalent for at least 5 days before cyclosporine. The efficacy measure was need of early surgery (within 3 months). RESULTS From 1998 to 2005, 34 patients were treated in 1 institution (derivation cohort) and 38 patients in the second institution (validation cohort). Eleven patients in the derivation cohort and 9 patients in the validation cohort underwent early colectomy. Univariate analysis in the derivation cohort demonstrated a significant association of colectomy with C-reactive protein (P = 0.012) and the Ho index before initiation of cyclosporine (P = 0.013). Regression analysis showed that only the Ho index (P = 0.011) had an independent predictive value. The Ho index predicted need of colectomy, with an area under the characteristic receiver operating curve of 0.79 (95% confidence interval [CI], 0.59-0.99) in the derivation cohort and 0.74 (95% CI, 0.53-0.96) in the validation cohort. The cutoff point with the best sensitivity and specificity ratio was > or =5. CONCLUSIONS The Ho-based predictive score is a good predictor of response to cyclosporine and avoidance of colectomy, and may aid in the indication of this treatment for management of steroid-resistant UC.
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Affiliation(s)
- Montserrat Aceituno
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBER-EHD, Barcelona, Spain
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17
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Baudet A, Rahmi G, Bretagne AL, Gloro R, Justum AM, Reimund JM. Severe ulcerative colitis: present medical treatment strategies. Expert Opin Pharmacother 2008; 9:447-57. [PMID: 18220494 DOI: 10.1517/14656566.9.3.447] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A total of 15-19% of ulcerative colitis patients have a severe attack at some time during their illness. As a consequence of its high associated mortality and morbidity rates, a close collaboration between gastroenterologists and surgeons in their management is mandatory, in order to define, as best as possible, the timing of surgery (i.e., colectomy) when patients fail to respond to medical treatment or worsen despite optimal medical treatment. The first step in medical treatment consists of using intravenous corticosteroids as they have been demonstrated to reduce drastically the mortality rates. However, at 1 year approximately 25% of patients become corticosteroid dependent and 30% require colectomy, which can consistently affect their quality of life. Therefore, intravenous ciclosporin has been proposed as a rescue therapy, with a further improvement of short-term efficacy and reduction of surgery requirement. Nevertheless, its use is associated with a risk of toxicity and intravenous ciclosporin is not easy to use in non-specialised centres. In addition, long-term studies suggest that colectomy is often only delayed and relapse frequent. Consequently, some authors evaluate the potential use of infliximab. Available data are encouraging, reporting a significant short-term reduction in colectomy rate. Nevertheless, additional trials are required to better define the more effective and safe treatment option(s), for both the short- and long-term, in this patient setting; a question addressed in ongoing trials.
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Affiliation(s)
- Agnès Baudet
- Service d'Hépato-Gastro-Entérologie et Nutrition, Centre Hospitalier Universitaire de Caen, Hôpital Côte de Nacre, Avenue Côte de Nacre, 14033 Caen Cedex, France
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18
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Kozuch PL, Hanauer SB. Treatment of inflammatory bowel disease: a review of medical therapy. World J Gastroenterol 2008; 14:354-77. [PMID: 18200659 PMCID: PMC2679125 DOI: 10.3748/wjg.14.354] [Citation(s) in RCA: 166] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2007] [Revised: 07/04/2007] [Indexed: 02/06/2023] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor (TNF) alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non-systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine (6-MP) and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn's disease, and infliximab is also approved for the treatment of UC.
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19
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Carbonnel F. Prise en charge d’une rectocolite hémorragique sévère ou corticorésistante. ACTA ACUST UNITED AC 2007; 31:398-403. [PMID: 17483777 DOI: 10.1016/s0399-8320(07)89399-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Franck Carbonnel
- Service de Gastroentérologie et Nutrition, CHU Jean Minjoz, Besançon, France.
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20
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Abstract
Ulcerative colitis (UC) and Crohn’s disease (CD) are the major forms of idiopathic inflammatory bowel disease (IBD). Both UC and CD are debilitating chronic disorders that afflict millions of individuals throughout the world with symptoms which impair function and quality of life. The etiology of IBD is inadequately understood and therefore, drug therapy has been empirical instead of being based on sound understanding of IBD pathogenesis. This is a major factor for poor drug efficacy and drug related side effects that often add to the disease complexity. The development of biologicals notably infliximab to intercept tumor necrosis factor (TNF)-α reflects some progress, albeit major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD seems to be perpetuated by inflammatory cytokines like TNF-α, interleukin (IL)-1β, IL-6 and IL-8 for which activated peripheral granulocytes and monocytes/macrophages (GM) are major sources. Further, in IBD, peripheral GMs are elevated with activation behavior, increased survival time and are found in vast numbers within the inflamed intestinal mucosa; they are suspected to be major factors in the immunopathogenesis of IBD. Hence, peripheral blood GMs should be appropriate targets of therapy. The Adacolumn is a medical device developed for selective depletion of GM by receptor-mediated adsorption (GMA). Clinical data show GMA, in patients with steroid dependent or steroid refractory UC, is associated with up to 85% efficacy and tapering or discontinuation of steroids, while in steroid naïve patients (the best responders), GMA spares patients from exposure to steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse suppresses relapse thus sparing the patients from the morbidity associated with IBD relapse. Further, GMA appears to reduce the number of patients being submitted to colectomy or exposure to unsafe immunosupressants. First UC episode, steroid naivety and short disease duration appear good predictors of response to GMA and based on the available data, GMA seems to have an excellent safety profile.
