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Background and Aim: Anti-tumor necrosis factor (TNF) antibodies are effective in maintaining remission in Crohn's disease. However, a significant proportion of patients lose response to these agents with time. This study aimed to determine whether the introduction of a thiopurine in patients who have lost response to anti-TNF monotherapy results in regained response., Methods: Five patients (four males; aged 22-38 years) with active Crohn's disease, who had an initial response to anti-TNF therapy but had lost response, were commenced on azathioprine or mercaptopurine at standard doses while continuing anti-TNF therapy. All had previously failed thiopurine therapy prior to starting anti-TNF treatment., Results: All patients experienced improved clinical symptoms within 2-6 months, with benefit sustained over a mean follow-up of 19 months. Two patients with an elevated C-reactive protein at the time of thiopurine addition demonstrated a fall in C-reactive protein. Colonoscopy before and after thiopurine addition in four patients showed improvement in all, with mucosal healing achieved in two. No adverse effects of treatment were noted., Conclusions: Addition of a thiopurine in patients who have lost response to anti-TNF monotherapy is an effective strategy to recapture response even if the patient has previously failed thiopurine therapy. Thiopurines may reduce immunogenicity or act synergistically with anti-TNF therapy., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background and Aim: In irritable bowel syndrome (IBS), the gut microbiota may be altered. Probiotic bacteria appear to be therapeutically effective. We characterized the mucosa-associated microbiota, and determined the clinical and microbiological effects of orally administered probiotic bacteria, in patients with IBS., Methods: Mucosal microbiota from rectal biopsies of IBS patients and controls were assessed on the V1 and V2 variable regions of the 16S ribosomal RNA gene amplified using 454 pyrosequencing. Clinical symptoms and changes in mucosal microbiota were assessed in IBS patients before and after 4 weeks of treatment with probiotic mix VSL#3., Results: Ten IBS subjects (eight female; mean age 46 years) were included. At week 4 of probiotic therapy, six patients showed symptom improvement on global symptom assessment compared with baseline (P = 0.031). Before therapy, intestinal microbiota of IBS subjects differed significantly from that of healthy controls, with less diversity and evenness than controls (n = 9; P < 0.05), increased abundance of Bacteroidetes (P = 0.014) and Synegitestes (P = 0.017), and reduced abundance of Actinobacteria (P = 0.004). The classes Flavobacteria (P = 0.028) and Epsilonproteobacteria (P = 0.017) were less enriched in IBS. Abundance differences were largely consistent from the phylum to genus level. Probiotic treatment in IBS patients was associated with a significant reduction of the genus Bacteroides (all taxonomy levels; P < 0.05) to levels similar to that of controls., Conclusion: In this pilot study, global and deep molecular analysis demonstrates an altered mucosal microbiota composition in IBS. Probiotic leads to detectable changes in the microbiota. These effects of probiotic bacteria may contribute to their therapeutic benefit., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: Mucosal dye spraying (chromoendoscopy [CE]) has been shown in controlled studies to enhance lesion detection in colitis surveillance. Narrow band imaging (NBI) potentially offers a more convenient mode of highlighting mucosal lesions. The primary objectives of this study were to compare CE and NBI in colitis surveillance with respect to lesion detection. A secondary objective was to assess the accuracy of the mucosal pit pattern (Kudo classification) with NBI in predicting mucosal histology., Methods: Patients with colitis of 8 years or greater disease duration underwent screening colonoscopy with NBI, followed immediately by CE by 2 endoscopists blinded to each other's results. All lesions were biopsied to confirm histology. Diagnostic yield of each modality for dysplastic lesions. Accuracy of Kudo classification by NBI for neoplasia., Results: Forty-four participants were enrolled. One hundred forty-four colonic lesions were identified in total. Overall, CE identified more lesions than NBI (131 versus 102, P < 0.001); however, most were nondysplastic. CE detected 23 neoplastic (dysplastic or indefinite for dysplasia) lesions in 11 patients and NBI 20 lesions in 10 patients, P = 0.180. Kudo assessment by NBI had low sensitivity for dysplasia (42%) and modest accuracy (74%) for dysplasia., Conclusions: NBI detected fewer lesions than CE in chronic colitis; however, most were not dysplastic. There was a nonsignificant trend in favor of CE for detection of dysplasia. At present, NBI cannot be recommended as an alternative to CE for dysplasia surveillance in colitis.

Background: Previously a disease of the West and rarely seen in China, inflammatory bowel disease (IBD) is now increasing in incidence in China. However, its true incidence is unknown. The incidence of IBD in Wuhan, a major city in central China, was investigated using population-based methods., Methods: A prospective, population-based IBD incidence study was conducted between January 1, 2010, and December 31, 2010. New IBD cases were identified by gastroenterologists and from hospital case records in 17 central hospitals covering the health care service of central Wuhan. Cases were confirmed by follow-up and assessed by a specialist IBD group every 3 months. The population at risk was 6,085,556., Results: Overall, 131 new cases of IBD were identified during the 1-year period, including 97 cases of ulcerative colitis (UC) and 34 cases of Crohn's disease (CD). The age-adjusted incidence for all IBD, UC, and CD were 1.96 per 100,000 (95% confidence interval [CI], 1.62-2.30 per 100,000), 1.45 (95% CI, 1.16-1.75), and 0.51 (95% CI, 0.33-0.68), respectively. CD affected the small bowel only in 15%, colon only in 24%, and ileocolonic in 61%. CD often presented with complicated phenotype: inflammatory (44%), stricturing (29%), and penetrating (24%). Among patients with UC, complications included proctitis (34.5%), left-sided colitis (44.6%), and extensive colitis (19.5%)., Conclusions: There is a substantial incidence of IBD in China. Although still lower than in the West, the emergence of IBD will necessitate specific health care planning and education and offers the possibility of identifying causative factors in a population with a rapidly increasing incidence.

Background & Aims: Inflammatory bowel diseases (IBD) are becoming more common in Asia, but epidemiologic data are lacking. The Asia-Pacific Crohn's and Colitis Epidemiology Study aimed to determine the incidence and phenotype of IBD in 8 countries across Asia and in Australia., Methods: We performed a prospective, population-based study of IBD incidence in predefined catchment areas, collecting data for 1 year, starting on April 1, 2011. New cases were ascertained from multiple overlapping sources and entered into a Web-based database. Cases were confirmed using standard criteria. Local endoscopy, pathology, and pharmacy records were searched to ensure completeness of case capture., Results: We identified 419 new cases of IBD (232 of ulcerative colitis [UC], 166 of Crohn's disease [CD], and 21 IBD-undetermined). The crude annual overall incidence values per 100,000 individuals were 1.37 for IBD in Asia (95% confidence interval: 1.25-1.51; 0.76 for UC, 0.54 for CD, and 0.07 for IBD-undetermined) and 23.67 in Australia (95% confidence interval: 18.46-29.85; 7.33 for UC, 14.00 for CD, and 2.33 for IBD-undetermined). China had the highest incidence of IBD in Asia (3.44 per 100,000 individuals). The ratios of UC to CD were 2.0 in Asia and 0.5 in Australia. Median time from symptom onset to diagnosis was 5.5 months (interquartile range, 1.4-15 months). Complicated CD (stricturing, penetrating, or perianal disease) was more common in Asia than Australia (52% vs 24%; P = .001), and a family history of IBD was less common in Asia (3% vs 17%; P < .001)., Conclusions: We performed a large-scale population-based study and found that although the incidence of IBD varies throughout Asia, it is still lower than in the West. IBD can be as severe or more severe in Asia than in the West. The emergence of IBD in Asia will result in the need for specific health care resources, and offers a unique opportunity to study etiologic factors in developing nations., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Dendritic cells (DC) migrate to lymph nodes on expression of C-C motif chemokine receptor 7 (CCR7) and control immune activity. Leptin, an immunomodulatory adipokine, functions via leptin receptors, signaling via the long isoform of receptor, LepRb. Leptin promotes DC maturation and increases CCR7 expression on blood DC. Increased mesenteric fat and leptin occur early in Crohn's disease (CD), suggesting leptin-mediated change in intestinal CCR7 expression on DC as a pro-inflammatory mechanism. We have demonstrated CCR7 expression and capacity to migrate to its ligand macrophage inflammatory protein 3β in normal human ileal DC but not colonic or blood DC. In CD, functional CCR7 was expressed on DC from all sites. Only DC populations containing CCR7-expressing cells produced LepRb; in vitro exposure to leptin also increased expression of functional CCR7 in intestinal DC in a dose-dependent manner. In conclusion, leptin may regulate DC migration from gut, in homeostatic and inflammatory conditions, providing a link between mesenteric obesity and inflammation.

