A Method Using Longitudinal Laboratory Data to Predict Future Intestinal Complication in Patients with Crohn's Disease.

BACKGROUND: Stenosis, fistulization, and perforation of the bowel are severe outcomes which can occur in patients with Crohn's disease. Accurate prediction of these events may enable clinicians to alter treatment strategies and avoid these outcomes. AIMS: To study the correlation between longitudinal laboratory testing and subsequent intestinal complications in patients with Crohn's disease. METHODS: An observational cohort of patients with Crohn's disease at a single center were analyzed between 01/01/1994 and 06/30/2016. A complication was defined as the development of an intestinal fistula, stenosis, or perforation. Exploratory analysis using Cox regression was performed to select the best statistical method to represent longitudinal laboratory data. Cox regression was used to identify laboratory variables independently associated with the development of a subsequent complication. A clinical scoring tool was designed. RESULTS: In 246 patients observed over a median of 5.72 years, 134 complications occurred. Minimum or maximum value in a preceding window period of one year was most strongly associated with subsequent complication. A Longitudinal Laboratory score of ≥ 2 (maximum albumin level < 39 g/L = 1, maximum mean cell volume < 88 fL = 1, minimum platelet count > 355 × 109/L = 1, minimum C reactive protein > 5 mg/L = 1) was 62% sensitive and 91% specific in identifying patients who develop a subsequent complication. CONCLUSION: A consistent reduction in serum albumin and mean cell volume, and a consistent increase in platelet count and C reactive protein were associated with a subsequent complication in patients with Crohn's disease. Longitudinal laboratory tests may be used as described in this paper to provide a rational for earlier escalation of therapy.

Microbiota links to neural dynamics supporting threat processing.

There is growing recognition that the composition of the gut microbiota influences behaviour, including responses to threat. The cognitive-interoceptive appraisal of threat-related stimuli relies on dynamic neural computations between the anterior insular (AIC) and the dorsal anterior cingulate (dACC) cortices. If, to what extent, and how microbial consortia influence the activity of this cortical threat processing circuitry is unclear. We addressed this question by combining a threat processing task, neuroimaging, 16S rRNA profiling and computational modelling in healthy participants. Results showed interactions between high-level ecological indices with threat-related AIC-dACC neural dynamics. At finer taxonomic resolutions, the abundance of Ruminococcus was differentially linked to connectivity between, and activity within the AIC and dACC during threat updating. Functional inference analysis provides a strong rationale to motivate future investigations of microbiota-derived metabolites in the observed relationship with threat-related brain processes.

Multicenter Study of Drain Fluid Amylase as a Biomarker for the Detection of Anastomotic Leakage After Ileal Pouch Surgery Without a Diverting Ileostomy.