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Affiliation(s)
- Hiroyuki Hanai
- Center for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, 26 Shirowacho, Hamamatsu 4300846, Japan
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21
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Weber A, Fein F, Koch S, Dupont-Gossart AC, Mantion G, Heyd B, Carbonnel F. Treatment of ulcerative colitis refractory to steroid therapy by oral microemulsion cyclosporine (Neoral). Inflamm Bowel Dis 2006; 12:1131-5. [PMID: 17119387 DOI: 10.1097/01.mib.0000235096.78736.8e] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Intravenous cyclosporine is active in 60% to 80% of patients with ulcerative colitis (UC) who failed to respond to intravenous corticosteroids. Several studies have suggested that cyclosporine in microemulsion form (Neoral) has some efficacy in this setting, but the optimal dose, blood level, time to response, and remission need to be better defined. The aim of this study was to evaluate the response to Neoral and its toxicity in active corticosteroid-refractory UC. METHODS Between March 2002 and August 2005, 20 courses of Neoral [initial dose, 2.3 mg/kg (range, 1.8 to 2.8 mg/kg) every 12 hours] were prescribed in 19 consecutive patients for a UC attack that did not respond to intravenous methylprednisolone. All patients received prophylaxis against Pneumocystis carinii. RESULTS Response was obtained in 17 of 20 attacks (85%) after 3.5 days (range, 1 to 7). Remission was obtained in 15 of 20 attacks (75%) after 13 days (range, 2 to 30 days). Four responders relapsed and underwent colectomy 21 to 900 days after the start of Neoral. Overall, 14 of 19 patients (74%) were colectomy free after a median follow-up of 8 months (range, 1 to 41 months). Cyclosporine blood levels were measured at fasting (C0) and 2 hours after Neoral administration (C2) in a subgroup of 10 responders. The results were 103 ng/mL (range, 32 to 240 ng/mL) for C0 and 761 ng/mL (183 to 1390 ng/mL) for C2. One severe bedridden patient with neonatal encephalopathy died. Main side effects observed were mild transient renal impairment (n = 2), hypertension (n = 1), cytomegalovirus infection (n = 2), and esophageal candidiasis (n = 1). CONCLUSIONS In active corticosteroid-refractory UC, Neoral seems to have the same efficacy and toxicity as the intravenous form. Trough target cyclosporine blood levels should not exceed 100 ng/mL for C0 and 700 ng/mL for C2.
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Affiliation(s)
- Audrey Weber
- Service de Gastroentérologie et Nutrition, Hôpital Universitaire, F-25000 Besançon, France
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22
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Castro M, Papadatou B, Ceriati E, Knafelz D, De Angelis P, Ferretti F, Gambarara M, Diamanti A, De Peppo F, Rivosecchi M. Role of cyclosporin in preventing or delaying colectomy in children with severe ulcerative colitis. Langenbecks Arch Surg 2006; 392:161-4. [PMID: 16909296 DOI: 10.1007/s00423-006-0068-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2006] [Accepted: 04/28/2006] [Indexed: 12/25/2022]
Abstract
BACKGROUND Oral cyclosporin (CyA) has been widely and successfully used in adult patients with severe ulcerative colitis (UC) to delay or avoid colectomy. AIM To determine if treatment with oral CyA is similarly effective in pediatric patients MATERIALS AND METHODS Data on all patients with severe UC treated with oral CyA in our unit were collected retrospectively. Patients were treated with CyA if dependent on or resistant to steroids, and therefore, candidates for colectomy. RESULTS Thirty-two patients with severe UC were treated with CyA administered orally at a dose needed to obtain therapeutic blood levels (150-250 ng/ml). Twenty-eight of 32 patients (87%) had an immediate response within 11 days. Four (13%) did not respond and underwent colectomy. One patient had two cycles of treatment and is in remission. Two patients underwent three cycles of treatment because of relapse, but both eventually underwent elective colectomy. Three other patients underwent elective colectomy. A total of nine colectomies were performed. CONCLUSIONS Treatment with oral CyA altered the course of UC in 28/32 (87%) of patients; 4/32 (13%) did not respond to oral CyA and underwent colectomy. Of the 28 patients that responded to CyA, five underwent later elective colectomy. Overall, in 72% of patients, colectomy was avoided. We, therefore, suggest a trial of oral CyA in all children with severe UC who are dependent or resistant to corticosteroids.
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Affiliation(s)
- M Castro
- Gastroenterology Unit, Ospedale Bambino Gesù, Rome, Italy
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23
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Abstract
To evaluate the efficacy of infliximab in hospitalized ulcerative colitis (UC) patients refractory to intravenous corticosteroids. Treatment options for steroid-refractory UC patients are limited and include cyclosporine and colectomy. Although two recent studies (ACT I/II) demonstrate a benefit from infliximab in outpatients with moderate to severely active UC, the utility of infliximab in severe i.v. steroid-refractory UC is less clear. We report our open-label experience with infliximab in hospitalized UC patients at the University of Pittsburgh Medical Center. All hospitalized UC patients who had received infliximab were identified. Age, sex, extent of UC, duration of disease, concomitant medication, hospital course, and response to infliximab were recorded. Response to infliximab was defined as avoidance of colectomy and cessation of corticosteroids. There were 12 UC inpatients refractory to intravenous corticosteroids and subsequently treated with infliximab. Nine of the 12 patients (75%) failed to respond to infliximab and required a colectomy; median time to colectomy was 3 months. Three patients (25%) did respond to infliximab and were able to withdraw from corticosteroids. In this open-label analysis, infliximab was not effective for the majority of UC patients refractory to intravenous corticosteroids. Whether earlier use of infliximab would prevent the need for hospitalization and colectomy is uncertain.
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Affiliation(s)
- Miguel Regueiro
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
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24
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Creed TJ, Probert CSJ, Norman MN, Moorghen M, Shepherd NA, Hearing SD, Dayan CM. Basiliximab for the treatment of steroid-resistant ulcerative colitis: further experience in moderate and severe disease. Aliment Pharmacol Ther 2006; 23:1435-42. [PMID: 16669958 DOI: 10.1111/j.1365-2036.2006.02904.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Preliminary data have suggested that interleukin-2 receptor blockade with basiliximab may increase steroid sensitivity. We have previously reported a small case series demonstrating the potential of basiliximab as a novel agent for the treatment of steroid-resistant ulcerative colitis. AIM To report further experience of the efficacy and safety of treatment with the interleukin-2 receptor blocking monoclonal antibody basiliximab, in addition to steroids, for the treatment of severe and moderate steroid-resistant ulcerative colitis. METHODS Twenty patients were enrolled - 13 patients with moderate steroid-resistant ulcerative colitis (Ulcerative Colitis Symptom Score: >or=6) and seven patients with severe steroid-resistant ulcerative colitis. All were given a single dose of 40 mg basiliximab plus standard steroid therapy in an open-label, uncontrolled trial. Primary end point was clinical remission within 8 weeks (Ulcerative Colitis Symptom Score: <or=2). RESULTS Within 8 weeks, 10 of 20 (50%) patients achieved clinical remission (seven of 13 moderate, and three of seven severe). At 24 weeks, 13 of 20 (65%) patients were in clinical remission. Five patients required colectomy (four severe, one moderate ulcerative colitis) and one required rescue ciclosporin (moderate ulcerative colitis). Two patients developed herpes zoster, but treatment was generally well tolerated. CONCLUSIONS Basiliximab appears to promote prolonged remission after a single treatment. Taken in combination with previously reported data, basiliximab shows particular promise in moderate steroid-resistant ulcerative colitis.
