A Multicenter Randomized Controlled Trial Comparing Two Bowel Cleansing Regimens for Colonoscopy After Failed Bowel Preparation.

BACKGROUND & AIMS: Failed bowel preparation for colonoscopy occurs commonly, but the optimal regimen for the subsequent attempt is unknown. High-volume preparations often are used but are not well studied. The objective of this study was to compare the efficacy, tolerability, and safety of 2 regimens for use after failed bowel preparation. METHODS: A multicenter, endoscopist-blinded randomized controlled trial was conducted in patients who previously failed bowel preparation despite adequate compliance. Patients were randomized to 1 of 2 split polyethylene glycol (PEG) regimens, preceded by 15 mg bisacodyl: PEG 2 L the evening before and 2 L the day of colonoscopy (PEG 2+2L+bisacodyl), or 4 L and 2 L (PEG 4+2L+bisacodyl). All patients followed a low-fiber diet on both the third and second day before the procedure, followed by a clear fluid diet the day before and the morning of the colonoscopy. The primary outcome was adequate bowel preparation, defined as a Boston Bowel Preparation Scale total score of 6 or higher, with all segment scores of 2 or higher. Secondary outcomes included adenoma detection rate, advanced adenoma detection rate, sessile serrated lesion detection, cecal intubation rate, tolerability, and adverse events. RESULTS: A total of 196 subjects were randomized at 4 academic centers in Canada (mean age, 60.7 y; SD, 11.4 y; 44.9% were women). There were no significant differences between the PEG 2+2L+bisacodyl and the PEG 4+2L+bisacodyl groups in achieving adequate bowel preparation (91.2% vs 87.6%; P = .44). There were no significant differences with regard to mean adenoma detection rate (37.4% vs 31.5%; P = .41), advanced adenoma detection rate (18.7% vs 11.2%; P = .16), sessile serrated lesion detection (8.8% vs 5.6%; P = .41), and cecal intubation rate (96.7% vs 92.1%; P = .19). The 2 regimens were similarly well tolerated, but PEG 2+2L+bisacodyl was associated with a higher willingness to repeat the bowel preparation (91.2% vs 66.2%; P < .001). CONCLUSIONS: Split-dose 4 L-PEG with 15 mg bisacodyl, along with dietary restrictions, has similar efficacy as a higher-volume preparation, and should be considered for patients who previously failed bowel preparation (ClinicalTrials.gov number, NCT02976805).

Biopsies From Ascending and Descending Colon Are Sufficient for Diagnosis of Microscopic Colitis.

BACKGROUND & AIMS: Lymphocytic and collagenous colitis are types of microscopic colitis (MC) that commonly cause chronic watery diarrhea, but there are no macroscopic features of MC that can be detected during colonoscopy. Endoscopists therefore often collect multiple random colonic biopsies, potentially oversampling, increasing times of colonoscopy and slide review. We sought to identify sites from which biopsies could be taken and analyzed to identify patients with MC with a high level of sensitivity and determine the appropriate number of biopsies to take at these sites. METHODS: We performed a retrospective study using biopsies from 101 consecutive patients with MC (52 cases of collagenous colitis, 42 cases of lymphocytic colitis, 7 combined cases), without comorbidities, from 2017 through 2018. Slides were reviewed, and the proportion of biopsies that were diagnostic of MC were calculated at each biopsy site. RESULTS: The proportions of biopsy fragments from each site of the colon found to be positive for MC were as follows: cecum, 90.0%; ascending colon, 96.9%; hepatic flexure, 77.8%; transverse colon, 95.7%; splenic flexure, 75.0%; descending colon, 85.0%; sigmoid colon, 90.9%; and rectum, 82.2%. For biopsies labeled random, 95.7% were positive for MC. When findings from ascending and descending colon biopsies were combined, 100% of MC cases were detected. CONCLUSIONS: MC can be detected with certainty by analyzing biopsies from the ascending and descending colon. Fewer biopsies than were collected from our cases are sufficient for diagnosis. We propose a Western protocol (taking 2 biopsies from each of the ascending and descending colon) in evaluation of patients for MC.

Crohn's Disease Is Associated with Decreased CYP3A4 and P-Glycoprotein Protein Expression.

Cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) have broad substrate overlap and are involved in the metabolism and transport of nearly 50% of currently prescribed medications. In the intestine, CYP3A4 and P-gp are coexpressed in the enterocytes at the intestinal villous tip and act in a coordinated manner to limit drug and xenobiotic oral bioavailability prior to further metabolism and disposition in the liver. Crohn's disease (CD), a form of inflammatory bowel disease, introduces a transmural intestinal insult that disrupts the intestinal barrier function; it therefore has the potential to affect intestinal drug metabolism and transport. We hypothesized that individuals with CD have reduced intestinal expression of CYP3A4 and P-gp. We obtained intestinal biopsy samples from individuals with and without CD and quantified the expression of CYP3A4 and P-gp. When we carried out Western analysis for protein expression, we observed a significant reduction in ileal (45% decrease) and colonic (78% decrease) CYP3A4 protein expression in subjects with CD compared with those without. Similarly, an 85% reduction in colonic P-gp protein expression was seen in the CD patients. Our data highlight important and novel findings pertaining to CD-associated changes to the intestinal expression of CYP3A4 and P-gp that are of relevance to better predict substrate drug dosing for patients with CD.