BACKGROUND: Anastomotic leak is the anathema of colorectal surgery. Early diagnosis is an essential segue to early intervention. A temporary defunctioning ileostomy does not prevent an anastomotic leak and presents inherent complications of its own. Drain fluid biomarkers have been studied in colorectal surgery but not in ileal pouch surgery. OBJECTIVE: This study aimed to assess drain fluid amylase as a biomarker of anastomotic leak after ileal pouch surgery and without a diverting ileostomy. DESIGN: This was a multicenter prospective observational cohort study. SETTINGS: The study was conducted at 4 tertiary hospitals in Queensland, Australia. PATIENTS: This study included elective patients undergoing restorative proctectomy and ileal pouch surgery. INTERVENTIONS: Measurement of rectal tube amylase and drain fluid amylase. MAIN OUTCOME MEASURES: The primary measure was observation of increased drain fluid amylase on the day of anastomotic leak. RESULTS: Fifty-three patients were studied. On the day of anastomotic leak, 4 patients in the anastomotic leak group who experienced an early anastomotic leak recorded a median drain fluid amylase of 21,897 U/L compared with a median drain fluid amylase of 25 U/L for those in the no anastomotic leak group ( p < 0.0001). LIMITATIONS: This study relies on the anastomotic leak occurring while the pelvic drain is in situ. CONCLUSIONS: The measurement of drain fluid amylase is a sensitive biomarker of early clinical anastomotic leak in patients undergoing restorative proctectomy with an ileal pouch and when a diverting ileostomy is not incorporated. This simple, inexpensive, and noninvasive test should be considered in all patients with ileal pouches as an adjunct to the clinical diagnosis and differentiation of anastomotic leak from other postoperative complications. See Video Abstract at http://links.lww.com/DCR/B958 .Estudio multicéntrico de la amilasa del líquido de drenaje como biomarcador para la detección de fugas anastomóticas después de una cirugía de reservorio ileal sin ileostomía de derivación. ANTECEDENTES: La fuga anastomótica es el anatema de la cirugía colorrectal. El diagnóstico precoz es una transición esencial a la intervención temprana. Una ileostomía desfuncionalizante temporal no evita una fuga anastomótica y presenta sus propias complicaciones inherentes. Los biomarcadores del líquido de drenaje se han estudiado en la cirugía colorrectal, pero no en la cirugía del reservorio ileal. OBJETIVO: El objetivo fue evaluar la amilasa del líquido de drenaje como biomarcador de fuga anastomótica después de cirugía de reservorio ileal y sin ileostomía de derivación. DISEO: Este fue un estudio de cohorte observacional prospectivo multicéntrico. AJUSTES: El estudio se realizó en 4 hospitales terciarios en Queensland, Australia. PACIENTES: Se incluyeron pacientes electivos sometidos a proctectomía restauradora y cirugía de reservorio ileal. INTERVENCIONES: Medición de la amilasa del tubo rectal y amilasa del líquido de drenaje. PRINCIPALES MEDIDAS DE RESULTADO: La medida principal fue la observación del aumento de la amilasa en el líquido de drenaje el día de la fuga anastomótica. RESULTADOS: Cincuenta y tres pacientes fueron estudiados. Los 4 pacientes que experimentaron una fuga anastomótica temprana registraron una mediana de amilasa en el líquido de drenaje de 21 897 U/L el día de la fuga anastomótica en comparación con una mediana de amilasa en el líquido de drenaje de 25 U/L para aquellos en el grupo sin fuga anastomótica (p < 0,0001). LIMITACIONES: Este estudio se basa en que la anastomosis ocurre mientras el drenaje pélvico está in situ. CONCLUSIONES: La medición de amilasa en el líquido de drenaje es un biomarcador sensible de fuga anastomótica clínica temprana en pacientes sometidos a proctectomía restauradora con reservorio ileal y cuando no se incorpora ileostomía derivativa. Esta prueba simple, económica y no invasiva se debe considerar en todos los pacientes con reservorio ileal como complemento del diagnóstico clínico y la diferenciación de la fuga anastomótica de otras complicaciones posoperatorias. Consulte Video Resumen en http://links.lww.com/DCR/B958 . (Traducción-Dr Yolanda Colorado ).

Delivering inflammatory bowel disease care across distance.

BACKGROUND: Inflammatory bowel disease (IBD) patients living in regional or remote Queensland are often disadvantaged by limited access to IBD specialist care. Telehealth clinics could potentially address this disparity and improve patient outcomes. AIM: We report the impact of the Royal Brisbane and Women's Hospital (RBWH) IBD telehealth clinics from March 2011 to December 2017, including patient satisfaction and healthcare activity. METHODS: Patient satisfaction surveys were collected prospectively between March 2011 and March 2012. Healthcare activity was assessed through occasions of service (OOS), number of enrolled patients on biologics and IBD related admissions to RBWH. RESULTS: Overall, 3764 OOS were completed including 576 new patient and 3188 follow-up visits. Mean age at first telehealth visit was 44 years (range: 16-87 years). The IBD telehealth clinics were well accepted with 99% of the first 153 patients surveyed choosing to continue with telehealth and 94% rated the telehealth experience as very good or excellent. The net number of patients under active review increased from 125 patients in 2011 to 345 patients in 2017. Enrolled patients on biologics also increased from 9 patients in 2011 to 63 patients in 2017. There was an initial dip in annual IBD related admissions to RBWH in 2011 but these have progressively increased over time although the average length of inpatient stay annually has remained stable. CONCLUSION: The RBWH IBD telehealth clinics have shown that telemedicine is well received and can be used successfully to deliver IBD specialist care to patients living in regional or remote areas.

