Severe Steroid-refractory Ulcerative Colitis Research Articles

Letter: ciclosporin or infliximab in acute ulcerative colitis - still undecided

SIRS, The management of steroid-refractory severe ulcerative colitis is still a difficult terrain for the clinical gastroenterologist. The decision between insisting on medical management and indicating colectomy remains a delicate one. 2 The CYSIF study recently showed, in a prospective multicentre European series, that infliximab and ciclosporin were equivalent in this setting, with similar success and colectomy rates. Recently, a paper by Croft et al. seems to dispute these findings. The authors found infliximab clearly superior to ciclosporin as rescue therapy in steroid-refractory severe ulcerative colitis. However, we feel that some aspects of their work deserve a comment that could shed a different light on their conclusions. First and foremost, this paper does not report on a randomised clinical trial, but on the outcomes observed in a real-life clinical series. Treatment allocation was thus not random, and the preferences of the managing physician may have influenced the choice of drug. Also, there is a chronological difference between ciclosporinand infliximab-treated patients: at the beginning of the period considered, only ciclosporin was available, and other local factors may have been at work in those early days, that explain the difference in the results of both drugs. Besides, this work represents a single-centre experience, which may have introduced local preferences and preconceptions in the therapeutic decisions. Possibly, ciclosporin use was not optimized in this study, as reflected by the fact that patients failing to reach therapeutic levels were excluded, instead of being managed with higher doses. However, the most important factor that seriously influences the authors’ findings is that the definition of treatment failure is not clearly stated at all, being instead purely subjective and not predetermined. Therefore, the most important variable was left at the managing clinician’s discretion, without predefined endpoints that could have been applied similarly to both patient populations. As the authors state, the ongoing CONSTRUCT trial will probably add new data to this fascinating clinical situation, but in the meantime, we must insist the following: in this clinical series, treatment allocation was not random, management of both patient populations was not necessarily similar and, most importantly, the decision of declaring medical treatment failure was open, not predefined and apparently left to subjectivity.

Infliximab in patients with severe steroid-refractory ulcerative colitis: Indian experience

The role of infliximab in the treatment of acute severe ulcerative colitis is established. However, all the data available in the literature are from western countries. This is the first report on the use of infliximab in patients with severe steroid-refractory ulcerative colitis from India. Retrospective analysis of 28 patients who had received infliximab therapy for induction of remission, with three doses of 5 mg/kg at 0, 2, and 6 weeks, was performed. Twenty-four (85.6 %) patients had shown a clinical response by week 8 and, hence, avoided urgent colectomy. In 2 years of follow up, 9/16 (56 %) patients had not required colectomy. Infliximab averted colectomy in a proportion of patients with severe steroid-refractory ulcerative colitis.

PTH-096 Oral Ciclopsorin in Steroid Refractory, Acute, Severe Ulcerative Colitis

IntroductionCiclosporin (CsA) has been shown to be effective in treatment of steroid refractory severe ulcerative colitis and reducing the need for colectomy1. Most published evidence concerns intravenous infusions; however oral...

Su1229 Predictors of Response to Infliximab As Salvage Therapy for Severe Steroid Refractory Ulcerative Colitis

G A A b st ra ct s therapy for 6 months prior to drug withdrawal, and minimum 12 months follow-up. The primary outcome was disease relapse requiring AZA reinitiation, steroids or colectomy within 12 months of AZA/MP withdrawal, with secondary outcome assessed at 24 months. Clinical/ laboratory predictors of relapse were sought. Results Data was obtained on 97 patients with CD and 78 with UC. Median age at diagnosis was 26y (interquartile range [IQR] 20-38), and 49% were female. Median duration of thiopurine use was 73 months (IQR 54-104). Median duration of follow-up was 39 months (IQR 24-65 months). CD was associated with a significantly higher risk of relapse than UC on Kaplan Meier analysis (Figure 1, p=0.024). The moderate-severe relapse rate for 12 months was 27% for CD and 14% for UC. For 24 months, relapse rates were 41% for CD and 28% for UC. Elevated CRP was predictive of relapse at 12 months for CD (0=0.017), while elevated platelet count was predictive of relapse at 24 months for UC (0.021). Retreatment with a thiopurine after relapse was successful in 34/39 (87%) for CD and 17/18 (94%) cases for UC. Conclusion Relapse rates after withdrawal of a thiopurine are high, particularly for CD, and predicting this remains difficult. The findings regarding CRP and CD in this data highlight the importance of ensuring patients are in deep remission prior to drug withdrawal. Further studies should evaluate the role of faecal calprotectin in this.