Cannabis for the treatment of Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a chronic immune-mediated condition of transmural inflammation in the gastrointestinal tract, associated with significant morbidity and decreased quality of life. The endocannabinoid system provides a potential therapeutic target for cannabis and cannabinoids and animal models have shown benefit in decreasing inflammation. However, there is also evidence to suggest transient adverse events such as weakness, dizziness and diarrhea, and an increased risk of surgery in people with CD who use cannabis. OBJECTIVES: The objectives were to assess the efficacy and safety of cannabis and cannabinoids for induction and maintenance of remission in people with CD. SEARCH METHODS: We searched MEDLINE, Embase, AMED, PsychINFO, the Cochrane IBD Group Specialized Register, CENTRAL, ClinicalTrials.Gov, and the European Clinical Trials Register up to 17 October 2018. We searched conference abstracts, references and we also contacted researchers in this field for upcoming publications. SELECTION CRITERIA: Randomized controlled trials comparing any form of cannabis or its cannabinoid derivatives (natural or synthetic) to placebo or an active therapy for adults with Crohn's disease were included. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results, extracted data and assessed bias using the Cochrane risk of bias tool. The primary outcomes were clinical remission and relapse. Remission is commonly defined as a Crohn's disease activity index (CDAI) of < 150. Relapse is defined as a CDAI > 150. Secondary outcomes included clinical response, endoscopic remission, endoscopic improvement, histological improvement, quality of life, C-reactive protein (CRP) and fecal calprotectin measurements, adverse events (AEs), serious AEs, withdrawal due to AEs, and cannabis dependence and withdrawal effects. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. For continuous outcomes, we calculated the mean difference (MD) and 95% CI. Data were combined for analysis when the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). Data were analyzed on an intention-to-treat basis and the overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: Three studies (93 participants) that assessed cannabis in people with active CD met the inclusion criteria. One ongoing study was also identified. Participants in two of the studies were adults with active Crohn's disease who had failed at least one medical treatment. The inclusion criteria for the third study were unclear. No studies that assessed cannabis therapy in quiescent CD were identified. The studies were not pooled due to differences in the interventional drug.One small study (N = 21) compared eight weeks of treatment with cannabis cigarettes containing 115 mg of D9-tetrahydrocannabinol (THC) to placebo cigarettes containing cannabis with the THC removed in participants with active CD. This study was rated as high risk of bias for blinding and other bias (cannabis participants were older than placebo). The effects of cannabis on clinical remission were unclear. Forty-five per cent (5/11) of the cannabis group achieved clinical remission compared with 10% (1/10) of the placebo group (RR 4.55, 95% CI 0.63 to 32.56; very low certainty evidence). A difference was observed in clinical response (decrease in CDAI score of >100 points) rates. Ninety-one per cent (10/11) of the cannabis group achieved a clinical response compared to 40% (4/10) of the placebo group (RR 2.27, 95% CI 1.04 to 4.97; very low certainty evidence). More AEs were observed in the cannabis cigarette group compared to placebo (RR 4.09, 95% CI 1.15 to 14.57; very low certainty evidence). These AEs were considered to be mild in nature and included sleepiness, nausea, difficulty with concentration, memory loss, confusion and dizziness. This study did not report on serious AEs or withdrawal due to AEs.One small study (N = 22) compared cannabis oil (5% cannabidiol) to placebo oil in people with active CD. This study was rated as high risk of bias for other bias (cannabis participants were more likely than placebo participants to be smokers). There was no difference in clinical remission rates. Forty per cent (4/10) of cannabis oil participants achieved remission at 8 weeks compared to 33% (3/9) of the placebo participants (RR 1.20, 95% CI 0.36 to 3.97; very low certainty evidence). There was no difference in the proportion of participants who had a serious adverse event. Ten per cent (1/10) of participants in the cannabis oil group had a serious adverse event compared to 11% (1/9) of placebo participants (RR 0.90, 95% CI 0.07 to 12.38, very low certainty evidence). Both serious AEs were worsening Crohn's disease that required rescue intervention. This study did not report on clinical response, CRP, quality of life or withdrawal due to AEs.One small study (N= 50) compared cannabis oil (15% cannabidiol and 4% THC) to placebo in participants with active CD. This study was rated as low risk of bias. Differences in CDAI and quality of life scores measured by the SF-36 instrument were observed. The mean quality of life score after 8 weeks of treatment was 96.3 in the cannabis oil group compared to 79.9 in the placebo group (MD 16.40, 95% CI 5.72 to 27.08, low certainty evidence). After 8 weeks of treatment, the mean CDAI score was118.6 in the cannabis oil group compared to 212.6 in the placebo group (MD -94.00, 95%CI -148.86 to -39.14, low certainty evidence). This study did not report on clinical remission, clinical response, CRP or AEs. AUTHORS' CONCLUSIONS: The effects of cannabis and cannabis oil on Crohn's disease are uncertain. Thus no firm conclusions regarding the efficacy and safety of cannabis and cannabis oil in adults with active Crohn's disease can be drawn. The effects of cannabis or cannabis oil in quiescent Crohn's disease have not been investigated. Further studies with larger numbers of participants are required to assess the potential benefits and harms of cannabis in Crohn's disease. Future studies should assess the effects of cannabis in people with active and quiescent Crohn's disease. Different doses of cannabis and delivery modalities should be investigated.

Cannabis for the treatment of ulcerative colitis.

BACKGROUND: Cannabis and cannabinoids are often promoted as treatment for many illnesses and are widely used among patients with ulcerative colitis (UC). Few studies have evaluated the use of these agents in UC. Further, cannabis has potential for adverse events and the long-term consequences of cannabis and cannabinoid use in UC are unknown. OBJECTIVES: To assess the efficacy and safety of cannabis and cannabinoids for the treatment of patients with UC. SEARCH METHODS: We searched MEDLINE, Embase, WHO ICTRP, AMED, PsychINFO, the Cochrane IBD Group Specialized Register, CENTRAL, ClinicalTrials.Gov and the European Clinical Trials Register from inception to 2 January 2018. Conference abstracts and references were searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing any form or dose of cannabis or its cannabinoid derivatives (natural or synthetic) to placebo or an active therapy for adults (> 18 years) with UC were included. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results, extracted data and assessed bias using the Cochrane risk of bias tool. The primary outcomes were clinical remission and relapse (as defined by the primary studies). Secondary outcomes included clinical response, endoscopic remission, endoscopic response, histological response, quality of life, C-reactive protein (CRP) and fecal calprotectin measurements, symptom improvement, adverse events, serious adverse events, withdrawal due to adverse events, psychotropic adverse events, and cannabis dependence and withdrawal effects. We calculated the risk ratio (RR) and corresponding 95% confidence interval for dichotomous outcomes. For continuous outcomes, we calculated the mean difference (MD) and corresponding 95% CI. Data were pooled for analysis when the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). Data were analyzed on an intention-to-treat basis. GRADE was used to evaluate the overall certainty of evidence. MAIN RESULTS: Two RCTs (92 participants) met the inclusion criteria. One study (N = 60) compared 10 weeks of cannabidiol capsules with up to 4.7% D9-tetrahydrocannabinol (THC) with placebo capsules in participants with mild to moderate UC. The starting dose of cannabidiol was 50 mg twice daily increasing to 250 mg twice daily if tolerated. Another study (N = 32) compared 8 weeks of therapy with two cannabis cigarettes per day containing 0.5 g of cannabis, corresponding to 23 mg THC/day to placebo cigarettes in participants with UC who did not respond to conventional medical treatment. No studies were identified that assessed cannabis therapy in quiescent UC. The first study was rated as low risk of bias and the second study (published as an abstract) was rated as high risk of bias for blinding of participants and personnel. The studies were not pooled due to differences in the interventional drug.The effect of cannabidiol capsules (100 mg to 500 mg daily) compared to placebo on clinical remission and response is uncertain. Clinical remission at 10 weeks was achieved by 24% (7/29) of the cannabidiol group compared to 26% (8/31) in the placebo group (RR 0.94, 95% CI 0.39 to 2.25; low certainty evidence). Clinical response at 10 weeks was achieved in 31% (9/29) of cannabidiol participants compared to 22% (7/31) of placebo patients (RR 1.37, 95% CI 0.59 to 3.21; low certainty evidence). Serum CRP levels were similar in both groups after 10 weeks of therapy. The mean CRP in the cannabidiol group was 9.428 mg/L compared to 7.638 mg/L in the placebo group (MD 1.79, 95% CI -5.67 to 9.25; moderate certainty evidence). There may be a clinically meaningful improvement in quality of life at 10 weeks, measured with the IBDQ scale (MD 17.4, 95% CI -3.45 to 38.25; moderate certainty evidence). Adverse events were more frequent in cannabidiol participants compared to placebo. One hundred per cent (29/29) of cannabidiol participants had an adverse event, compared to 77% (24/31) of placebo participants (RR 1.28, 95% CI 1.05 to1.56; moderate certainty evidence). However, these adverse events were considered to be mild or moderate in severity. Common adverse events included dizziness, disturbance in attention, headache, nausea and fatigue. None (0/29) of the cannabidiol participants had a serious adverse event compared to 13% (4/31) of placebo participants (RR 0.12, 95% CI 0.01 to 2.11; low certainty evidence). Serious adverse events in the placebo group included worsening of UC and one complicated pregnancy. These serious adverse events were thought to be unrelated to the study drug. More participants in the cannabidiol group withdrew due to an adverse event than placebo participants. Thirty-four per cent (10/29) of cannabidiol participants withdrew due to an adverse event compared to 16% (5/31) of placebo participants (RR 2.14, 95% CI 0.83 to 5.51; low certainty evidence). Withdrawls in the cannabidiol group were mostly due to dizziness. Withdrawals in the placebo group were due to worsening UC.The effect of cannabis cigarettes (23 mg THC/day) compared to placebo on mean disease activity, CRP levels and mean fecal calprotectin levels is uncertain. After 8 weeks, the mean disease activity index score in cannabis participants was 4 compared with 8 in placebo participants (MD -4.00, 95% CI -5.98 to -2.02). After 8 weeks, the mean change in CRP levels was similar in both groups (MD -0.30, 95% CI -1.35 to 0.75; low certainty evidence). The mean fecal calprotectin level in cannabis participants was 115 mg/dl compared to 229 mg/dl in placebo participants (MD -114.00, 95% CI -246.01 to 18.01). No serious adverse events were observed. This study did not report on clinical remission, clinical response, quality of life, adverse events or withdrawal due to adverse events. AUTHORS' CONCLUSIONS: The effects of cannabis and cannabidiol on UC are uncertain, thus no firm conclusions regarding the efficacy and safety of cannabis or cannabidiol in adults with active UC can be drawn.There is no evidence for cannabis or cannabinoid use for maintenance of remission in UC. Further studies with a larger number of patients are required to assess the effects of cannabis in UC patients with active and quiescent disease. Different doses of cannabis and routes of administration should be investigated. Lastly, follow-up is needed to assess the long term safety outcomes of frequent cannabis use.