Nudix hydrolase 15 (NUDT15) loss-of-function variants in an Australian inflammatory bowel disease population.

BACKGROUND: Thiopurine-related adverse events such as leukopenia, liver dysfunction and pancreatitis are associated with variants in the NUDT15 gene. Loss-of-function (low or no enzyme activity) alleles are more common in Asian and Hispanic populations. The prevalence of these variants in the Australian inflammatory bowel disease (IBD) population has not yet been reported. AIM: To evaluate the presence of NUDT15 loss-of-function alleles *2,*3,*9 in the Australian IBD population. METHODS: The NUDT15 screening cohort included 423 IBD patients from Brisbane, Australia. Study patients were recruited by: (i) retrospective review of clinical charts for thiopurine-related severe adverse events; (ii) pathology data (white blood cell (WBC) and neutrophil counts). NUDT15 genotyping was performed using polymerase chain reaction (PCR)-high-resolution melt (HRM), TaqMan genotyping and Sanger sequencing. RESULTS: NUDT15 mutation R139C (allele *3) was identified in 8 of 423 (1.9%) IBD patients. Seven of eight patients were R139C heterozygous (C/T) and one patient was R139C homozygous (T/T). One of the C/T group and the T/T patient developed thiopurine-induced myelosuppression (TIM) within 60 days of dosing. One patient in the C/T group developed TIM after 60 days of thiopurine dosing. The remaining five patients in the C/T group did not show TIM; however, other thiopurine-related events could not be ruled out and therefore careful monitoring over a long period is recommended. CONCLUSIONS: This is the first study to report the frequency of NUDT15 haplotypes *2,*3,*9 in an Australian IBD population. The most common variant detected was the R139C mutation. PCR and Sanger sequencing are efficient and cost-effective approaches for NUDT15 genotyping.

Intestinal ultrasound as first-line investigation in low-risk gastrointestinal symptoms: a new model of care.

BACKGROUND: Functional gut disorders (FGD) are common. Diagnosis is symptom based, although symptoms may be indistinguishable from inflammatory bowel disease. As a result of this, investigations are common, diagnostic yield is low. A streamlined novel model of care may reduce costly investigations. AIM: To compare a new model of care for patients with low-risk gastrointestinal symptoms to a matched historical cohort. METHODS: Data were prospectively collected over 12 months. General practitioner referrals for low-risk abdominal symptoms were triaged to a new multidisciplinary clinic structure utilising intestinal ultrasound. Outcomes were compared to the historical model in the preceding 12 months. Duration of care (time from referral to discharge), number of contact episodes and investigations ordered were reviewed. RESULTS: Thirty-seven patients meeting strict inclusion criteria completed their care. Compared with the historical cohort, colonoscopies reduced from 0.7 to 0.05 per patient (P < 0.0001). Gastroenterology consults reduced from 1.5 to 1.2 (P = 0.303) and dietitian review increased from 0.8 to 1.5 (P < 0.0001). Total contact episodes reduced from 3.2 to 1.8 (P < 0.0001). Duration of care reduced from a median of 252 days to 130 days (interquartile ranges (IQR) 287 and 69, respectively; P < 0.0001). Time from first consultation to discharge reduced from 125 to 42 days (IQR 188 and 63; P < 0.0001). CONCLUSION: This multidisciplinary approach to care of low-risk abdominal symptoms significantly reduced contact episodes, time in care and invasive investigations. It decreased costly gastroenterology consultation and increased allied health exposure. It demonstrates improved health service outcomes.

Airway Mucus Hyperconcentration in Non-Cystic Fibrosis Bronchiectasis.