Background and Aim: Intestinal failure (IF) is a rare but devastating complication of Crohn's disease (CD). The clinical and surgical factors that predispose to IF are poorly understood. The aim of this study was to define clinical factors that predispose to IF., Methods: A retrospective case-control study was performed using consecutive CD patients with IF who were identified from a prospective database. Local population-based controls were selected with which to compare demographic, phenotypic, and clinical outcomes., Results: Eighty-two CD patients requiring long-term intravenous fluids or nutrition were studied. Diagnosis at age 16 years or less (P = 0.01) and a family history of inflammatory bowel disease (P = 0.02) were associated with a significantly higher risk for developing IF. Among the IF group, 53% had perioperative complications from intestinal resections contributing to long-term IF. Furthermore, these patients had more abdominal surgeries (P = 0.05) and stricturing disease was less common than in patients with primary active CD (P = 0.01). IF due to primary active CD was associated with penetrating behavior (P = 0.02) and early age at first surgery (P = 0.004). The need for intravenous nutrition as opposed to intravenous fluids correlated inversely with small intestine length (P < 0.001)., Conclusions: CD resulting in IF relates to earlier age at diagnosis, family history of inflammatory bowel disease, stricturing disease, younger age at first surgery, and operative complications. These factors deserve consideration when planning therapy for CD patients., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Aim: Eighty per cent of patients with Crohn's disease require surgery, of whom 70% will require a further operation. Recurrence occurs at the anastomosis. Although often recommended, the impact of postoperative colonoscopy and treatment adjustment is unknown., Method: Patients with a bowel resection over a 10-year period were reviewed and comparison made between those who did and did not have a postoperative colonoscopy within 1 year of surgery, and those who did or did not have a step-up in drug therapy., Results: Of 222 patients operated on, 136 (65 men, mean age 33 years, mean disease duration 8 years, median follow-up 4 years) were studied. Of 70 patients with and 66 without postoperative colonoscopy, clinical recurrence occurred in 49% and 48% (NS) and further surgery in 9% and 5% (NS). Eighty-nine per cent of colonoscoped patients had a decision based on the colonoscopic findings: of these, 24% had a step-up of drug therapy [antibiotics (n =10), aminosalicylates (n=2), thiopurine (n=5), methotrexate (n=1)] and 76% had no step-up in drug therapy. In colonoscoped patients clinical recurrence occurred in 9 (60%) of 15 patients with, and 23 (49%) of 47 without step-up and surgical recurrence in 2 (13%) of 15 and 4 (9%) of 47 (NS)., Conclusion: Clinical recurrence occurs in a majority of patients soon after surgery. In this cohort, there was no clinical benefit from colonoscopy or increased drug therapy within 1 year after operation. However, the response to the endoscopic findings was not standardized and immunosuppressive therapy was uncommon. Standardizing timing of colonoscopy and drug therapy, including more intense therapy, may improve outcome, although this remains to be proven., (© 2012 The Authors. Colorectal Disease © 2012 The Association of Coloproctology of Great Britain and Ireland.)

Background: Inflammatory bowel disease can impact on a patient's ability to maintain normal physical and mental function, and fulfil their social, family and work roles. Aspects of disability in IBD have received little attention., Aim: To develop, validate and apply a questionnaire directed towards evaluating these disease aspects., Methods: A literature review on disability in IBD was undertaken, and opinion about aspects of disability to measure was sought from six IBD-specialised gastroenterologists. A questionnaire was developed, and IBD patients completed the new disability questionnaire, the SF-36 and the short-IBD (SIBDQ - 10 point). A subgroup of patients completed the questionnaire again 4 weeks later. Healthy volunteers were studied as a control group., Results: A total of 116 IBD out-patients were approached, of whom 81 (52 Crohn's disease and 28 ulcerative colitis) participated. Nineteen patients were re-evaluated at 4 weeks. Twenty-five controls were studied. All subscales demonstrated good Cronbach's alpha reliability and reproducibility. There was a significant inverse correlation between the disability score and the SIBDQ and between the disability score and the SF36 and a positive correlation with the Crohn's Disease Activity Index (CDAI) (all P < 0.001). Disability differed between ulcerative colitis and controls, but not between active and inactive disease., Conclusions: The new disability questionnaire is sensitive for detecting disability, is reliable and reproducible, and correlates with disease activity in Crohn's disease, but not ulcerative colitis. Further prospective testing is now needed in the longer term, larger patient populations and in different countries and ethnicities., (© 2012 Blackwell Publishing Ltd.)

The traditional goals of Crohn's disease therapy, to induce and maintain clinical remission, have not clearly changed its natural history. In contrast, emerging evidence suggests that achieving and maintaining mucosal healing may alter the natural history of Crohn's disease, as it has been associated with more sustained clinical remission and reduced rates of hospitalization and surgical resection. Induction and maintenance of mucosal healing should therefore be a goal toward which therapy is now directed. Unresolved issues pertain to the benefit of achieving mucosal healing at different stages of the disease, the relationship between mucosal healing and transmural inflammation, the intensity of treatment needed to achieve mucosal healing when it has not been obtained using standard therapy, and the means by which mucosal healing is defined using current endoscopic disease activity indices. The main clinical challenge relates to defining the means of achieving high rates of mucosal healing in clinical practice.

Background: Anti-tumor necrosis factor (TNF) therapy heals many Crohn's disease (CD) anal fistulas clinically but the rate, extent, and durability of deep tissue healing and factors influencing long-term outcome are unknown., Methods: Consecutive patients with CD-related perianal (anal, rectovaginal, anolabial) fistulas treated with infliximab or adalimumab were monitored prospectively both clinically and radiologically using magnetic resonance imaging (MRI)., Results: Forty-one consecutive patients with CD-related perianal fistulas were treated with infliximab (n = 32) or adalimumab (n = 9; following infliximab failure) in combination with a thiopurine (unless intolerant). Fifty-eight percent of all patients, comprising 66% and 43% of infliximab and adalimumab-treated patients, respectively, demonstrated remission or response at 3 years. Thirty-three percent of infliximab treated patients maintained clinical remission at 3 years. Radiological healing lagged behind clinical remission by a median of 12 months. The likelihood of clinical remission at any time was five times greater in patients who had early clinical response within 6 weeks than those without. A higher number of fistula tracts was associated with reduced clinical remission. All patients who achieved radiological healing maintained healing on infliximab treatment, while only 43% maintained healing after cessation of anti-TNF therapy., Conclusions: Combination anti-TNF and thiopurine therapy provides sustained benefit in patients with perianal CD fistula. Early clinical response is associated with subsequent clinical remission. Radiological healing is slower than clinical healing. Radiologically healed fistula tracts maintain healing on infliximab but can recur after cessation of therapy., (Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.)

