Aliment Pharmacol Ther 2011; 34: 113–124
Summary
Background There is no international agreement on scoring systems used to measure disease activity in ulcerative colitis, nor is there a validated ...definition for disease remission.
Aim To review the principles and components for defining remission in ulcerative colitis and propose a definition that will help improve patient outcomes.
Methods A review of current standards of remission from the perspective of clinical trials, guidelines, clinical practice and patients was conducted by the authors. Selected literature focused on the components of a definition of remission, the utility of a definition and treatment strategies, based on current definitions.
Results Different definitions of remission affect the assessment of outcome and make it difficult to compare trials. In the clinic, endoscopy is rarely used to confirm remission, because mucosal healing has only recently begun to be related to the duration of subsequent remission in a way that will affect clinical practice. Histopathology may be the ultimate arbiter of mucosal healing. There is no agreement on the definition of remission in current guidelines. Patient‐defined remission may predict endoscopic remission, but has yet to be shown to predict duration of remission.
Conclusions A standard based on clinical symptoms and endoscopy is proposed. Histopathology is a third dimension of remission that may have prognostic value. The definition of remission should help predict long‐term outcome. The expectations of patients and their physicians need to be raised, as the goal of treatment of active ulcerative colitis should be to induce remission.
Parenteral methotrexate induces clinical remission but not endoscopic improvement of mucosal inflammation in patients with ulcerative colitis (UC). We performed a randomized, placebo-controlled trial ...to assess the efficacy of parenteral methotrexate in maintaining steroid-free response or remission in patients with UC after induction therapy with methotrexate and steroids.
We performed a 48-week trial, from February 2012 through May 2016, of 179 patients with active UC (Mayo score of 6–12 with endoscopy subscore ≥ 2) despite previous conventional or biological therapy. The study comprised a 16-week open label methotrexate induction period followed by a 32-week double-blind, placebo-controlled maintenance period. Patients were given subcutaneous methotrexate (25 mg/wk) and a 12-week steroid taper. At week 16, steroid-free responders were randomly assigned to groups that either continued methotrexate (25 mg/wk, n = 44) or were given placebo (n = 40) until week 48. We compared the efficacy of treatment by analyzing the proportion of patients who remained relapse free and were in remission at week 48 without use of steroids or other medications to control disease activity.
Ninety-one patients (51%) achieved response at week 16, and 84 patients were included in the maintenance period study. During this period, 60% of patients in the placebo group (24/40) and 66% in the methotrexate group (29/44) had a relapse of UC (P = .75). At week 48, 30% of patients in the placebo group (12/40) and 27% of patients in the methotrexate group (12/44) were in steroid-free clinical remission without need for additional therapies (P = .86). No new safety signals for methotrexate were detected.
Parenteral methotrexate (25 mg/wk) was not superior to placebo in preventing relapses of UC in patients who achieved steroid-free response during induction therapy. ClinicalTrials.gov, Number: NCT01393405.
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To determine the diagnostic accuracy of magnetic resonance cholangiopancreatography (MRCP) for detection of primary sclerosing cholangitis (PSC) in patients with biochemical cholestasis.
Two ...reviewers searched MEDLINE, EMBASE, and other electronic databases to identify prospective studies in which MRCP was evaluated and compared with endoscopic retrograde cholangiopancreatography (ERCP), clinical examination, and/or histologic analysis for diagnosis of PSC in cholestasis and control cases. Main study inclusion criteria were (a) use of ERCP or percutaneous transhepatic cholangiography (PTC) as part of the reference standard for the diagnosis of PSC, (b) inclusion of patients with hepatobiliary disease other than PSC (ie, nonhealthy control subjects), (c) blinding of MRCP image readers to reference-standard results, (d) prospective study with ERCP or MRCP performed after subject recruitment into the study, and (e) inclusion of raw data (for true-positive, false-positive, true-negative, and false-negative results) that could be found or calculated from the original study data. Major exclusion criteria were duplicate article (on a primary study) that contained all or some of the original study data and inclusion of fewer than 10 patients with PSC. Methodologic quality was assessed by using the Quality Assessment of Diagnostic Accuracy Studies tool. Bivariate random-effects meta-analytic methods were used to estimate summary, sensitivity, specificity, and receiver operating characteristic (ROC) curves.
