Induction Of Remission In Ulcerative Colitis Research Articles

Influence of Corticosteroid Use on Short- and Long-Term Outcomes of Biologic Therapy for Inflammatory Bowel Diseases.

Corticosteroids (CS) are widely used to treat Crohn's disease (CD) and ulcerative colitis (UC), but are not recommended as maintenance therapy. Biologic drugs are widely used as an alternative to or in conjunction with CS to induce and maintain remission. This meta-analysis tested the hypothesis that CS use is associated with differential response to biologics. We identified published placebo-controlled clinical trials of biologic drugs approved for the treatment of CD or UC. Pooled estimates of the risk difference (RD) and 95% confidence intervals were derived from random effects models for induction of response and remission and maintenance of remission comparing biologic with CS versus biologic alone. Heterogeneity of response was estimated using I2. Fifteen studies met the inclusion criteria. Pooled estimates of the RD and I2 comparing biologic plus CS versus biologic alone were as follows: induction of UC response 0.15 (0.05, 0.25), I2 = 57.29% and CD response 0.02 (- 0.03, 0.06), I2 = 0.01%; induction of UC remission 0.03 (- 0.01, 0.08), I2 = 0.00% and CD remission 0.08(0.02, 0.14), I2 = 7.81%; and maintenance of UC remission - 0.06 (- 0.13, 0.01), I2 = 0.00% and CD remission - 0.06 (- 0.14, 0.03), I2 = 11.24%. Patients in the placebo arm of CD trials who were receiving CS were less likely to achieve remission during the induction phase (pooled RD - 0.05 (- 0.09, - 0.00), I2 = 0.00%). In this meta-analysis of placebo-controlled trials, CS use was associated with higher biologic response rates for UC and remission rates for CD during the induction phase, but were not associated with improved maintenance of remission.

Faecal Microbial Transplantation is as Effective as Targeted Therapies for Induction of Clinical and Endoscopic Remission in Ulcerative Colitis: A Systematic Review and Network Meta-Analysis

Background: Microbiome manipulation with fecal microbiota transplantation (FMT) has shown efficacy in induction of remission in ulcerative colitis (UC), yet information on the comparative efficacy of FMT with other targeted therapies is lacking. We did a network meta-analysis to compare the efficacy and safety of FMT with targeted therapies for induction of remission in UC. Methods: We analyzed data from randomized controlled trials(RCTs) evaluating induction of remission in adults with UC treated with anti-TNF (infliximab and adalimumab), anti-integrin (vedolizumab), anti-IL23(ustekinumab), Janus kinase (JAK) inhibitors (tofacitinib), and FMT, compared with placebo or another active agent. The outcomes assessed were induction of clinical remission, clinical response, endoscopic remission, and adverse events. Both pairwise and network meta-analysis were performed, and ranking was assessed using surface under the cumulative ranking(SUCRA) probabilities. Findings: Overall nineteen studies were included, among which there was only one head to head RCT (adalimumab vs. vedolizumab). All interventions including FMT were superior to placebo in inducing clinical remission (except adalimumab-OR 1.66; 95% CI, 0.97-2.85), clinical response and endoscopic remission. FMT was comparable with other agents for all efficacy outcomes including clinical remission and response, and endoscopic remission. Infliximab was ranked highest in inducing clinical remission (SUCRA, 0.8), vedolizumab in clinical response (SUCRA, 0.9) and tofacitinib in endoscopic remission (SUCRA, 0.9). There was no difference in safety outcomes between FMT and other targeted therapies, among which ustekinumab ranked the safest. Interpretation: FMT is as effective as targeted therapies in inducing clinical remission, response and endoscopic remission in patients with ulcerative colitis. Funding Statement: None Declaration of Interests: None.

Evaluation of The Role of Fecal Microbiota Transplantation in The Management of Ulcerative Colitis in Egyptian Patients