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Affiliation(s)
- T J Creed
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, Bristol, UK.
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García-López S, Gomollón-García F, Pérez-Gisbert J. Cyclosporine in the treatment of severe attack of ulcerative colitis: a systematic review. GASTROENTEROLOGIA Y HEPATOLOGIA 2006; 28:607-14. [PMID: 16373009 DOI: 10.1016/s0210-5705(05)71523-5] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Intravenous steroid therapy is the standard treatment in severe attacks of ulcerative colitis (UC), but 20% to 60% of patients fail to respond and require colectomy. Cyclosporine (CyA) has shown efficacy in steroid failures and could avoid surgery, but controversy remains. AIM The objective of this study was to conduct a systematic review to evaluate the effectiveness and safety of CyA in inducing remission in patients with a severe attack of UC. METHODS We did a systematic review using Cochrane methodology, including data from published (in English, French, Spanish or German) clinical trials done in adults using intravenous or oral CyA in UC. Data on efficacy are obtained from controlled and observational clinical trials, and for safety issues case reports are also considered. RESULTS 31 studies were identified which met the inclusion criteria, 22 (18 uncontrolled, 4 controlled) with intravenous CyA, and 9 (all uncontrolled) using oral CyA. Only 4 controlled trials (one in abstract form) are available, and only one compares CyA to placebo. However, efficacy results are very consistent in these 4 trials, and very similar to those in observational studies. CyA achieves remission in 91,4% and 71.4% of patients in controlled and uncontrolled studies using intravenous route, and in 71,2% using oral route. Two mg/kg/day seems so efficacious and safer as previous standard 4 mg/kg/day dose. Minor side effects are rather common but do not seriously limit therapy. Severe side effects, specially infections, are uncommon but clinically relevant with several deaths reported. CONCLUSION CyA (intravenous, 2 mg/kg/day) constitutes an efficacious and relatively safe alternative in the treatment of severe, steroid-refractory, attack of UC. To optimize treatment, the correct selection of patients, a standardized protocol and clinical surveillance are recommended.
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Affiliation(s)
- S García-López
- Servicio de Aparato Digestivo, Hospital Universitario Miguel Servet, Zaragoza, Spain.
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Kanai T, Hibi T, Watanabe M. The logics of leukocytapheresis as a natural biological therapy for inflammatory bowel disease. Expert Opin Biol Ther 2006; 6:453-66. [PMID: 16610976 DOI: 10.1517/14712598.6.5.453] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are debilitating idiopathic inflammatory bowel diseases (IBDs) with symptoms that impair ability to function and quality of life. The aetiology of IBD is inadequately understood and, therefore, drug therapy has been empirical instead of based on sound understanding of the disease mechanisms. This has been a major factor for poor drug efficacy and treatment-related side effects that often add to disease complications. The development of biologicals, notably infliximab, to block TNF-alpha reflects some progress, but there is major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD by its very nature is exacerbated and perpetuated by inflammatory cytokines, including TNF-alpha, IL-6 and IL-12, for which activated peripheral blood lymphocytes, monocytes/macrophages and granulocytes are major sources. Hence, activated leukocytes should be appropriate targets of therapy. At present, three strategies are available for removing excess and activated leukocytes by leukocytapheresis: centrifugation, Adacolumn and Cellsorba. Centrifugation can deplete lymphocytes or total leukocytes, whereas Adacolumn selectively adsorbs granulocytes and monocytes together with a smaller fraction of lymphocytes (FcgammaR- and complement receptor-bearing leukocytes), and Cellsorba non-selectively removes all three major leukocyte populations. Efficacy has ranged from 'none' to an impressive 93% together with excellent safety profiles and downmodulation of inflammation factors. Furthermore, leukocytapheresis has shown strong drug-sparing effects and reduced the number of patients requiring colectomy or exposure to unsafe immunosuppressants, such as cyclosporin A. Leukocytapheresis removes from the body cells that contribute to IBD and, therefore, unlike drugs, it is not expected to induce dependency or refractoriness.
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Affiliation(s)
- Takanori Kanai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
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27
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Abstract
OBJECTIVE To evaluate evidence for the use of cyclosporine in treating patients with severe ulcerative colitis. DATA SOURCES A literature search was performed using MEDLINE, EMBASE, Cochrane Database, and ISI Web of Knowledge (1966-November 2005) with the search terms cyclosporine, cyclosporin A, CsA, ulcerative colitis, UC, inflammatory bowel disease, IBD, steroid-refractory, and immunosuppression. Additional papers were located by hand-searching relevant references. Only human studies in adults and literature published in English were included. DATA SYNTHESIS Intravenous cyclosporine has been evaluated for the treatment of severe ulcerative colitis in 4 randomized, controlled trials, as well as in many open-label and retrospective studies. Studies that evaluated cyclosporine for severe ulcerative colitis were reviewed. All 4 controlled trials showed an initial positive clinical response as defined by the Crohn's Activity Index when intravenous cyclosporine 4 mg/kg/day was administered as monotherapy or combined with intravenous corticosteroids. One of the 4 trials indicated that high-dose cyclosporine (4 mg/kg/day) has no additional clinical benefit over the low-dose (2 mg/kg/day) and that the lower dose may improve safety related to dose-dependent adverse effects. CONCLUSIONS There is evidence to support the use of intravenous cyclosporine for patients with severe ulcerative colitis who are refractory to corticosteroid therapy. Because most of the adverse effects associated with cyclosporine are dose dependent, therapy should be initiated with the lower 2 mg/kg/day dose. Subsequent doses should be adjusted based on cyclosporine blood concentrations of 150-250 ng/mL. Cyclosporine should be used only to induce remission and serve as a "bridge" to azathioprine or 6-mercaptopurine maintenance therapy. At this time, there are insufficient data to support the long-term use of cyclosporine monotherapy for avoidance of surgery or maintenance of remission.
