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Background Strictures are the commonest complication in Crohn’s disease. Surgery and endoscopic dilation are the main treatments; drug therapy has been considered contra-indicated. Given that most strictures have an inflammatory component we aimed to assess the efficacy of anti-inflammatory therapy, and to identify the optimal treatment. Methods In this randomised trial patients with symptomatic Crohn’s disease strictures and inflammation were assessed by imaging (MRI, colonoscopy, intestinal ultrasound) and for inflammation (faecal calprotectin and CRP). Symptoms were assessed using an Obstructive Symptom Score (OSS). Patients with short endoscopically-accessible strictures had a baseline endoscopic balloon dilation if indicated. Patients were then randomised 2:1 to high dose adalimumab induction (160mg weekly for 4 weeks) with 40mg fortnightly maintenance plus thiopurine, with therapy increased for ongoing inflammation at 4 and 8 months, versus standard dose adalimumab mono-therapy. At 12 months primary endpoint was improved OSS. Secondary outcomes: disease activity, treatment failure, stricture morphology, inflammation, psychological well-being, disability, and quality of life. MRI was assessed blindly. Results 52 patients were randomised to the intensive and 25 to the standard treatment arm. 27 of 52 (52%) intensive treatment patients dose escalated at 4 or 8 months. Improved OSS at 12 months occurred in 41 (79%) intensive treatment and 16 (64%) standard treatment arms (P=0.17). Treatment failure was less common in the intensive treatment arm (10%) versus the standard treatment arm (28%) (P=0·045). Faecal calprotectin normalised (25% on ultrasound was seen in 22/43 (51%) and 7/21 (33%) respectively (P=0.18). MRI complete stricture resolution was seen in 10/51 (20%) and 4/25 (16%) (P=0.7). At 12 month colonoscopy 22/48 (46%) v 9/25 (36%) strictures were passable (P=0.42). 12 month median drug levels were 13.2µg/ml and 6.6µg/ml respectively (P Conclusion Crohn’s disease strictures are responsive to drug therapy. A majority of patients experience symptom improvement and many have improved stricture morphology. Treat-to-target therapy intensification results in less treatment failure, less stricture-associated inflammation, and greater improvement in stricture morphology.

Background Medical therapies that suppress various pathways involved in inflammation comprise the mainstay of inflammatory bowel disease (IBD) treatment. Adverse events, including the development of serious infection and malignancy, have been associated with these therapies. This study evaluates the current evidence regarding serious adverse events associated with immunosuppressive agents in the IBD patient population. Methods A systematic search was conducted in September 2019 by combining three key research themes: inflammatory bowel disease, immunosuppression, and adverse events. For this systematic review, adverse events are defined as either the development or recurrence of malignancy or the development of serious infection necessitating hospital admission. Results There is a demonstrated association between thiopurine use and increased risk of both nonmelanoma skin cancer (NMSC) or lymphoma. The length of thiopurine exposure required to increase NMSC risk is, however, unclear. Of the papers reporting on exposure length and NMSC risk, the thiopurine exposure duration required to result in a statistically significant increase in NMSC risk varied from 6 months to 5 years. Among the studies retrieved, there is a lack of consensus on malignancy risk associated with the use of anti-TNF agents. From 5 studies on malignancy risk associated with the use of anti-TNF agents, one concluded that malignancy risk is increased while three concluded that risk is unchanged from baseline. The fifth study is inconclusive on any possible association. Confounding by past or concurrent thiopurine exposure remains an issue. There is a clear association between combination therapy with both thiopurines and anti-TNF agents and increased malignancy risk when compared with exposure to either thiopurine or anti-TNF therapy alone. Anti-integrin agents were not found to be associated with an increase in adverse effects when compared with placebo, while nil studies on ustekinumab were retrieved. Individual studies on infection risk do not consistently stratify infections according to severity, limiting any analysis. Conclusion An established association between thiopurine use and increased risk of both lymphoma or NMSC exists. However, the duration of thiopurine exposure necessary to increase NMSC risk is uncertain. There is a lack of consensus on whether anti-TNF agents increase malignancy risk due to confounding from past or concurrent thiopurine exposure. Combination therapy increases malignancy risk when compared with exposure to either thiopurine or anti-TNF therapy alone. Limited studies on the newer biologic therapies were retrieved. Finally, evidence which stratifies infections according to severity is lacking.