Background and Aims: Fecal Microbiota Transplantation (FMT) is a novel form of therapeutic microbial manipulation aims to restore the intestinal microbiota in diseased individuals by transferring intestinal microbiota of healthy donors. We aimed to establish the efficacy of, multi donor, fecal microbiota transplantation in active ulcerative colitis(UC) in Egyptian patients. Subjects and Methods: known UC patients (n-50) were divided in two groups, Group one included 25 patients who treated with medical treatment alone and then follow up was done for 24 weeks. Group two included 25 patients who treated with medical treatment and underwent FMT via complete colonoscopy every three weeks until the 9th week and then follow up was done for the24th week by clinical picture, laboratory investigation ,complete colonoscopy at 0, 3, 6, 9, 18 and 24 weeks of study. Results: We found statistically significant difference between both groups as regard clinical remission(reduction in mayo score≤2) was achieved in 18(72%)patients of group II compared to only 5(20%) patients of group I achieved clinical remission p value(0.001) and statistically significant difference between both groups as reduction in leucocytic count which is more prominent in group II(5.8) rather than group I(6.2) p value (0.008) and statistically significant difference between both groups as improvement in anemia which is better in group II(12.4) than group I(11.9) p value (0.027). Conclusion: FMT appears to be effective for induction of remission in UC, Further studies are needed to explore its feasibility, efficacy and safety as a maintenance agent.

Budesonide MMX: efficacy and safety profile in the treatment of ulcerative colitis

ABSTRACTIntroduction: Ulcerative colitis is an idiopathic, chronic inflammatory disease of the colonic mucosa. Its clinical course is unpredictable, marked by alternating periods of exacerbation and remission.Traditional oral corticosteroids are still the mainstay treatment for the induction of ulcerative colitis remission in patients failing or intolerant to aminosalicylates, but the risk of side effects and complications limits their usefulness. Based on these considerations, new steroids with low systemic bioavailability, such as Beclomethasone dipropionate and Budesonide, have been developed.Areas covered: We reviewed the current literature about the efficacy, safety and the role of budesonide MMX in the treatment of ulcerative colitis. The evidence reviewed in this article is a summation of relevant scientific publications, expert opinion statements, and current practice guidelines.Expert opinion: Budesonide MMX is a novel formulation that uses a Multi‐Matrix System (MMX) technology to facilitate the release of high concentrations of active drug into the colon. Budesonide MMX at the dose of 9 mg/day for 8 weeks is effective and safe in inducing clinical and endoscopic remission in patients with mild to moderate UC, who had an inadequate response or were intolerant to either first line conventional therapy with topical and oral 5-aminosalicylic acid.

Systematic review with meta-analysis: faecal microbiota transplantation for the induction of remission for active ulcerative colitis.

Faecal microbiota transplantation (FMT) is emerging as a novel therapy for ulcerative colitis (UC). Interpretation of efficacy of FMT for UC is complicated by differences among studies in blinding, FMT administration procedures, intensity of therapy and donor stool processing methods. To determine whether FMT is effective and safe for the induction of remission in active UC. Medline (Ovid), Embase and the Cochrane Library were searched from inception through February 2017. Original studies reporting remission rates following FMT for active UC were included. All study designs were included in the systematic review and a meta-analysis performed including only randomised controlled trials (RCTs). There were 14 cohort studies and four RCTs that used markedly different protocols. In the meta-analysis of RCTs, clinical remission was achieved in 39 of 140 (28%) patients in the donor FMT groups compared with 13 of 137 (9%) patients in the placebo groups; odds ratio 3.67 (95% CI: 1.82-7.39, P<.01). Clinical response was achieved in 69 of 140 (49%) donor FMT patients compared to 38 of 137 (28%) placebo patients; odds ratio 2.48 (95% CI: 1.18-5.21, P=.02). In cohort studies, 39 of 168 (24%; 95% CI: 11%-40%) achieved clinical remission. Despite variation in processes, FMT appears to be effective for induction of remission in UC, with no major short-term safety signals. Further studies are needed to better define dose frequency and preparation methods, and to explore its feasibility, efficacy and safety as a maintenance agent.

Systematic review: second‐generation vs. conventional corticosteroids for induction of remission in ulcerative colitis

Oral corticosteroids are the mainstay treatment for induction of ulcerative colitis remission in patients failing or intolerant to aminosalicylate therapy, but the poor tolerability profile of these drugs limits their usefulness. Second-generation, gut-selective corticosteroids may offer a safe alternative to systemic agents. To review the efficacy and safety of systemic and second-generation oral corticosteroids for the induction of remission in ulcerative colitis. The PubMed database was searched for randomised, controlled, and open-label trials of orally administered corticosteroids published between January 1950 and September 2015. Additional trials were identified from review of citation lists. Trials that compared oral corticosteroids with non-oral agents or in combination with agents other than aminosalicylates were excluded. Of the 240 studies identified, 21 were eligible for inclusion. Few trials directly compared oral systemic and second-generation corticosteroids (n = 4). Some second-generation corticosteroids had questionable efficacy vs. placebo or mesalazine (mesalamine), but beclomethasone dipropionate and budesonide MMX demonstrated a comparative benefit. Only beclomethasone dipropionate was similar to conventional corticosteroids for induction of remission and other clinical endpoints. Direct comparative trials for budesonide MMX were unavailable. Second-generation corticosteroids had an overall favourable safety profile, with minimal adverse effects on cardiovascular and metabolic parameters and a low incidence of adverse events. Beclomethasone dipropionate and budesonide MMX provide greater induction of remission in ulcerative colitis than placebo or mesalazine but additional active-comparator trials are needed to firmly establish the efficacy profile vs. systemic corticosteroids. Second-generation corticosteroids have a more favourable safety and tolerability profile than systemic corticosteroids.