Rationale: Non-cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized.Objectives: This study was designed to: 1) measure mucus concentration and biophysical properties of bronchiectasis mucus; 2) identify the secreted mucins contained in bronchiectasis mucus; 3) relate mucus properties to airway epithelial mucin RNA/protein expression; and 4) explore relationships between mucus hyperconcentration and disease severity.Methods: Sputum samples were collected from subjects with bronchiectasis, with and without chronic erythromycin administration, and healthy control subjects. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B (mucin 5B) polymorphisms were identified by quantitative PCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline-induced sputa were collected, and mucus/mucin concentrations were measured.Measurements and Main Results: Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within subjects with bronchiectasis, sputum percent solids correlated inversely with FEV1 and positively with bronchiectasis extent, as measured by high-resolution computed tomography, and inflammatory mediators. No difference was detected in MUC5B rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced non-cystic fibrosis bronchiectasis mucus concentration by 5%.Conclusions: Hyperconcentrated airway mucus is characteristic of subjects with bronchiectasis, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy.

Crohn's Colitis Care (CCCare): bespoke cloud-based clinical management software for inflammatory bowel disease.

BACKGROUND: Adherence to evidence-based management is variable in inflammatory bowel disease (IBD), which leads to worse patient outcomes and higher healthcare utilization. Solutions include electronic systems to enhance care, but these have often been limited by lack of clinician design input, poor usability, and low perceived value. A cloud-based IBD-specific clinical management software - 'Crohn's Colitis Care' (CCCare) was developed by Australia and New Zealand Inflammatory Bowel Disease Consortium clinicians and software developers to improve this. METHODS: CCCare captures patient-reported disease activity and medical assessment, medication monitoring, cancer screening, preventative health, and facilitates communication with the IBD team and referring doctor. De-identified longitudinal data are stored separately in a clinical quality registry for research. CCCare was tested for feasibility and usability in routine clinical settings at two large Australian hospitals. Users' experience was evaluated with System Usability Scale (SUS). Value to clinicians and patients was assessed by qualitative feedback. Security was assessed by penetration testing. RESULTS: Users (n = 13; doctors, nurses, patients) reported good usability and learnability (mean SUS score 75 (range 50-95), sub-scores were 77 (50-94) and 68 (38-100), respectively). Patients reported better communication with clinical team and greater ability to track disease. Clinicians highlighted structured management plans, medication adherence, and centralised data repository as positive features. Penetration testing was passed successfully. CONCLUSIONS: Initial evaluation demonstrates CCCare is usable, secure, and valued in clinical use. It is designed to measure outcomes of clinical care, including efficacy, quality, cost, and complications for individuals, and to audit these at hospital and national level.

Level of UV Exposure, Skin Type, and Age Are More Important than Thiopurine Use for Keratinocyte Carcinoma Development in IBD Patients.

BACKGROUND: Retrospective studies observe an increased risk of keratinocyte carcinomas (KCs) in patients with inflammatory bowel disease (IBD) on thiopurine (TP) medication. The role of traditional risk factors such as skin type and sun protection behavior has not been studied in this population. This study aimed to examine traditional KC risk factors and thiopurine use on skin cancer development in an IBD cohort. METHODS: Consecutive IBD patients were recruited from four specialist centers in Australia and New Zealand, each with varying UV exposure indices. Data pertaining to race, skin color, freckling and sun protection behavior, dose of TP therapy, and skin cancer development were elicited through a self-reported questionnaire. RESULTS: A total of 691 IBD patients were included with 62 reporting KC development. Thiopurine usage was similar among patients who developed skin cancer compared with those who did not (92% vs. 89%, p = 0.3). There was no statistically significant association between KC development and TP dose or 6-thioguanine nucleotide levels. In multivariate modeling, four factors were independently and significantly associated with KC: age over 61 years old versus less than 30 years old (OR 6.76; 95% CI 2.38-19.18), residing in Brisbane versus Christchurch (OR 3.3; 95% CI 1.6-6.8), never staying in the shade versus staying in the shade ≥ 50% of the time (OR 3.8; 95% CI 1.4-10.5), and having a skin type that never tanned versus other skin types (OR 6.9; 95% CI 2.9-16.0). CONCLUSION: Skin type, age, and sun protection behavior are more important risk factors for KC development than thiopurine medication use in this IBD population.

Short-term colectomy is avoided in over half of regional patients failing medical therapy for acute severe ulcerative colitis with co-ordinated transfer and tertiary care.

