Methyl-deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress.

BACKGROUND: Methyl donor deficiency (MDD) aggravates experimental colitis in rats and increases endoplasmic reticulum (ER) stress through decreased sirtuin 1 (SIRT1) in neuronal cells and myocardium. ER stress plays a key role in IBD pathogenesis. AIM: We investigated whether the influence of MDD on colitis resulted from an ER stress response triggered by decreased SIRT1 expression. DESIGN: The unfolded protein response (UPR), chaperones proteins, heat shock factor protein 1 (HSF1) and SIRT1 were examined in rats with MDD and dextran sulfate sodium (DSS)-induced colitis in a Caco-2 cell model with stable expression of transcobalamin-oleosin (TO) chimera, which impairs cellular availability of vitamin B12, and in IBD. The effects of SIRT1 activation were studied both in vitro and in vivo. RESULTS: MDD aggravated DSS-induced colitis clinically, endoscopically and histologically. MDD activated ER stress pathways, with increased phosphorylate-PKR-like ER kinase, P-eiF-2α, P-IRE-1α, activating transcription factor (ATF)6, XBP1-S protein and ATF4 mRNA expression levels in rats. This was accompanied by reduced SIRT1 expression level and greater acetylation of HSF1, in relation with a dramatic decrease of chaperones (binding immunoglobulin protein (BIP), heat shock protein (HSP)27 and HSP90). Adding either vitamin B12, S-adenosylmethionine or an SIRT1 activator (SRT1720) reduced the UPR in vitro. In rats, SIRT1 activation by SRT1720 prevented colitis by reducing HSF1 acetylation and increasing expression of BIP, HSP27 and HSP90. Immunohistochemistry showed impaired expression of SIRT1 in the colonic epithelium of patients with IBD. CONCLUSIONS: SIRT1 is a master regulator of ER stress and severity of experimental colitis in case of MDD. It could deserve further interest as a therapeutic target of IBD.

Preoperative use of anti-TNF therapy and postoperative complications in inflammatory bowel diseases: a meta-analysis.

BACKGROUND AND AIMS: About one-third of inflammatory bowel disease (IBD) patients still require surgery. A growing number of them receive anti-tumor necrosis factor (TNF) therapy before surgery. The present meta-analysis studied the risk of postoperative complications in IBD patients treated with anti-TNF. METHODS: MEDLINE was searched (up to January 2012) to identify observational studies reporting the prevalence of postoperative complications in IBD patients. The prevalence of overall, infectious, and non-infectious postoperative complications was extracted for all studies, and according to preoperative anti-TNF treatment where reported. Pooled prevalence, as well as odds ratios (ORs), with 95% confidence intervals (CIs) was calculated. RESULTS: The search identified 86 citations. Twenty-one studies, containing 4251 subjects, reported the prevalence of postoperative complications according to preoperative anti-TNF treatment. Pooled prevalence of any postoperative complication was 21%, 35%, and 26% in Crohn's disease (CD), ulcerative colitis (UC) or inflammatory bowel disease unspecified (IBD-U) and IBD, respectively. The prevalence of any postoperative complication was increased in IBD patients who underwent preoperative anti-TNF therapy (OR: 1.25; 95% CI: 1.02-1.53). Pooled prevalence of infectious postoperative complications was 16%, 17%, and 15% in CD, UC/IBD-U and IBD, respectively. The prevalence of infectious postoperative complications was increased in CD patients who underwent preoperative anti-TNF therapy (OR: 1.45; 95% CI: 1.03-2.05). The confounding effect of concomitant therapies could not be studied. CONCLUSIONS: Preoperative anti-TNF use slightly increases the occurrence of overall postoperative complications in IBD patients, and particularly infectious complications in CD patients. Postoperative complications are not increased in UC.

Adherence to anti-TNF therapy in inflammatory bowel diseases: a systematic review.

BACKGROUND: Nonadherence to medications may affect disease outcomes. The aim of this article was to review methods of assessment, prevalence, and predictors of nonadherence to anti-tumor necrosis factor therapy in inflammatory bowel diseases (IBD). METHODS: Studies were identified through the electronic database of MEDLINE (up to January 2012) and the annual meetings of Digestive Disease Week, the American College of Gastroenterology, the United European Gastroenterology Week, and the European Crohn's and Colitis Organization. RESULTS: Among 1783 citations identified, 13 studies evaluated adherence to biologics in IBD. Several methods were used to assess adherence to anti-tumor necrosis factor, including the medication possession ratio, the medication refill adherence, and the Morisky Medication Adherence Scale 8. Pooled adherence to anti-tumor necrosis factor therapy was 82.6%. Pooled adherence was 83.1% in adalimumab and 70.7% in infliximab-treated patients. Female gender, smoking, constraints related to treatment, anxiety, and moodiness were associated with nonadherence to both infliximab and adalimumab. Concomitant immunomodulator use and time since first infusion more than 18 weeks were predictors for nonadherence to infliximab . Regimen of 40 mg every other week, syringe use (versus pen), internal medicine center prescription (versus gastroenterology center prescription), retail pharmacy (versus speciality pharmacy) and new user (versus previous user) were predictors for adalimumab nonadherence. CONCLUSIONS: More than three-quarters of patients with IBD adhere to biologics. Predictors of nonadherence include female gender, smoking, constraints related to treatment, anxiety, and moodiness. These data could be used to develop intervention studies aimed at improving adherence to biologics in IBD.