P394 Pooled clinical trial analysis of MMX mesalazine safety: Focus on 4.8 g/d dose long-term exposure

Background: Mesalazine (5-aminosalicylic acid) is standard first-line treatment for mild-to-moderate ulcerative colitis (UC), and has been studied for the treatment of diverticulitis (DV). Although there is some evidence of improved efficacy in induction of remission in UC with high-dose treatment, data are limited on the safety of long-term high-dose mesalazine treatment. This analysis examines the safety profile of highdose (4.8 g/d) MMX mesalazine administered for 2 years to patients with DV, pooled from 2 studies. Methods: Two Phase 3, randomized, double-blind, placebocontrolled, multicenter studies (PREVENT1, NCT00545740; PREVENT2, NCT00545103; sponsor, Shire Development LLC) evaluated the efficacy and safety of 3 dose regimens of oncedaily MMX mesalazine (1.2 g, 2.4 g, or 4.8 g) versus placebo in the prevention of recurrent DV in adult patients over a period of 104 wks. Results: A total of 1,182 total patients were enrolled in PREVENT1 and PREVENT2, and 301 were randomized to receive 4.8 g/d MMX mesalazine. Of these, 299 were administered 1 dose of MMX mesalazine (mean [SD] age, 55.6 [11.9] y; 46.8% male). Mean (SD) treatment exposure was 64.4 (42.7)wks. Among patients who received 1 dose of MMX mesalazine, 211 (70.6%) reported 1 treatment-emergent adverse event (TEAE; 1006 events reported); 59 (19.7%) patients experienced only mild TEAEs, 114 (38.1%) experienced TEAEs with a maximum severity of moderate, and 38 (12.7%) experienced severe TEAEs. Serious TEAEs were reported by 32 (10.7%) patients (38 events). A total of 51 (17.1%) patients experienced TEAEs determined to be related to study treatment (102 events), and 4 (1.3%) patients reported serious TEAEs related to study treatment (4 events). A total of 36 (12.0%) patients experienced TEAEs that led to withdrawal from their respective studies. The most frequently reported TEAEs (>5%) were abdominal pain (11.0%), diarrhoea (10.0%), headache (9.3%), back pain (6.3%), urinary tract infection (6.0%), nausea (5.3%), and upper respiratory tract infection (5.3%). Conclusions: Pooled analysis of adverse event data from longterm exposure to MMX mesalazine 4.8 g/d in patients with a history of DV showed that high-dose MMX mesalazine was welltolerated for 2 years.

Are Endoscopic Endpoints Reliable in Therapeutic Trials of Ulcerative Colitis?

The consistency of endoscopic and histologic findings in patients with ulcerative colitis (UC) has not been elucidated. Choice of assessment may affect study outcomes. Post hoc analyses were performed using data from 2 randomized, controlled multicenter trials: (1) SAG-26, mesalazine granules for induction of remission in UC (n = 380), and (2) SAG-27, mesalazine granules for maintenance of UC remission (n = 647). Assessments included Clinical Activity Index, Endoscopic Index, modified Disease Activity Index, and Histology Index. In SAG-26, 52 of 380 patients (13.7%) with clinically (Clinical Activity Index >4) and endoscopically (Endoscopic Index ≥4) active UC showed no histological signs of active inflammation (Histology Index ≤1) at baseline. Among endoscopically and histologically active patients, 246 of 327 (75.2%) reached clinical remission versus 48 of 52 patients (92.3%) with active endoscopy but no inflammation on histology (difference, 17.1%; P = 0.006). The difference in the proportion of patients achieving clinical remission according to endoscopy and histology in clinically inactive (Clinical Activity Index ≤4) patients was 30.8% in SAG-26 (at the study end) and 28.1% in SAG-27 (at baseline). In SAG-27, clinical relapse occurred in 21.2% of patients with endoscopic and histologic remission at baseline and 27.1% of patients with some histological inflammation at baseline (P = 0.111). Using the modified Disease Activity Index ≤1 (mucosal healing) instead of the Endoscopic Index score, the difference was similar (21.2% versus 28.0%, P = 0.073). Endoscopic and histologic assessments differ in both active and inactive UC. Overdiagnosis of inflammation using endoscopy versus histology can significantly affect outcomes, at least in studies using induction of clinical remission as an endpoint. The assessment criteria for trials in UC should be reconsidered.

