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Comparative efficacy and tolerability of pharmacological agents for management of mild to moderate ulcerative colitis: a systematic review and network meta-analyses.

ABSTRACT: BACKGROUND:The majority of patients with ulcerative colitis have mildly to moderately active disease. To inform the management of patients with left-sided or extensive mildly to moderately active ulcerative colitis, we assessed the comparative efficacy and tolerability of different therapies. METHODS:In this systematic review and network meta-analysis, we searched Epub, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and Web of Science from inception to Dec 14, 2015, and updated on MEDLINE on March 1, 2018, for randomised controlled trials in adults (age ?17 years) with left-sided or extensive mild to moderate ulcerative colitis. Studies were included if patients were treated with oral sulfasalazine, diazo-bonded 5-aminosalicylates (5-ASAs), mesalazine (low dose <2 g/day, standard dose 2-3 g/day, or high dose >3 g/day), controlled ileal-release budesonide, or budesonide multimatrix, alone or in combination with rectal 5-ASA therapy, and were compared with each other or placebo for induction or maintenance of clinical remission. The minimum duration of therapy was 4 weeks for trials of induction and 24 weeks for trials of maintenance therapy. We did pairwise and random-effects network meta-analysis using a frequentist approach, and calculated odds ratios (ORs) and 95% CIs; agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to appraise quality of evidence. We examined heterogeneity with the I2 statistic. FINDINGS:Our search identified 1316 unique studies, from which 75 randomised trials with 12?215 patients were eligible for analysis. Based on 48 induction randomised trials (8020 participants) that met inclusion criteria, combined oral and rectal 5-ASAs (SUCRA 0·99) and high-dose mesalazine (>3 g/day; SUCRA 0·82) were ranked highest for induction of remission. Both interventions were superior to standard-dose mesalazine (2-3 g/day; failure to induce remission with combined oral and rectal 5-ASAs OR 0·41, 95% CI 0·22-0·77; high-dose mesalazine 0·78, 0·66-0·93) with moderate confidence in estimates. On the basis of 28 randomised trials (4218 participants) that met inclusion criteria, all interventions were superior to placebo for maintenance of remission; however, neither combined oral and rectal 5-ASAs nor high-dose mesalazine were superior to standard-dose mesalazine. INTERPRETATION:In patients with mildly to moderately active left-sided or extensive ulcerative colitis, combined oral and topical mesalazine therapy and high-dose mesalazine are superior to standard-dose mesalazine for induction of remission, but not maintenance of remission. Standard-dose mesalazine might be preferred for maintenance in most patients. FUNDING:None.

SUBMITTER: Nguyen NH

PROVIDER: S-EPMC6821871 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Comparative efficacy and tolerability of pharmacological agents for management of mild to moderate ulcerative colitis: a systematic review and network meta-analyses.

Nguyen Nghia H NH Fumery Mathurin M Dulai Parambir S PS Prokop Larry J LJ Sandborn William J WJ Murad Mohammad Hassan MH Singh Siddharth S

The lancet. Gastroenterology & hepatology 20180817 11

<h4>Background</h4>The majority of patients with ulcerative colitis have mildly to moderately active disease. To inform the management of patients with left-sided or extensive mildly to moderately active ulcerative colitis, we assessed the comparative efficacy and tolerability of different therapies.<h4>Methods</h4>In this systematic review and network meta-analysis, we searched Epub, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trial ...[more]

PMID: 30122356

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Project description:A subset of patients with ulcerative colitis (UC) present with, or progress to, moderate to severe disease activity. These patients are at high risk for colectomy, hospitalization, corticosteroid dependence, and serious infections. The risk of life-threatening complications and emergency colectomy is particularly high among those patients hospitalized with acute severe ulcerative colitis. Optimal management of outpatients or inpatients with moderate to severe UC often requires the use of immunomodulator and/or biologic therapies, including thiopurines, methotrexate, cyclosporine, tacrolimus, TNF-? antagonists, vedolizumab, tofacitnib, or ustekinumab, either as monotherapy or in combination (with immunomodulators), to mitigate these risks. Decisions about optimal drug therapy in moderate to severe UC are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Therefore, the American Gastroenterological Association prioritized development of clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the Grading of Recommendations Assessment, Development and Evaluation framework. Focused questions in adult outpatients with moderate to severe UC included: (1) overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to TNF-? antagonists, (2) comparative efficacy and safety of biologic monotherapy vs combination therapy with immunomodulators, (3) comparative efficacy of top-down (upfront use of biologics and/or immunomodulator therapy) vs step-up therapy (acceleration to biologic and/or immunomodulator therapy only after failure of 5-aminosalicylates, and (4) role of continuing vs stopping 5-aminosalicylates in patients being treated with immunomodulator and/or biologic therapy for moderate to severe UC. Focused questions in adults hospitalized with acute severe ulcerative colitis included: (5) overall and comparative efficacy of pharmacologic interventions for inpatients refractory to corticosteroids, in reducing risk of colectomy, (6) optimal dosing regimens for intravenous corticosteroids and infliximab in these patients, and (7) role of adjunctive antibiotics in the absence of confirmed infections.