Long-term outcome of perianal fistulizing Crohn's disease treated with infliximab.

BACKGROUND & AIMS: Little is known about the long-term efficacy of infliximab for patients with fistulizing perianal Crohn's disease. We evaluated outcomes and predictors of outcomes in these patients. METHODS: The medical records of 156 patients treated with infliximab for fistulizing perianal Crohn's disease at 2 referral centers from 1999 through 2010 were reviewed through September 2011. Cumulative probabilities of fistula closure and recurrence were estimated by using the Kaplan-Meier method. Predictors of outcomes were identified by using a Cox proportional hazards model. RESULTS: When infliximab treatment began, only 17.9% of patients had a simple fistula; seton drainage was performed for 97 patients (62%). Concomitant immunosuppressants were given to 90 patients (56%). After a median follow-up period of 250 weeks, 108 patients (69%) had at least 1 fistula closure. Cumulative probabilities of first fistula closure were 40% and 65% at 1 and 5 years, respectively. Factors that predicted fistula closure were ileocolonic disease (hazard ratio [HR] = 1.88), concomitant immunosuppressants (HR = 2.58), duration of seton drainage <34 weeks (HR = 2.31), and long duration of infliximab treatment (HR = 1.76). Of the 108 patients with fistula closure, cumulative probabilities of first fistula recurrence were 16.6% and 40.1% at 1 and 5 years, respectively. Forty-four patients (28.9%) developed an abscess during follow-up. A number of infliximab infusions greater than 19 was associated with less abscess recurrence (HR = 0.33). At the maximal follow-up time, 55% of patients had fistula closure. CONCLUSIONS: About two-thirds of patients with fistulizing perianal Crohn's disease had fistula closure, and one-third had fistula recurrence after infliximab initiation. Combination therapy, duration of seton drainage less than 34 weeks, and long-term treatment with infliximab were associated with better outcomes.

5-Aminosalicylates and renal function monitoring in inflammatory bowel disease: a nationwide survey.

BACKGROUND AND AIM: 5-Aminosalicylates (ASA) are widely used in inflammatory bowel disease (IBD). Nephrotoxicity has been described in some IBD patients treated with 5-ASA. Whether physicians managing these patients are monitoring renal function in daily practice is unknown. The aims of this paper were to investigate how private gastroenterologists monitor renal function and manage renal failure in IBD patients treated with oral 5-ASA therapy. METHODS: This was a web-based cross sectional national survey which was conducted among private gastroenterologists. RESULTS: A total of 249 practitioners completed the survey. Eighty two percent (n=205) of responders declared that they always monitor renal function. The respondents monitored twice a year Glomerular Filtration Rate (eGFR) using Modification of Diet in Renal Disease (MDRD) [90% (n=225)] and Creatinine Clearance (CCr) using a 24-hour urine collection [51% (n=126)]. Blood electrolytes, 24-hour urinary protein rate and dipsticks are performed by 41%, 39% and 22% of practitioners, respectively. Before oral 5-ASA initiation, 59% (n=148) of respondents screen for renal failure. In case of elevated serum creatinine, a nephrologist's opinion is asked by 80% (n=200) of responders and by 76% (n=189) of respondents before treatment initiation. CONCLUSIONS: Most gastroenterologists are monitoring renal function once or twice a year in IBD patients on 5-ASA. Less than two thirds of them screen for renal failure before treatment initiation. MDRD is mainly used, but a wide range of parameters is evaluated.

Development of the Paris definition of early Crohn's disease for disease-modification trials: results of an international expert opinion process.

We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen experts on inflammatory bowel diseases held an international expert opinion meeting to discuss and agree on a definition for early CD to be used in disease-modification trials. The process included literature searches for the relevant basic-science and clinical evidence. A published preliminary definition of early CD was used as the basis for development of a proposed definition that was discussed at the expert opinion meeting. The participants then derived a final definition, based on best current knowledge, that it is hoped will be of practical use in disease-modification trials in CD.

Plasma soluble triggering receptor expressed on myeloid cells-1 in Crohn's disease.