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Affiliation(s)
- Co Q D Pham
- University of Michigan College of Pharmacy, Ann Arbor, MI 48109-1065, USA
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28
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Abstract
Although colectomy for ulcerative colitis is curative, long-term quality of life is reduced. Intravenous ciclosporin 4 mg/kg/day has significant toxicity. There is now evidence that low-dose ciclosporin (2 mg/kg daily by intravenous infusion, or 5-6 mg/kg daily in a twice daily oral dosage) has an acceptable safety profile, even when used in combination with corticosteroids. Drug dosage should be adjusted to the levels of 150-250 ng/mL initially (random levels during intravenous infusion, or trough levels for oral use). Ciclosporin should be considered not only in those who have failed 7 days of corticosteroids, but also in fulminant colitis at day 3, if not responding to corticosteroids. The drug should be avoided in frail or elderly patients with significant comorbidity, and also where colectomy is likely to be necessary in the short to medium term. Ciclosporin should not be continued for more than 7 days, unless there is a definite response. A 70-80% initial response is likely, and responders are discharged on oral ciclosporin, adding thiopurines and tailing prednisolone rapidly. The drug should be continued for 3 months. The likelihood of avoiding colectomy over 2-3 years is 40-50%. More studies are needed to evaluate the use of oral ciclosporin in corticosteroid-refractory colitis in out-patients, and to assess whether monotherapy (without corticosteroids) is significantly safer, without loss of efficacy.
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Affiliation(s)
- D Durai
- Department of Medicine, University Hospital of Wales, Heath Park, Cardiff, UK
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Kugathasan S, Dubinsky MC, Keljo D, Moyer MS, Rufo PA, Wyllie R, Zachos M, Hyams J. Severe colitis in children. J Pediatr Gastroenterol Nutr 2005; 41:375-85. [PMID: 16205502 DOI: 10.1097/01.mpg.0000186272.65559.ce] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Subra Kugathasan
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
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de Saussure P, Soravia C, Morel P, Hadengue A. Low-dose oral microemulsion ciclosporin for severe, refractory ulcerative colitis. Aliment Pharmacol Ther 2005; 22:203-8. [PMID: 16091057 DOI: 10.1111/j.1365-2036.2005.02552.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND The optimal modalities of treatment with oral microemulsion ciclosporin in patients with severe, steroid-refractory ulcerative colitis are uncertain. AIM To assess the applicability, in terms of efficacy and tolerability, of a standard oral microemulsion ciclosporin treatment protocol targeting relatively low blood ciclosporin concentrations, in patients with severe, steroid-resistant ulcerative colitis. PATIENTS AND METHODS Patients with a severe attack of ulcerative colitis and no satisfactory response to intravenous corticosteroids were started on oral microemulsion ciclosporin. Dosages were adapted according to a standard protocol, targeting a blood predose ciclosporin concentration (C0) of 100-200 ng/mL. Patients without a clinical response on day 8 were scheduled for colectomy. RESULTS Sixteen patients were enrolled. A clinical response was observed in 14/16 (88%). The mean clinical activity index scores and concentrations of C-reactive protein on days 0, 4 and 8 were 11.8, 6.7 and 4.1, and 50.3, 19.3 and 9.7 mg/L respectively. The mean C0 (days 0-8) was 149 pg/mL. The mean creatinine clearance rates on days 0 and 8 were 88 and 96 mL/min. One patient had an acute elevation of transaminases that resulted in discontinuing ciclosporin. CONCLUSIONS Even when dosed for a target C0 of 100-200 ng/mL, oral microemulsion ciclosporin for severe, steroid-refractory ulcerative colitis achieves an efficacy similar to that attained with higher, potentially more toxic levels. The oral route should replace intravenous treatment in this clinical setting.
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Affiliation(s)
- P de Saussure
- Department of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland.
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Message L, Bourreille A, Laharie D, Quinton A, Galmiche JP, Lamouliatte H, Alamdari A, Zerbib F. Efficacy of intravenous cyclosporin in moderately severe ulcerative colitis refractory to steroids. ACTA ACUST UNITED AC 2005; 29:231-5. [PMID: 15864171 DOI: 10.1016/s0399-8320(05)80754-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVE The efficacy of intravenous cyclosporin (CSA) in acute severe ulcerative colitis (UC) is well established. The aim of this study was to evaluate its efficacy in moderately severe colitis refractory to steroids. METHODS Twenty-six patients (17 men, mean age 41 +/- 14 yr) with UC refractory to steroids treated with CSA were included in this study. Severity was defined according to Truelove criteria. A clinical activity score below 10 during 2 consecutive days defined clinical response. RESULTS According to Truelove criteria, all patients had moderate UC. CSA was administered IV at a mean daily dose of 3.7 +/- 0,5 mg/kg until response and then orally for 3.5 +/- 2.6 months. A clinical response was achieved in 20/26 patients (76,9%) within 5.7 +/- 2.8 days (5/6 failures were treated by proctocolectomy). During a follow-up of 27.8 +/- 20.8 months, relapse rate was 60% (12/20): 7 patients underwent proctocolectomy and 5 had clinical remission with CSA retreatment (N=4) and steroids (N=1). At the end of follow-up, 12 patients (46%) were in clinical remission, 12 (46%) required colectomy, 1 had chronic active UC and 1 was lost of follow-up. The probability to avoid surgery was 52% at 78 months. The only factor associated with avoidance of surgery was concomitant treatment with azathioprine (P=0.007). Ten reversible adverse events occurred in 9 patients. CONCLUSION This study shows that CSA is safe and effective in moderately severe steroid resistant UC. Concomitant treatment with azathioprine significantly decreases the rate of subsequent surgery. CSA may act as a "bridge" until the therapeutic action of azathioprine is achieved for maintenance treatment. These results should be further confirmed by a prospective controlled study.