The incidence and prevalence of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are lower in Asia than in the West. However, across Asia the incidence and prevalence of IBD has increased rapidly over the last two to four decades. These changes may relate to increased contact with the West, westernization of diet, increasing antibiotics use, improved hygiene, vaccinations, or changes in the gut microbiota. Genetic factors also differ between Asians and the Caucasians. In Asia, UC is more prevalent than CD, although CD incidence is rapidly increasing in certain areas. There is a male predominance of CD in Asia, but a trend towards equal sex distribution for UC. IBD is diagnosed at a slightly older age than in the West, and there is rarely a second incidence peak as in the West. A positive family history is much less common than in the West, as are extra-intestinal disease manifestations. There are clear ethnic differences in incidence within countries in Asia, and an increased incidence in IBD in migrants from Asia to the West. Research in Asia, an area of rapidly changing IBD epidemiology, may lead to the discovery of critical etiologic factors that lead to the development of IBD., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

The diagnosis of inflammatory bowel disease (IBD) is traditionally based on a combination of clinical, endoscopic, histological, and radiological criteria. However, further testing is needed in cases of diagnostic uncertainty and in predicting disease course. This systematic review focuses on the potential for 10 serological antibodies to fill these roles: pANCA, ASCA, anti-OmpC, anti-CBir1, anti-I2, ALCA, ACCA, AMCA, anti-L, and anti-C. We discuss their prevalence in IBD and health; their role in disease diagnosis and risk stratification; their stability over time; their presence in unaffected relatives; their association with genetic variants; and differences across ethnic groups. Serological antibodies have some role in primary diagnosis and in differentiating between Crohn's disease and ulcerative colitis. In indeterminate colitis, preoperative measurement of serological antibodies can help to predict the likelihood of complications among patients undergoing pouch surgery. The combined presence and magnitude of a large panel of antibodies appear to be of value in predicting disease progression. There is currently insufficient evidence to recommend the use of antibody testing to predict responses to treatment or surgery in patients with IBD., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Background: Patients with Crohn's disease (CD) have an intestinal dysbiosis with components of the microbiota exerting differential immune effects. Smoking is associated with an increased incidence of CD, more frequent relapse, and greater burden of surgery. This study aimed to investigate the association between smoking and the intestinal microbiota in patients with active CD., Methods: Patients with active CD (n = 103) and healthy controls (n = 66) were recruited and demographic and clinical data recorded including current smoking behavior. Fecal samples were collected and analyzed by fluorescent in situ hybridization using probes targeting 16S rRNA of bacteria previously shown to be altered in active CD (bifidobacteria, bacteroides, Clostridium coccoides-Eubacterium rectale, Escherichia coli, and Faecalibacterium prausnitzii)., Results: In total, 29/101 (29%) patients with CD and 8/58 (14%) controls were current smokers (P = 0.032). Following multivariate analysis, smoking was found to have a significant and independent effect on the microbiota of patients with CD, with higher Bacteroides-Prevotella in smokers (38.4%) compared with nonsmokers (28.1%) (F((1,93)) = 12.6, P = 0.001). Healthy controls who smoked also had higher Bacteroides-Prevotella (34.8%) than nonsmokers (24.1%) (F((1,55)) = 4.5, P = 0.038). In the pooled multivariate analysis, patients with CD had higher bifidobacteria (F((1,156)) = 30.5, P < 0.001), higher Bacteroides-Prevotella (F((1,156)) = 6.5, P = 0.012), and lower F. prausnitzii (F((1,156)) = 3.8, P = 0.052) compared with healthy controls., Conclusions: Smokers have luminal microbiota that consist of significantly higher bacteroides. Investigation of whether this is one mechanism through which the negative effects of smoking on CD are mediated is warranted., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Background: Inflammatory bowel diseases (IBD) result from an interaction between genetic and environmental factors. Preliminary findings suggest that susceptibility genes differ between IBD patients in Asia and the West. We aimed to evaluate disease-predisposing genes in Asian IBD patients., Methods: A systematic review and meta-analysis were performed of published studies from 1950 to 2010 using keyword searches in MEDLINE, EMBASE, EBM Reviews, and BIOSIS Previews., Results: In all, 477 abstracts were identified and data extracted from 93 studies, comprising 17,976 IBD patients and 27,350 age- and sex-matched controls. Major nucleotide oligomerization domain (NOD)-2 variants in Western Crohn's disease (CD) patients were not associated with CD in Han Chinese, Japanese, South Korean, Indian, and Malaysian populations. New NOD2 mutations were, however, associated with CD in Malaysians (JW1), Han Chinese, and Indians (P268S). Autophagy-related protein 16-linked 1 (ATG16L1) was not associated with CD in East Asians (odds ratio [OR] 0.97; 95% confidence interval [CI] 0.84-1.13). Interleukin (IL)-23R was associated with CD in South Koreans (OR 1.8; 95% CI 1.16-2.82) and a single nucleotide polymorphism in IL-23R (Gly149Arg) was protective of CD in Han Chinese (OR 0.3; 95% CI 0.15-0.60). Tumor necrosis factor (TNF) superfamily gene-15 (SF15) polymorphisms were associated with CD (OR 2.68; 95% CI 1.86-3.86), while TNF-308 polymorphisms (OR 1.82; 95% CI 1.15-2.9), cytotoxic T lymphocyte antigen (CTLA)-4 (OR 2.75; 95% CI 1.22-6.22) and MICA allele (OR 2.41; 95% CI 1.89-3.07) were associated with ulcerative colitis in Asians., Conclusions: Genetic mutations of IBD in Asians differ from Caucasians. New mutations and susceptibility genes identified in Asian IBD patients provide an opportunity to explore new disease-associated mechanisms in this population of rising incidence., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Background and Aim: Inflammatory bowel disease (IBD), common in Melbourne, was rare but is now increasing in incidence in Hong Kong (HK). To investigate whether these are the same diseases in the West and East, potential causes of changing incidence, and to plan resource needs, an appreciation of clinical characteristics in contrasting populations is essential., Methods: Disease characteristics were collected from prospectively populated IBD databases in two specialist centers in Melbourne, Australia and HK., Results: Of 795 patients (Crohn's disease [CD] : ulcerative colitis [UC] Melbourne 272:159 and HK 161:203), the age of diagnosis was higher, there were proportionally more male patients with CD but no UC sex difference, fewer patients were current or ex-smokers (CD 8% vs 50%; UC 17% vs 35%) and a family history of IBD was less common (2% vs 11%; P < 0.001) in HK compared to Melbourne. Stricturing and perianal CD were more common in HK (12% vs 6%; P < 0.001; and 29% vs 16%; P = 0.001, respectively). In HK for UC, more patients had extensive disease at diagnosis (42% vs 22%) but colectomy was less common (7% vs 20%; P < 0.001). In Melbourne there was greater steroid use at diagnosis and patients were more likely to receive an immunomodulator or anti-tumor necrosis factor agent., Conclusions: IBD in HK was diagnosed at an older age, and had more complicated disease behavior than in Melbourne. Medical therapy, however, was less intense in HK. These differences may relate to real differences in disease or delayed diagnosis due to late presentation and less disease recognition in HK., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Despite improved immunosuppressive therapy, surgical resection is still often required for uncontrolled inflammatory disease and the stenosing and perforating complications of Crohn's disease. However, surgery is not curative. A majority of patients develop disease recurrence at or above the anastomosis. Subclinical endoscopically identifiable recurrence precedes the development of clinical symptoms; identification and treatment of early mucosal recurrence may therefore prevent clinical recurrence. Therapy to achieve mucosal healing should now be the focus of postoperative therapy. A number of clinical risk factors for the development of earlier postoperative recurrence have been identified, and reasonable evidence is now available regarding the efficacy of drug therapies in preventing recurrence. This evidence now needs to be incorporated into prospective treatment strategies., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

The enteric bacterial flora play a key role in maintaining health. Inflammatory bowel disease is associated with quantitative and qualitative alterations in the microbiota. Early characterization of the microbiota involved culture-dependent techniques. The advent of metagenomic techniques, however, allows for structural and functional characterization using culture-independent methods. Changes in diversity, together with quantitative alterations in specific bacterial species, have been identified. The functional significance of these changes, and their pathogenic role, remain to be elucidated., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Background: Chronic intestinal pseudo-obstruction is a disabling condition for which there are no established drug therapies. The condition is caused by a diverse range of intestinal myopathies and neuropathies., Aim: To assess the therapeutic efficacy of prucalopride, a selective high-affinity 5-HT(4) receptor agonist, we employed a multiple n = 1 study design. Each patient acted as his/her own control, each day counting as one treatment episode, allowing comparison of 168 days on each of active drug and placebo., Methods: Double-blind, randomised, placebo-controlled, cross-over trial of four 12-week treatment periods, with 2-4 mg prucalopride or placebo daily. In each of the first and second 6 months there was a prucalopride and a placebo treatment. Patients with proven chronic intestinal pseudo-obstruction, including dilated gut, were included. Evaluation was by patient diary and global evaluation., Results: Seven patients participated (mean 42 years, five female, median symptom duration 11 years). Three discontinued, two due to study length, and one on prucalopride due to unrelated malnutrition and bronchopneumonia. Four patients (three visceral myopathy and one visceral neuropathy) completed the study; prucalopride significantly improved pain in three of four patients, nausea in two, vomiting in one, bloating in four and analgesic intake. Bowel function was not changed substantially., Conclusions: n = 1 studies in rare conditions allow drug efficacy assessment. Prucalopride relieves symptoms in selected patients with chronic pseudo-obstruction., (© 2011 Blackwell Publishing Ltd.)

