Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn’s disease

Background Crohn’s disease (CD) is a chronic relapsing inflammatory condition. Many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues have been used to maintain surgically-induced remission in CD, but the effectiveness of these agents is unclear. Objectives The objectives were to evaluate the efficacy and safety of purine analogues for maintenance of surgically-induced remission in CD. Search methods We searched the following databases from inception to 30 April 2014: PubMed, MEDLINE, EMBASE, CENTRAL, and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register).We also searched the reference lists of all included studies, and contacted personal sources and drug companies to identify additional studies. The searches were not limited by language. Selection criteria Randomised controlled trials (RCTs) that compared purine analogues to placebo or another intervention, with treatment durations of at least six months were considered for inclusion. Participants were patients of any age with CD in remission following surgery. Data collection and analysis Two authors independently assessed trial eligibility and extracted data. Methodological quality was assessed using the Cochrane risk of bias tool. The primary outcome measures were clinical and endoscopic relapse as defined by the primary studies. Secondary outcomes included adverse events, withdrawal due to adverse events and serious adverse events. Data were analysed on an intention-to-treat basis where patients with missing final outcomes were assumed to have relapsed. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. The Chi2 and I2 statistics were used to assess heterogeneity. The overall quality of the evidence supporting the primary outcomes and selected secondary outcomes was assessed using the GRADE criteria. Main results Seven RCTs (n = 584 patients) were included in the review. Three studies compared azathioprine to 5-aminosalicylic acid (5-ASA).One small study compared azathioprine to both 5-ASA and adalimumab. One study compared azathioprine to placebo and another study compared 6-mercaptopurine to 5-ASA and placebo. One small study compared azathioprine to infliximab. Three studies were judged to be at low risk of bias. Four studies were judged to be at high risk of bias due to blinding. The study (n = 22) comparing azathioprine to infliximab found that the effects on the proportion of patients who had a clinical (RR 2.00, 95% CI 0.21 to 18.98) or endoscopic relapse (RR 4.40, 95% CI 0.59 to 3.07) were uncertain. One study (n = 33) found decreased clinical (RR 5.18, 95% CI 1.35 to 19.83) and endoscopic relapse (RR 10.35, 95% CI 1.50 to 71.32) rates favouring adalimumab over azathioprine. A pooled analysis of two studies (n = 168 patients) showed decreased clinical relapse rates at one or two years favouring purine analogues over placebo. Forty eight per cent of patients in the purine analogue group experienced a clinical relapse compared to 63% of placebo patients (RR 0.74, 95% CI 0.58 to 0.94). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to high risk of bias (one study was single-blind) and sparse data (93 events). One study (87 patients) found a reduction in endoscopic relapse rates favouring 6-mercaptopurine over placebo. Seventeen per cent of 6-mercaptopurine patients had an endoscopic relapse at two years compared to 42% of placebo patients (RR 0.40, 95% CI 0.19 to 0.83). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (25 events). A pooled analysis of five studies (n = 425 patients) showed no difference in clinical relapse rates at one or two years between purine analogues and 5-ASA agents. Sixty-three per cent of patients in the purine analogues group experienced a clinical relapse compared to 54% of 5-ASA patients (RR 1.15, 95% CI 0.99 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to high risk of bias (two open-label studies), sparse data (249 events) and moderate heterogeneity (I2 = 45%). There was no difference in endoscopic relapse at 12 months between azathioprine and 5-ASA (RR 0.78, 95% CI 0.52 to 1.17; 1 study, 35 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to high risk of bias (open-label study) and very sparse data (26 events). There was a reduction in endoscopic relapse at 24 months favouring 6-mercaptopurine over 5-ASA patients. Seventeen per cent of 6-mercaptopurine patients had an endoscopic relapse compared to 48% of 5-ASA patients (RR 0.36, 95% CI 0.18 to 0.72; 1 study, 91 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (29 events). Adverse events that required withdrawal were more common in the purine analogue group compared to 5-ASA. Twenty per cent of patients in the purine analogue group withdrew due to adverse events compared to 10% of 5-ASA patients (RR 2.07, 95% CI 1.26 to 3.39; 5 studies, 423 patients).The results for withdrawal due to adverse events between purine analogues and placebo or for other comparisons were uncertain. Commonly reported adverse events across all studies included leucopenia, arthralgia, abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis, anaemia, exacerbation of Crohn’s disease, nasopharyngitis, and flatulence. Authors’ conclusions Purine analogues may be superior to placebo for maintenance of surgically-induced remission in patients with CD, although this is based on two small studies. The results for efficacy outcomes between purine analogues and 5-ASA agents were uncertain. However, patients taking purine analogues were more likely than 5-ASA patients to discontinue therapy due to adverse events. No firm conclusions can be drawn from the two small studies that compared azathioprine to infliximab or adalimumab. Adalimumab may be superior to azathioprine but further research is needed to confirm these results. Further research investigating the efficacy and safety of azathioprine and 6-mercaptopurine in comparison to other active medications in patients with surgically-induced remission of CD is warranted