BACKGROUND: No definite conclusions can be drawn from available data on the accuracy of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) to assess disease activity in Crohn's disease. AIMS: Plasma sTREM-1 levels were correlated with disease activity markers in Crohn's disease. METHODS: 191 consecutive patients from a single referral centre (Nancy IBD cohort) were prospectively enrolled between June 1, 2005 and December 12, 2008. Plasma sTREM-1 levels were also assessed amongst 20 healthy controls. RESULTS: The sTREM-1 was detectable in 87 Crohn's disease patients (46%). Plasma sTREM-1 level was higher in Crohn's disease patients (interquartile range, 0-356) than in healthy controls (interquartile range, 0-15.1; P=0.01). It was neither correlated with Crohn's disease activity index (r=0.05, P=0.56), C-reactive protein (r=0.06, P=0.53), nor with albumin (r=-0.041, P=0.66). Crohn's disease activity index, C-reactive protein and albumin median levels were similar between patients with positive sTREM-1 levels and those with undetectable sTREM-1 levels. Azathioprine (P=0.06), infliximab (P=0.68) and methotrexate (P=0.56) did not influence sTREM-1 levels. CONCLUSION: Plasma sTREM-1 does not appear to be an accurate marker of disease activity in Crohn's disease and cannot be recommended for assessing disease activity in these patients.

Ulcerative colitis as a progressive disease: the forgotten evidence.

In the management of Crohn's disease, earlier aggressive treatment is becoming accepted as a strategy to prevent or retard progression to irreversible bowel damage. It is not yet clear, however, if this same concept should be applied to ulcerative colitis. Hence, we review herein the long-term structural and functional consequences of this latter disease. Disease progression in ulcerative colitis takes six principal forms: proximal extension, stricturing, pseudopolyposis, dysmotility, anorectal dysfunction, and impaired permeability. The precise incidence of these complications and the ability of earlier, more aggressive treatment to prevent them have yet to be determined.

Incidence of and impact of medications on colectomy in newly diagnosed ulcerative colitis in the era of biologics.

BACKGROUND: The cumulative incidence of colectomy and the impact of 5-aminosalicylates (5-ASA), azathioprine, and antitumor necrosis factor (TNF) treatment on the long-term need for surgery are unknown in ulcerative colitis (UC) in the era of biologics. METHODS: This was an observational study of a referral center cohort. The cumulative incidence of UC-related colectomy was estimated using the Kaplan-Meier method. Independent predictors of surgery were identified using Cox proportional hazards regression with propensity scores adjustment. The electronic charts of 151 incident cases of UC from Nancy University Hospital, France, diagnosed between 2000 and 2008, were reviewed through January 2010. RESULTS: The median follow-up time per patient was 58 months. Twenty-one (14%) underwent surgery. The cumulative probabilities of colectomy were respectively 1.3% and 13.5% at 1 and 5 years from the time of diagnosis. The probability of receiving oral mesalamine at 5 years was 68.1%. The corresponding figures were 48.9% for azathioprine and 29.0% for infliximab. For corticosteroids, methotrexate, and cyclosporin these figures were 75%, 8.8%, and 11.5%, respectively. Using multivariate Cox proportional hazards regression analysis after propensity score adjustment, previous use of cyclosporin was the only independent predictor for colectomy (hazard ratio = 4.41; 95% confidence interval 1.75-1.13). CONCLUSIONS: About one-tenth of patients still require colectomy for UC at 5 years in the era of biologics. Oral 5-ASA, azathioprine, and anti-TNF therapy are not associated with a reduced need for colectomy.

Urinary tract infections in hospitalized inflammatory bowel disease patients: a 10-year experience.

BACKGROUND: Cystitis is the most common genitourinary complication in Crohn's disease (CD). We assessed the prevalence of and risk factors for urinary tract infections (UTI) in inflammatory bowel diseases (IBD). METHODS: Among the 1173 IBD patients of the "Nancy IBD cohort" seen between January 1, 2000 and December 31, 2009, 56 hospitalized patients had 76 documented UTI. Prevalence of UTI in IBD was calculated using rates of UTI among non-IBD patients hospitalized during the same period. The cases were compared to 175 matched IBD patients without UTI hospitalized during the same period to identify risk factors for UTI. RESULTS: Prevalence of UTI was 4% in IBD patients versus 3.3% in non-IBD patients (P = 0.1). Prevalence of UTI was 4.5% and 2.1% in ulcerative colitis (UC) and CD patients, respectively (P = 0.6). Risk factors for UTI in CD patients were perianal disease (odds ratio [OR] = 2.28, 95% confidence interval [CI], 1.06-4.89; P = 0.04) and colonic disease (OR = 2.42, 95% CI, 1.05-5.58; P = 0.04). Male gender (OR = 0.38, 95% CI, 0.17-0.85, P = 0.02) and noncomplicated behavior (OR = 0.26, 95% CI, 0.11-0.60, P = 0.002) were protective factors against UTI in CD. In UC patients, age over 40 years (OR = 9.59, 95% CI, 1.93-47.74; P = 0.006) and disease duration over 11 months (OR = 10.77, 95% CI, 1.68-68.89, P = 0.01) were risk factors for UTI. Male gender was negatively associated with UTI (OR = 0.04, 95% CI, 0.01-0.36, P = 0.00006). CONCLUSIONS: Hospitalized IBD patients are not at increased risk of UTI. Risk factors for UTI include perianal disease and colonic disease in CD and age and longer disease duration in UC.