Review article: ulcerative colitis, smoking and nicotine therapy

Smoking is the best-characterised environmental association of ulcerative colitis (UC). Smoking has been observed to exert protective effects on both the development and progression of UC. To examine the association between UC and smoking, possible pathogenic mechanisms and the potential of nicotine as a therapeutic agent in the treatment of UC. A literature search was conducted through MEDLINE, using the MeSH search terms 'ulcerative colitis' and 'smoking' or 'nicotine'. Relevant articles were identified through manual review. The reference lists of these articles were reviewed to include further appropriate articles. Ulcerative colitis is less prevalent in smokers. Current smokers with a prior diagnosis of UC are more likely to exhibit milder disease than ex-smokers and nonsmokers. There is conflicting evidence for smokers having reduced rates of hospitalisation, colectomy and need for oral corticosteroids and immunosuppressants to manage their disease. Multiple potential active mediators in smoke may be responsible for these clinical effects, including nicotine and carbon monoxide, but the precise mechanism remains unknown. Nicotine has demonstrated variable efficacy in the induction of remission in UC when compared to placebo and conventional medicines. Despite this, the high frequency of adverse events limits its clinical significance. Nicotine's application as a therapeutic treatment in ulcerative colitis is limited. Presently, it may be an option considered only in selected cases of acute ulcerative colitis refractory to conventional treatment options. This review also questions whether nicotine is the active component of smoking that modifies risk and inflammation in ulcerative colitis.

Extended-Release Mesalamine Granules for Ulcerative Colitis

To evaluate the efficacy and safety of extended-release mesalamine granules in the maintenance of remission in ulcerative colitis (UC). Literature was obtained through searches of MEDLINE (1990-June 2012) using the terms mesalamine granules, ulcerative colitis, Apriso, and Salofalk. Bibliographies from retrieved articles were searched for additional citations. All English-language articles reporting on use of extended-release mesalamine granules in humans identified through the search were evaluated and included. The preferred initial treatment for induction and maintenance of remission in mild to moderate UC is agents from the 5-aminosalicylate class (balsalazide, mesalamine, olsalazine, sulfasalazine). Mesalamine granules are available as an encapsulated product in the US and as a nonencapsulated formulation in Europe. Data evaluating encapsulated mesalamine granules for induction of remission are lacking; however, the European mesalamine granule formulation has been evaluated for induction of remission. Patients receiving mesalamine granules for induction achieved clinical and endoscopic remission more frequently than those receiving placebo. Two pivotal, randomized, double-blind, placebo-controlled, multicenter studies have evaluated encapsulated mesalamine granules for maintenance in 562 adults in remission from UC. In both studies, the proportion of patients who remained relapse-free at 6 months was higher for those receiving encapsulated mesalamine granules than placebo. Mesalamine granules are well tolerated, with headache, nausea, and upper respiratory infections being the most frequently reported adverse effects. Current evidence supports the use of extended-release mesalamine granules for maintenance of remission in mild to moderate UC. Further studies are necessary to examine the ideal dose and regimen of encapsulated mesalamine granules for induction of remission in UC.