Background: An individual's psychological adjustment to illness is influenced by disease severity, illness perceptions, and coping strategies. A more precise understanding of the contribution of each of these factors to a patient's well-being may influence the kind of psychological support required by patients. This study therefore aimed to characterize the contributors to psychological well-being in patients with Crohn's disease (CD). The design was a cross-sectional questionnaire-based study., Methods: Ninety-six CD patients (34 males, 62 females, mean age 38 years) attending a tertiary hospital inflammatory bowel disease outpatient clinic were studied. Disease severity was evaluated according to the Crohn's Disease Activity Index (CDAI), coping styles assessed with the Carver Brief COPE scale, illness perceptions explored with the Brief Illness Perceptions Questionnaire (BIPQ), and anxiety and depression measured using the Hospital Anxiety and Depression Scale (HADS)., Results: Combining the questionnaire data using structural equation modeling resulted in a final model with an excellent fit (χ(2) (7) = 10.42, P = 0.17, χ(2) /N = 1.49, root mean square error of approximation (RMSEA) < 0.07, comparative fit index (CFI) > 0.97, Goodness-of-fit index (GFI) > 0.97). Disease activity had a significant direct influence on illness perceptions (β = 51, P < 0.001). In turn, illness perceptions had a significant direct influence on depression and anxiety (β = 41, P < 0.001, β = 0.40, P < 0.001, respectively). Use of emotional coping strategies was associated significantly (P < 0.001) with the presence of anxiety and depression., Conclusions: There is an interrelationship between disease activity, illness perceptions, coping strategies, and depression and anxiety. These aspects of psychological processing provide a framework and direction for the psychological support that patients with CD require., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Anti-tumor necrosis factor (TNF) therapy to treat inflammatory bowel disease has been available for more than a decade. Although extensive data on the outcome of anti-TNF therapy from individual clinical trials and patient cohorts are available, integrated guidance on the best use of such therapy to achieve optimal clinical outcomes when managing patients with luminal Crohn's disease is lacking. This review combines published data to establish practical strategies for anti-TNF therapy with respect to effective and safe timing of introduction, use of concurrent immunosuppressive therapy, dose escalation, managing relapse, changing drugs, pregnancy and breast feeding, and stopping drug treatment., (Copyright © 2011 Crohn's & Crohn's & Colitis Foundation of America, Inc.)

Background: Altered intestinal dendritic cell (DC) function underlies dysregulated T-cell responses to bacteria in Crohn's disease (CD) but it is unclear whether composition of the intestinal microbiota impacts local DC function. We assessed the relationship between DC function with disease activity and intestinal microbiota in patients with CD., Methods: Surface expression of Toll-like receptor (TLR)-2, TLR-4, and spontaneous intracellular interleukin (IL)-10, IL-12p40, IL-6 production by freshly isolated DC were analyzed by multicolor flow cytometry of cells extracted from rectal tissue of 10 controls and 28 CD patients. Myeloid DC were identified as CD11c(+) HLA-DR(+lin-/dim) cells (lin = anti-CD3, CD14, CD16, CD19, CD34). Intestinal microbiota were analyzed by fluorescent in situ hybridization of fecal samples with oligonucleotide probes targeting 16S rRNA of bifidobacteria, bacteroides-prevotella, C. coccoides-E. rectale, and Faecalibacterium prausnitzii., Results: DC from CD produced higher amounts of IL-12p40 and IL-6 than control DC. IL-6(+) DC were associated with the CD Activity Index (r = 0.425; P = 0.024) and serum C-reactive protein (CRP) (r = 0.643; P = 0.004). DC expression of TLR-4 correlated with disease activity. IL-12p40(+) DC correlated with ratio of bacteroides: bifidobacteria (r = 0.535, P = 0.003). IL-10(+) DC correlated with bifidobacteria, and IL-6(+) DC correlated negatively with F. prausnitzii (r = -0.50; P = 0.008). The amount of TLR-4 on DC correlated negatively with the concentration of F. prausnitzii., Conclusions: IL-6 production by intestinal DC is increased in CD and correlates with disease activity and CRP. Bacterially driven local IL-6 production by intestinal DC may overcome regulatory activity, resulting in unopposed effector function and tissue damage. Intestinal DC function may be influenced by the composition of the commensal microbiota., (Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.)

The substantial morbidity and mortality associated with Crohn's disease underlines the importance of accurate assessment at presentation, during follow-up, when investigating complications, and when evaluating the response to therapeutic interventions. Accurate methods are required to quantify the severity and extent of disease., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Background: Treatments that achieve sustainable steroid-free clinical remission in Crohn's disease are needed; however, long-term steroid-sparing efficacy data are limited., Aim: To evaluate steroid-sparing efficacy and the impact of steroid discontinuation on adverse events during treatment of Crohn's disease with adalimumab in the phase III randomised, double-blind 1-year CHARM trial and for an additional 2 years in its open-label extension ADHERE., Methods: Steroid-free remission and response and steroid-sparing (≥50% steroid dose reduction) remission rates were evaluated over 3 years in patients who were taking corticosteroids at CHARM baseline., Results: Of 778 patients randomised in CHARM (including those who did not achieve clinical response to open-label induction therapy), 313 patients (40%) were on corticosteroids at baseline. In the 206 patients randomised to adalimumab, rates of steroid-free remission at 1 year and 3 years were 26% and 23% respectively; corresponding rates were 29% and 25% for steroid-sparing remission and 32% and 28% for steroid-free response. Although the incidence of serious infections with adalimumab treatment during CHARM was higher in patients taking steroids at baseline than those who were not, the rates of overall adverse events, serious infections and opportunistic infections were lower in patients who were able to discontinue corticosteroids than those who remained on steroids., Conclusion: Adalimumab therapy resulted in modest but clinically meaningful rates of steroid-free remission, sustained over 3 years of treatment, in a heavily pretreated population of patients with Crohn's disease receiving steroids at the start of therapy (http://www.clinicaltrials.gov number: NCT00077779)., (© 2011 Blackwell Publishing Ltd.)

The risk of colorectal cancer is increased in patients with long-standing ulcerative colitis. Traditional surveillance has centered around regular standard white-light colonoscopy, with multiple biopsies aimed at detecting dysplasia or the identification of early cancer. This has resulted in only a modest reduction in cancer incidence and mortality. A better understanding of disease risk factors may allow endoscopic resources to be more focused on patients at higher risk. In addition, advanced endoscopic techniques have the potential to improve dysplasia detection, minimize the need for routine biopsies, and allow for the removal of dysplastic lesions, avoiding the need for surgery. Techniques such as magnification colonoscopy, chromoendoscopy, narrow band imaging, autofluorescence, and confocal endomicroscopy may all have a role to play in improving the benefits of endoscopic surveillance. Revised endoscopic surveillance strategies are proposed, incorporating aspects of risk stratification, a well-established practice in noncolitis-related colorectal cancer screening, and some of these new technologies.

Background: There is no international agreement on scoring systems used to measure disease activity in ulcerative colitis, nor is there a validated definition for disease remission., Aim: To review the principles and components for defining remission in ulcerative colitis and propose a definition that will help improve patient outcomes., Methods: A review of current standards of remission from the perspective of clinical trials, guidelines, clinical practice and patients was conducted by the authors. Selected literature focused on the components of a definition of remission, the utility of a definition and treatment strategies, based on current definitions., Results: Different definitions of remission affect the assessment of outcome and make it difficult to compare trials. In the clinic, endoscopy is rarely used to confirm remission, because mucosal healing has only recently begun to be related to the duration of subsequent remission in a way that will affect clinical practice. Histopathology may be the ultimate arbiter of mucosal healing. There is no agreement on the definition of remission in current guidelines. Patient-defined remission may predict endoscopic remission, but has yet to be shown to predict duration of remission., Conclusions: A standard based on clinical symptoms and endoscopy is proposed. Histopathology is a third dimension of remission that may have prognostic value. The definition of remission should help predict long-term outcome. The expectations of patients and their physicians need to be raised, as the goal of treatment of active ulcerative colitis should be to induce remission., (© 2011 Blackwell Publishing Ltd.)

