Characterisation and therapeutic manipulation of the gut microbiome in inflammatory bowel disease.

Inflammatory bowel diseases are thought to develop as a result of dysregulation of the relationship that exists between the gut microbiota, host genetics and the immune system. The advent of culture-independent techniques has revolutionised the ability to characterise the role of the gut microbiota in health and disease based on the microbiota's genetic make-up. Inflammatory bowel diseases are characterised by dysbiosis which is an imbalance between pro- and anti-inflammatory bacteria and a reduction in bacterial diversity. Emerging data suggest that it is not only the presence of the gut microbiota but the functional activity of the microbiota that appears to play an important role in health and disease. Current strategies to manipulate therapeutically the gut microbiota using dietary modification, prebiotics, probiotics, antibiotics and faecal microbiota transplantation aim to restore the balance to a state of normobiosis. However, the ability of such strategies to correct dysbiosis and thereby achieve therapeutic benefit is yet to be fully characterised.

Perspectives of paediatric and adult gastroenterologists on transfer and transition care of adolescents with inflammatory bowel disease.

BACKGROUND: Programmes specific to inflammatory bowel disease (IBD) that facilitate transition from paediatric to adult care are currently lacking. AIM: We aimed to explore the perceived needs of adolescents with IBD among paediatric and adult gastroenterologists and to identify barriers to effective transition. METHODS: A web-based survey of paediatric and adult gastroenterologists in Australia and New Zealand employed both ranked items (Likert scale; from 1 not important to 5 very important) and forced choice items regarding the importance of various factors in facilitating effective transition of adolescents from paediatric to adult care. RESULTS: Response rate among 178 clinicians was 41%. Only 23% of respondents felt that adolescents with IBD were adequately prepared for transition to adult care. Psychological maturity (Mean = 4.3, standard deviation (SD) = 0.70) and readiness as assessed by adult caregiver (Mean = 4, SD = 0.72) were prioritised as the most important factors in determining timing of transfer. Self-efficacy and readiness as assessed by adult caregiver were considered the two most important factors to determine timing of transition by both groups of gastroenterologists. Poor medical and surgical handover (Mean = 4.10, SD = 0.8) and patients' lack of responsibility for their own care (Mean= 4.10, SD = 0.82) were perceived as major barriers to successful transition by both paediatric and adult gastroenterologists. CONCLUSIONS: Deficiencies exist in current transition care of adolescents with IBD in Australia and New Zealand. Standardising transition care practices with strategies aimed at optimising communication, patient education, self-efficacy and adherence may improve outcomes.

Ustekinumab as induction and maintenance therapy for ulcerative colitis - national extended follow-up and a review of the literature.

INTRODUCTION: Ustekinumab use in ulcerative colitis had shown low adverse event and high persistence rates to 3 years via the UNIFI long-term extension study. Outcomes beyond 3 years have not been previously described. We describe the safety signals of the entire UNIFI Australian population beyond 3 years. METHODS: This retrospective multicenter observational cohort study recruited from all Australian UNIFI centers. The primary outcome was safety via adverse events. Secondary outcomes included the clinical relapse rate on ustekinumab, and the need to switch from ustekinumab to an alternate agent. RESULTS: There were 14 patients [11 male, mean age 47 (±14) years], with a median diagnosis of 10.8 (±4.5) years prior to UNIFI enrollment. Median follow-up was 298 weeks (5.7 years) (Interquartile range (IQR): 220-311 weeks). Within the long-term extension, there were three serious adverse events and one minor event. 42.9% (6/14) patients had clinical relapses, of which clinical remission was recaptured in 83.3% (5/6). 85.7% (12/14) persisted on ustekinumab in the long-term, with 7.1% (1/14) electively ceasing ustekinumab and 7.1% (1/14) changed from ustekinumab due to clinical relapse. CONCLUSION: For moderate-to-severe UC in Australia, ustekinumab maintained efficacy beyond 3 years with a high persistence rate and no new safety signals. TRIAL REGISTRATION: The trial is registered at ANZCTR (identifier: ACTRN12622001332718).

