Effect of food additives on key bacterial taxa and the mucosa-associated microbiota in Crohn's disease. The ENIGMA study.

Food additives have been linked to the pro-inflammatory microbial dysbiosis associated with Crohn's disease (CD) but the underlying ecological dynamics are unknown. Here, we examine how selection of food additives affects the growth of multiple strains of a key beneficial bacterium (Faecalibacterium prausnitzii), axenic clinical isolates of proinflammatory bacteria from CD patients (Proteus, Morganella, and Klebsiella spp.), and the consortia of mucosa-associated microbiota recovered from multiple Crohn's disease patients. Bacterial growth of the axenic isolates was evaluated using a habitat-simulating medium supplemented with either sodium sulfite, aluminum silicate, carrageenan, carboxymethylcellulose, polysorbate 80, saccharin, sucralose, or aspartame, intended to approximate concentrations found in food. The microbial consortia recovered from post-operative CD patient mucosal biopsy samples were challenged with either carboxymethylcellulose and/or polysorbate 80, and the bacterial communities compared to unchallenged consortia by 16S rRNA gene amplicon profiling. Growth of all F. prausnitzii strains was arrested when either sodium sulfite or polysorbate 80 was added to cultures at baseline or mid-exponential phase of growth, and the inhibitory effects on the Gram-negative bacteria by sodium sulfite were conditional on oxygen availability. The effects from polysorbate 80, saccharin, carrageenan, and/or carboxymethylcellulose on these bacteria were strain-specific. In addition to their direct effects on bacterial growth, polysorbate 80 and/or carboxymethylcellulose can drive profound changes in the CD mucosa-associated microbiota via niche expansion of Proteus and/or Veillonellaceae - both implicated in early Crohn's disease recurrence. These studies on the interaction of food additives with the enteric microbiota provide a basis for dietary management in Crohn's disease.

Novel strain-level resolution of Crohn's disease mucosa-associated microbiota via an ex vivo combination of microbe culture and metagenomic sequencing.

The mucosa-associated microbiota is widely recognized as a potential trigger for Crohn's disease pathophysiology but remains largely uncharacterised beyond its taxonomic composition. Unlike stool microbiota, the functional characterisation of these communities using current DNA/RNA sequencing approaches remains constrained by the relatively small microbial density on tissue, and the overwhelming amount of human DNA recovered during sample preparation. Here, we have used a novel ex vivo approach that combines microbe culture from anaerobically preserved tissue with metagenome sequencing (MC-MGS) to reveal patient-specific and strain-level differences among these communities in post-operative Crohn's disease patients. The 16 S rRNA gene amplicon profiles showed these cultures provide a representative and holistic representation of the mucosa-associated microbiota, and MC-MGS produced both high quality metagenome-assembled genomes of recovered novel bacterial lineages. The MC-MGS approach also produced a strain-level resolution of key Enterobacteriacea and their associated virulence factors and revealed that urease activity underpins a key and diverse metabolic guild in these communities, which was confirmed by culture-based studies with axenic cultures. Collectively, these findings using MC-MGS show that the Crohn's disease mucosa-associated microbiota possesses taxonomic and functional attributes that are highly individualistic, borne at least in part by novel bacterial lineages not readily isolated or characterised from stool samples using current sequencing approaches.

Visceral adiposity predicts post-operative Crohn's disease recurrence.

BACKGROUND: Excessive visceral adipose tissue has been associated with poorer outcomes in patients with inflammatory bowel disease. AIM: To determine whether body composition is associated with outcome in a prospective study of post-operative Crohn's disease patients. METHODS: The POCER study evaluated management strategies for prevention of post-operative Crohn's disease recurrence; subjects were enrolled after resection of all macroscopic Crohn's disease and were randomised to early endoscopy and possible treatment escalation, or standard care. The primary endpoint was endoscopic recurrence at 18 months. 44 subjects with cross-sectional abdominal imaging were studied, and body composition analysis performed using established techniques to measure visceral adipose tissue area, subcutaneous adipose tissue area, and skeletal muscle area. RESULTS: The body composition parameter with the greatest variance was visceral adipose tissue. Regardless of treatment, all subjects with visceral adipose tissue/height2 >1.5 times the gender-specific mean experienced endoscopic recurrence at 18 months (compared to 47%) [relative risk 2.1, 95% CI 1.5-3.0, P = 0.012]. Waist circumference correlated strongly with visceral adipose tissue area (ρ = 0.840, P < 0.001). Low skeletal muscle was prevalent (41% of patients), but did not predict endoscopic recurrence; however, appendicular skeletal muscle indices correlated inversely with faecal calprotectin (ρ = 0.560, P = 0.046). CONCLUSIONS: Visceral adiposity is an independent risk factor for endoscopic recurrence of Crohn's disease after surgery. Sarcopenia correlates with inflammatory biomarkers. Measures of visceral adipose tissue may help to stratify risk in post-operative management strategies.

Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high-risk patients - a POCER study analysis.

BACKGROUND: Crohn's disease recurs in the majority of patients after intestinal resection. AIM: To compare the relative efficacy of thiopurines and anti-TNF therapy in patients at high risk of disease recurrence. METHODS: As part of a larger study comparing post-operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine-intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment. RESULTS: A total of 101 patients [50% male; median (IQR) age 36 (25-46) years] were included. There were no differences in disease history between thiopurine- and adalimumab-treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2-i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab-treated patients [intention-to-treat (ITT); P = 0.028] or 24 of 62 (39%) vs. 3 of 24 (13%) respectively [per-protocol analysis (PPA); P = 0.020]. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab). CONCLUSIONS: In Crohn's disease patients at high risk of post-operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.