BACKGROUND AND AIMS: Many patients presenting with an acute severe ulcerative colitis to a regional hospital are transferred to a metropolitan hospital for specialised care. This study aimed to evaluate the outcomes and characteristics of these patients. METHOD: A retrospective observational cohort study was conducted to examine the 30-day colectomy rate using prospectively collected data on 69 consecutive index cases of acute severe ulcerative colitis transferred from regional hospitals to our metropolitan hospital meeting Truelove and Witts criteria. Those that avoided colectomy were followed out to 1 year to examine outcomes. RESULTS: The 30-day colectomy rate was 46.4% (32/69) in regional transfer patients. Rescue therapy was administered to 65% (45/69) of patients after transfer to our metropolitan hospital. Colectomy was avoided in 55% of these patients at 30 days. Colectomy free status was maintained in 78% (29/39) of these patients. Mortality was 0% at 30 days and 1 year. CONCLUSION: Over 50% of the patients failing therapy in a regional centre and requiring transfer avoided short term colectomy with co-ordinated referral for rescue therapy in a tertiary metropolitan inflammatory bowel disease unit. These patients would have ultimately required colectomy in their regional hospital without intervention.

Detectable Laboratory Abnormality Is Present up to 12 Months Prior to Diagnosis in Patients with Crohn's Disease.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) often have subjective symptoms for months or years prior to their diagnosis. Blood tests taken prior to diagnosis may provide objective evidence of duration of pre-diagnosis disease. We aim to describe the pre-diagnosis laboratory pattern of patients with IBD. METHODS: A total of 838 patients diagnosed with IBD between 01/01/1996 and 01/03/2014, with pre-diagnosis laboratory testing available, contributed data for analysis. C-reactive protein, erythrocyte sedimentation rate, hemoglobin level, mean cell volume (MCV) platelet count, white blood cell count, neutrophil count, albumin level, ferritin level, serum iron level, alanine transaminase level, and fecal calprotectin were examined in the 24 months leading up to diagnosis and compared to baseline data taken between 24 and 36 months prior to diagnosis. RESULTS: For patients with Crohn's disease, a significant drop in serum albumin and MCV levels and a significant rise in platelet count were observed between 115 and 385 days prior to diagnosis (p < 0.01, two-tailed t test). For patients with ulcerative colitis, a significant change in albumin level, MCV, hemoglobin level, platelet count, and serum iron level was observed at diagnosis (p < 0.01, two-tailed t test) but was not detectable before. CONCLUSIONS: These data provide objective evidence of duration of delay between disease onset and diagnosis in a cohort of patients with IBD. Expediting diagnostic testing in patients presenting with symptoms consistent with IBD, who also have abnormal laboratory results, may reduce diagnostic delay, speed access to therapy, and improve clinical outcomes.

Evaluating a risk assessment tool to improve triaging of patients to colonoscopies.

BACKGROUND: Colonoscopy is the gold standard in the diagnosis of significant bowel disease (SBD), including colorectal cancer, high-risk adenoma and inflammatory bowel disease. As the demand for colonoscopy services is placing significant pressure on hospital resources, new solutions are needed to manage patients more efficiently and effectively. AIM: We investigated the impact of using a risk assessment tool (RAT) to improve selection of patients for colonoscopy procedures to detect SBD. METHODS: A hybrid simulation model was constructed to replicate the current patient triage bookings and waiting times in a large metropolitan hospital. The model used data on 327 patients who were retrospectively assessed for risk of SBD. Risk assessment incorporated blood and faecal immunochemical test results, gender and age in addition to patient symptoms. The model was calibrated over 12 months to current outcomes and was compared with the RAT and a third scenario where low-risk patients did not proceed to a colonoscopy. One-way sensitivity analyses were undertaken. RESULTS: Using the RAT was expected to shorten waiting times by 153 days for moderately-urgent patients and 138 days for non-urgent patients. If low-risk patients did not proceed to colonoscopy, waiting times were expected to reduce for patients with SBD by 17 days producing cost-savings of AU$373 824 through avoided colonoscopies. CONCLUSIONS: A hybrid model that combines patient-level characteristics with hospital-level resource constraints can demonstrate improved efficiency in a hospital clinic. Further research on risk assessment is required to improve quality patient care and reduce low-value service delivery.