“Dramatische taalvaardigheid” and how to remediate it - Developing and evaluating a remedial writing programme in a Dutch-medium secondary school

This study is a piece of practitioner-research that investigates the impact of an intervention that incorporates a process-based view on writing and Self-Regulated Strategies Development. The participants were final-year pupils in a Dutch-medium school in Brussels, Belgium, with a multilingual background. Following the principles of action research, the project has taken a cyclical approach. In a first cycle, the available literature was surveyed to develop a fitting remedial writing programme. This was implemented during an additional weekly remedial lesson over a period of three weeks and consisted of small-group (4 pupils) need-based support and ad hoc modelling of strategic writing behaviour by the tutor. The assignment was a collaboration with the economics teacher, employing writing as a tool to learn. Analysis of the teacher diary and a focus group interview with the tutees found that the intervention lacked sufficient structure and that more explicit attention to metacognition was required. To overcome these shortcomings, in the second cycle, the acrostic OREO was introduced to incorporate explicit verbalisations of strategic behaviour at the level of the paragraph, the text and the writing process. Seven pupils received remediation following the OREO method and engaged in cross-curricular writing for two assignments, each consisting of three weeks of dedicated support for one period a week. A mixed methodology was used to assess the impact of the intervention on learners’ writing proficiency (measured in terms of complexity, accuracy and fluency), self-efficacy and self-regulated strategy use when writing in Dutch. Data were collected via a survey, focus group, keystroke logging, stimulated recall and an interview pre- and post-treatment. No improvement in complexity and accuracy was found but fluency showed a positive trend in all tutees for whom keystroke logging data were available (n: 4). Pupils reported increased self-efficacy in the focus group and an increase in strategy use was observed in the stimulated recall and interview, though these changes were not visible in the quantitative data. The study concludes that the school’s envisaged aim for remediation -being tailor-made support for pupils’ individual language issues- is difficult to reconcile with the heterogeneity of the class-group. It also indicates that the school is not sufficiently aware of these discrepancies in pupils’ proficiency, in the absence of any form of standardized or benchmarked testing, and hence does not have a clear idea of which pupils are in need of extra support. Accordingly, a call for further research establishing a normative database for proficiency measures, including for multilingual learners, is made. The findings indicate that the strategies included in the OREO approach and its use of writing as a tool to learn in other subjects can fill a lacuna that is currently present in the teaching of writing both in the language classroom and in other subjects. Further research for more extended periods of time, with more participants and a control group is now advised, to further explore how an intervention of this kind can impact the writing of adolescent multilingual learners

A prospective evaluation of the predictive value of faecal calprotectin in quiescent Crohn’s disease

Background: The faecal calprotectin (FC) test is a non-invasive marker for gastrointestinal inflammation. Aim: To determine whether higher FC levels in individuals with quiescent Crohn’s disease are associated with clinical relapse over the ensuing 12 months.<p></p> Methods: A single centre prospective study was undertaken in Crohn's disease patients in clinical remission attending for routine review. The receiver operating characteristic (ROC) curve for the primary endpoint of clinical relapse by 12 months, based on FC at baseline, was calculated. Kaplan-Meier curves of time to relapse were based on the resulting optimal FC cutoff for predicting relapse.<p></p> Results: Of 97 patients recruited, 92 were either followed up for 12 months without relapsing, or reached the primary endpoint within that period. Of these, 10 (11%) had relapsed by 12 months. The median FC was lower for non-relapsers, 96µg/g (IQR 39-237), than for relapsers, 414µg/g (IQR 259-590), (p=0.005). The area under the ROC curve to predict relapse using FC was 77.4%. An optimal cutoff FC value of 240µg/g to predict relapse of quiescent Crohn’s had sensitivity of 80.0% and specificity of 74.4%. Negative predictive value was 96.8% and positive predictive value was 27.6%. FC≥240μg/g was associated with likelihood of relapse 5.7 (95% CI 1.9-17.3) times higher within 2.3 years than lower values (p=0.002).<p></p> Conclusions: In this prospective dataset, FC appears to be a useful, non-invasive tool to help identify quiescent Crohn’s disease patients at a low risk of relapse over the ensuing 12 months. FC of 240µg/g was the optimal cutoff in this cohort.<p></p&gt

Current misunderstandings in the management of ulcerative colitis

Past and ongoing therapeutic concepts for ulcerative colitis have only been moderately successful. A significant proportion of patients with ulcerative colitis will still have to undergo colectomy and overall half of the patients do not achieve sustained remission, leading to impairment of physical and mental health, social life, employment issues and sexual activity. Reluctance to treat patients early on with sufficiently potent drug regimens is obvious. Several popular misconceptions might have led to this situation. First, ulcerative colitis is still considered a more 'benign' disease than Crohn's disease. Furthermore, the general assumption is often that colectomy can 'cure' the disease. Mucosal healing as a therapeutic target has not been widely accepted. Finally, the use of antitumour necrosis factor antibodies in ulcerative colitis has been low because this treatment is considered to be less effective than in Crohn's disease. In the current review we try to disprove these misunderstandings by discussing relevant studies showing how harmful this disease can be and explaining why future studies targeting sustained suppression of inflammation could have an enormous impact on the natural course of the disease. Until these studies are available, we encourage physicians to intensify and maintain treatment until sustained remission and mucosal healing has been reached