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.

Gastroenterology training in Australia: how much is enough?

BACKGROUND: Advanced training in gastroenterology currently consists of 2 years of core training and 1 elective (non-core) year. We surveyed gastroenterologists 2-7 years following completion of training to determine the strengths and weaknesses of their training. METHODS: All gastroenterologists were invited to participate in an anonymous online survey. RESULTS: There was a 46% response rate (49/110). Eighty-one per cent were male with most aged 36-45. Respondents felt that the current training programme prepared them well for public practice and endoscopy but less well for private practice, ambulatory care, surgical aspects of gastroenterology and functional gastrointestinal disorders. Most had faced challenges transitioning to consultant practice. The majority (53%) spent more than the standard 3 years to complete training in gastroenterology. The top three subspecialty Fellowships were in endoscopy (45%), inflammatory bowel disease (29%) and hepatology (23%). In their elective year, 42% undertook a predominantly clinical year (registrar-type position in general or subspecialty gastroenterology), 28% engaged in research while 24% trained in another specialty. Seventy-eight per cent were in full-time work, and 36% were supervising trainees. Ninety-eight per cent felt that it was beneficial for trainees to move between hospitals during the core years of their advanced training. CONCLUSIONS: The current Australian gastroenterology training programme is generally adequate in preparing trainees for consultant practice but could be improved by increased emphasis on areas such as private practice, ambulatory gastroenterology and functional gastrointestinal diseases. Exposure to a variety of experiences by training in several different hospitals during core training was universally viewed as being important.

Gastroenterology training in Australia: a perspective from the coal face.

BACKGROUND: The Royal Australasian College of Physicians is developing curricula for training. AIMS: We surveyed gastroenterology trainees on their training experience to establish whether training needs were being met. METHODS: An online anonymous survey of all gastroenterology trainees in 2009. RESULTS: Ninety-one per cent of trainees responded (105/115). Of these, 92% were adult, and 8% were paediatric trainees. Seventy four were core, and 31 were noncore trainees. Of those who had completed core training, the majority (86%) felt that their training had prepared them adequately for independent practice as a gastroenterologist. However, most respondents felt that core advanced training should be 3 years instead of 2 years. The majority (86%) saw a benefit in moving between hospitals during core training. Of the trainees managing inpatients, 57% were managing 10 or more per day, and 63% had three or more consultant ward rounds per week. The top three noncore fellowships were advanced endoscopy (44%), hepatology (28%) and inflammatory bowel disease (17%). Sixty-one per cent and 39% were undertaking a clinical and research fellowship respectively. Seventy-two per cent of core trainees attended up to three endoscopy lists per week, and 76% were on the on-call urgent endoscopy roster. For on-call endoscopy, 27% of third-year noncore trainees and 5% of core trainees were unsupervised. CONCLUSIONS: The majority of trainees felt that their core training would prepare them adequately for independent practice as gastroenterologists. Overall, trainees valued movement between hospitals during training and felt that core training should be 3 years. Some trainees had inadequate consultant support for out-of-hours emergency endoscopy.

Cerebral venous thrombosis associated with ulcerative colitis.

Thromboembolic complications, such as deep venous thrombosis and pulmonary embolism, are well recognized in patients with inflammatory bowel disease (IBD). We describe three cases of cerebral venous thrombosis complicating ulcerative colitis. Cerebral venous thrombosis is a rare but potentially devastating complication of IBD, and the diagnosis needs to be considered in any patient with IBD presenting with neurological symptoms.

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.

Infliximab vs. adalimumab in Crohn's disease: results from 327 patients in an Australian and New Zealand observational cohort study.