Development and evaluation of a risk assessment tool to improve clinical triage accuracy for colonoscopic investigations.

BACKGROUND: Gastroenterology Departments at hospitals within Australia receive thousands of General Practitioner (GP)-referral letters for gastrointestinal investigations every month. Many of these requests are for colonoscopy. This study aims to evaluate the performance of the current symptoms-based triage system compared to a novel risk score using objective markers. METHODS: Patients with lower abdominal symptoms referred by their GPs and triaged by a Gastroenterology consultant to a colonoscopy consent clinic were recruited into the study. A risk assessment tool (RAT) was developed using objective data (clinical, demographic, pathology (stool test, FIT), standard blood tests and colonoscopy outcome). Colonoscopy and histology results were scored and then stratified as either significant bowel disease (SBD) or non-significant bowel disease (non-SBD). RESULTS: Of the 467 patients in our study, 45.1% were male, the mean age was 54.3 ± 13.8 years and mean BMI was 27.8 ± 6.2. Overall, 26% had SBD compared to 74% with non-SBD (42% of the cohort had a normal colonoscopy). Increasing severity of referral symptoms was related to a higher triage category, (rectal bleeding, P = 2.86*10-9; diarrhoea, P = 0.026; abdominal pain, P = 5.67*10-4). However, there was no significant difference in the prevalence of rectal bleeding (P = 0.991) or diarrhoea (P = 0.843) for SBD. Abdominal pain significantly reduced the risk of SBD (P = 0.0344, OR = 0.52, CI = 0.27-0.95). Conversely, the RAT had a very high specificity of 98% with PPV and NPV of SBD prediction, 74% and 77%, respectively. The RAT provided an odds ratio (OR) of 9.0, 95%CI 4.29-18.75, p = 2.32*10-11), higher than the FIT test (OR = 5.3, 95%CI 2.44-11.69, p = 4.88*10-6), blood score (OR = 2.8, 95%CI 1.72- 4.38, p = 1.47*10-5) or age (OR = 2.5, 95%CI 1.61-4.00, 5.12*10-5) independently. Notably, the ORs of these individual objective measures were higher than the current practice of symptoms-based triaging (OR = 1.4, 95%CI 0.88-2.11, p = 0.153). CONCLUSIONS: It is critical that individuals with high risk of having SBD are triaged to the appropriate category with the shortest wait time. Here we provide evidence that a combination of blood markers, demographic markers and the FIT test have a higher diagnostic accuracy for SBD than FIT alone.

Predicting response after infliximab salvage in acute severe ulcerative colitis.

BACKGROUND AND AIM: Acute severe ulcerative colitis (ASUC) is a medical emergency requiring prompt therapeutic intervention. Although infliximab has been used as salvage therapy for over 15 years, clinical predictors of treatment success are lacking. We performed a retrospective analysis to identify factors that predict colectomy and may guide dose intensification. METHODS: Fifty-four hospitalized patients received infliximab for ASUC at seven Australian centers (April 2014-May 2015). Follow-up was over 12 months. The data were primarily analyzed for predictors of colectomy. Accelerated (AI) versus standard (SI) infliximab induction strategies were also compared. RESULTS: Of 54 patients identified, the overall colectomy rate was 15.38% (8/52) at 3 months and 26.92% (14/52) at 12 months. Two patients were lost to follow-up. There was a numerically higher colectomy rate in those treated with AI compared with SI (P = 0.3); however, those treated with AI had more severe biochemical disease. A C-reactive protein (CRP)/albumin ratio cut-off of 0.37 post-commencement of infliximab and before discharge was a significant predictor of colectomy with an area under receiver operating curve of 0.73. Pretreatment CRP and albumin levels were not predictive of colectomy. A Mayo Endoscopic Score of 2 had a 94% PPV for avoidance of colectomy following infliximab salvage. CONCLUSIONS: The baseline Mayo Endoscopic Score and the CRP/albumin ratio following infliximab salvage are significant predictors of treatment response for ASUC and identify patients at high risk of colectomy. Whether this risk can be mitigated using infliximab dose intensification requires prospective evaluation before the CRP/albumin ratio can be integrated into ASUC management algorithms.