Six manuscripts with 456 subjects (with 623 independent readings)--185 with PSC--met the study inclusion criteria. The summary area under the ROC curve was 0.91. High heterogeneity (inconsistency index, 78%) was found but became moderate (inconsistency index, 36%) with the exclusion of one study in which the diagnostic threshold was set for high sensitivity. There was no evidence of publication bias (P = .27, bias coefficient analysis). Sensitivity and specificity of MRCP for PSC detection across all studies were 0.86 and 0.94, respectively. Positive and negative likelihood ratios with MRCP were 15.3 and 0.15, respectively. In patients with high pretest probabilities, MRCP enabled confirmation of PSC; in patients with low pretest probabilities, MRCP enabled exclusion of PSC. Worst-case-scenario (pretest probability, 50%) posttest probabilities were 94% and 13% for positive and negative MRCP results, respectively.
MRCP has high sensitivity and very high specificity for diagnosis of PSC. In many cases of suspected PSC, MRCP is sufficient for diagnosis, and, thus, the risks associated with ERCP can be avoided.
Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in ...patients with moderate-to-severe Crohn's disease (CD).
We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study.
180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments.
Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib.
NCT01393626 and NCT01393899.
Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD) that is usually the consequence of chronic inflammation. Although the currently available anti-inflammatory therapies ...have had little impact on intestinal fibrosis in Crohn’s disease (CD), increased understanding of the pathophysiology and the development of therapies targeting fibrogenic pathways hold promise for the future. One of the critical challenges is how reduction or reversal of intestinal fibrosis should be defined and measured in the setting of clinical trials and drug approval. The International Organization for Inflammatory Bowel Disease (IOIBD) organized a workshop in Amsterdam, The Netherlands, on December 19th and 20th, 2018 in an attempt to review the current knowledge of the biological background, diagnosis, treatment of intestinal fibrosis and clinical trial endpoints. Basic and clinical scientists discussed the pathophysiology of intestinal fibrosis, the current status of biomarkers and imaging modalities in stenosing CD, and recent clinical studies in this area. Researchers from outside of the IBD field presented advances in the understanding of fibrotic processes in other organs, such as the skin, liver and lungs. Lastly, the design of clinical trials with antifibrotic therapy for IBD was discussed, with priority on patient populations, patient reported outcomes (PROs) and imaging. This report summarizes the key findings, discussions and conclusions of the workshop.
Abstract
Objective
It is difficult to predict relapse in quiescent ulcerative colitis (UC), but newer endoscopic and histological indices could improve this. This study aimed to determine in UC ...patients in clinical remission (1) the prevalence of active endoscopic and histological disease; (2) the correlation between endoscopic and histological scores; and (3) the predictive power of these scores for clinical relapse.
Design
This multicenter prospective cohort study conducted by the Crohn’s and Colitis Foundation Clinical Research Alliance included 100 adults with UC in clinical remission undergoing surveillance colonoscopy for dysplasia. Endoscopic activity was assessed using the Mayo endoscopic score (MES), ulcerative colitis endoscopic index of severity (UCEIS), and ulcerative colitis colonoscopic index of severity (UCCIS). Histology was assessed with the Riley index subcomponents, total Riley score, and basal plasmacytosis.
Results
Only 5% of patients had an MES of 0, whereas 38% had a score of 2 to 3; using the UCEIS, the majority of patients had at least mild activity, and 15% had more severe activity. Many patients also had evidence of histological disease activity. The correlations among endoscopic indices, histological subcomponents, and total score were low; the highest correlations occurred with the subcomponent architectural irregularity (ρ = 0.43–0.44), total Riley score (ρ = 0.35–0.37), and basal plasmacytosis (ρ = 0.35–0.36). Nineteen patients relapsed clinically over 1 year, with the subcomponent architectural irregularity being the most predictive factor (P = 0.0076).
Conclusions
This multicenter prospective study found a high prevalence of both endoscopic and histological disease activity in clinically quiescent UC. The correlations between endoscopy and histology were low, and the power to predict clinical relapse was moderate.
Assessing risk of adverse outcomes among patients with chronic liver disease has been challenging due to non-linear disease progression. We previously developed accurate prediction models for ...fibrosis progression and clinical outcomes among patients with advanced chronic hepatitis C (CHC). The primary aim of this study was to validate fibrosis progression and clinical outcomes models among a heterogeneous patient cohort.