P452 Long-term efficacy and safety of cyclosporine as a rescue therapy in acute, steroid-refractory severe ulcerative colitis

Background: Although cyclosporine is an accepted and effective therapeutic choice in patients with severe ulcerative colitis (UC), long term colectomy rate varies between 60 88% among patients in whom cyclosporine initially induced remission. The aim of our study was to evaluate the long-term outcome and the optimal duration of cyclosporine therapy in patients with acute, severe UC. Methods: 73 (40 females, 33 males; mean age at the diagnosis 31.7 years, mean disease duration 13.4 years) of 183 patients hospitalized for severe exacerbation of UC between January 1998 and June 2009 revealed steroid-refractory after intravenous methylprednisolone therapy. They underwent intravenous cyclosporine treatment for 5 days following oral treatment in the case of a good initial response. Results: The mean follow up after the initiation of cyclosporine therapy was 4.2 years. The median duration of cyclosporine therapy was 9.6 months. Side effects developed in 37 patients. 20 patients underwent early colectomy. Cyclosporine therapy had to be discontinued due to intolerable or severe side effects in 22 patients. Cyclosporine failed and late colectomy was performed in 14 of the 53 responders during the longterm follow up. Duration of cyclosporine treatment was significantly longer in those who avoided colectomy (5.4 vs. 13.3 months, p = 0.009). The optimal cut-point of the duration of cyclosporine therapy to avoid colectomy was 4.5 months. No association was revealed between the duration of cyclosporine therapy and the development of side effects. Conclusions: Cyclosporine is effective in acute, severe UC. After a median follow up of more than 4 years, 53.4% of the patients remained colectomy free. The optimal time for cyclosporine treatment proved to be 4.5 months.

Steroid-refractory ulcerative colitis—ciclosporin or infliximab?

Ciclosporin and infliximab are used as rescue therapies for the treatment of severe steroid-refractory ulcerative colitis. Now, an open-label, head-to-head randomized controlled trial has demonstrated that these drugs are well-tolerated and have equivalent efficacy in inducing short-term clinical response, mucosal healing and decreasing colectomy rates at 3 months.

Infliximab versus cyclosporine as rescue therapy in acute severe steroid-refractory ulcerative colitis: a systematic review and meta-analysis

Acute severe colitis affects 25 % of patients with ulcerative colitis (UC). Up to 30-40 % of these patients are resistant to intensive steroid therapy and therefore require rescue therapy to prevent emergent colectomy. Data comparing rescue therapy using infliximab and cyclosporine are limited and equivocal. This study evaluates the outcomes of UC patients receiving infliximab or cyclosporine as rescue therapy in acute severe steroid-refractory exacerbations. Electronic databases (PubMed, EMBASE, and Cochrane database) were searched for studies directly comparing infliximab and cyclosporine in UC, and references of included studies were screened. Two independent reviewers identified relevant studies and extracted data. Meta-analyses were performed using the random effect model. Outcome measures included 3- and 12-month colectomy rates, adverse drug reactions, and postoperative complications. Six retrospective cohort studies describing 321 patients met the inclusion criteria. The meta-analysis did not show significant differences between infliximab and cyclosporine in the 3-month colectomy rate (odds ratio (OR) = 0.86, 95 % confidence interval (CI) = 0.31-2.41, p = 0.775), in the 12-month colectomy rate (OR = 0.60, 95 % CI = 0.19-1.89, p = 0.381), in adverse drug reactions (OR = 0.76, 95 % CI = 0.34-1.70, p = 0.508), and in postoperative complications (OR = 1.66, 95 % CI = 0.26-10.50, p = 0.591). Funnel plot revealed no publication bias. Infliximab and cyclosporine are comparable when used as rescue therapy in acute severe steroid-refractory UC. Randomized trials are required to further evaluate these agents.