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Affiliation(s)
- Laurent Message
- Service d'Hépato-gastroentérologie, Hôpital Saint-André, Bordeaux
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Seksik P, Contou JF, Ducrotté P, Faucheron JL, de Parades V. [The treatment of distal ulcerative colitis]. ACTA ACUST UNITED AC 2005; 28:964-73. [PMID: 15672568 DOI: 10.1016/s0399-8320(04)95174-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Philippe Seksik
- Service d'hépato-gastroentérologie, Hôpital Européen Georges Pompidou, 75015 Paris
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Shibolet O, Regushevskaya E, Brezis M, Soares-Weiser K. Cyclosporine A for induction of remission in severe ulcerative colitis. Cochrane Database Syst Rev 2005:CD004277. [PMID: 15674937 DOI: 10.1002/14651858.cd004277.pub2] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) is characterized by a life-long chronic course with remissions and exacerbations. Approximately 15% of patients have a severe attack requiring hospitalization at some time during their illness. These patients are traditionally treated with intravenous corticosteroids, with a response rate of approximately 60%. The patients who do not respond to steroid treatment usually require surgical removal of the large bowel (proctocolectomy or colectomy with an anal pouch). This surgical procedure essentially cures the patient from the disease but is associated with complications such as pouchitis. Few alternative treatments exist for severe ulcerative colitis: immunosuppressive medications (such as azathioprine) have a slow onset of action and are therefore usually ineffective. Antibiotics are not proven to be effective and biological treatments such as infliximab are still under investigation. The introduction of cyclosporine-A (CsA) for use in patients with severe ulcerative colitis (UC) has provided an alternative to patients previously facing only surgical options. Cyclosporine acts mainly by inhibiting T lymphocyte function, which is essential for the propagation of inflammation. Unlike most other immunosuppressive agents, CsA does not suppress the activity of other hematopoietic cells, does not cause bone marrow suppression and has a rapid onset of action. This reviews aims to systematically assess the effectiveness and safety of CsA for severe UC. OBJECTIVES This review aimed to evaluate the effectiveness of cyclosporine A for patients with severe ulcerative colitis. SEARCH STRATEGY Electronic searches of The Cochrane Library (Issue 1, 2004), EMBASE (1980-2004), and MEDLINE (1966-2004); hand searching the references of all identified studies; contacting the first author of each included trial. SELECTION CRITERIA Randomised clinical trials comparing cyclosporine A with placebo or no intervention to obtain and maintain remission of idiopathic ulcerative colitis. DATA COLLECTION AND ANALYSIS Two reviewers independently appraised the quality of each trial and extracted the data from the included trials. Relative risks (RR) with 95% confidence intervals (CI) were estimated. The reviewers assumed an intention to treat analysis for the outcome measures. MAIN RESULTS Only two randomized controlled trials were identified that satisfied the inclusion criteria. These two trials could not be pooled for analysis because of major differences in design and patient populations. In the first trial, 11 patients received intravenous cyclosporine (4 mg/kg) and 9 received placebo. Two of 11 in the treatment group failed to respond to therapy compared with nine of nine in the placebo group (RR 0.18, 95% CI 0.05 - 0.64). However, 3/11 and 4/9 eventually underwent colectomy in the treatment and placebo groups respectively and follow-up was less than a month. In the second trial 15 patients were treated with intravenous cyclosporine and 15 with intravenous methylprednisolone. Five of 15 patients in the cyclosporine group failed to respond to therapy as compared to 7/15 in the methylprednisolone group (RR 0.71, 95% CI 0.29 - 1.75). After 1 year 7/9 responders in the cyclosporine group were still in remission compared with 4/8 in the steroid group (p > 0.05) and the colectomy rate was similar in both groups. The mean time to response in the cyclosporine group in the 2 trials was short (7 days and 5.2 days). These results should be interpreted with caution given the small numbers of trials and patients evaluated for comparison, and limited follow-up (few weeks in one trial to a year in the other). The precise assessment of the occurrence of adverse events was difficult because the trials described different adverse reactions, which reversed after discontinuation of cyclosporine. There was no evidence in the trials reviewed that cyclosporine was more effective than standard treatment for preventing colectomy but this effect cannot be excluded due to the small sample size and rarity of this outcome. Additional limitations of current research include lack of data on quality of life, costs and long-term results of cyclosporine therapy. AUTHORS' CONCLUSIONS There is limited evidence that cyclosporine is more effective than standard treatment alone for severe ulcerative colitis. The relatively quick response makes the short-term use of cyclosporine potentially attractive, but the long-term benefit is unclear, when adverse events such as cyclosporine-induced nephrotoxicity may become more obvious. There is a need for additional research on quality of life, costs and long-term results from cyclosporine therapy in severe ulcerative colitis.
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Affiliation(s)
- O Shibolet
- Gastroenterology Unit GRJ715, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 04122, USA.
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Bouhnik Y, Alvès A, Beau P, Carbonnel F, Lévy P. Traitement de la rectocolite ulcéro-hémorragique dans sa forme grave. ACTA ACUST UNITED AC 2004; 28:984-91. [PMID: 15672570 DOI: 10.1016/s0399-8320(04)95176-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Yoram Bouhnik
- Service d'hépato-gastroentérologie, Hôpital Lariboisière Louis, 75010 Paris
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Loftus CG, Egan LJ, Sandborn WJ. Cyclosporine, tacrolimus, and mycophenolate mofetil in the treatment of inflammatory bowel disease. Gastroenterol Clin North Am 2004; 33:141-69, vii. [PMID: 15177532 DOI: 10.1016/j.gtc.2004.02.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
In the past decade, immunosuppressive drugs have come to play an integral role in the treatment of patients with inflammatory bowel disease. Cyclosporine, microemulsion cyclosporine, tacrolimus, and mycophenolate mofetil can be considered for the treatment of patients with refractory inflammatory Crohn's disease, fistulizing Crohn's disease, and severe ulcerative colitis. This article reviews the use of cyclosporine, tacrolimus, and mycophenolate mofetil in patients with inflammatory bowel disease, with emphasis on pharmacology, results in controlled clinical trials, and safety, and issues related to dosing and toxicity monitoring.
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Affiliation(s)
- Conor G Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN 55905, USA
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Ho GT, Mowat C, Goddard CJR, Fennell JM, Shah NB, Prescott RJ, Satsangi J. Predicting the outcome of severe ulcerative colitis: development of a novel risk score to aid early selection of patients for second-line medical therapy or surgery. Aliment Pharmacol Ther 2004; 19:1079-87. [PMID: 15142197 DOI: 10.1111/j.1365-2036.2004.01945.x] [Citation(s) in RCA: 202] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The failure rate of medical therapy in severe ulcerative colitis is high. A risk index, to aid the identification of patients of not responding at an early stage to intravenous corticosteroid therapy, would be useful to facilitate second-line treatment or surgery. METHODS We recruited 167 consecutive patients with severe ulcerative colitis between January 1995 and March 2002; and employed multiple logistic regression to analyse parameters within the first 3 days of medical therapy. We applied statistical modelling to formulate a risk score according to the likelihood of medical failure. RESULTS Sixty-seven (40%) patients failed to respond to medical therapy. Multiple logistic regression analysis identified mean stool frequency and colonic dilatation within the first 3 days and hypoalbuminaemia as independent predictors of outcome (P < 0.001, 0.001 and 0.002 respectively). A numerical risk score was formulated based on these variables. Patients with scores of 0-1, 2-3 and > or =4 had a medical therapy failure rate of 11%, 43% and 85% respectively. Receiver-operator characteristic analysis of this score yielded area under curve of 0.88, with a sensitivity of 85% and specificity of 75% using score > or =4 in predicting non-response. CONCLUSION This risk score allows the early identification of patients with severe ulcerative colitis who would be suitable for second-line medical therapy or surgery.