Low dose naltrexone for induction of remission in Crohn's disease.

BACKGROUND: Crohn's disease is a transmural, relapsing inflammatory condition afflicting the digestive tract. Opioid signalling, long known to affect secretion and motility in the gut, has been implicated in the inflammatory cascade of Crohn's disease. Low dose naltrexone, an opioid antagonist, has garnered interest as a potential therapy. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of low dose naltrexone for induction of remission in Crohn's disease. SEARCH METHODS: A systematic search of MEDLINE, Embase, PubMed, CENTRAL, and the Cochrane IBD Group Specialized Register was performed from inception to 15 January 2018 to identify relevant studies. Abstracts from major gastroenterology conferences including Digestive Disease Week and United European Gastroenterology Week and reference lists from retrieved articles were also screened. SELECTION CRITERIA: Randomized controlled trials of low dose naltrexone (LDN) for treatment of active Crohn's disease were included. DATA COLLECTION AND ANALYSIS: Data were analyzed on an intention-to-treat basis using Review Manager (RevMan 5.3.5). The primary outcome was induction of clinical remission defined by a Crohn's disease activity index (CDAI) of < 150 or a pediatric Crohn's disease activity index (PCDAI) of < 10. Secondary outcomes included clinical response (70- or 100-point decrease in CDAI from baseline), endoscopic remission or response, quality of life, and adverse events as defined by the included studies. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. MAIN RESULTS: Two studies were identified (46 participants). One study assessed the efficacy and safety of 12 weeks of LDN (4.5 mg/day) treatment compared to placebo in adult patients (N = 34). The other study assessed eight weeks of LDN (0.1 mg/kg, maximum 4.5 mg/day) treatment compared to placebo in pediatric patients (N = 12). The primary purpose of the pediatric study was to assess safety and tolerability. Both studies were rated as having a low risk of bias. The study in adult patients reported that 30% (5/18) of LDN treated patients achieved clinical remission at 12 weeks compared to 18% (3/16) of placebo patients, a difference that was not statistically significant (RR 1.48, 95% CI 0.42 to 5.24). The study in children reported that 25% of LDN treated patients achieved clinical remission (PCDAI < 10) compared to none of the patients in the placebo group, although it was unclear if this result was for the randomized placebo-controlled trial or for the open label extension study. In the adult study 70-point clinical response rates were significantly higher in those treated with LDN than placebo. Eighty-three per cent (15/18) of LDN patients had a 70-point clinical response at week 12 compared to 38% (6/16) of placebo patients (RR 2.22, 95% CI 1.14 to 4.32). The effect of LDN on the proportion of adult patients who achieved a 100-point clinical response was uncertain. Sixty-one per cent (11/18) of LDN patients achieved a 100-point clinical response compared to 31% (5/16) of placebo patients (RR 1.96, 95% CI 0.87 to 4.42). The proportion of patients who achieved endoscopic response (CDEIS decline > 5 from baseline) was significantly higher in the LDN group compared to placebo. Seventy-two per cent (13/18) of LDN patients achieved an endoscopic response compared to 25% (4/16) of placebo patients (RR 2.89; 95% CI 1.18 to 7.08). However, there was no statistically significant difference in the proportion of patients who achieved endoscopic remission. Endoscopic remission (CDEIS < 3) was achieved in 22% (4/18) of the LDN group compared to 0% (0/16) of the placebo group (RR 8.05; 95% CI 0.47 to 138.87). Pooled data from both studies show no statistically significant differences in withdrawals due to adverse events or specific adverse events including sleep disturbance, unusual dreams, headache, decreased appetite, nausea and fatigue. No serious adverse events were reported in either study. GRADE analyses rated the overall quality of the evidence for the primary and secondary outcomes (i.e. clinical remission, clinical response, endoscopic response, and adverse events) as low due to serious imprecision (sparse data). AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence to allow any firm conclusions regarding the efficacy and safety of LDN used to treat patients with active Crohn's disease. Data from one small study suggests that LDN may provide a benefit in terms of clinical and endoscopic response in adult patients with active Crohn's disease. Data from two small studies suggest that LDN does not increase the rate of specific adverse events relative to placebo. However, these results need to be interpreted with caution as they are based on very small numbers of patients and the overall quality of the evidence was rated as low due to serious imprecision. Further randomized controlled trials are required to assess the efficacy and safety of LDN therapy in active Crohn's disease in both adults and children.

The utility of fecal calprotectin in predicting the need for escalation of therapy in inflammatory bowel disease.

BACKGROUND AND AIMS: Fecal calprotectin is an important biomarker used in the evaluation of inflammatory bowel disease. It has proven to be an effective tool in initial screening as well monitoring response to therapy. The aim of this study is to examine the utility of fecal calprotectin both as a predictor for the escalation of therapy in established inflammatory bowel disease and as a predictor of de novo diagnosis. METHODS: Patients with signs and symptoms concerning for inflammatory bowel disease presenting to outpatient clinics were recruited to provide fecal calprotectin stool samples prior to endoscopic evaluation. Patients were followed up for at least one year and monitored clinically for any change in symptomatology, escalation of therapy or development of IBD, confirmed endoscopically. RESULTS: A total of 126 patients, of whom 72 were known to have underlying inflammatory bowel disease, were included in the final analysis. Among the patients with elevated fecal calprotectin levels and known inflammatory bowel disease, 66% (33/50) went on to have escalation of therapy within 12 months compared to 18% (4/22) if the fecal calprotectin levels were in the normal range (p < .0001). For the remaining patients who at baseline did not have inflammatory bowel disease and a normal endoscopic evaluation, elevated fecal calprotectin resulted in no cases (0/17) of a new diagnosis in the next 12 months. CONCLUSIONS: Fecal calprotectin is a useful test for predicting escalation of therapy in established inflammatory bowel disease.

Interventions for treating lymphocytic colitis.