Introduction: The commensal intestinal microbiota drive the inflammation associated with Crohn's disease. However, bacteria such as bifidobacteria and Faecalibacterium prausnitzii appear to be immunoregulatory. In healthy subjects the intestinal microbiota are influenced by prebiotic carbohydrates such as fructo-oligosaccharides (FOS). Preliminary data suggest that FOS increase faecal bifidobacteria, induce immunoregulatory dendritic cell (DC) responses and reduce disease activity in patients with Crohn's disease., Aims and Methods: To assess the impact of FOS in patients with active Crohn's disease using an adequately powered randomised double-blind placebo-controlled trial with predefined clinical, microbiological and immunological end points. Patients with active Crohn's disease were randomised to 15 g/day FOS or non-prebiotic placebo for 4 weeks. The primary end point was clinical response at week 4 (fall in Crohn's Disease Activity Index of ≥ 70 points) in the intention-to-treat (ITT) population., Results: 103 patients were randomised to receive FOS (n = 54) or placebo (n = 49). More patients receiving FOS (14 (26%) vs 4 (8%); p = 0.018) withdrew before the 4-week end point. There was no significant difference in the number of patients achieving a clinical response between the FOS and placebo groups in the ITT analysis (12 (22%) vs 19 (39%), p = 0.067). Patients receiving FOS had reduced proportions of interleukin (IL)-6-positive lamina propria DC and increased DC staining of IL-10 (p < 0.05) but no change in IL-12p40 production. There were no significant differences in the faecal concentration of bifidobacteria and F prausnitzii between the groups at baseline or after the 4-week intervention., Conclusion: An adequately powered placebo-controlled trial of FOS showed no clinical benefit in patients with active Crohn's disease, despite impacting on DC function. ISRCTN50422530.

Background & Aims: Although stimulant laxatives have been used for many years to treat patients with constipation, their clinical value has been questioned, and there have been few high-quality trials to assess their efficacy. We tested the efficacy and safety of 4 weeks of treatment with oral bisacodyl tablets in patients with chronic constipation, defined by Rome III criteria., Methods: This randomized, double-blind, placebo-controlled, parallel-group study was conducted in 27 centers in the United Kingdom. After a 2-week baseline period without study medication, patients were randomly assigned, in a 2:1 ratio, to groups that were given 10 mg bisacodyl (n = 247) or placebo (n = 121), once daily, for 4 weeks. Patients used an electronic diary each day to record information relating to their constipation., Results: The mean (± standard error of the mean [SEM]) number of complete spontaneous bowel movements (CSBMs) per week during the treatment period increased from 1.1 ± 0.1 in both groups to 5.2 ± 0.3 in the bisacodyl group and 1.9 ± 0.3 in the placebo group (P < .0001). All secondary end points (number of complete spontaneous bowel movements for each single week, number of spontaneous bowel movement (SBMs), and constipation-associated symptoms) differed significantly between groups, demonstrating efficacy for bisacodyl (P < .0001). Compared with baseline, there was a statistically significant improvement in the overall Patient Assessment of Constipation quality of life (PAC-QOL) score and all subscales (satisfaction, physical discomfort, psychosocial discomfort, worries and concerns) in the bisacodyl-treated patients, compared with those that received placebo (P ≤ .0070). Treatment with bisacodyl was well-tolerated., Conclusions: Oral bisacodyl is an effective and well-tolerated treatment for patients with chronic constipation. It improves bowel function, constipation-related symptoms, and disease-related QOL., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage., (Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.)

The objective of this study was to determine whether cortical evoked potentials (CEPs) can define neurophysiological patterns in irritable bowel syndrome (IBS). In this prospective study of consecutive patients attending secondary and tertiary centers, patients with Rome II-defined IBS underwent rectal sensory and pain threshold (RST and RPT, respectively) testing with electrical stimulation on three separate visits. CEPs were collated for 75% pain thresholds, and anxiety [Spielberger State-Trait Anxiety Inventory (SSTAI)] questionnaires were completed. Subjects were 33 IBS patients (27 female, mean age 40.1 yr) and 21 healthy controls (14 female, mean age 31.4 yr). At visit 3, RPT was significantly lower [mean (95% CI)] in IBS patients than in control subjects: 58.2 mA (48.0-68.5) vs. 79.5 mA (69.3-89.6) (P < 0.01). No significant differences were observed in CEP latencies and amplitudes between visits 1, 2, and 3 within each group, except P2 latency for controls (P = 0.04) and N2 latency (P = 0.04) and N2 amplitude (P = 0.02) for IBS patients. Group comparisons showed significant differences in 3-day mean RPT, CEP amplitudes, and CEP latencies between IBS patients and controls. RPT <50 mA and P1 latency >106 ms were identified four IBS subgroups: 24% were hypersensitive, 12% were hypervigilant, 15% were hyposensitive, and 49% exhibited normal P1 latency and pain threshold. CEPs are reliable and reproducible measures of early sensory processing. Identification of four IBS neurophysiological patterns highlights its heterogeneous nature. These findings mark the first step toward personalized medicine in IBS, whereby therapy may be directed at the underlying physiological process.

Crohn and Rosenberg first highlighted the increased risk of colorectal cancer in ulcerative colitis in 1925. Cancer rates as high as 34 percent after 30 yrs of disease have been reported in several population-based studies, although the reported risk varies substantially. Lower rates have been reported in: population-versus specialist centre-cohorts, local practices with a high colectomy rate and high 5-aminosalicylate usage, and more recent as opposed to older reports. Despite this variation in reported risk, and lack of controlled evidence for cancer reduction, colonoscopic surveillance programmes are a routine part of care in many centres. Cancer is believed to arise most commonly in dysplastic epithelium, and the detection of either dysplasia or early cancer forms the basis of such programmes. Further confusion stems from the variety of terms used to describe dysplastic change.

Dendritic cells (DCs) play a key role in discriminating between commensal microorganisms and potentially harmful pathogens and in maintaining the balance between tolerance and active immunity. The regulatory role of DC is of particular importance in the gut where the immune system lies in intimate contact with the highly antigenic external environment. Intestinal DC constantly survey the luminal microenvironment. They act as sentinels, acquiring antigens in peripheral tissues before migrating to secondary lymphoid organs to activate naive T cells. They are also sensors, responding to a spectrum of environmental cues by extensive differentiation or maturation. Recent studies have begun to elucidate mechanisms for functional specializations of DC in the intestine that may include the involvement of retinoic acid and transforming growth factor-β. Specialized CD103(+) intestinal DC can promote the differentiation of Foxp3(+) regulatory T cells via a retinoic acid-dependent process. Different DC outcomes are, in part, influenced by their exposure to microbial stimuli. Evidence is also emerging of the close interaction between bacteria, epithelial cells, and DC in the maintenance of intestinal immune homeostasis. Here we review recent advances of functionally specialized intestinal DC and their mechanisms of antigen uptake and recognition. We also discuss the interaction of DC with intestinal microbiota and their ability to orchestrate protective immunity and immune tolerance in the host. Lastly, we describe how DC functions are altered in intestinal inflammation and their emerging potential as a therapeutic target in inflammatory bowel disease.

Background: In ulcerative colitis (UC) gut bacteria drive inflammation. Bacterial recognition and T-cell responses are shaped by intestinal dendritic cells (DCs); therapeutic effects of probiotic bacteria may relate to modulation of intestinal DC. The probiotic mixture, VSL#3, increases interleukin (IL)-10 and downregulates IL-12p40 production by DC in vitro. We evaluated in vivo effects of oral VSL#3 and steroids on colonic DC in patients with acute UC., Methods: Rectal biopsies were obtained from patients with active UC before and after treatment with VSL#3, corticosteroids, or placebo, and from healthy controls. Myeloid colonic DC were studied from freshly isolated lamina propria cells using multicolor flow cytometry. Surface expression of activation markers, CD40, CD86, pattern recognition receptors, Toll-like receptor (TLR)-2 and TLR-4 were assessed. Changed function was measured from ongoing intracellular IL-10, IL-12p40, IL-6, and IL-13 production., Results: Acute UC colonic myeloid DC were producing more IL-10 and IL-12p40 than control DC (P = 0.01). In VSL#3-treated patients DC TLR-2 expression decreased (P < 0.05), IL-10 production increased and IL-12p40 production decreased (P < 0.005); 10/14 patients on VSL#3 showed a clinical response. Corticosteroids also resulted in increased IL-10 and reduced IL-12p40 production by DC. Conversely, in patients on placebo, TLR-2 expression and intensity of staining for IL-12p40 and IL-6 increased (all P < 0.05); 5/14 patients on placebo showed a clinical response (P = NS)., Conclusions: Despite small numbers of human colonic DC available, we showed that treatment of UC patients with probiotic VSL#3 and corticosteroids induced "favorable" intestinal DC function in vivo, increasing regulatory cytokines and lowering proinflammatory cytokines and TLR expression. These effects may contribute to therapeutic benefit.