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Affiliation(s)
- G T Ho
- University Department of Gastroenterology, Western General Hospital, Edinburgh EH4 2XU, Scotland, UK.
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Moussata D, Nancey S, Flourié B, Bonvoisin SC, Cenni JC, Descos L. Rectocolite ulcéro-hémorragique chronique active. Presse Med 2004; 33:590-4. [PMID: 15226690 DOI: 10.1016/s0755-4982(04)98682-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE To know whether the therapeutic protocol applied in the case of severe acute ulcerative colitis (UC) associating ciclosporine and azathioprine was also effective in the case of moderate chronic active ulcerative colitis (UC). SUBJECTS AND METHODS in this retrospective study 10 patients (31-65 years, 6 distal colitis, 1 left colitis, 3 pancolitis) moderately active and corticosteroid-resistant or dependent were included. Patients received ciclosporine intraveinously (4 mg/kg/d) and were evaluated 10 days later. If efficient, ciclosporine was given orally for 3 Months, azathioprine was introduced and steroids were progressively tapered. RESULTS on inclusion the clinical score, based on the Mayo Clinic score, was of 5.7 +/- 0.5. On Day 10, the score decreased significantly (2.1 +/- 0.7, p<0.001) and the therapeutic effect was sustained at the third Month (1.8 +/- 0.7). With azathioprine, 4 patients were still in remission with a mean follow up of 23.3 +/- 15.5 Months. CONCLUSION therapeutic scheme proposed in severe acute UC failing to respond to steroids may be helpful in some patients with a chronic active UC. Clinical improvement is rapid and long-term response is maintained in about 1 patient out of 2.
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Arts J, D'Haens G, Zeegers M, Van Assche G, Hiele M, D'Hoore A, Penninckx F, Vermeire S, Rutgeerts P. Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis. Inflamm Bowel Dis 2004; 10:73-8. [PMID: 15168804 DOI: 10.1097/00054725-200403000-00002] [Citation(s) in RCA: 152] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Iv cyclosporin A (CSA) is an effective therapy in patients with severe ulcerative colitis (UC). It remains unclear if this treatment affects the course of the disease in the long run. We investigated the long-term efficacy and safety in 86 patients with ulcerative colitis treated with i.v. CSA at our center. METHODS The records of all patients treated with i.v. CSA between 11/1992 and 11/2000 were reviewed. RESULTS Seventy-two of 86 patients (83.7%) responded to i.v. CSA therapy, administered for a mean of 9 +/- 2 days. Following the initial treatment, 69 patients (96%) were discharged on oral CSA with mean blood CSA concentrations of 192 +/- 55 ng/mL. Azathioprine was added in 64 (89%) patients. A second treatment with CSA was necessary in 11 patients; 1 patient received three courses of i.v. treatment. The duration of follow-up averaged 773 +/- 369 days. Patients who were responders but were still having certain symptoms at discharge had a higher incidence of colectomy during follow-up. Of all initial responders, 18 (25%) underwent colectomy after a mean interval of 178 +/- 141 days. The life-table predicts that of all treated patients, 55% will avoid a colectomy during a period of 3 years. Complications of CSA treatment were mostly reversible, but 3 patients (3.5%) died of opportunistic infections (1 of Pneumocystis carinii pneumonia and 2 of Aspergillus fumigatus pneumoniae). One patient with anaphylactic shock caused by the CSA solvent was successfully resuscitated. CONCLUSIONS CSA is an effective treatment of the majority of patients with severe attacks of UC, although the toxicity and even mortality associated with its use necessitates careful evaluation, selection, and follow-up.
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Affiliation(s)
- Joris Arts
- Department of Internal Medicine, University Hospital, Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
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Abstract
Patients with ulcerative colitis have no increased mortality compared to population controls and the disease can be cured be colectomy. This review concentrates on the medical management of ulcerative colitis including the management of active colitis, acute severe colitis and first presentation of colitis, maintenance of remission and long-term complications.
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Affiliation(s)
- Adrian Thuraisingam
- Department of Gastroenterology, Royal Liverpool and Broadgreen University Hospitals, Liverpool L7 8XP
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40
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Affiliation(s)
- R N Fedorak
- Division of Gastroenterology, University of Alberta, Edmonton, Alta., Canada T6G 2C8.
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41
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Abstract
Emergency complications of IBD are rare, but may be life-threatening, require surgery, and result in permanent end organ damage. The most common complications associated with UC are fulminant colitis, toxic megacolon, and bleeding. Each of these complications may resolve with aggressive medical therapy but often result in a total proctocolectomy. The most common complications associated with CD are abscesses and intestinal obstruction. Although initial treatment includes medical treatment, these Crohn's-related complications usually require a surgical intervention and intestinal resection. Finally, the most common extraintestinal manifestations that present as an emergency include thromboembolic events, ocular complications, and hepatobiliary disease. Some of these complications may parallel the course of the underlying disease and respond to IBD treatment, but thromboemboli, uveitis, and PSC do not. In the last decade there has been an explosion of knowledge and discovery into the pathogenesis of IBD. These findings have led to better and earlier treatment of IBD that it is hoped will alter the natural course of disease and prevent many of the complications outlined in this article.
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Affiliation(s)
- Onki Cheung
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Scaife Hall, Room 566, 3550 Terrace Street, Pittsburgh, PA 15261, USA
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Alves A, Panis Y, Bouhnik Y, Maylin V, Lavergne-Slove A, Valleur P. Subtotal colectomy for severe acute colitis: a 20-year experience of a tertiary care center with an aggressive and early surgical policy. J Am Coll Surg 2003; 197:379-85. [PMID: 12946792 DOI: 10.1016/s1072-7515(03)00434-4] [Citation(s) in RCA: 100] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Management of severe acute colitis (SAC) complicating inflammatory bowel disease remains a challenge despite significant advances in medical therapy. The aim of this study was to report a 20-year experience with subtotal colectomy (STC) performed for SAC. STUDY DESIGN A total of 164 consecutive patients with a mean age of 37 +/- 15 years (range 16 to 86 years) underwent STC for SAC defined according to the criteria of Truelove and Witts. The decision for surgical treatment was based on clinical, biologic, radiologic, and endoscopic severity criteria both at entry and during hospitalization after failure to improve under medical treatment. A Brooke ileostomy was made to the right iliac fossa and a sigmoidostomy was made to the midline incision. All complications before discharge were recorded as in-hospital morbidity or mortality. RESULTS Colonoscopy was performed in 153 patients and endoscopic diagnosis of SAC was confirmed by pathologic examination in 84% of the cases. STC was performed on an emergency basis in 40 patients with complications and only after failure of medical treatment in the remaining 124 patients. The mortality rate was 0.6%. The overall morbidity rate was 33%; 24 patients required reoperation, including 8% undergoing reoperation during followup for small bowel obstruction. Definitive pathologic diagnosis changed in one half of the patients; the final diagnosis was Crohn's disease in 110 cases, ulcerative colitis in 35, and indeterminate colitis in 19. CONCLUSIONS Our results demonstrated the safety of STC performed in a tertiary care center for patients with SAC who presented with complications or failed to respond to intensive medical therapy.