BACKGROUND: Lymphocytic colitis is a cause of chronic diarrhea. It is a subtype of microscopic colitis characterized by chronic, watery, non-bloody diarrhea and normal endoscopic and radiologic findings. The etiology of this disorder is unknown.Therapy is based mainly on case series and uncontrolled trials, or by extrapolation of data for treating collagenous colitis, a related disorder. This review is an update of a previously published Cochrane review. OBJECTIVES: To evaluate the efficacy and safety of treatments for clinically active lymphocytic colitis. SEARCH METHODS: The MEDLINE, PUBMED and EMBASE databases were searched from inception to 11 August 2016 to identify relevant papers. Manual searches from the references of included studies and relevant review articles were performed.Abstracts from major gastroenterological meetings were also searched to identify research submitted in abstract form only. The trial registry web site www.ClinicalTrials.gov was searched to identify registered but unpublished trials. Finally, the Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register were searched for other studies. SELECTION CRITERIA: Randomized controlled trials assessing medical therapy for patients with biopsy-proven lymphocytic colitis were considered for inclusion DATA COLLECTION AND ANALYSIS: Data was independently extracted by at least two authors. Any disagreements were resolved by consensus. Data were analyzed on an intention-to-treat (ITT) basis. The primary outcome was clinical response as defined by the included studies. Secondary outcome measures included histological response as defined by the included studies, quality of life as measured by a validated instrument and the occurrence of adverse events. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. Data were combined for analysis if they assessed the same treatments. Dichotomous data were combined using a pooled RR along with corresponding 95% CI. A fixed-effect model was used for the pooled analysis. MAIN RESULTS: Five RCTs (149 participants) met the inclusion criteria. These studies assessed bismuth subsalicylate versus placebo, budesonide versus placebo, mesalazine versus mesalazine plus cholestyramine and beclometasone dipropionate versus mesalazine. The study which assessed mesalazine versus mesalazine plus cholestyramine and the study which assessed beclometasone dipropionate versus mesalazine were judged to be at high risk of bias due to lack of blinding. The study which compared bismuth subsalicylate versus us placebo was judged as low quality due to a very small sample size and limited data. The other 3 studies were judged to be at low risk of bias. Budesonide (9 mg/day for 6 to 8 weeks) was significantly more effective than placebo for induction of clinical and histological response. Clinical response was noted in 88% of budesonide patients compared to 38% of placebo patients (2 studies; 57 participants; RR 2.03, 95% CI 1.25 to 3.33; GRADE = low). Histological response was noted in 78% of budesonide patients compared to 33% of placebo patients (2 studies; 39 patients; RR 2.44, 95% CI 1.13 to 5.28; GRADE = low). Forty-one patients were enrolled in the study assessing mesalazine (2.4 g/day) versus mesalazine plus cholestyramine (4 g/day). Clinical response was noted in 85% of patients in the mesalazine group compared to 86% of patients in the mesalazine plus cholestyramine group (RR 0.99, 95% CI 0.77 to 1.28; GRADE = low). Five patients were enrolled in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks versus placebo). There were no differences in clinical (P=0.10) or histological responses (P=0.71) in patients treated with bismuth subsalicylate compared with placebo (GRADE = very low). Forty-six patients were enrolled in the trial studying beclometasone dipropionate (5 mg/day or 10 mg/day) versus mesalazine (2.4 g/day). There were no differences in clinical remission at 8 weeks (RR 0.97; 95% CI 0.75 to 1.24; GRADE = low) and 12 months of treatment (RR 1.29; 95% CI 0.40 to 4.18; GRADE = very low). Although patients receiving beclometasone dipropionate (84%) and mesalazine (86%) achieved clinical remission at 8 weeks, it was not maintained at 12 months (26% and 20%, respectively). Adverse events reported in the budesonide studies include nausea, vomiting, neck pain, abdominal pain, hyperhidrosis and headache. Nausea and skin rash were reported as adverse events in the mesalazine study. Adverse events in the beclometasone dipropionate trial include nausea, sleepiness and change of mood. No adverse events were reported in the bismuth subsalicylate study. AUTHORS' CONCLUSIONS: Low quality evidence suggests that budesonide may be effective for the treatment of active lymphocytic colitis. This benefit needs to be confirmed by a large placebo -controlled trial. Low quality evidence also suggests that mesalazine with or without cholestyramine and beclometasone dipropionate may be effective for the treatment of lymphocytic colitis, however this needs to be confirmed by large placebo-controlled studies. No conclusions can be made regarding bismuth subsalicylate due to the very small number of patients in the study, Further trials studying interventions for lymphocytic colitis are warranted.

Interventions for treating collagenous colitis.

BACKGROUND: Collagenous colitis is a cause of chronic diarrhea. This updated review was performed to identify therapies for collagenous colitis that have been assessed in randomized controlled trials (RCTs). OBJECTIVES: The primary objective was to assess the benefits and harms of treatments for collagenous colitis. SEARCH METHODS: We searched CENTRAL, the Cochrane IBD Group Specialized Register, MEDLINE and EMBASE from inception to 7 November 2016. SELECTION CRITERIA: We included RCTs comparing a therapy with placebo or active comparator for the treatment of active or quiescent collagenous colitis. DATA COLLECTION AND ANALYSIS: Data were independently extracted by two authors. The primary outcome was clinical response or maintenance of response as defined by the included studies. Secondary outcome measures included histological response, quality of life and the occurrence of adverse events. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The Cochrane risk of bias tool was used to assess bias. The overall quality of the evidence was assessed using the GRADE criteria. MAIN RESULTS: Twelve RCTs (476 participants) were included. These studies assessed bismuth subsalicylate, Boswellia serrata extract, mesalamine, cholestyramine, probiotics, prednisolone and budesonide therapy. Four studies were low risk of bias. One study assessing mesalamine and cholestyramine was judged to be high risk of bias due to no blinding. The other studies had an unclear risk of bias for random sequence generation (five studies) allocation concealment (six studies), blinding (one study), incomplete outcome data (one study) and selective outcome reporting (one study). Clinical response occurred in 100% (4/4) of patients who received bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks) compared to 0% (0/5) of patients who received placebo (1 study; 9 participants; RR 10.80, 95% CI 0.75 to 155.93; GRADE = very low). Clinical response occurred in 44% (7/16) of patients who received Boswellia serrata extract (three 400 mg/day capsules for 8 weeks) compared to 27% (4/15) of patients who received placebo (1 study; 31 participants; RR 1.64, 95% CI 0.60 to 4.49; GRADE = low). Clinical response occurred in 80% (24/30) of budesonide patients compared to 44% (11/25) of mesalamine patients (1 study; 55 participants; RR 1.82, 95% CI 1.13 to 2.93; GRADE = low). Histological response was observed in 87% (26/30) of budesonide patients compared to 44% (11/25) of mesalamine patients (1 study, 55 participants; RR 1.97, 95% CI 1.24 to 3.13; GRADE = low). There was no difference between the two treatments with respect to adverse events (RR 0.69, 95% CI 0.43 to 1.10; GRADE = low), withdrawals due to adverse events (RR 0.09, 95% CI 0.01 to 1.65; GRADE = low) and serious adverse events (RR 0.12, 95% CI 0.01 to 2.21; GRADE = low). Clinical response occurred in 44% (11/25) of mesalamine patients (3 g/day) compared to 59% (22/37) of placebo patients (1 study; 62 participants; RR 0.74, 95% CI 0.44 to 1.24; GRADE = low). Histological response was observed in 44% (11/25) and 51% (19/37) of patients receiving mesalamine and placebo, respectively (1 study; 62 participants; RR 0.86, 95% CI 0.50 to 1.47; GRADE = low). There was no difference between the two treatments with respect to adverse events (RR 1.26, 95% CI 0.84 to 1.88; GRADE = low), withdrawals due to adverse events (RR 5.92, 95% CI 0.70 to 49.90; GRADE = low) and serious adverse events (RR 4.44, 95% CI 0.49 to 40.29; GRADE = low). Clinical response occurred in 63% (5/8) of prednisolone (50 mg/day for 2 weeks) patients compared to 0% (0/3) of placebo patients (1 study, 11 participants; RR 4.89, 95% CI 0.35 to 68.83; GRADE = very low). Clinical response occurred in 29% (6/21) of patients who received probiotics (2 capsules containing 0.5 x 1010 CFU each of L. acidophilus LA-5 and B. animalis subsp. lactis strain BB-12 twice daily for 12 weeks) compared to 13% (1/8) of placebo patients (1 study, 29 participants, RR 2.29, 95% CI 0.32 to 16.13; GRADE = very low). Clinical response occurred in 73% (8/11) of patients who received mesalamine (800 mg three times daily) compared to 100% (12/12) of patients who received mesalamine + cholestyramine (4 g daily) (1 study, 23 participants; RR 0.74, 95% CI 0.50 to 1.08; GRADE = very low). Clinical response occurred in 81% (38/47) of patients who received budesonide (9 mg daily in a tapering schedule for 6 to 8 weeks) compared to 17% (8/47) of placebo patients (3 studies; 94 participants; RR 4.56, 95% CI 2.43 to 8.55; GRADE = low). Histological response was higher in budesonide participants (72%, 34/47) compared to placebo (17%, 8/47) (RR 4.15, 95% CI 2.25 to 7.66; GRADE = low). Clinical response was maintained in 68% (57/84) of budesonide patients compared to 20% (18/88) of placebo patients (3 studies, 172 participants, RR 3.30 95% CI 2.13 to 5.09; GRADE = low). Histological response was maintained in 48% (19/40) of budesonide patients compared to 15% (6/40) of placebo patients (2 studies; 80 participants; RR 3.17, 95% CI 1.44 to 6.95; GRADE = very low). No difference was found between budesonide and placebo for adverse events (5 studies; 290 participants; RR 1.18, o95% CI 0.92 to 1.51; GRADE = low), withdrawals due to adverse events (5 studies, 290 participants; RR 0.97, 95% CI 0.43 to 2.17; GRADE = very low) or serious adverse events (4 studies, 175 participants; RR 1.11, 95% CI 0.15 to 8.01; GRADE = very low). Adverse effects reported in the budesonide studies include nausea, vomiting, neck pain, abdominal pain, excessive sweating and headache. Adverse effects reported in the mesalamine studies included nausea and skin rash. Adverse effects in the prednisolone study included abdominal pain, headache, sleep disturbance, mood change and weight gain. AUTHORS' CONCLUSIONS: Low quality evidence suggests that budesonide may be effective for inducing and maintaining clinical and histological response in patients with collagenous colitis. We are uncertain about the benefits and harms of therapy with bismuth subsalicylate, Boswellia serrata extract, mesalamine with or without cholestramine, prednisolone and probiotics. These agents and other therapies require further study.