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.

BACKGROUND: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. METHODS: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. FINDINGS: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)). INTERPRETATION: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. FUNDING: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

Efficacy of Rectal Tacrolimus for Induction Therapy in Patients With Resistant Ulcerative Proctitis.

BACKGROUND & AIMS: Resistant ulcerative proctitis can be extremely difficult to manage. Topically administered tacrolimus, however, may be effective in difficult-to-treat proctitis. This was a randomized, double-blind, placebo-controlled induction trial of rectal tacrolimus in patients with active ulcerative colitis. METHODS: Eleven patients received rectal tacrolimus (0.5 mg/mL), and 10 placebo, for 8 weeks. The primary endpoint was clinical response by using the Mayo Clinic score. RESULTS: A planned interim analysis after 20 patients had completed the study demonstrated highly significant differences between the groups and the study was closed because of ethical considerations with patients already recruited allowed to complete the study. The primary endpoint was met in 8 of 11 patients receiving rectal tacrolimus and 1 of 10 patients receiving placebo (73% vs 10%; P = .004). Of the secondary endpoints, 5 patients with rectal tacrolimus achieved clinical remission compared with none receiving placebo (45% vs 0%; P = .015). Mucosal healing at Week 8 was achieved in 8 patients receiving rectal tacrolimus compared with 1 (73% vs 10%) receiving placebo (P = .004). The Inflammatory Bowel Disease Questionnaire increased ≥16 points over baseline in 5 of the tacrolimus and 2 (45% vs 20%) of the placebo patients (P = .36). Finally, the average partial Mayo score was numerically lower in the tacrolimus-treated group compared with placebo at Week 2 (4.3 ± 0.74 vs 5.8 ± 0.64; P = .15) and Week 4 (3.7 ± 0.96 vs 5.8 ± 0.6; P = .08) but was significantly lower at Week 8 (3.3 ± 1.2 vs 6.7 ± 0.62; P = .01). There were no safety issues identified with rectal tacrolimus use. CONCLUSIONS: Rectal tacrolimus was more effective than placebo for induction of a clinical response, clinical remission, and mucosal healing in resistant ulcerative proctitis (Clinicaltrials.gov registration: NCT01418131).

Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection.

BACKGROUND & AIMS: Little is known about in utero exposure to and postnatal clearance of anti-tumor necrosis factor (anti-TNF) agents in neonates. We investigated the concentrations of adalimumab and infliximab in umbilical cord blood of newborns and rates of clearance after birth, and how these correlated with drug concentrations in mothers at birth and risk of infection during the first year of life. METHODS: We performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 through November 2014: 36 received adalimumab and 44 received infliximab; 39 received concomitant thiopurines during pregnancy. Data were collected from medical records on disease activity and treatment before, during, and after pregnancy. Concentrations of anti-TNF agents were measured in blood samples from women at delivery and in umbilical cords, and in infants for every 3 months until the drug was no longer detected. RESULTS: The time from last exposure to anti-TNF agent during pregnancy correlated inversely with the concentration of the drugs in the umbilical cord (adalimumab: r = -0.64, P = .0003; infliximab: r = -0.77, P < .0001) and in mothers at time of birth (adalimumab, r = -0.80; infliximab, r = -0.80; P < .0001 for both). The median ratio of infant:mother drug concentration at birth was 1.21 for adalimumab (95% confidence interval [CI], 0.94-1.49) and 1.97 for infliximab (95% CI, 1.50-2.43). The mean time to drug clearance in infants was 4.0 months for adalimumab (95% CI, 2.9-5.0) and 7.3 months for infliximab (95% CI, 6.2-8.3; P < .0001). Drugs were not detected in infants after 12 months of age. Bacterial infections developed in 4 infants (5%) and viral infections developed in 16 (20%), all with benign courses. The relative risk for infection was 2.7 in infants whose mothers received the combination of an anti-TNF agent and thiopurine, compared with anti-TNF monotherapy (95% CI, 1.09-6.78; P = .02). CONCLUSIONS: In a prospective study of infants born to mothers who received anti-TNF agents during pregnancy, we detected the drugs until 12 months of age. There was an inverse correlation between the time from last exposure during pregnancy and drug concentration in the umbilical cord. Infliximab was cleared more slowly than adalimumab from the infants. The combination of an anti-TNF agent and thiopurine therapy during pregnancy increased the relative risk for infant infections almost 3-fold compared with anti-TNF monotherapy. Live vaccines therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition.