Induction of Remission in Ulcerative Colitis with Dabigatran: A Case Report

Purpose: To report the first case of inducing remission in ulcerative colitis (UC) with dabigatran, a direct thrombin inhibitor. A 54-year-old man with a long history of steroid-dependent UC presents with dyspnea. A chest CT reveals an acute pulmonary embolism. Treatment with warfarin is begun, but later stopped due to the inconvenience of monitoring; dabigatran, an oral direct thrombin inhibitor, is started. Shortly after beginning therapy with dabigatran, the symptoms of UC improve with normalization of bowel habits. A subsequent colonoscopy reveals healing of colitis with marked improvement in endoscopic inflammation. The patient is able to discontinue steroids for the first time in 21 years. He remains on dabigatran and continues in remission for one year off steroids on maintenance mesalamine. There are reports of induction of remission of UC with unfractionated and low molecular weight heparin, findings thought due to the anti-inflammatory effects of heparin, rather than to its anticoagulant effects. This represents the first known report describing induction of remission in UC with dabigatran, a direct thrombin inhibitor. The mechanism of action for dabigatran in UC is uncertain; however, in a murine model of interstitial lung disease, dabigatran has been associated with reduced levels of transforming growth factor-β1 and platelet derived growth factor, both proteins implicated in the pathogenesis of inflammatory bowel disease. How the anticoagulant effects of dabigatran relate to healing of UC in this patient remains unclear. Direct thrombin inhibitors, such as dabigatran, may represent a novel therapeutic class in the treatment of ulcerative colitis.Figure: [1253] Colitis, prior to dabigatran.Figure: [1253] Healed colitis, post dabigatran use.

Probiotics for maintenance of remission in ulcerative colitis

<h3>Background</h3> Several studies have demonstrated the importance of intestinal bacterial flora in the pathogenesis of inflammatory bowel disease. It has therefore been suggested that modifying the bacterial flora with probiotics will attenuate the inflammatory process and prevent relapses in ulcerative colitis (UC). <h3>Aim</h3> To evaluate the available evidence on the use of probiotics for the maintenance of remission in UC and to assess the occurrence of adverse events associated with the use of probiotics. <h3>Design</h3> Systematic review and meta-analysis of randomised controlled trials (RCTs) published between 1966 and October 2009. <h3>Methods</h3> Data sources were MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Inflammatory Bowel Disease Specialised Register, and reference lists of retrieved articles. We aimed to include trials which compared probiotics with either placebo or other interventions. Data extraction and assessment of methodological quality were performed independently by two reviewers. <h3>Results</h3> Three RCTs met the inclusion criteria. All three trials compared probiotics with mesalazine and no placebo-controlled studies were identified. Meta-analysis of the results of the three RCTs, which involved 555 patients, showed no statistically significant difference in relapse rates between patients who received probiotics and those who received mesalazine (pooled odds ratio 1.45, 95% CI 0.99 to 2.13). The incidence of adverse events was not statistically significantly different between the probiotic and mesalazine groups (pooled odds ratio 1.21, 95% CI 0.80 to 1.84). <h3>Conclusion</h3> The available evidence does not demonstrate a statistically significant difference between probiotics and mesalazine for the maintenance of remission in UC. However, two of the included studies had relatively small sample sizes and there is insufficient evidence to make any definite conclusions about the efficacy of probiotics for induction of remission in UC. Further well-designed randomised controlled trials including those that compare probiotics with placebo are needed to investigate whether probiotics are effective for the maintenance of remission in UC.

MMX Mesalamine for the Treatment of Active Mild-to-Moderate Ulcerative Colitis

Purpose: Current mesalamine (5-ASA) treatments for ulcerative colitis (UC) are often associated with complex dosing regimens that may lead to poor compliance and reduced efficacy. SPD476–302, a randomized, placebo-controlled, phase III study recently demonstrated the efficacy of MMX™ mesalamine (SPD476), a high-strength (1.2g/tablet) 5-ASA formulation designed for once-daily dosing, in inducing remission in patients with mild-to-moderately active UC. Given the importance of evidence-based medicine for patient care, number needed to treat (NNT) analyses are frequently used for making treatment decisions in clinical practice. The purpose of this analysis is to assess the NNT associated with MMX mesalamine-related induction of remission in UC. Methods: In study SPD476–302, patients with mild-to-moderate UC received MMX mesalamine 2.4g/day given once daily (QD), MMX mesalamine 4.8g/day given QD, Asacol® given three times daily (TID) or placebo. The primary endpoint was clinical and endoscopic remission (modified UC-disease activity index score of ≤1, with a rectal bleeding and stool frequency score of 0, no mucosal friability, and ≥1 point reduction in sigmoidoscopy score from baseline) after 8 weeks' treatment. An NNT analysis was completed for remission at 8 weeks. Results: See table.Table: Evidence-based analysis of remission.Conclusions: NNT analysis shows that, versus placebo, for one patient with mild-to-moderately active UC to achieve clinical and endoscopic remission (using stringent criteria) at week 8, six patients need to be treated with MMX mesalamine (2.4g/day or 4.8g/day given QD) while 10 patients need to be treated with Asacol 2.4g/day given TID. This research was funded by Shire Pharmaceuticals Inc., Wayne, PA, USA