Anti-tuberculous therapy for maintenance of remission in Crohn's disease.

BACKGROUND: There have been a number of studies with conflicting results which have examined the effect of anti-tuberculous therapy in Crohn's disease. A meta-analysis was performed to evaluate the use of anti-tuberculous therapy for the maintenance of remission in Crohn's disease. OBJECTIVES: To evaluate the effects of anti-tuberculous therapy for the maintenance of remission in patients with Crohn's disease. SEARCH METHODS: We searched MEDLINE, EMBASE, the Cochrane LIbrary, and the Cochrane IBD Group Specialized Register from inception to June 22, 2015. SELECTION CRITERIA: Randomized controlled trials (RCTs) of anti-tuberculous therapy compared to placebo or another active therapy in patients with quiescent Crohn's disease were considered for inclusion. DATA COLLECTION AND ANALYSIS: At least two authors independently extracted data and assessed the quality of included studies using the Cochrane risk of bias tool. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for dichotomous outcomes.. The primary outcome was relapse. Secondary outcomes included adverse events, withdrawals due to adverse events and serious adverse events. All data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the primary and secondary outcomes was evaluated using the GRADE criteria. MAIN RESULTS: Four placebo-controlled RCTs including 206 participants were included. Three trials included an 8 to 16 week induction phase with tapering corticosteroids (prednisone, prednisolone or methylprednisolone) as induction therapy. Anti-tuberculous therapy included monotherapy with clofazimine, combination therapy with clofazimine, rifampin, ethambutol, and dapsone or combination therapy with clarithromycin, rifabutin and clofazimine. All of the studies were rated as unclear risk of bias for allocation concealment, three were rated as unclear risk of bias for random sequence generation and two were rated as unclear risk of bias for blinding or participants and personnel. There was a statistically significant difference in relapse rates favoring anti-tuberculous therapy over placebo. Thirty-nine per cent (44/112) of patients in the anti-tuberculous therapy group relapsed at 9 months to 2 years compared to 67% (63/94) of placebo patients (RR 0.58, 95% CI 0.45 to 0.75, I(2) = 47%). A GRADE analysis indicates that the overall quality of the evidence supporting this outcome was very low due to unknown risk of bias and sparse data. Adverse events occurred more frequently in the anti-tuberculous therapy group (37/159) compared to the placebo group (14/163) with a pooled RR of 2.57 (95% CI 1.45 to 4.55; N=322; studies=4, I(2)=64%). A GRADE analysis indicates that the overall quality of the evidence supporting this outcome was very low due to unknown risk of bias, unexplained heterogeneity and sparse data. There was no difference in withdrawals due to adverse events. Nine per cent (14/159) of anti-tuberculous therapy patients withdrew due to adverse events compared to 7% (11/163) of placebo patients (RR 1.29, 95% CI 0.60 to 2.77, I(2) = 0%). Common adverse events included increased skin pigmentation and rashes. No serious adverse events were reported in any of the included studies. AUTHORS' CONCLUSIONS: Anti-tuberculous therapy may provide a benefit over placebo for the prevention of relapse in participants with Crohn's disease in remission. However, this result is very uncertain due to unclear study quality and the small numbers of patients assessed. Further studies are needed to provide better quality evidence for the use of anti-tuberculous therapy for maintaining remission in people with quiescent Crohn's disease.

Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease.

BACKGROUND: The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease have been conflicting and controversial. An updated meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease. OBJECTIVES: The primary objective was to determine the efficacy and safety of azathioprine and 6-mercaptopurine for induction of remission in active Crohn's disease. SEARCH METHODS: We searched MEDLINE, EMBASE and the Cochrane Library from inception to 30 October 2015. Review articles and conference proceedings were also searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients with active Crohn's disease were selected for inclusion. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent observers based on the intention-to-treat principle. Outcomes of interest included: clinical remission, clinical improvement, fistula improvement or healing, steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. We calculated the pooled relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria. MAIN RESULTS: Thirteen RCTs (n = 1211 patients) of azathioprine and 6-mercaptopurine therapy in adult patients were identified: nine included placebo comparators and six included active comparators. The majority of included studies were rated as low risk of bias. There was no statistically significant difference in clinical remission rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (95/197) of patients receiving antimetabolites achieved remission compared to 37% (68/183) of placebo patients (5 studies, 380 patients; RR 1.23, 95% CI 0.97 to 1.55). There was no statistically significant difference in clinical improvement rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (107/225) of patients receiving antimetabolites achieved clinical improvement or remission compared to 36% (75/209) of placebo patients (8 studies, 434 patients; RR 1.26, 95% CI 0.98 to 1.62). There was a statistically significant difference in steroid sparing (defined as prednisone dose < 10 mg/day while maintaining remission) between azathioprine and placebo. Sixty-four per cent (47/163) of azathioprine patients were able to reduce their prednisone dose to < 10 mg/day compared to 46% (32/70) of placebo patients (RR 1.34, 95% CI 1.02 to 1.77). GRADE analyses rated the overall quality of the evidence for the outcomes clinical remission, clinical improvement and steroid sparing as moderate due to sparse data. There was no statistically significant difference in withdrawals due to adverse events or serious adverse events between antimetabolites and placebo. Ten percent of patients in the antimetabolite group withdrew due to adverse events compared to 5% of placebo patients (8 studies, 510 patients; RR 1.70, 95% CI 0.94 to 3.08). Serious adverse events were reported in 14% of patients receiving azathioprine compared to 4% of placebo patients (2 studies, 216 patients; RR 2.57, 95% CI 0.92 to 7.13). Common adverse events reported in the placebo controlled studies included: allergic reactions. leukopenia, pancreatitis and nausea. Azathioprine was significantly inferior to infliximab for induction of steroid-free clinical remission. Thirty per cent (51/170) of azathioprine patients achieved steroid-free remission compared to 44% (75/169) of infliximab patients (1 study, 339 patients; RR 0.68, 95% CI 0.51 to 0.90). The combination of azathioprine and infliximab was significantly superior to infliximab alone for induction of steroid-free clinical remission. Sixty per cent (116/194) of patients in the combined azathioprine and infliximab group achieved steroid-free remission compared to 48% (91/189) of infliximab patients (2 studies, 383 patients; RR 1.23, 95% CI 1.02 to 1.47). Azathioprine or 6-mercaptopurine therapy was found to be no better at inducing steroid free clinical remission compared to methotrexate (RR 1.13, 95% CI 0.85 to 1.49) and 5-aminosalicylate or sulfasalazine (RR 1.24, 95% CI 0.80 to 1.91). There were no statistically significant differences in withdrawals due to adverse events between azathioprine or 6-mercaptopurine and methotrexate (RR 0.78, 95% CI 0.23 to 2.71); between azathioprine or 6-mercaptopurine and 5-aminosalicylate or sulfasalazine (RR 0.98, 95% CI 0.38 to 2.54); between azathioprine and infliximab (RR 1.47, 95% CI 0.96 to 2.23); or between the combination of azathioprine and infliximab and infliximab (RR 1.16, 95% CI 0.75 to 1.80). Common adverse events in the active comparator trials included nausea, abdominal pain, pyrexia and headache. AUTHORS' CONCLUSIONS: Azathioprine and 6-mercaptopurine offer no advantage over placebo for induction of remission or clinical improvement in active Crohn's disease. Antimetaboilte therapy may allow patients to reduce steroid consumption. Adverse events were more common in patients receiving antimetabolites although differences with placebo were not statistically significant. Azathioprine therapy is inferior to infliximab for induction of steroid-free remission. However, the combination of azathioprine and infliximab was superior to infliximab alone for induction of steroid-free remission.