Purpose: In patients with faecal incontinence related to isolated internal anal sphincter (IAS) disruption, conservative management is the mainstay of treatment. Surgical repair of the internal sphincter is not successful. This study evaluated the use of sacral nerve stimulation (SNS) in those with faecal incontinence and IAS disruption in whom medical and behavioural treatments had failed., Methods: Nine patients (seven women, median age 44 years, range 39-62 years), with a history of obstetric or iatrogenic anal sphincter trauma, underwent a trial of SNS. All had passive faecal incontinence, low resting anal sphincter pressure and full thickness IAS muscle disruption of greater than 30 degrees radial extent. The effect of SNS on symptoms was measured by a bowel habit diary and validated questionnaires used to assess impact on quality of life., Results: Eight (89%) patients benefited from temporary stimulation and proceeded to permanent device implantation. Follow-up was at a mean of 46 months (range 2-81). Faecal incontinence decreased from a mean (SD) of 9.9 (10.9) to 1.0 (2.4) episodes per week (p = 0.031), and soiling decreased from 6.1 (1.6) to 1.7 (2.4) episodes per week (p = 0.031), with chronic stimulation. At latest follow-up, three patients had no incontinence, three patients had episodes of minor soiling only, one patient had >75% reduction of incontinent episodes, and two patients remained incontinent., Conclusions: Sacral nerve stimulation is effective in treating faecal incontinence related to a structurally and functionally abnormal internal anal sphincter. Treatment should not be refused on the basis of IAS disruption.

Objectives: Although it has been used as a laxative for many years, high-quality trials assessing the efficacy of the laxative sodium picosulfate (SPS) are lacking. The purpose of this study was to assess the efficacy and safety of 4-week treatment with SPS in patients with functional constipation as defined by the Rome III diagnostic criteria., Methods: This study was a randomized, double-blind, placebo-controlled, parallel-group study in 45 general practices in Germany. A total of 468 patients with chronic constipation presenting to their general practitioner and fulfilling the Rome III diagnostic criteria were screened. After a 2-week baseline period, 367 patients were randomized to either SPS drops or matching placebo in a 2:1 ratio for 4 weeks. Dose titration was permitted throughout treatment. Patients without a bowel movement for more than 72 h were allowed to use a "rescue" bisacodyl suppository. The primary end point was the mean number of complete spontaneous bowel movements (CSBMs) per week. A spontaneous bowel movement (SBM) was defined as a stool not induced by rescue medication, whereas a CSBM was defined as an SBM associated with a sensation of complete evacuation., Results: The mean number (+/-s.e.) of CSBMs per week increased from 0.9+/-0.1 to 3.4+/-0.2 in the SPS group and from 1.1+/-0.1 to 1.7+/-0.1 in the placebo group (P<0.0001). The percentage of patients reaching an increase of > or =1 in the mean number of CSBMs per week compared to baseline was 65.5% vs. 32.3%, respectively (P<0.0001). The percentage of patients reaching a mean number of at least three CSBMs per week was 51.1% in the SPS group and 18.0% in the placebo group (P<0.0001). After 24 h, approximately 69% of patients in the SPS group and 53% in the placebo group had their first SBM. The SPS dose was titrated down during the study by nearly 50% of patients. Assessment of quality of life (QoL) by the constipation-related Patient Assessment of Constipation (PAC)-QoL questionnaire showed significant improvement in SPS-treated patients compared to the placebo group., Conclusions: Treatment of chronic constipation with SPS improves bowel function, symptoms, and QoL and is well tolerated. The dose can be adjusted individually while maintaining benefit.

Objectives: To perform a cost-utility analysis of a new formulation of mesalazine (Mezavant XL, MMX mesalazine) versus an existing oral mesalazine (Asacol; mesalazine) from the UK National Health Service perspective., Methods: A 5-year Markov cohort model was developed. Costs were obtained from the literature and utilities from an independent study. Uncertainty was evaluated using one-way and probabilistic sensitivity analyses (PSA). The potential effect of dosing frequency on adherence and possible long-term effects of remission maintenance on colorectal cancer (CRC) rates were also investigated., Results: The model suggested that 5-year therapy with MMX mesalazine was likely to generate gains when compared with mesalazine, including a gain of 0.011 QALYs per patient, 19 more remission days, and 12% fewer hospitalizations and surgical episodes. These gains came at an increase in total NHS direct cost of £8, resulting in an incremental cost-effectiveness ratio (ICER) of £749. The PSA suggested that MMX mesalazine had a 62% chance of resulting in cost savings, and a 74% chance of being cost-effective (£20,000 threshold). Extended analysis including adherence and CRC effects suggested further incremental benefit of MMX mesalazine over mesalazine could be expected. Limitations include uncertainty in extrapolation to a 5-year time horizon and impact of adherence and drug acquisition costs on outcomes., Conclusion: The pharmacoeconomic analysis suggested that MMX mesalazine is likely to produce small, but worthwhile, increases in total NHS direct cost while increasing time in remission and associated quality of life, when compared with mesalazine. Advantages in adherence to treatment with MMX mesalazine relative to mesalazine suggested that further health gains and cost savings can be obtained. Overall, these results suggest that MMX mesalazine is a cost-effective treatment for UC.

Objective: Traditional surgical procedures for intractable idiopathic constipation are associated with a variable outcome and substantial morbidity. The symptomatic response, physiological effect and effect on quality of life of sacral nerve stimulation (SNS) were evaluated in patients with constipation (slow transit and normal transit with impaired evacuation)., Methods: In a prospective study at five European sites patients who failed conservative treatment underwent 21 days test stimulation. Patients with >50% improvement in symptoms underwent permanent neurostimulator implantation. Primary end points were increased defecation frequency, decreased straining and decreased sensation of incomplete evacuation., Results: 62 patients (55 female, median age 40 years) underwent test stimulation, of whom 45 (73%) proceeded to chronic stimulation. 39 (87%) of these 45 patients achieved treatment success. After a median 28 (range 1-55) months follow-up, defecation frequency increased from 2.3 to 6.6 evacuations per week (p<0.001). Days per week with evacuation increased from 2.3 to 4.8 (p<0.001). There was a decrease in time spent toileting (10.5 to 5.7 min, p=0.001), straining (75-46% of successful evacuations, p<0.001), perception of incomplete evacuation (71.5-46% of successful evacuations, p<0.001) and subjective rating of abdominal pain and bloating (p<0.001). Cleveland Clinic constipation score (0=no to 30=severe constipation) decreased from 18 to 10 (p<0.001). Visual analogue scale (VAS) score (0=severe to 100=no symptoms) increased from 8 to 66 (p<0.001). Patients with slow and normal transit benefited. Quality of life significantly improved. Colonic transit normalised in half of those with baseline slow transit (p=0.014)., Conclusion: SNS is effective in the treatment of idiopathic slow and normal transit constipation resistant to conservative treatment. Clinical Trial Number NCT00200005.

Background: In contrast to the US and Europe, prevalence and laxative use for self-defined constipation among adults was previously reported to be unassociated with age among adults in South Korea and Brazil., Aim: To determine whether observations in South Korea and Brazil are reflective of other Asian and South American countries., Methods: A total of 8100 adults from Argentina, Colombia, Indonesia and China completed a questionnaire identical to that previously used in South Korea and Brazil., Results: Prevalence of constipation was similar to that reported for Brazil and South Korea and was 2.17-fold (95% CI: 1.71-2.64) higher amongst women than amongst men. Prevalence increased with age amongst all adults in Argentina and China and only among men in Colombia and Brazil. With the exception of Indonesia, the majority of those with constipation had symptoms at least once weekly, and for < or =3 years. Less than one-third of adults reported using laxatives to treat constipation. Laxative use was not associated with gender and increased with age in Argentina and Colombia., Conclusions: No clear geographical or cultural tendencies were observed in the prevalence of constipation and laxative use among the South American and Asian countries studied in this survey.