BACKGROUND: Maintenance anti-tumour necrosis factor-α (anti-TNFα) treatment for Crohn's disease is the standard of care for patients with an inadequate response to corticosteroids and immunomodulators. AIM: To compare the efficacy and safety of infliximab and adalimumab in clinical practice and assess the value of concomitant immunomodulator therapy. METHODS: We performed an observational cohort study in consecutive patients with Crohn's disease qualifying for anti-TNFα treatment in Australia and New Zealand between 2007 and 2011. Demographic and clinical data were prospectively recorded to identify independent factors associated with induction and maintenance of response to infliximab or adalimumab, or to either anti-TNFα therapy. RESULTS: Three hundred and twenty-seven patients (183 infliximab, 144 adalimumab) successfully applied for treatment. Eighty-nine percent responded in all groups and median maintenance of response was similar for the two agents. Concomitant immunomodulator with infliximab, but not adalimumab, demonstrated a significantly longer response overall (P = 0.002), and significantly fewer disease and treatment-related complications (P = 0.017). Corticosteroids at baseline, and/or in the preceding 12 months, were associated with a 9-13 times greater risk of disease flare during maintenance treatment as compared to no corticosteroids (P < 0.0001). Maintenance of response was similar in the anti-TNF naïve and anti-TNF experienced subgroups. CONCLUSIONS: In this large, real-life study, we demonstrate infliximab and adalimumab to have similar response characteristics. However, infliximab requires concomitant immunomodulator to achieve optimal maintenance of response comparable to adalimumab monotherapy. The results of this study will assist clinicians in further optimising patient care in their day-to-day clinical practice.

Review article: the practical management of acute severe ulcerative colitis.

BACKGROUND: Acute severe ulcerative colitis (ASUC) is a life-threatening condition for which optimal management strategies remain ill-defined. AIM: To review the evidence regarding the natural history, diagnosis, monitoring and treatment of ASUC to inform an evidence-based approach to management. METHODS: Relevant articles addressing the management of ASUC were identified from a search of MEDLINE, the Cochrane Library and conference proceedings. RESULTS: Of ASUC, 31-35% is steroid-refractory. Infliximab and ciclosporin salvage therapies have improved patient outcomes in randomised controlled trials. Short-term response rates (within 3 months) have ranged from 40% - 54% for ciclosporin and 46-83% for infliximab. Long-term clinical response rates (≥1 year) have ranged from 42%-50% for ciclosporin and 50-65% for infliximab. Short-term and long-term colectomy rates have been respectively: 26-47% and 36-58% for ciclosporin, and 0-50% and 35-50% for infliximab. Mortality rates for ciclosporin and infliximab-treated patients have been: 0-5% and 0-2%, respectively. At present, management challenges include the selection, timing and assessment of response to salvage therapy, utilisation of therapeutic drug monitoring and long-term maintenance of remission. CONCLUSIONS: Optimal management of acute severe ulcerative colitis should be guided by risk stratification using predictive indices of corticosteroid response. Timely commencement and assessment of response to salvage therapy is critical to reducing morbidity and mortality. Emerging pharmacokinetic models and therapeutic drug monitoring may assist clinical decision-making and facilitate a shift towards individualised acute severe ulcerative colitis therapies.

Systematic review: predicting and optimising response to anti-TNF therapy in Crohn's disease - algorithm for practical management.