Project description:Background & aimsLittle is known about the association between rectal bleeding and increased stool frequency with endoscopic findings in patients with mild to moderate ulcerative colitis (UC). We evaluated the associations between rectal bleeding or stool frequency and endoscopic remission in this population.MethodsWe performed a post-hoc analysis of data from a phase 3 non-inferiority trial of 817 adults with mild to moderate UC who received treatment with mesalazine. We obtained information on rectal bleeding, stool frequency, and Mayo endoscopic subscores (MESs) at weeks 0, 8, and 38. The sensitivity, specificity, and positive and negative predictive values with which rectal bleeding and stool frequency identified patients with MESs of 0 and/or 1 were calculated at weeks 8 and 38 of treatment. The associations between change in rectal bleeding and stool frequency and change in MES after treatment were quantified using the Spearman's rank correlation coefficient.ResultsAmong patients with a MES of 0, 7/82 patients (9%) had a rectal bleeding score of 1 or more and 40/82 patients (49%) had a stool frequency score of 1 or more at week 8; at week 38, 6/167 patients (4%) had a rectal bleeding score of 1 or more and 63/167 patients (38%) had a stool frequency score of 1 or more. Among patients with MESs of 0 or 1, 50/310 patients (16%) had a rectal bleeding score of 1 or more and 162/310 patients (52%) had had a stool frequency score of 1 or more at week 8; at week 38, 18/363 patients (5%) had a rectal bleeding score of 1 or more and 141/363 patients (39%) had a stool frequency score of 1 or more. The Spearman rank correlation coefficients for change in rectal bleeding and stool frequency with change in MES at week 8 were 0.39 (95% CI, 0.32-0.45) and 0.34 (95% CI, 0.27-0.40), respectively. In patients with reduced MESs at week 8, 39/389 patients (10%) had unchanged or worsening rectal bleeding and 81/389 patients (21%) had unchanged or increasing stool frequencies.ConclusionsIn a post-hoc analysis of data from a phase 3 trial of adults with mild to moderate UC treated with mesalazine, we found absence of rectal bleeding to identify patients in endoscopic remission. However, many patients in remission still have increased stool frequency, indicating that it may not be a sensitive marker of disease activity in patients with mild to moderate UC.

Project description:Background & aimsFirmicutes bacteria produce metabolites that maintain the intestinal barrier and mucosal immunity. Firmicutes are reduced in the intestinal microbiota of patients with ulcerative colitis (UC). In a phase 1b trial of patients with UC, we evaluated the safety and efficacy of SER-287, an oral formulation of Firmicutes spores, and the effects of vancomycin preconditioning on expansion (engraftment) of SER-287 species in the colon.MethodsWe conducted a double-blind trial of SER-287 in 58 adults with active mild-to-moderate UC (modified Mayo scores 4-10, endoscopic subscores ?1). Participants received 6 days of preconditioning with oral vancomycin (125 mg, 4 times daily) or placebo followed by 8 weeks of oral SER-287 or placebo. Patients were randomly assigned (2:3:3:3) to groups that received placebo followed by either placebo or SER-287 once weekly, or vancomycin followed by SER-287 once weekly, or SER-287 once daily. Clinical end points included safety and clinical remission (modified Mayo score ?2; endoscopic subscores 0 or 1). Microbiome end points included SER-287 engraftment (dose species detected in stool after but not before SER-287 administration). Engraftment of SER-287 and changes in microbiome composition and associated metabolites were measured by analyses of stool specimens collected at baseline, after preconditioning, and during and 4 weeks after administration of SER-287 or placebo.ResultsProportions of patients with adverse events did not differ significantly among groups. A higher proportion of patients in the vancomycin/SER-287 daily group (40%) achieved clinical remission at week 8 than patients in the placebo/placebo group (0%), placebo/SER-287 weekly group (13.3%), or vancomycin/SER-287 weekly group (17.7%) (P = .024 for vancomycin/SER-287 daily vs placebo/placebo). By day 7, higher numbers of SER-287 dose species were detected in stool samples from all SER-287 groups compared with the placebo group (P < .05), but this difference was not maintained beyond day 7 in the placebo/SER-287 weekly group. In the vancomycin groups, a greater number of dose species were detected in stool collected on day 10 and all subsequent time points through 4 weeks post dosing compared with the placebo group (P < .05). A higher number of SER-287 dose species were detected in stool samples on days 7 and 10 from subjects who received daily vs weekly SER-287 doses (P < .05). Changes in fecal microbiome composition and metabolites were associated with both vancomycin/SER-287 groups.ConclusionsIn this small phase 1b trial of limited duration, the safety and tolerability of SER-287 were similar to placebo. SER-287 after vancomycin was significantly more effective than placebo for induction of remission in patients with active mild to moderate UC. Engraftment of dose species was facilitated by vancomycin preconditioning and daily dosing of SER-287. ClinicalTrials.gov ID NCT02618187.

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Comparative efficacy and tolerability of pharmacological agents for management of mild to moderate ulcerative colitis: a systematic review and network meta-analyses.

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Comparative efficacy and tolerability of pharmacological agents for management of mild to moderate ulcerative colitis: a systematic review and network meta-analyses.

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