The inflammatory bowel diseases (IBDs) are associated with a reduced quality of life. The impact of IBD on disability remains largely unknown. With the International Classification of Functioning, Disability, and Health (ICF) of the World Health Organization (WHO), we can now rely on a globally agreed-upon framework and system for classifying the typical spectrum of problems in the functioning of persons with a specific disease given the environmental context in which they live. The aim of this article is to outline the methods to be utilized to develop ICF Core Sets for IBD. The project is a cooperation between the ICF Research Branch of the WHO, the IPNIC group, the International Society of Physical Rehabilitation Medicine (ISPRM), and the International Organization on Inflammatory Bowel Disease (IOIBD). Four worldwide studies will be conducted from 2009 to 2010. ICF categories relevant for IBD will be identified by systematic literature review of outcomes and measures used in IBD research, semistructured patient interviews, Internet-based expert survey, and cross-sectional study for clinical applicability. The final definition of ICF Core Sets for IBD will be determined at a Consensus Conference. Field testing will then be used to validate the ICF Core Sets. ICF Core Sets are being designed to provide useful standards for research and clinical practice. This tool will enable research that improves understanding of functioning, disability, and health in IBD, and may lead to interventions to improve and maintain functioning and minimize disability among IBD patients throughout the world.

Background and Aim: The prevalence and incidence of inflammatory bowel disease (IBD) differs worldwide. While the prevalence of IBD has stabilized in Europe, the USA and Japan, an increasing trend has been observed in Asia. However, there are no data on the current clinical practice for the management of IBD in the region. The present study aims to investigate the number of existing and new cases of IBD and to understand the current practice of diagnosis and treatment of IBD in different Asian countries., Methods: A self-administered questionnaire, designed according to European and US guidelines, was distributed to IBD specialists throughout Asia. The questionnaire estimated the annual incidence of existing and new IBD cases in physicians' clinical practices and evaluated their procedures of diagnosis and preference for therapeutic treatment and maintenance treatment., Results: Eighty-seven questionnaires were received out of the 107 distributed. In the clinical practices of these 87 respondents, there were 502 existing and 73 new cases per year for ulcerative colitis (UC) and 202 existing and 32 new cases per year for Crohn's disease (CD). Colonoscopy and histology were the most commonly used methods for the diagnosis of UC and CD, but clinical practice regarding the diagnosis of IBD varied. The treatment of choice for mild-to-moderate UC and CD was 5-aminosalicylic acid (5-ASA), which is also the preferred choice for the maintenance treatment of UC and CD., Conclusion: Clinical practice with regards to IBD diagnosis and management varies within Asia.5-ASA is the preferred treatment and maintenance therapy for mild-to-moderate IBD.

Objectives: Anti-tumor necrosis factor (TNF) therapy heals Crohn's fistulas clinically, but the rate, extent, and duration to achieve fistula track healing are unknown., Methods: We sought to monitor deep healing, as indicated by magnetic resonance imaging (MRI), and to use this to determine treatment duration. Clinical and MRI fistula healing (at 6, 12, and 18 months), Crohn's Disease Activity Index (CDAI), Perianal Crohn's Disease Activity Index (PDAI), and the Inflammatory Bowel Disease Questionnaire were prospectively assessed., Results: Thirty-four consecutive patients with perineal fistulas were treated with infliximab (19), adalimumab (7; all infliximab failures) and thalidomide (8). Median follow-up was 110 weeks (range, 74-161). Baseline MRI: 38% >or=2 tracks, 21% anolabial/rectovaginal. At latest follow-up, clinical fistula 'response' and 'closure' were seen in 50 and 46% of antibody-treated patients, respectively. All patients stopped thalidomide early due to side effects. Of 26 antibody-treated patients, at 6 (n=25), 12 (n=25), and 18 (n=20) months, respectively, MRI showed complete healing (20, 28, and 30%, respectively), improvement (68, 72, and 65%), no change (12, 0, and 0%) or worsening (0, 0, and 5%). MRI healing at 6 months (n=5) persisted at 12 and 18 months, including in two patients who stopped treatment at 6 months. Fistula history length and complexity did not influence the outcome. The only surgical intervention was seton insertion in one patient. The PDAI and CDAI scores decreased, and quality of life improved significantly at last follow-up., Conclusions: MRI fistula resolution was variable and slower than clinical healing. Prolonged treatment is often required for internal track resolution. Preliminary data suggest once MRI healing has occurred fistulas remain healed, while remaining on, or stopping anti-TNFalpha therapy. The use of a second antibody is clinically valuable.

Ulcerative colitis (UC) involves inappropriate mucosal immune responses to intestinal microbiota. Gut dendritic cells (DC) are central immunoregulators of the response to commensal bacteria, and the subset of CD11c(+) cells within the human leucocyte antigen D-related (HLA-DR(+)) lineage (lin)(-/dim) population are activated in inflammatory bowel disease. We hypothesized that CD11c(-) cells within this population may also be involved in intestinal inflammation. HLA-DR(+) lin(-/dim) cells were identified in freshly isolated lamina propria mononuclear cells by multi-colour flow cytometry in 54 UC patients and 22 controls. Proportion and number of CD11c(+) and CD11c(-) cells, and surface expression of activation markers CD40, CD86, Toll-like receptor (TLR)-2, TLR-4, and CD56(+)[natural killer (NK) marker], were determined. Cytokine production was assessed by intracellular staining. Lamina propria colonic CD11c(-) HLA-DR(+) lin(-/dim) cells were increased significantly in inflamed and 'non-inflamed' UC tissue, compared with control tissue. CD11c(+) HLA-DR(+) lin(-/dim) cells were unchanged. Fewer CD11c(-) cells expressed activation markers and produced intracellular cytokines than their CD11c(+) counterparts, and they were weakly stimulatory in mixed leucocyte reactions. Few CD11c(-) cells expressed blood plasmacytoid DC markers, but a major subset expressed high levels of CD56. CD11c(-) cells decreased after inflammation resolved. Intestinal inflammation in UC is associated with the presence of cells that share phenotypic features of both DC and NK cells. This novel population of human colonic CD56(+) HLA-DR(+) cells may play a role in immune regulation or tissue repair. Their increase in quiescent UC may be a marker of subclinical inflammation.

Background: The factors leading to faecal incontinence in males are less well understood than those in females. In this prospective study we aimed to compare the physiological, anatomical, psychological and behavioural characteristics of male and female patients presenting with symptoms of faecal incontinence., Method: One hundred and nine patients presenting with symptoms of faecal incontinence were studied. They underwent anorectal physiological studies, endoanal ultrasonography, and completed a St Mark's Incontinence Score, a locally developed pad questionnaire, a bowel symptom questionnaire, the Short Form 36 (SF-36) Health Survey questionnaire, the Hospital Anxiety and Depression Scale and the Maudsley Obsessive Compulsive Inventory., Results: Thirty-four men (mean age 59 years, SD 14 years, range 33-80) and 75 women (mean age 55 years, SD 15 years, range 21-86) participated in the study. Twenty-one patients (38% of men and 11% of women) had normal manometry and endoanal ultrasonography. There was no significant difference in the resting pressures of men compared with women, but men had significantly higher squeeze pressures. Rectal capacity was significantly higher in men but anal and rectal electrosensitivities were the same. Men placed a tissue at the anus more commonly than women while women were more likely to use a pad and to carry a spare pair of underwear around with them. Psychological profiles were very similar in the two sexes., Conclusions: Nearly 40% of men with faecal incontinence report it in the absence of a definable functional or structural sphincter abnormality. There are differences in physiological characteristics and coping behaviours of men and women with faecal incontinence.