BACKGROUND: Nonresponse and loss of response to anti-TNF therapies in Crohn's disease represent significant clinical problems for which clear management guidelines are lacking. AIM: To review the incidence, mechanisms and predictors of primary nonresponse and secondary loss of response to formulate practical clinical algorithms to guide management. METHODS: Through a systematic literature review, 503 articles were identified which fit the inclusion criteria. RESULTS: Primary nonresponse to anti-TNF treatment affects 13-40% of patients. Secondary loss of response to anti-TNF occurs in 23-46% of patients when determined according to dose intensification, and 5-13% of patients when gauged by drug discontinuation rates. Recent evidence suggests that the mechanisms underlying primary nonresponse and secondary loss of response are multifactorial and include disease characteristics (phenotype, location, severity); drug (pharmacokinetic, pharmacodynamic or immunogenicity) and treatment strategy (dosing regimen) related factors. Clinical algorithms that employ therapeutic drug monitoring (using anti-TNF tough levels and anti-drug antibody levels) may be used to determine the underlying cause of primary nonresponse and secondary loss of response respectively and guide clinicians as to which patients are most likely to respond to anti-TNF therapy and help optimise drug therapy for those who are losing response to anti-TNF therapy. CONCLUSIONS: Nonresponse or loss of response to anti-TNF occurs commonly in Crohn's disease. Clinical algorithms utilising therapeutic drug monitoring may establish the mechanisms for treatment failure and help guide the subsequent therapeutic approach.

Intestinal Failure and Transplant: The Australian Experience (2009 to 2014).

BACKGROUND: A joint adult and pediatric intestinal transplant (ITx) program for Australia was developed in 2009 to provide life-saving ITx to patients with irreversible intestinal failure (IF). We aimed to analyze the outcomes of patients treated by our service over the past 5 years. METHODS: A retrospective medical record review was conducted on all IF patients referred to our service. Patient demographics, underlying disease, nutrition support, TPN complications, and current transplant program status were evaluated. RESULTS: Fifty-seven patients (35 adults, 40.4 ± 12.4 years; 22 children, 6.3 ± 4.3 years) throughout Australia and New Zealand have been referred. Leading causes of IF were short bowel syndrome followed by pseudo-obstruction. Forty patients (70%) exhibited at least 1 life-threatening complication of PN at referral: liver failure, impending loss of venous access, and/or recurrent line sepsis. Three patients have undergone ITx with 100% survival (median follow-up, 1161 days). Four patients (8%) are listed for transplant, 6 patients (12%) are awaiting transplant assessment, and 4 patients (8%) have died (2 while awaiting transplantation, 2 during assessment period). Causes of death included sepsis and intracranial bleed. Two-thirds of all referred patients (n = 40) were deferred or rejected from wait-listing. CONCLUSIONS: After 5 years of establishing the first dedicated ITx program in Australia and New Zealand, early results indicate that ITx is an available and life-saving option for IF patients in these countries. Current barriers to ITx in Australia include a shortage of appropriate donors and a high rate of donor-specific antibodies among potential recipients. Growing awareness of the service and early referral to assist appropriate patient selection will aid in the program's success.

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.

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.

An Interesting Case of Recurrent Small Bowel Obstruction.

Sclerosing mesenteritis is associated with a spectrum of diseases which include mesenteric lipodystrophy and mesenteric panniculitis. This inflammatory and fibrosing disorder can affect the small and large bowel wall and mesenteric vessels by exerting a mass effect. The following case highlights the difficulties with diagnosing and managing this unusual disease. A 64-year-old man presented with acute central abdominal pain, radiating to his back, and profuse vomiting. He was diagnosed clinically with small bowel obstruction. He had had an episode of small bowel obstruction 6 years earlier. At this time, he underwent an exploratory laparotomy, and a mass was identified in the small bowel mesentery. The features were thought to be in keeping with sclerosing mesenteritis. He had a dramatically favourable response to the initiation of prednisolone. He continued to be well and asymptomatic for a further 5 years on long-term maintenance low-dose steroids and 6-mercaptopurine. He re-presented in 2009 (six years after initial presentation) with very severe acute abdominal pain and vomiting. He had no recent change in weight or appetite, and had not had time off work. He underwent a second laparotomy and the tissue diagnosis was of metastatic carcinoid tumour involving the small bowel mesentery. This is the first case to our knowledge where sclerosing mesenteritis has been confirmed histologically on biopsy and then subsequently diagnosed with histologically proven carcinoid tumour. For this particular reason it must be always remembered that sclerosing mesenteritis is a 'pathological' and not a radiological diagnosis and that a large proportion of cases are associated with neoplasia.