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Affiliation(s)
- Arnaud Alves
- Department of Surgery, Lariboisiére Hospital, Paris, France
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Rayner CK, McCormack G, Emmanuel AV, Kamm MA. Long-term results of low-dose intravenous ciclosporin for acute severe ulcerative colitis. Aliment Pharmacol Ther 2003; 18:303-8. [PMID: 12895214 DOI: 10.1046/j.1365-2036.2003.01618.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Intravenous ciclosporin for acute, severe colitis is usually administered in a dose of 4 mg/kg/day, with concurrent intravenous steroids. This is associated with considerable morbidity. We have been using a low-dose regimen, most commonly without concurrent steroids, for seven years, and present the outcome. METHODS Records of all patients admitted for severe ulcerative colitis, treated by one physician over seven years, were reviewed. RESULTS Thirty-one patients received low-dose intravenous ciclosporin (2 mg/kg/day) for a median 8 days. Eleven early patients received concurrent intravenous corticosteroids. Three patients had hypertension requiring dose reduction, one elevated creatinine and one elevated liver enzymes (all transient), and four experienced infection (two arm cellulitis, one perianal abscess, one post-operative wound infection). Twenty-four patients (77%) avoided urgent colectomy, and were discharged on oral ciclosporin and azathioprine. After a median 18 months (range 3-77), 14 patients (45% of total) avoided colectomy, of whom eight had flares responding to medical therapy and two had persistent, mildly active disease. CONCLUSIONS Low-dose intravenous ciclosporin (2 mg/kg/day), usually used as a monotherapy and followed by azathioprine, achieves similar long-term efficacy to higher dose ciclosporin combined with steroids in severe acute ulcerative colitis. Morbidity appears to be low.
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Affiliation(s)
- C K Rayner
- Department of Medicine, St Mark's Hospital, London, UK
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Creed TJ, Norman MR, Probert CSJ, Harvey RF, Shaw IS, Smithson J, Anderson J, Moorghen M, Gupta J, Shepherd NA, Dayan CM, Hearing SD. Basiliximab (anti-CD25) in combination with steroids may be an effective new treatment for steroid-resistant ulcerative colitis. Aliment Pharmacol Ther 2003; 18:65-75. [PMID: 12848627 DOI: 10.1046/j.1365-2036.2003.01639.x] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Steroid resistance represents a major clinical problem in the treatment of ulcerative colitis. In vitro, interleukin-2 renders lymphocytes steroid resistant. AIM To explore the therapeutic potential of interleukin-2 receptor blockade in steroid-resistant ulcerative colitis with both in vitro measures and a pilot in vivo study. METHODS Ten patients with steroid-resistant ulcerative colitis received a single bolus of 40 mg of intravenous basiliximab plus steroid treatment in an open-label, uncontrolled, 24-week study. The outcome was assessed using the Ulcerative Colitis Symptom Score, rectal biopsy and Inflammatory Bowel Disease Questionnaire. Lymphocyte steroid sensitivity was measured in vitro in 39 subjects in the presence or absence of basiliximab. RESULTS Nine of the 10 patients achieved clinical remission within 8 weeks. At 24 weeks, seven patients were in clinical remission. Marked improvement in the Ulcerative Colitis Symptom Score was seen by 1 week (P = 0.004) and on rectal biopsy and Inflammatory Bowel Disease Questionnaire by 2 weeks (both P < 0.05). Improvements persisted to 24 weeks (Ulcerative Colitis Symptom Score, Inflammatory Bowel Disease Questionnaire, both P < 0.005). Eight of the nine responders relapsed (median, 9 weeks), but remission was re-achieved with further corticosteroids and the addition of azathioprine. At 24 weeks, seven patients were in full clinical remission, five off all steroid therapy. In vitro measurement of lymphocyte steroid sensitivity demonstrated steroid resistance in 22% of subjects. All were rendered steroid sensitive in the presence of basiliximab. CONCLUSIONS Basiliximab appears to be effective at inducing remission in steroid-resistant ulcerative colitis. In vitro, basiliximab also produced a dramatic increase in lymphocyte steroid sensitivity in healthy subjects. Confirmation in randomized controlled studies is required.
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Affiliation(s)
- T J Creed
- University Research Centre for Neuroendocrinology, Bristol Royal Infirmary, Bristol, UK
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Kornbluth A. Is there still a role for cyclosporine in the treatment of inflammatory bowel disease? Pro argument. Inflamm Bowel Dis 2003; 9:194-7; discussion 202-4. [PMID: 12792226 DOI: 10.1097/00054725-200305000-00008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Abstract
Early identification of patients with acute severe colitis is essential so that prompt treatment can be instigated. Corticosteroids have remained the mainstay of treatment since 1955. The introduction of ciclosporin into the pharmacological armamentarium has reduced early colectomy rates but even with modern medical management up to 30% of patients will still undergo colectomy on the same admission. The overall mortality is now less than 1% in specialist centres compared to 30% in the pre-steroid era. The future promises further advances in treatment through medications that are targeted directly at the underlying inflammatory process.