PWE-236 White cell aphaeresis (WCA) with adacolumn is effective in selected cases of chronic refractory colitis with high histological activity

IntroductionTreatment options for patients with chronic refractory colitis are limited. White cell aphaeresis (WCA) is effective in inducing clinical remission in chronic refractory colitis in patients with a strong inflammatory...

PWE-237 Ciclosporin in acute severe ulcerative colitis: a meta-analysis

IntroductionThe efficacy of intravenous Ciclosporin in the treatment of acute severe steroid refractory ulcerative colitis is variable in several small studies.1 2 The benefit of immunosuppression in initial responders for...

Surgery is a real alternative to rescue therapy in patients with steroid-refractory ulcerative colitis

Dear Editor: The life-time risk of a fulminant flare of ulcerative colitis, which is a potentially life-threatening condition, is approximately 15–20 %. The mainstay of conventional therapy is intravenous corticosteroids of 1 mg/bwkg, however approximately one third of the patients fail to respond to a 3to 5-day intensive intravenous regimen, which sets up an interdisciplinary challenge for the surgeon and internist alike. The three options to be considered are intravenous cyclosporin (CsA) therapy, infliximab (IFX) treatment or total proctocolectomy. With the introduction of CsA in the early 1990, the rate of urgent colectomies decreased, since 76 % to 86 % of the patients will initially respond to CsA rescue medication, thus avoiding colectomy in the short run. However, 88 % of patients initially responding to CsA rescue therapy will require colectomy upon 7 years of follow-up and CsA use is still restricted by potential serious adverse events. Colectomy and receiving even a temporary stoma are of the most fearful complications for patients with inflammatory bowel disease. The recommended surgical procedure is restorative proctocolectomy with ileal pouch anal anastomosis (IPAA), which is considered to be a cure for ulcerative colitis; however, reports on functional outcome and postoperative quality of life are contradictory and a variety of complications can occur after surgery. In steroid-refractory ulcerative colitis our therapeutic decision between medical rescue and colectomy remains theoretical in the lack of comparative data. The aim of our study was to evaluate and compare long-term disease outcome in patients with steroid-refractory colitis who either responded to CsA rescue therapy or had to be operated on due to failure of rescue medication. Data of 90 patients with steroid-refractory severe ulcerative colitis were analyzed, of whom 44 patients responded to CsA rescue therapy (CsA responders) and 46 patients underwent colectomy due to early or late failure of rescue therapy (colectomy group). Clinical disease severity was assessed by the Lichtiger score. CsA was introduced intravenously, 4 mg/bwkg initially, which was changed to oral administration after 1 week and maintained for 6–12 months (earlier discontinuation of the therapy was either due to side effects or loss of therapeutic effect); the dosing was continuously monitored by drug serum level. Twenty-six patients received corticosteroids and 17 patients were on immunomodulator therapy at the time of the initiation of CsA rescue. The indication of colectomy was severe disease activity with early failure of the rescue medication or relapse after rescue medication. The mean disease duration was 10 years at the time of surgery. Twenty-five patients K. Gecse :K. Farkas : Z. Szepes : F. Nagy : T. Wittmann : T. Molnar (*) First Department of Internal Medicine, University of Szeged, H-6720, Koranyi fasor 8, Szeged, Hungary e-mail: molnar.tamas@med.u-szeged.hu

Sa1916 A Combination of Serum Albumin and Band Neutrophil Count is Predictive of Short- Term Colectomy Following Infliximab Treatment for Severe Steroid Refractory Ulcerative Colitis

Sa1916 A Combination of Serum Albumin and Band Neutrophil Count is Predictive of Short- Term Colectomy Following Infliximab Treatment for Severe Steroid Refractory Ulcerative Colitis

Sa1890 White Cell Apheresis (WCA) With Adacolumn is Effective in Selected Cases of Chronic Refractory Colitis With High Histological Activity