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.

BACKGROUND: Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial. OBJECTIVES: To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis. SEARCH METHODS: The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included. SELECTION CRITERIA: Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes. MAIN RESULTS: Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported. AUTHORS' CONCLUSIONS: Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (September 2012).

Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology.

BACKGROUND & AIMS: Guidelines for the management of venous thromboembolism (VTE) from the American College of Chest Physicians do not address patients with inflammatory bowel disease (IBD), a group with a high risk of both VTE and gastrointestinal bleeding. We present recommendations for the prevention and treatment of VTE in patients with IBD. METHODS: A systematic literature search was performed to identify studies on VTE in IBD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Statements were developed through an iterative online platform, then finalized and voted on by a working group of adult and pediatric gastroenterologists and thrombosis specialists. RESULTS: IBD patients have an approximately 3-fold higher risk of VTE compared with individuals without IBD, and disease flares further increase this risk. Anticoagulant thromboprophylaxis is recommended for IBD patients who are hospitalized with IBD flares without active bleeding and is suggested when bleeding is nonsevere. Anticoagulant thromboprophylaxis is suggested during moderate-severe IBD flares in outpatients with a history of VTE provoked by an IBD flare or an unprovoked VTE, but not otherwise. The recommended duration of anticoagulation after a first VTE is based on the presence of provoking factors. Specific suggestions are made for the prevention and treatment of VTE in pediatric and pregnant IBD patients. CONCLUSIONS: Using the American College of Chest Physicians' guidelines as a foundation, we have integrated evidence from IBD studies to develop specific recommendations for the management of VTE in this high-risk population.

C-Reactive Protein, Fecal Calprotectin, and Stool Lactoferrin for Detection of Endoscopic Activity in Symptomatic Inflammatory Bowel Disease Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: Persistent disease activity is associated with a poor prognosis in inflammatory bowel disease (IBD). Therefore, monitoring of patients with intent to suppress subclinical inflammation has emerged as a treatment concept. As endoscopic monitoring is invasive and resource intensive, identification of valid markers of disease activity is a priority. The objective was to evaluate the diagnostic accuracy of C-reactive protein (CRP), fecal calprotectin (FC), and stool lactoferrin (SL) for assessment of endoscopically defined disease activity in IBD. METHODS: Databases were searched from inception to November 6, 2014 for relevant cohort and case-control studies that evaluated the diagnostic accuracy of CRP, FC, or SL and used endoscopy as a gold standard in patients with symptoms consistent with active IBD. Sensitivities and specificities were pooled to generate operating property estimates for each test using a bivariate diagnostic meta-analysis. RESULTS: Nineteen studies (n=2499 patients) were eligible. The pooled sensitivity and specificity estimates for CRP, FC, and SL were 0.49 (95% confidence interval (CI) 0.34-0.64) and 0.92 (95% CI 0.72-0.96), 0.88 (95% CI 0.84-0.90) and 0.73 (95% CI 0.66-0.79), and 0.82 (95% CI 0.73-0.88) and 0.79 (95% CI 0.62-0.89), respectively. FC was more sensitive than CRP in both diseases and was more sensitive in ulcerative colitis than Crohn's disease. CONCLUSIONS: Although CRP, FC, and SL are useful biomarkers, their value in managing individual patients must be considered in specific clinical contexts.

Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis.

BACKGROUND: There are a limited number of treatment options for patients with ulcerative colitis (UC). An increased risk of thrombosis in UC coupled with an observation that UC patients being treated with anticoagulant therapy for thrombotic events had an improvement in their bowel symptoms led to trials examining the use of unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in patients with active UC. OBJECTIVES: To review randomized trials examining the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis. SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD/FBD group specialized trials register up to June 2014. We also searched review papers on ulcerative colitis and references from identified papers in an effort to identify additional randomized trials studying UFH or LMWH use in patients with ulcerative colitis. We searched abstracts from major gastroenterological meetings to identify research published in abstract form. SELECTION CRITERIA: Randomized controlled trials comparing UFH or LMWH to placebo or a control therapy for induction of remission in ulcerative colitis were included. Studies published in abstract form only were included if the authors could be contacted for further information. DATA COLLECTION AND ANALYSIS: A data extraction form was developed and used to extract data from included studies. Two authors independently extracted data. Any disagreements were resolved by consensus. The Cochrane Risk of Bias tool was used to assess study quality. Data were analyzed on an intention-to-treat basis. The primary outcome was induction of remission, as defined by the studies. Secondary outcomes measures included: endoscopic remission as defined by the authors; clinical, histological or endoscopic improvement as defined by the authors; the occurrence of adverse events; the occurrence of bleeding; and improvements in quality of life as measured by a validated instrument. We calculated the risk ratio (RR) and corresponding 95% confidence interval for dichotomous outcomes. Data were combined for analysis if they assessed the same treatments (UFH or LMWH versus placebo or other therapy). The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: Five studies were eligible for inclusion (329 patients). Three studies (270 patients) compared low molecular weight heparin to placebo, one study (34 patients) compared LMWH in addition to standard therapy, and one study (25 patients) compared UFH to corticosteroids. The study comparing UFH to corticosteroids was rated at high risk of bias due to a single-blind design. The study that compared the addition of LMWH to standard therapy to standard therapy alone was rated at high risk of bias due to open-label design. The other three studies were rated as low risk of bias. LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission (very low quality of evidence), and clinical, endoscopic, or histological improvement. High dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (RR 1.39; 95% CI 1.09 to 1.77 ; P = 0.008; very low quality of evidence), clinical improvement (RR 1.28; 95% CI 1.06 to 1.55; P = 0.01; very low quality of evidence), and endoscopic improvement (RR 1.21; 95% CI 1.00 to 1.47 ; P = 0.05) but not endoscopic remission or histologic improvement. LMWH was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission or endoscopic improvement. LMWH was well-tolerated but provided no significant benefit for quality of life. One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement. More patients assigned to UFH had rectal hemorrhage as an adverse event. AUTHORS' CONCLUSIONS: There is evidence to suggest that LMWH may be effective for the treatment of active UC. When administered by extended colon-release tablets, LMWH was more effective than placebo for treating outpatients with mild to moderate disease. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC. A further trial of UFH in patients with mild disease may also be justified. Any benefit found would need to be weighed against a possible increased risk of rectal bleeding in patients with active UC.