Inflammatory bowel disease cancer surveillance in a tertiary referral hospital: attitudes and practice.

BACKGROUND: Physician adherence to guidelines for colorectal cancer (CRC) surveillance in inflammatory bowel disease (IBD) is often poor. This may lead to adverse patient outcomes and excess endoscopic workload. AIMS: To assess the attitudes and practice of IBD specialists in a tertiary centre towards colonoscopic surveillance. METHODS: First, a questionnaire evaluating attitudes and approach to CRC surveillance was issued to 36 clinicians at one tertiary referral hospital. Second, a retrospective audit of IBD surveillance colonoscopy practice over a 2-year period was performed. RESULTS: Questionnaire response rate was 97%. Sixty-nine per cent of respondents were aware of, and used, Australian guidelines. Surveillance was undertaken by all clinicians in patients with extensive colitis, 83% in patients with left-sided colitis and 51% in patients with proctitis. Seventy-six per cent used chromoendoscopy, and 47% took 10 to 20 random biopsies. Colectomy was considered appropriate in 0% for unifocal low-grade dysplasia, 35% for multifocal low-grade dysplasia and 83% for high-grade dysplasia. Sixty-six per cent would remove elevated dysplastic lesions endoscopically. The audit identified 103 surveillance colonoscopies in 81 patients. Chromoendoscopy was used in 21% of cases, and the median number of random biopsies was 13. Sixty-two per cent of colonoscopies were performed outside the guidelines in relation to colonoscopic frequency. Following colonoscopy, an appropriate recommendation for subsequent surveillance was documented in 40% of cases. CONCLUSIONS: Knowledge and practice of CRC surveillance in IBD vary among specialist clinicians and often deviate from guidelines. Many clinicians perform surveillance earlier and more frequently than recommended. These findings have implications for patient outcomes and workload.

Development and validation of a patient-reported disability measurement tool for patients with inflammatory bowel disease.

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.

Postoperative recurrence of Crohn's disease: impact of endoscopic monitoring and treatment step-up.

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.

A mechanistic role for leptin in human dendritic cell migration: differences between ileum and colon in health and Crohn's disease.

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 3ß 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.

Relationship between human intestinal dendritic cells, gut microbiota, and disease activity in Crohn's disease.

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.

Adalimumab sustains steroid-free remission after 3 years of therapy for Crohn's disease.

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).

Review article: defining remission in ulcerative colitis.

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.

Diagnosis and treatment of chronic constipation--a European perspective.

BACKGROUND: Although constipation can be a chronic and severe problem, it is largely treated empirically. Evidence for the efficacy of some of the older laxatives from well-designed trials is limited. Patients often report high levels of dissatisfaction with their treatment, which is attributed to a lack of efficacy or unpleasant side-effects. Management guidelines and recommendations are limited and are not sufficiently current to include treatments that became available more recently, such as prokinetic agents in Europe. PURPOSE: We present an overview of the pathophysiology, diagnosis, current management and available guidelines for the treatment of chronic constipation, and include recent data on the efficacy and potential clinical use of the more newly available therapeutic agents. Based on published algorithms and guidelines on the management of chronic constipation, secondary pathologies and causes are first excluded and then diet, lifestyle, and, if available, behavioral measures adopted. If these fail, bulk-forming, osmotic, and stimulant laxatives can be used. If symptoms are not satisfactorily resolved, a prokinetic agent such as prucalopride can be prescribed. Biofeedback is recommended as a treatment for chronic constipation in patients with disordered defecation. Surgery should only be considered once all other treatment options have been exhausted.

Preliminary examination of the relations between disease activity, illness perceptions, coping strategies, and psychological morbidity in Crohn's disease guided by the common sense model of illness.

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 (ß = 51, P < 0.001). In turn, illness perceptions had a significant direct influence on depression and anxiety (ß = 41, P < 0.001, ß = 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.

A novel population of human CD56+ human leucocyte antigen D-related (HLA-DR+) colonic lamina propria cells is associated with inflammation in ulcerative colitis.

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.

Prospective assessment of the effect on quality of life of anti-tumour necrosis factor therapy for perineal Crohn's fistulas.

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.

Improving the efficacy of sacral nerve stimulation for faecal incontinence by alteration of stimulation parameters.

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.

Adalimumab for the treatment of fistulas in patients with Crohn's disease.

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.

Economic evaluation of sacral nerve stimulation for faecal incontinence.

BACKGROUND: Sacral nerve stimulation (SNS) is an established treatment for faecal incontinence in patients who have failed conservative management. This study established the cost-effectiveness of treating patients with SNS compared with non-surgical treatment. METHODS: A decision analysis model was performed. Data from 70 patients were obtained from medical records, bowel habit diaries and Short Form 36 quality of life questionnaires. Direct medical and non-medical costs were ascertained using the 2005/2006 national tariff, national statistics, and medication, pad and device costs. Indirect non-medical costs were also estimated. RESULTS: Incontinence episodes were reduced from a median of 12 per fortnight at baseline to one per fortnight with SNS. Based on direct medical and non-medical costs, the incremental cost-effectiveness ratio (ICER) for SNS was pound25 070 per QALY gained. It cost pound1038 more per year to treat patients with SNS for a median reduction of 286 incontinence episodes, equating to pound3.63 per episode reduced. When indirect non-medical costs were included the ICER was reduced to pound12 959 per QALY gained. CONCLUSION: The ICER of pound25 070 is within the pound30 000 per QALY threshold recommended by the National Institute for Health and Clinical Excellence as an effective use of National Health Service resources with proper justification.