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Affiliation(s)
- Paul Dunckley
- Gastroenterology Unit, John Radcliffe Hospital, Oxford, United Kingdom
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Hanai H, Watanabe F, Takeuchi K, Iida T, Yamada M, Iwaoka Y, Saniabadi A, Matsushita I, Sato Y, Tozawa K, Arai H, Furuta T, Sugimoto K, Bjarnason I. Leukocyte adsorptive apheresis for the treatment of active ulcerative colitis: a prospective, uncontrolled, pilot study. Clin Gastroenterol Hepatol 2003; 1:28-35. [PMID: 15017514 DOI: 10.1053/jcgh.2003.50005] [Citation(s) in RCA: 159] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Active ulcerative colitis (UC) is characterized by infiltration of activated granulocytes and monocytes/macrophages (GM) within the large bowel mucosa. GM are major sources of inflammatory cytokines, and in UC they are elevated with increased survival time. We investigated the possibility that reducing the level of these cells might promote remission of active UC. METHODS Thirty-one patients with active corticosteroid refractory (refractory) UC, mean age of 42 years, duration of UC 6 years, clinical activity index (CAI) of 15, disease activity index (DAI) of 10, and 8 corticosteroid naive patients (naive), mean age of 36 years, duration of UC 2 years, CAI of 11, DAI of 8 were recruited. Each patient was treated with up to 11 cycles of granulocyte and monocyte adsorptive apheresis over 11 weeks by using a 335-mL capacity column filled with cellulose acetate beads that adsorb GM. RESULTS At week 12, 81% of refractory (CAI, 3; P < 0.001 and DAI, 4; P < 0.001) and 88% of naive (CAI, 1; P = 0.012 and DAI, 3; P = 0.011) patients achieved remission. Early relapse was not a feature, and at 12 months, 26 of 33 patients had maintained their remission. The treatment was well tolerated, and no severe side effects were observed. CONCLUSIONS The outcome of this study suggests that reduction of circulating granulocytes and monocytes results in alleviation of inflammation and promotes clinical remission in patients with severe active UC that has not responded to intensive corticosteroid treatment. These data suggest that formal controlled studies are warranted.
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Affiliation(s)
- Hiroyuki Hanai
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University, Japan.
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Escher JC, Taminiau JAJM, Nieuwenhuis EES, Büller HA, Grand RJ. Treatment of inflammatory bowel disease in childhood: best available evidence. Inflamm Bowel Dis 2003; 9:34-58. [PMID: 12656136 DOI: 10.1097/00054725-200301000-00006] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
The physician treating children with inflammatory bowel disease is confronted with a number of specific problems, one of them being the lack of randomized, controlled drug trials in children. In this review, the role of nutritional therapy is discussed with a focus on primary treatment, especially for children with Crohn's disease. Then, the available medical therapies are highlighted, reviewing the evidence of effectiveness and side effects in children, as compared with what is known in adults. Nutritional therapy has proven to be effective in inducing and maintaining remission in Crohn's disease while promoting linear growth. Conventional treatment consists of aminosalicylates and corticosteroids, whereas the early introduction of immunosuppressives (such as azathioprine or 6-mercaptopurine) is advocated as maintenance treatment. If these drugs are not tolerated or are ineffective, methotrexate may serve as an alternative in Crohn's disease. Cyclosporine is an effective rescue therapy in severe ulcerative colitis, but only will postpone surgery. A novel strategy to treat Crohn's disease is offered by infliximab, a monoclonal antibody to the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. Based on the best-available evidence, suggested usage is provided for separate drugs with respect to dosage and monitoring of side effects in children.
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Affiliation(s)
- Johanna C Escher
- Department of Pediatric Gastroenterology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, The Netherlands.
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Hyde GM, Jewell DP, Warren BF. Histological changes associated with the use of intravenous cyclosporin in the treatment of severe ulcerative colitis may mimic dysplasia. Colorectal Dis 2002; 4:455-8. [PMID: 12790919 DOI: 10.1046/j.1463-1318.2002.00392.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND During six years experience of intravenous cyclosporin (i.v. Cy) for severe ulcerative colitis we have noted that changes of villous architecture and epithelial regeneration occur even when the disease fails to enter clinical remission and colectomy is required. OBJECTIVE To describe the histological changes in patients who received i.v. Cy and steroids compared with those treated with i.v. steroids alone. PATIENTS AND METHODS Two groups of histological sections were reviewed. The first group was of 23 colectomy specimens from patients who had been treated with i.v. Cy and steroids. For 11 patients pre-Cy histological sections were available. The second group was of 10 colectomy specimens from patients who had received i.v. steroids alone. Biopsies were scored for their histological disease activity (HDAI), villous architecture and epithelial regeneration. The HDAI assesses the degree of acute and chronic inflammation. RESULTS The post-Cy group had higher median scores for villous architecture and epithelial regeneration compared to the pre-Cy and poststeroid groups. For the patients where both pre- and post-Cy histological sections were available 63% increased their villous score post-Cy and 82% increased their epithelial regeneration score post-Cy. CONCLUSION Although villous transformation and epithelial regeneration may be seen in UC they are more frequent and more severe in those patients who received i.v. Cy and i.v. steroids, compared to controls who received i.v. steroids alone. These histological changes may mimic dysplasia. Increased awareness of this potential mimic of dysplasia is crucial for patient management.
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Affiliation(s)
- G M Hyde
- John Radcliffe Hospital, Oxford, UK
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Actis GC, Bruno M, Pinna-Pintor M, Rossini FP, Rizzetto M. Infliximab for treatment of steroid-refractory ulcerative colitis. Dig Liver Dis 2002; 34:631-4. [PMID: 12405249 DOI: 10.1016/s1590-8658(02)80205-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Success achieved in two subtypes of Crohn's disease has persuaded a few investigators to experiment the monoclonal anti-tumour necrosis factor antibody infliximab in the treatment of ulcerative colitis. So far, however, the results (achieved in some 30 steroid-refractory patients included in two independent full-papers) indicate a rate of initial response of 50% and of remission of 25%. AIMS To analyse data of an open trial conducted on consecutive steroid-refractory severely ill patients admitted to our referral Unit. PATIENTS AND METHODS In 9 months, infliximab was given to 8 patients (4 male, 4 female aged 20-60 years) with uncontrolled ulcerative colitis of whom 6 were non-responders to parenteral steroids. All received the first infliximab dose as an intravenous infusion of 5 mg/kg. RESULTS Of the 8, 4 (50%) did not respond to the first injection and were submitted to urgent colectomy; the other four responded clinically. Two have maintained clinical remission for 7 months, without the need for steroids; both have received daily azathioprine at 2 mg/kg, and only one has received two further infliximab injections. Of the other two, one received a second injection at week 5, despite this relapsed, and underwent elective colectomy at that time; the other relapsed at 6 months and showed a partial response to a repeat infliximab infusion. Thus, the rate of sustained response is 2/8 (25%) in this study. CONCLUSION These results, achieved in an open uncontrolled fashion, seem to reflect those of other independent studies. In our opinion, these findings warrant an in-depth reappraisal of the indication to use infliximab as rescue treatment for refractory ulcerative colitis.
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Affiliation(s)
- G C Actis
- Department of Digestive Diseases, Molinette Hospital, Turin, Italy.
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