ANTECEDENTES: Es limitado el número de opciones terapéuticas para los pacientes con colitis ulcerosa (CU). Un mayor riesgo de trombosis en la CU, junto con una observación de que los pacientes con CU tratados con tratamiento anticoagulante para los eventos trombóticos presentaron una mejoría en sus síntomas intestinales, generó ensayos que examinaron el uso de la heparina no fraccionada (HNF) y las heparinas de bajo peso molecular (HBPM) en los pacientes con CU activa. OBJETIVOS: Examinar los ensayos aleatorizados sobre la eficacia de la heparina no fraccionada (HNF) o las heparinas de bajo peso molecular (HBPM) para la inducción de la remisión en los pacientes con colitis ulcerosa. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en MEDLINE, EMBASE, CENTRAL y en el registro de ensayos especializados del Grupo Cochrane de EII/TFI hasta junio de 2014. También se realizaron búsquedas en los documentos de revisión sobre la colitis ulcerosa y en las referencias de los documentos identificados, con el fin de identificar ensayos aleatorizados adicionales que estudiaran el uso de HNF o HBPM en pacientes con colitis ulcerosa. Se realizaron búsquedas en los resúmenes de los principales encuentros de gastroenterología para identificar las investigaciones publicadas en forma de resumen. CRITERIOS DE SELECCIÓN: Se incluyeron ensayos controlados aleatorizados que comparaban la HNF o la HBPM con el placebo o un tratamiento de control para la inducción de la remisión en la colitis ulcerosa. Los estudios publicados sólo como resúmenes se incluyeron cuando se pudo establecer contacto con los autores para obtener información adicional. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se desarrolló y utilizó un formulario de extracción de datos de los estudios incluidos. Dos autores de la revisión de forma independiente extrajeron los datos. Los desacuerdos se resolvieron por consenso. Se utilizó la herramienta Cochrane de Riesgo de Sesgo para evaluar la calidad de los estudios. Los datos se analizaron por intención de tratar. El resultado principal fue la inducción de la remisión, según la definición de los estudios. Las medidas de resultados secundarios incluían: remisión endoscópica según la definición de los autores; mejoría clínica, histológica o endoscópica según la definición de los autores; aparición de eventos adversos; aparición de hemorragias; y mejoras en la calidad de vida según la medición de un instrumento validado. Se calculó el riesgo relativo (RR) y el intervalo de confianza (IC) del 95% correspondiente para los resultados dicotómicos. Los datos se combinaron para el análisis si evaluaban los mismos tratamientos (HNF o HBPM versus placebo u otro tratamiento). La calidad general de la evidencia que apoya los resultados se evaluó mediante los criterios GRADE. RESULTADOS PRINCIPALES: Cinco estudios fueron elegibles para su inclusión (329 pacientes). Tres estudios (270 pacientes) compararon la heparina de bajo peso molecular con el placebo, un estudio (34 pacientes) comparó la HBPM además del tratamiento estándar, y un estudio (25 pacientes) comparó la HNF con los corticosteroides. El estudio que comparaba la HNF con los corticosteroides fue calificado como de alto riesgo de sesgo debido a un diseño de cegamiento simple. El estudio que comparó la adición de HBPM a la terapia estándar con la terapia estándar sola se calificó con un alto riesgo de sesgo debido al diseño de etiqueta abierta. Los otros tres estudios fueron calificados como de bajo riesgo de sesgo. Las HBPM administradas por vía subcutánea no mostraron ningún beneficio sobre el placebo para ningún resultado, incluyendo la remisión clínica (muy baja calidad de la evidencia), y la mejoría clínica, endoscópica o histológica. Las HBPM en dosis altas administradas mediante un comprimido de liberación prolongada del colon demostraron beneficios sobre el placebo para la remisión clínica (RR 1,39; IC del 95%: 1,09 a 1,77; P = 0,008; muy baja calidad de la evidencia), la mejoría clínica (RR 1.28; IC del 95%: 1,06 a 1,55; p = 0,01; muy baja calidad de la evidencia), y la mejoría endoscópica (RR 1,21; IC del 95%: 1,00 a 1,47; p = 0,05), pero no la remisión endoscópica o la mejoría histológica. La HBPM no fue beneficiosa cuando se agregó al tratamiento estándar para la remisión clínica, la mejoría clínica, la remisión endoscópica ni la mejoría endoscópica. La HBPM se toleró bien pero no proporcionó un beneficio significativo para la calidad de vida. Un estudio que examinó HNF versus corticosteroides en el tratamiento de la CU grave demostró la inferioridad de la HNF para la mejoría clínica. Una mayor cantidad de pacientes asignados a la HNF presentó hemorragia rectal como un evento adverso. CONCLUSIONES DE LOS AUTORES: La evidencia indica que la HBPM puede ser efectiva para el tratamiento de la CU activa. Cuando se administró mediante comprimidos de liberación prolongada en el colon, la HBPM fue más efectiva que placebo para tratar a los pacientes ambulatorios con enfermedad leve a moderada. Este beneficio se debe confirmar en estudios controlados aleatorizados. Los mismos beneficios no se observaron cuando la HBPM se administró por vía subcutánea a dosis inferiores. No hay evidencia que apoye el uso de HNF para el tratamiento de la CU activa. Un ensayo adicional de HNF en pacientes con enfermedad leve también puede estar justificado. Todo beneficio hallado deberá compararse contra un posible riesgo mayor de hemorragia rectal en los pacientes con CU activa.

Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease.

BACKGROUND: The therapeutic role of 6-mercaptopurine (6-MP) and azathioprine (AZA) remains controversial due to their perceived relatively slow-acting effect and adverse effects. An updated meta-analysis was performed to evaluate the efficacy of these agents for the maintenance of remission in quiescent Crohn's disease. OBJECTIVES: To assess the efficacy of AZA and 6-MP for maintenance of remission in quiescent Crohn's disease. SEARCH METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library from inception to June 30, 2015. SELECTION CRITERIA: Randomized controlled trials of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients (> 18 years) with quiescent Crohn's disease were considered for inclusion. Patients with surgically-induced remission were excluded. DATA COLLECTION AND ANALYSIS: At least two authors independently extracted data and assessed study quality using the Cochrane risk of bias tool. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (CI). The primary outcomes was maintenance of remission. Secondary outcomes included steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. All data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. MAIN RESULTS: Eleven studies (881 participants) were included. Comparisons included AZA versus placebo (7 studies, 532 participants), AZA or 6-MP versus mesalazine or sulfasalazine (2 studies, 166 participants), AZA versus budesonide (1 study, 77 participants), AZA and infliximab versus infliximab (1 study, 36 patients), 6-MP versus methotrexate (1 study, 31 patients), and early AZA versus conventional management (1 study, 147 participants). Two studies were rated as low risk of bias. Three studies were rated as high risk of bias for being non-blinded. Six studies were rated as unclear risk of bias. A pooled analysis of six studies (489 participants) showed that AZA (1.0 to 2.5 mg/kg/day) was significantly superior to placebo for maintenance of remission over a 6 to 18 month period. Seventy-three per cent of patients in the AZA group maintained remission compared to 62% of placebo patients (RR 1.19, 95% CI 1.05 to 1.34). The number needed to treat for an additional beneficial outcome was nine. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (327 events) and unclear risk of bias. A pooled analysis of two studies (166 participants) showed no statistically significant difference in the proportion of patients who maintained remission between AZA (1.0 to 2.5 mg/kg/day) or 6-MP (1.0 mg/day) and mesalazine (3 g/day) sulphasalazine (0.5 g/15 kg) therapy. Sixty-nine per cent of patients in the AZA/6-MP group maintained remission compared to 67% of mesalazine/sulphasalazine patients (RR 1.09, 95% CI 0.88 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (113 events) and high or unclear risk of bias. One small study found AZA (2.0 to 2.5 mg/kg/day) to be superior to budesonide (6 to 9 mg/day) for maintenance of remission at one year. Seventy-six per cent (29/38) of AZA patients maintained remission compared to 46% (18/39) of budesonide patients (RR 1.65, 95% CI 1.13 to 2.42). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (47 events) and high risk of bias. One small study found no difference in maintenance of remission rates at one year between combination therapy with AZA (2.5 mg/kg) and infliximab (5 mg/kg every 8 weeks) compared to infliximab monotherapy. Eighty-one per cent (13/16) of patients in the combination therapy group maintained remission compared to 80% (16/20) of patients in the infliximab group (RR 1.02, 95% CI 0.74 to 1.40). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (29 events) and unclear risk of bias. One small study found no difference in maintenance of remission rates at one year between 6-MP (1 mg/day) and methotrexate (10 mg/week). Fifty per cent (8/16) of 6-MP patients maintained remission at one year compared to 53% (8/15) of methotrexate patients (RR 0.94, 95% CI 0.47 to 1.85). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (16 events) and high risk of bias. One study (147 participants) failed to show any significant benefit for early azathioprine treatment over a conventional management strategy. In the early azathioprine treatment group 67% (11-85%) of the trimesters were spent in remission compared to 56% (29-73%) in the conventional management group. AZA when compared to placebo had significantly increased risk of adverse events (RR 1.29, 95% CI 1.02 to 1.64), withdrawal due to adverse events (3.12, 95% CI 1.59 to 6.09) and serious adverse events (RR 2.45, 95% CI 1.22 to 4.90). AZA/6-MP also demonstrated a significantly higher risk of serious adverse events when compared to mesalazine or sulphasalazine (RR 9.37, 95% CI 1.84 to 47.7). AZA/6-MP did not differ significantly from other active therapies with respect to adverse event data. Common adverse events included pancreatitis, leukopenia, nausea, allergic reaction and infection. AUTHORS' CONCLUSIONS: Low quality evidence suggests that AZA is more effective than placebo for maintenance of remission in Crohn's disease. Although AZA may be effective for maintenance of remission its use is limited by adverse effects. Low quality evidence suggests that AZA may be superior to budesonide for maintenance of remission but because of small study size and high risk of bias, this result should be interpreted with caution. No conclusions can be drawn from the other active comparator studies because of low and very low quality evidence. Adequately powered trials are needed to determine the comparative efficacy and safety of AZA and 6-MP compared to other active maintenance therapies. Further research is needed to assess the efficacy and safety of the use of AZA with infliximab and other biologics and to determine the optimal management strategy for patients quiescent Crohn's disease.