Update on Crohn's disease and ulcerative colitis.

The 6th European Crohn's and Colitis Organisation Congress took place in Dublin, Ireland, on the occasion of the 10th European Crohn's and Colitis Organisation anniversary. This key annual event attracted a record number of participants and presented updated information in the field of inflammatory bowel disease in children and adults. The extensive program combined the original basic scientific program that dealt with pathogenesis and new therapeutic targets, while the clinical program focused on the possibility of optimizing current therapies, the importance of mucosal healing and features of inflammatory bowel disease-related cancer.

Loss of response and need for adalimumab dose intensification in Crohn's disease: a systematic review.

The objective of this study was to review loss of response and need for adalimumab dose intensification in adult and pediatric patients with Crohn's disease. Studies were identified through the electronic databases of MEDLINE and the annual meetings of Digestive Disease Week, of the United European Gastroenterology Week, and of the American College of Gastroenterology and the European Crohn's and Colitis Organization meetings. Studies evaluating loss of efficacy and/or need for dose intensification were included. Thirty-nine studies were included. The mean percentage of loss of response to adalimumab among primary responders was 18.2% and the annual risk was 20.3% per patient-year. The mean percentage of patients who required dose intensification among primary responders to adalimumab was 37% and the annual risk was 24.8% per patient-year. When considering initial responders and patients with primary non-response, the mean percentage of patients who needed an adalimumab dose escalation was 21.4% and the annual risk was 24.4% per patient-year. Pooled analysis showed that dose escalation permitted response to be regained in 71.4% and remission in 39.9% of patients. Predictors for loss of response or dose escalation were male gender, current/former smoker status, family history of inflammatory bowel disease, isolated colonic disease, extra-intestinal manifestations, 80/40 mg induction therapy, longer disease duration, greater baseline Crohn's Disease Activity Index, concomitant corticosteroid use, no deep remission at week 12, low serum trough concentrations of adalimumab, previous infliximab non-response and being previously treated with an anti-tumor necrosis factor agent. Overall, around one fifth of adult patients require dose intensification and experience a loss of response after initiation of adalimumab therapy. Adalimumab dose escalation permits response to be regained in the majority of patients.

Adherence to adalimumab therapy in Crohn's disease: a French multicenter experience.

BACKGROUND: We evaluated adherence to adalimumab therapy in Crohn's disease (CD). METHODS: This was an observational multicenter study conducted in four French university hospitals between April 4, 2008 and January 1, 2010. Patients were systematically asked, at each clinical visit, whether or not they delayed or missed an injection of adalimumab over the past 3 months. Patients were also asked about the reasons for their nonadherence. RESULTS: Of the 108 patients analyzed, 33 (30.6%) delayed the administration of at least one injection and 16 (14.8%) missed at least one injection over the past 3 months. The main reasons for overall nonadherence were: forgetfulness (24.6%), infection (24.6%), and travel (20%). Other reasons for nonadherence were intentional nonadherence (10.8%), pharmaceutical supply issues (9.2%), side effects (7.7%), pregnancy (1.5%), and CD-related hospitalization (1.5%). Adalimumab regimen of 40 mg every other week was a positive predictor for injection delays (P = 0.02, odds ratio [OR] = 3.76, 95% confidence interval [CI], 1.28-11.05), whereas having at least one relapse in the past 12 months was associated with fewer delays (P = 0.02, OR = 0.37, 95% CI, 0.15-0.87). [correction made here after initial online publication]. Disease duration over 90 months negatively predicted failure to inject adalimumab (P = 0.009, OR = 0.17, 95% CI, 0.05-0.64). CONCLUSIONS: The overall nonadherence rate for adalimumab use was 45.4%. Most of the reasons for nonadherent behaviors could be avoided. An adalimumab regimen of 40 mg every other week was negatively related to adalimumab adherence; both the occurrence of at least one relapse in the past 12 months and disease duration over 90 months were positively related to adherence.