Adults with CHC with ≥3 years follow-up and without hepatic decompensation, hepatocellular carcinoma (HCC), liver transplant (LT), HBV or HIV co-infection at presentation were analyzed (N = 1007). Outcomes included: 1) fibrosis progression 2) hepatic decompensation 3) HCC and 4) LT-free survival. Predictors included longitudinal clinical and laboratory data. Machine learning methods were used to predict outcomes in 1 and 3 years.
The external cohort had a median age of 49.4 years (IQR 44.3-54.3); 61% were male, 80% white, and 79% had genotype 1. At presentation, 73% were treatment naïve and 31% had cirrhosis. Fibrosis progression occurred in 34% over a median of 4.9 years (IQR 3.2-7.6). Clinical outcomes occurred in 22% over a median of 4.4 years (IQR 3.2-7.6). Model performance for fibrosis progression was limited due to small sample size. The area under the receiver operating characteristic curve (AUROC) for 1 and 3-year risk of clinical outcomes was 0.78 (95% CI 0.73-0.83) and 0.76 (95% CI 0.69-0.81).
Accurate assessments for risk of clinical outcomes can be obtained using routinely collected data across a heterogeneous cohort of patients with CHC. These methods can be applied to predict risk of progression in other chronic liver diseases.
Background
Low rates of compliance with quality measures for inflammatory bowel disease (IBD) have been reported for US gastroenterologists.
Aims
We assessed the influence of quality improvement (QI) ...education on compliance with physician quality reporting system (PQRS) measures for IBD and measures related to National Quality Strategy (NQS) priorities.
Methods
Forty community-based gastroenterologists participated in the QI study; 20 were assigned to educational intervention and control groups, respectively. At baseline, randomly selected charts of patients with moderate-to-severe ulcerative colitis were retrospectively reviewed for the gastroenterologists’ performance of 8 PQRS IBD measures and 4 NQS-related measures. The intervention group participated in a series of accredited continuing medical education (CME) activities focusing on QI. Follow-up chart reviews were conducted 6 months after the CME activities. Independent
t
tests were conducted to compare between-group differences in baseline-to-follow-up rates of documented compliance with each measure.
Results
The analysis included 299 baseline charts and 300 follow-up charts. The intervention group had significantly greater magnitudes of improvement than the control group for the following measures: assessment of IBD type, location, and activity (+14 %,
p
= 0.009); influenza vaccination (+13 %,
p
= 0.025); pneumococcal vaccination (+20 %,
p
= 0.003); testing for latent tuberculosis before anti-TNF-α therapy (+10 %,
p
= 0.028); assessment of hepatitis B virus status before anti-TNF-α therapy (+9 %,
p
= 0.010); assessment of side effects (+17 %,
p
= 0.048), and counseling patients about cancer risks (+13 %,
p
= 0.013).
Conclusions
QI-focused CME improves community-based gastroenterologists’ compliance with IBD quality measures and measures aligned with NQS priorities.
Objectives Missing laboratory data is a common issue, but the optimal method of imputation of missing values has not been determined. The aims of our study were to compare the accuracy of four ...imputation methods for missing completely at random laboratory data and to compare the effect of the imputed values on the accuracy of two clinical predictive models. Design Retrospective cohort analysis of two large data sets. Setting A tertiary level care institution in Ann Arbor, Michigan. Participants The Cirrhosis cohort had 446 patients and the Inflammatory Bowel Disease cohort had 395 patients. Methods Non-missing laboratory data were randomly removed with varying frequencies from two large data sets, and we then compared the ability of four methods—missForest, mean imputation, nearest neighbour imputation and multivariate imputation by chained equations (MICE)—to impute the simulated missing data. We characterised the accuracy of the imputation and the effect of the imputation on predictive ability in two large data sets. Results MissForest had the least imputation error for both continuous and categorical variables at each frequency of missingness, and it had the smallest prediction difference when models used imputed laboratory values. In both data sets, MICE had the second least imputation error and prediction difference, followed by the nearest neighbour and mean imputation. Conclusions MissForest is a highly accurate method of imputation for missing laboratory data and outperforms other common imputation techniques in terms of imputation error and maintenance of predictive ability with imputed values in two clinical predicative models.
The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical ...characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.
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