Background The inflammatory bowel disease (IBD) Disk is a tool that has been developed from the IBD Disability Index in order to objectively measure the degree of disability in patients suffering from IBD. It provides a visual representation of disability state, thereby increasing the ease of application in a clinical setting. Currently, it has not yet been validated in any population. Our primary aim was to hence validate the IBD Disk in a clinical setting. Methods 40 patients were recruited from an outpatient setting in a tertiary centre in Australia. All patients completed four surveys, the IBD Disk, the IBD Disability Index (IBD-DI), the Hospital Anxiety and Depression Score (HADS) and the Shortened IBD Questionnaire (SIBDQ). Nineteen of these patients then elaborated on their answers in a semi-structured narrative interview based on the IBD Disk. After a consultation with a gastroenterologist, the treating doctors were also asked to fill out an IBD Disk based on their own perceptions of the participant’s degree of disability. The IBD Disk was assessed for its internal consistency, construct validity and factor structure. The qualitative data were analysed and coded using NVIVO and then associated to IBD Disk scores. Results Of the patients recruited 48% were female, 30% had ulcerative colitis and 52% were in clinical remission. Average IBD Disk score was 40.75. Our results suggest the IBD Disk is an internally consistent tool for clinical use when assessing disability (Cronbach’s Α = 0.888). This is supported by statistically significant differences in IBD Disk scores between patients in clinical remission and patients with active disease (p = 0.002). There is also a good correlation between the Patient-Reported IBD Disk scores and the IBD-DI scores (r = 0.864), Doctor Perceived IBD Disk scores (r = 0.794) and the HADS Depression score (r = 0.759). IBD Disk scores also negatively correlated with the Shortened IBD Questionnaire (r = −0.864). Qualitative data also correlate well thematically with IBD Disk scores. These results suggest an appropriate system for grading disability status via the IBD Disk is: 0–24 = no disability; 25–49 = mild disability; 50–74 = moderate disability; and, 75–100 = severe disability. Conclusion This study supports the use of the IBD Disk as a reliable and valid self-reporting tool in clinical situations. There is strong internal consistency, construct validity, factor structure and qualitative thematic association. However, more data are needed to further validate the IBD Disk. Most significantly though, the IBD Disk is likely to become a valuable tool for the practical assessment of disability in patients with IBD in the near future.

Background Perianal fistulas remain a debilitating and clinically challenging manifestation of Crohn’s disease (CD), given their prevalence and relative treatment resistance. Since the advent of biologic therapy, particularly the anti-TNFα agents infliximab and adalimumab, patient outcomes have improved. Serum trough levels have been associated with mucosal healing in luminal CD. However, the relationship between trough drug levels and healing of perianal fistulas remains less clear, with few studies assessing this cohort, and clinical healing typically defined as the primary endpoint. The aim of this study was to assess the relationship between radiological healing of perianal fistulising Crohn’s Disease (pfCD) on MRI, and serum trough drug levels, in patients treated with anti-TNFα therapy. Methods In this multi-centre, retrospective cross-sectional study, patients with pfCD who had trough levels measured within 6 months of a pelvic MRI were included. We collected patient demographics, infliximab and adalimumab trough levels, the presence or absence of anti-drug antibodies, concomitant steroid or antibiotic therapy, and Van Assche scores on MRI. The primary outcome, radiological response, was defined as a Van Assche score of 7 or less, while no response was defined as a score of greater than 7. Results A total of 99 patients were included (65 on infliximab, 34 on adalimumab). For patients receiving infliximab, the median drug levels for responders (n = 22) compared with non-responders (n = 43) were 5.5 mg/ml vs. 3.9 mg/ml respectively (p = 0.16). For patients receiving adalimumab, the median drug levels for responders (n = 14) compared with non-responders (n = 20) were 6.3 mg/ml vs. 3.1 mg/ml respectively (p = 0.09). On ROC curve analysis, the AUC for the association between radiological response and infliximab levels was 0.61, while for adalimumab it was 0.67. On quartile analysis, there appeared to be an increased response for increase in infliximab trough level quartile, with the exception of the highest quartile, however this association was not statistically significant (OR 1.36, 95% CI 0.85–2.16, p = 0.20). In comparison, the quartile analysis of adalimumab trough level and response demonstrated an exposure-response relationship (OR 2.24, 95% CI 1.11–4.52, p = 0.02). Conclusion Trough infliximab and adalimumab levels in patients who achieved radiological response were not significantly higher compared with those who did not, however quartiles analyses demonstrated trends toward an exposure-response relationship, in particular for adalimumab. The association between trough levels and radiological response could be further characterised with a larger, and ideally longitudinal, study.

Background The reasons why fistulas originate have been explained in idiopathic cases, with the cryptoglandular theory being widely accepted; however, in Crohn ́s disease, it is thought to involve interplay between microbiological, immunological and genetic factors. It remains unclear why fistulas persist. Novel investigative tools in systems biology are improving our understanding of pathogenesis, and one such tool is metabonomic profiling, whereby spectrometry is used to assess metabolic responses of complex systems in health and disease. These changes are mapped using analytical and statistical techniques. To the best our knowledge, these methodologies have not been applied to aid understanding of the pathogenesis of Crohn’s perianal fistula persistence. Methods Fistula tissue biopsy was obtained from the fistula tract of 30 patients with idiopathic perianal fistula and 20 patients with Crohn ́s anal fistula. Two analytical platforms were attempted to achieve broad metabolome coverage. Univariate (student t-test) and multivariate statistical data analyses were performed. From the latter principle component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), models were built to find metabolites that could predict tissue samples from patients with either Crohn’s or idiopathic anal fistula. Metabolite putative identification was conducted by matching accurate mass:charge ratio (m/z) measurements of detected chromatographic features to theoretical value from in-house databases and on-line databases and previous publications. Results Significant OPLS-DA predictive models (validated with CV-ANOVA p-value Conclusion Forty-one differentiating metabolites were discovered belonging to various classes of lipids, amino acids and nucleotides. Pathways involved included amino acid metabolism, phospholipid metabolism and glycerolipid metabolism amongst others. Further work in larger numbers is required to validate these findings as well as cross correlation with microbiome work to understand the impact of host gut interactions in the pathophysiology of Crohn’s and idiopathic perianal fistulas.