The safety and efficacy of adalimumab in patients with Crohn's disease: the experience of a single Canadian tertiary care centre.

BACKGROUND. Adalimumab (ADA), an antitumor necrosis factor (anti-TNF) monoclonal antibody, is effective in treating moderate-to-severely active Crohn's disease (CD). ADA has been associated with a variety of adverse events (AE). The purpose of this study is to determine the safety and efficacy of ADA in CD patients in clinical practice. METHODS. A retrospective analysis was performed on CD patients treated with ADA. Data extracted and analyzed included patient and CD demographics, remission and response rates with ADA, and safety and tolerability of ADA. RESULTS. A total of 149 ADA-treated CD patients were included. The mean duration of therapy with ADA was 20 months with 32% of patients discontinuing treatment. Anti-TNF-naïve and anti-TNF-exposed patients on ADA achieved clinical remission in 45% and 32%, had a clinical response in 23% and 23%, and had no clinical response in 32% and 45%, respectively. Anti-TNF-naïve and anti-TNF-exposed patients maintained remission in 82% and 67%, respectively. Fistulas healed in 19% and improved in 19%. AE occurred in 38% of patients with infection being the most common (20%). Serious infections lead to death in one (<1%). Logistic regression of AE did not identify statistically significant predictors except for colonic disease location (odds ratio [OR] = 0.31, 95% CI = 0.12-0.82, p = 0.018) and the rate of ADA discontinuation (OR = 3.24, 95% CI = 1.58-6.64, p = 0.0013). CONCLUSION. ADA is an effective treatment for CD. AE can occur commonly leading to discontinuation of medication and may be influenced by disease location. Although serious complications are rare, close monitoring of all patients on ADA is needed.

Low dose naltrexone for induction of remission in Crohn's disease.

BACKGROUND: Crohn's disease is a transmural, relapsing inflammatory condition afflicting the digestive tract. Opioid signalling, long known to affect secretion and motility in the gut, has been implicated in the inflammatory cascade of Crohn's disease. Low dose naltrexone, an opioid antagonist, has garnered interest as a potential therapy. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of low dose naltrexone for induction of remission in Crohn's disease. SEARCH METHODS: A systematic search of MEDLINE, EMBASE, CENTRAL, and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group Specialized Register was performed from inception to February 2013 to identify relevant studies. Abstracts from major gastroenterology conferences including Digestive Disease Week and United European Gastroenterology Week and reference lists from retrieved articles were also reviewed. SELECTION CRITERIA: Randomized controlled trials of low dose naltrexone (LDN) for treatment of active Crohn's disease were included. DATA COLLECTION AND ANALYSIS: Data were analyzed on an intention-to-treat basis using Review Manager (RevMan 5.2). The primary outcome was induction of clinical remission defined by a Crohn's disease activity index (CDAI) of < 150 or a pediatric Crohn's disease activity index (PCDAI) of < 10. Secondary outcomes included clinical response (70- or 100-point decrease in CDAI from baseline), endoscopic remission or response, quality of life, and adverse events as defined by the included studies. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. MAIN RESULTS: Two studies were identified (46 participants). One study assessed the efficacy and safety of 12 weeks of LDN (4.5 mg/day) treatment compared to placebo in adult patients (N = 34). The other study assessed eight weeks of LDN (0.1 mg/kg, maximum 4.5 mg/day) treatment compared to placebo in pediatric patients (N = 12). The primary purpose of the pediatric study was to assess safety and tolerability. Both studies were rated as having a low risk of bias. The study in adult patients reported that 30% (5/18) of LDN treated patients achieved clinical remission at 12 weeks compared to 18% (3/16) of placebo patients, a difference that was not statistically significant (RR 1.48, 95% CI 0.42 to 5.24). The study in children reported that 25% of LDN treated patients achieved clinical remission (PCDAI < 10) compared to none of the patients in the placebo group, although it was unclear if this result was for the randomized placebo-controlled trial or for the open label extension study. In the adult study 70-point clinical response rates were significantly higher in those treated with LDN than placebo. Eighty-three per cent (15/18) of LDN patients had a 70-point clinical response at week 12 compared to 38% (6/16) of placebo patients (RR 2.22, 95% CI 1.14 to 4.32). The effect of LDN on the proportion of adult patients who achieved a 100-point clinical response was uncertain. Sixty-one per cent (11/18) of LDN patients achieved a 100-point clinical response compared to 31% (5/16) of placebo patients (RR 1.96, 95% CI 0.87 to 4.42). The proportion of patients who achieved endoscopic response (CDEIS decline > 5 from baseline) was significantly higher in the LDN group compared to placebo. Seventy-two per cent (13/18) of LDN patients achieved an endoscopic response compared to 25% (4/16) of placebo patients (RR 2.89; 95% CI 1.18 to 7.08). However, there was no statistically significant difference in the proportion of patients who achieved endoscopic remission. Endoscopic remission (CDEIS < 3) was achieved in 22% (4/18) of the LDN group compared to 0% (0/16) of the placebo group (RR 8.05; 95% CI 0.47 to 138.87). Pooled data from both studies show no statistically significant differences in withdrawals due to adverse events or specific adverse events including sleep disturbance, unusual dreams, headache, decreased appetite, nausea and fatigue. No serious adverse events were reported in either study. GRADE analyses rated the overall quality of the evidence for the primary and secondary outcomes (i.e. clinical remission, clinical response, endoscopic response, and adverse events) as low due to serious imprecision (sparse data). AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence to allow any firm conclusions regarding the efficacy and safety of LDN used to treat patients with active Crohn's disease. Data from one small study suggests that LDN may provide a benefit in terms of clinical and endoscopic response in adult patients with active Crohn's disease. Data from two small studies suggest that LDN does not increase the rate of specific adverse events relative to placebo. However, these results need to be interpreted with caution as they are based on very small numbers of patients and the overall quality of the evidence was rated as low due to serious imprecision. Further randomized controlled trials are required to assess the efficacy and safety of LDN therapy in active Crohn's disease in both adults and children. One study is currently ongoing (NCT01810185).