Introduction Treatment options for patients with chronic refractory colitis are limited. White cell aphaeresis (WCA) is effective in inducing clinical remission in chronic refractory colitis in patients with a strong inflammatory burden at baseline and histologically active disease. Previous multinational sham controlled trials have demonstrated significant improvement when patients with high histological activity (modified Rileys score) are selected for treatment. Methods A prospective study was conducted in 30 patients with severe steroid -dependent or steroid -refractory ulcerative colitis referred for WCA. Inclusion criteria were (i) High disease activity score (partial Mayo score ≥6) (ii) Intractable symptoms despite treatment with steroids and/or immunosuppressants (iii) Severe disease at endoscopy and histologically. The aim was to induce clinical and IBD-Q remission at 12 weeks. A Mayo score ≤3 defined clinical remission. The 32 item Inflammatory Bowel Disease questionnaire (IBD-Q) was used to assess quality of life prior to treatment and at 12 weeks. Results Patient Characteristics : Prior to treatment 28 patients (93.3%) were prescribed 5-ASA compounds. 12 patients (40%) were prescribed topical therapies (5-ASA enemas or suppositories/steroids enemas). 27 patients (90%) were steroid dependent (Prednisolone mean dose 21.1 mg, median 20 mg). Three patients (10%) were steroid refractory (no response to high dose oral steroids). 13 patients (43.3%) were prescribed Azathioprine of the remainder all had documented intolerance or a contraindication. One patient (3.3%) was prescribed six Mercaptopurine. Five patients had failed Infliximab (16.6%) and in one patient (3.3%) it was contraindicated. 1 patient (3.3%) had failed intramuscular Methotrexate. Outcomes : At week 12 clinical remission (Mayo score ≤3) was achieved in 22 patients (73.3%), 18 patients (60%) were no longer prescribed oral steroids. IBD-Q remission at week 12 was achieved in 19 patients (63.3%). Of the remainder, five patients (16.6%) achieved an IBD-Q response. Of eight patients (26.6%) who failed to achieve clinical remission at 12 weeks, one achieved delayed remission at 20 weeks. Of the remaining seven treatment failures, five underwent colectomy (16.6%). Conclusion WCA can be effective in inducing clinical remission and improving quality of life (IBD-Q) indices in chronic severe steroid refractory ulcerative colitis with highly active disease histologically. This data series suggests WCA should be considered before colectomy in this challenging patient group. Competing interests None declared.

Future Therapeutic Approaches for Inflammatory Bowel Diseases

In this review, we speculate about future therapeutic approaches for inflammatory bowel diseases (IBDs), focusing on the need for better preclinical and clinical models and approaches beyond small molecules and systemically administered biologics. We offer ideas to change clinical trial programs and to use immunologic and genetic biomarkers to personalize medicine. We attempt to reconcile past therapeutic successes and failures to improve future approaches. Some of our ideas might be provocative, but we hope that the examples we provide will stimulate discussion about what will advance the field of IBD therapy.

Long-term Efficacy and Safety of Cyclosporine as a Rescue Therapy in Acute, Steroid-refractory Severe Ulcerative Colitis

Long-term Efficacy and Safety of Cyclosporine as a Rescue Therapy in Acute, Steroid-refractory Severe Ulcerative Colitis

Rapid endoscopic improvement is important for 1-year avoidance of colectomy but not for the long-term prognosis in cyclosporine A treatment for ulcerative colitis

Intravenous (IV) cyclosporine A (CSA) is one of the treatments of choice for patients with steroid-refractory severe ulcerative colitis (UC). In this study, we evaluated the overall experience with CSA treatment in UC patients, from their initial response to long-term prognosis. The medical records of 72 patients admitted to our hospital with a severe UC flare-up and treated with IV CSA between November 1996 and October 2008 were reviewed retrospectively. The initial response to CSA was assessed using a clinical activity index, and colectomy was assigned as the endpoint for the long-term prognosis. Overall, 53 of 72 (73.6%) patients responded initially to CSA. We could not determine any specific parameters that predicted an initial response. A life-table analysis for all patients revealed that 54.4% of patients required a colectomy within 11years. The long-term risk of surgery was associated with a shorter disease duration, history of adverse reactions against medications and lack of immunomodulator use. In addition, endoscopic improvement at day 14 was associated with colectomy at 1year, but not with the long-term prognosis. Although CSA can exert high initial efficacy for severe attacks of UC, >50% of patients who relapse require a colectomy. Specifically, mucosal healing evaluated by endoscopy was associated with the 1-year colectomy rate. In contrast, a history of adverse drug reactions was correlated with the long-term colectomy rate. Therefore, we propose that treatment of severe UC with CSA requires consideration of both initial remission and long-term maintenance as management goals.