Background: Recurrence of Crohn's disease (CD) after ileal or colonic resection is common. Myenteric plexitis in the proximal resection margin of an ileocolonic CD resection specimen may indicate ongoing pathology that relates to disease recurrence. We assessed risk factors for myenteric plexitis, the effect of plexitis on clinical recurrence, and whether preoperative medical therapies affect the intensity of plexitis., Methods: Ileocolonic resection specimens from 99 patients with CD were histologically scored for the presence and severity of plexitis. Myenteric plexitis was correlated with immunosuppressive therapy before index surgery. Univariate and multivariate analyses were performed to identify predictive factors for plexitis., Results: Myenteric plexitis was present in 43% and 85% of cases in the proximal resection margin and the affected resected segments of CD, respectively. Patients with a previous resection were more likely to have plexitis than those with no previous resection (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.21-10.15, P = 0.02), and those with a greater duration of disease were less likely to have plexitis in the proximal resection margin (OR 0.68, 95% CI 0.48-0.96, P = 0.03). Preoperative immunosuppressive therapy was not associated with a lesser incidence of plexitis. Twelve of 40 (30%) patients with plexitis and 9 of 54 (16%) patients without plexitis in the proximal resection margin subsequently developed clinical recurrence (median 10 months; P = 0.17)., Conclusions: Previous resections and shorter disease duration are associated with plexitis in proximal resection margin of CD. The prognostic value of plexitis in postoperative disease recurrence and risk stratification remain to be prospectively established.

Background: Anti-tumour necrosis factor (TNF) therapy effectively treats Crohn's perineal fistulas (CPF); the effect on health-related quality of life (HRQoL) remains unknown., Aims: To evaluate the effect of anti-TNF therapy on the HRQoL of patients with CPF in daily clinical practice., Methods: Prospective evaluation of clinical and magnetic resonance imaging (MRI) responses, disease activity (Perianal Disease Activity Index - PDAI), and HRQoL assessment [Inflammatory Bowel Disease Questionnaire (IBDQ)] in patients receiving anti-TNF therapy for CPF treated up to 12 months., Results: In all, 26 patients with CPF were treated (mean age 39 years; 19 infliximab, 7 adalimumab). At baseline, 85% patients had impaired IBDQ scores (mean 137; 'normal' >170). At 12 months, mean increases in IBDQ score for infliximab and adalimumab treated patients were 40 and 41 points respectively (P < 0.05). There were significant improvements in all IBDQ subscores (bowel, emotional, systemic, social) at 12 months (all P < or = 0.003). Fourteen patients (74%) on infliximab and six on adalimumab (86%) achieved IBDQ score > or =170. Mean increase in IBDQ score was 50, 34 and 16 points in patients with clinical fistula closure (P < 0.001), clinical response (P = 0.002) and no response (n = 1) respectively. IBDQ score increased for patients with MRI healing (P < 0.001) and MRI improvement (P = 0.016), but not for those with no MRI change (n = 2). IBDQ correlated significantly with PDAI at baseline and at 12 months., Conclusion: Anti-TNF therapy improves HRQoL in patients with CPF at 12 months and this improvement is most pronounced in patients with clinical and MRI healing.

The management of Crohn's disease is rapidly changing. The advent of potent immunomodulatory and biologic therapies has led to more demanding endpoints for clinical trials than only clinical response and remission. Complete withdrawal of corticosteroids, healing of endoscopically visible lesions, and prevention of structural damage are only a few new endpoints that are finding their way into the clinical trials of today and those that are being developed for the future. Given the importance of selecting the most appropriate and relevant endpoints, the International Organization for Inflammatory Bowel Diseases (IOIBD) decided to develop guidelines that could be used by individual researchers, the pharmaceutical industry, and the regulatory bodies. The current document is to be read as a "position paper," which is the result of several years of discussion and consensus finding that was finally approved by the entire membership of the group. The proposed instruments will need further validation and standardization to demonstrate that they are reliable in stable disease and responsive to change, and to determine the cutoff points for response and remission.

Study Design: Investigation of bowel function in 55 patients and 26 healthy volunteers using radiological, anorectal physiological and laser Doppler blood flow monitoring., Objectives: Bowel dysfunction is common after spinal cord injury (SCI). We aimed to determine whether hindgut testing of autonomic innervation provides insight into presence of symptoms, altered motor function (transit) and level of injury., Setting: St Mark's Hospital, UK and The Spinal Injuries Unit, Royal National Orthopaedic Hospital, UK., Methods: A total of 55 patients with chronic complete SCI and 26 healthy volunteers were studied. Twenty-four patients had lesions above T5 and 31 had lesions below T5. Thirty-five patients complained of constipation: 75% (18/24) of patients with lesions above T5 and 55% (17/31) of those with lesions below T5. Gut transit, rectal electrosensitivity and rectal blood flow were measured., Results: Slow gut transit occurred in 65% of patients and in all the 35 patients complaining of constipation. Delay was pancolonic. All patients had an elevated sensory threshold. The threshold was significantly higher in those with subjective constipation (P<0.01), slow transit (P<0.04) and high SCI (P=0.046). Mucosal blood flow was lower in SCI patients with constipation (P<0.04) and slow transit (P<0.03). It was higher than normal in high-SCI volunteers (P=0.056), reflecting loss of sympathetic inhibition., Conclusions: In SCI, subjective constipation correlates closely with slow gut transit. Delay is pancolonic, regardless of the site of lesion. Sensory testing provides evidence for completeness of lesion, offering further evidence for pain transmission through sympathetic pathways. Studies in SCI patients provide further evidence of mucosal blood flow as a marker of altered autonomic innervation.

Background: Sacral nerve stimulation (SNS) is an effective treatment for faecal incontinence, but only standard stimulation parameters have been used. This study assessed the clinical impact of altering the parameters., Methods: Twelve patients with partially improved faecal incontinence following SNS underwent acute testing to select optimal stimulation parameters; rectal compliance was used as a surrogate marker. Parameters tested were: stimulation off; frequency 14 (standard), 31 or 6.9 Hz; and pulse duration 210 (standard), 450 or 90 micros. Patients completed a 2-week bowel diary, St Mark's continence score (SMCS) and Rockwood faecal incontinence quality-of-life (FIQL) score before testing using standard settings, and after testing using optimized settings., Results: Optimal settings, determined by greatest increase in rectal compliance, were shorter pulse width in five patients and higher frequency in seven. Optimized stimulation resulted in a decrease in mean episodes of incontinence from 2.3 to 1.2 per week (P = 0.031), soiling from 3.3 to 1.7 days per week (P = 0.016), faecal urgency from 31 to 18 per cent of all evacuations (P = 0.055) and SMCS from 12.3 to 8.7 (P = 0.008); the FIQL coping/behaviour score improved (P = 0.008)., Conclusion: With a shorter pulse width and higher frequency, clinical efficacy in patients undergoing SNS for faecal incontinence can be improved., (Copyright 2009 British Journal of Surgery Society Ltd.)

Objective: To evaluate the efficacy of adalimumab in the healing of draining fistulas in patients with active Crohn's disease (CD)., Design: A phase III, multicentre, randomised, double-blind, placebo controlled study with an open-label extension was conducted in 92 sites., Patients: A subgroup of adults with moderate to severely active CD (CD activity index 220-450) for >or=4 months who had draining fistulas at baseline., Interventions: All patients received initial open-label adalimumab induction therapy (80 mg/40 mg at weeks 0/2). At week 4, all patients were randomly assigned to receive double-blind placebo or adalimumab 40 mg every other week or weekly to week 56 (irrespective of fistula status). Patients completing week 56 of therapy were then eligible to enroll in an open-label extension., Main Outcome Measures: Complete fistula healing/closure (assessed at every visit) was defined as no drainage, either spontaneous or with gentle compression., Results: Of 854 patients enrolled, 117 had draining fistulas at both screening and baseline (70 randomly assigned to adalimumab and 47 to placebo). The mean number of draining fistulas per day was significantly decreased in adalimumab-treated patients compared with placebo-treated patients during the double-blind treatment period. Of all patients with healed fistulas at week 56 (both adalimumab and placebo groups), 90% (28/31) maintained healing following 1 year of open-label adalimumab therapy (observed analysis)., Conclusions: In patients with active CD, adalimumab therapy was more effective than placebo for inducing fistula healing. Complete fistula healing was sustained for up to 2 years by most patients in an open-label extension trial.