Effect of liver transplantation on inflammatory bowel disease in patients with primary sclerosing cholangitis

This report investigates the influence of liver transplantation and concomitant immunosuppression on the course of progression of inflammatory bowel disease (IBD) and discusses statistical methodology appropriate for such settings. The data on 303 patients who underwent liver transplantation for primary sclerosing cholangitis (PSC) were analyzed using person-time analysis and Cox regression, with the duration of IBD as the time variable and transplantation as a segmented time-dependent covariate, to take into account both posttransplant and pretransplant history of IBD. The need for colectomy and appearance of colorectal cancer were taken as outcome measures. The only significant risk factor in the multivariate model for colectomy was transplantation itself, which increased the risk of colectomy due to intractable disease (Wald statistic; P =. 001). None of the variables available for analysis were found to influence the risk of colon cancer significantly. Graphs showing the dependence of the instantaneous risk of cancer on the time from onset of IBD and its independence from the latter in the case of colectomy are presented. The use of a unique statistical methodology described for the first time in this setting led us to the somewhat surprising conclusion that transplantation and concomitant use of immunosuppression accelerate the progression of IBD. At the same time, transplantation does not affect the incidence of colorectal cancer. These results confirm the findings of some recent studies and can potentially shed new light on the disease pathogenesis

Infliximab in paediatric inflammatory bowel disease

AbstractInfliximab has been widely used in paediatric Crohn's disease, mainly in luminal and fistulous disease refractory to standard treatment and for extraintestinal manifestations. Moreover, there is growing experience with its use in refractory ulcerative colitis. Infliximab has shown similar efficacy and safety in children as in adult population. It is postulated that its early use in paediatric inflammatory bowel disease, as a bridging treatment until the onset of action of other immunomodulators, could reduce the use of steroids and change the natural history of the disease as well. The effect of infliximab on mucosal healing could also contribute to the normal growth and sexual maturation in these patients

Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn's disease

AIM: To test the hypothesis of an association between polymorphism in FCGR3A (the gene coding for FcgammaRIIIa, which is expressed on macrophages and natural killer cells, is involved in antibody-dependent cell-mediated cytotoxicity and has recently been associated with a positive response to rituximab, a recombinant immunoglobulin G1 antibody used in non-Hodgkin's lymphomas) and response to infliximab in Crohn's disease. METHODS: FCGR3A-158 polymorphism was determined using an allele-specific polymerase chain reaction assay in 200 Crohn's disease patients who had received infliximab for either refractory luminal (n = 142) or fistulizing (n = 58) Crohn's disease. Clinical and biological responses (according to C-reactive protein levels) were assessed in 200 and 145 patients, respectively. RESULTS: There were 82.9% clinical responders in V/V patients vs. 72.7% in V/F and F/F patients (N.S.). Globally, the decrease in C-reactive protein was significantly higher in V/V patients than in F carriers (P = 0.0078). A biological response was observed in 100% of V/V patients, compared with 69.8% of F carriers (P = 0.0002; relative risk, 1.43; 95% confidence interval, 1.27-1.61). In the sub-group of patients with elevated C-reactive protein before treatment, the multivariate analysis selected the use of immunosuppressive drugs and FCGR3A genotype as independent factors influencing the clinical response to infliximab (P = 0.003). CONCLUSION: Crohn's disease patients with FCGR3A-158 V/V genotype have a better biological and, possibly, clinical response to infliximab

Characterization of Mucosal Lesions in Crohn's Disease Scored With Capsule Endoscopy: A Systematic Review

Background and Aims: There is little agreement on the nomenclature and description of Crohn’s disease (CD) lesions that can be found in the small and large bowel using capsule endoscopy (CE). We performed a systematic review to identify mucosal lesions that have been described using CE in CD, in both the small bowel and colon, with the aim to make propositions to homogenize such descriptions. Methods: A systematic literature search was conducted using Embase, Medline (OvidSP), and Cochrane Central on August 6, 2019. Clinical studies providing nomenclature and descriptions for small bowel and colonic inflammatory lesions using CE in CD were selected for data collection. Results: In total, 851 articles were included for abstract screening out of which 219 were analyzed for full-text review. Twenty-two articles were selected for data extraction. Seven items, accompanied by clear descriptions, were found for the small bowel: i.e., ulcer, erosion, aphthoid lesion, edema, fissure, cobblestone appearance, and villous atrophy. No studies were found describing inflammatory items using CE in colonic CD. Conclusions: The most frequently described CD lesions using CE were ulcers and erosions. Subjective interpretation of CE inflammatory findings plays an important role. Based on our findings, a range of suggestions regarding items and descriptions is made that might form the basis of a pan-enteric CE activity index