Prospective randomized open-label multicenter phase I/II dose escalation trial of visilizumab (HuM291) in severe steroid-refractory ulcerative colitis†

Visilizumab is a humanized IgG(2) monoclonal anti-CD3 antibody. We evaluated its safety and dose response in severe intravenous steroid-refractory ulcerative colitis (UC). In all, 104 patients were treated. In Stage I, 73 patients were randomly assigned to receive intravenous visilizumab 5, 7.5, 10, or 12.5 microg/kg/day for 2 consecutive days. In Stage II, 33 patients received visilizumab at the optimal clinical dose (OCD) of 5 microg/kg/day for 2 days. Symptomatic response and remission were defined by the modified Truelove-Witts severity index. Clinical response and remission were defined by the Mayo score. The rates of symptomatic response at day 15 in the 5, 7.5, 10, or 12.5 microg/kg dose groups were 71%, 70%, 50%, and 61%, respectively, in Stage I and in 54% in Stage II. The symptomatic remission rates were 35%, 5%, 22%, and 11% in Stage I and 18% in Stage II. The rates of clinical response at day 30 in the 5, 7.5, 10, or 12.5 microg/kg dose groups were 71%, 65%, 50%, and 67%, respectively, in Stage I and 55% in Stage II. The clinical remission rates were 6%, 5%, 0%, and 11% in Stage I and 6% in Stage II. All patients experienced adverse events. Serious adverse events included abdominal abscess, cytomegalovirus infection, atrial fibrillation, herpes zoster, and esophageal candidiasis. Treatment with visilizumab induced symptomatic response and clinical response. Results with 5 microg/kg/day were similar to those observed with higher doses.

Cyclosporine treatment of steroid-refractory ulcerative colitis during pregnancy

Cyclosporine is considered a safe and effective treatment of severe steroid-refractory ulcerative colitis (UC). However, few data are available concerning its safety profile in pregnant women. We report here the experience of 5 GETAID centers. In a retrospective study data on patients with severe UC treated with cyclosporine during pregnancy were extracted from medical records of consecutive patients treated between 2001 and 2007. Eight patients (median age 30.5 years old) were identified. At the time of flare-up the median duration of pregnancy was 11.5 weeks of gestation (range 4-25). Seven patients had pancolitis. All patients had more than 3 commonly used clinical and biological severity criteria. Three patients had severe endoscopic lesions and 5 patients had not. All patients received intravenous corticosteroids for at least 7 days before introduction of cyclosporine. Two patients received azathioprine during treatment with cyclosporine. No severe infections or other complications due to treatment were observed. Treatment was effective in 7/8 patients. One patient received infliximab due to cyclosporine therapy failure with a good outcome. No colectomy was performed during pregnancy. Seven pregnancies were conducted to term, but 1 in utero death occurred due to maternal absence of S-protein. Two newborns were premature, including 1 case of hypotrophy. No malformations were observed. In our experience, treatment with cyclosporine for steroid-refractory UC during pregnancy can be considered safe and effective.

Treatment of choice for acute severe steroid-refractory ulcerative colitis is colectomy

Treatment of choice for acute severe steroid-refractory ulcerative colitis is colectomy

Treatment of choice for acute severe steroid-refractory ulcerative colitis is Remicade

Treatment of choice for acute severe steroid-refractory ulcerative colitis is Remicade

How should we treat severe acute steroid-refractory ulcerative colitis?

How should we treat severe acute steroid-refractory ulcerative colitis?