BACKGROUND & AIMS: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). METHODS: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. RESULTS: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)). CONCLUSIONS: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

Performance of risk prediction for inflammatory bowel disease based on genotyping platform and genomic risk score method.

BACKGROUND: Predicting risk of disease from genotypes is being increasingly proposed for a variety of diagnostic and prognostic purposes. Genome-wide association studies (GWAS) have identified a large number of genome-wide significant susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC), two subtypes of inflammatory bowel disease (IBD). Recent studies have demonstrated that including only loci that are significantly associated with disease in the prediction model has low predictive power and that power can substantially be improved using a polygenic approach. METHODS: We performed a comprehensive analysis of risk prediction models using large case-control cohorts genotyped for 909,763 GWAS SNPs or 123,437 SNPs on the custom designed Immunochip using four prediction methods (polygenic score, best linear genomic prediction, elastic-net regularization and a Bayesian mixture model). We used the area under the curve (AUC) to assess prediction performance for discovery populations with different sample sizes and number of SNPs within cross-validation. RESULTS: On average, the Bayesian mixture approach had the best prediction performance. Using cross-validation we found little differences in prediction performance between GWAS and Immunochip, despite the GWAS array providing a 10 times larger effective genome-wide coverage. The prediction performance using Immunochip is largely due to the power of the initial GWAS for its marker selection and its low cost that enabled larger sample sizes. The predictive ability of the genomic risk score based on Immunochip was replicated in external data, with AUC of 0.75 for CD and 0.70 for UC. CD patients with higher risk scores demonstrated clinical characteristics typically associated with a more severe disease course including ileal location and earlier age at diagnosis. CONCLUSIONS: Our analyses demonstrate that the power of genomic risk prediction for IBD is mainly due to strongly associated SNPs with considerable effect sizes. Additional SNPs that are only tagged by high-density GWAS arrays and low or rare-variants over-represented in the high-density region on the Immunochip contribute little to prediction accuracy. Although a quantitative assessment of IBD risk for an individual is not currently possible, we show sufficient power of genomic risk scores to stratify IBD risk among individuals at diagnosis.

Serologic antibodies in relation to outcome in postoperative Crohn's disease.

BACKGROUND AND AIM: Disease recurs frequently after Crohn's disease resection. The role of serological antimicrobial antibodies in predicting recurrence or as a marker of recurrence has not been well defined. METHODS: A total of 169 patients (523 samples) were prospectively studied, with testing peri-operatively, and 6, 12 and 18 months postoperatively. Colonoscopy was performed at 18 months postoperatively. Serologic antibody presence (perinuclear anti-neutrophil cytoplasmic antibody [pANCA], anti-Saccharomyces cerevisiae antibodies [ASCA] IgA/IgG, anti-OmpC, anti-CBir1, anti-A4-Fla2, anti-Fla-X) and titer were tested. Quartile sum score (range 6-24), logistic regression analysis, and correlation with phenotype, smoking status, and endoscopic outcome were assessed. RESULTS: Patients with ≥ 2 previous resections were more likely to be anti-OmpC positive (94% vs 55%, ≥ 2 vs < 2, P = 0.001). Recurrence at 18 months was associated with anti-Fla-X positivity at baseline (49% vs 29%; positive vs negative, P = 0.033) and 12 months (52% vs 31%, P = 0.04). Patients positive (n = 28) for all four antibacterial antibodies (anti-CBir1, anti-OmpC, anti-A4-Fla2, and anti-Fla-X) at baseline were more likely to experience recurrence at 18 months than patients negative (n = 32) for all four antibodies (82% vs 18%, P = 0.034; odds ratio 6.4, 95% confidence interval 1.16-34.9). The baseline quartile sum score for all six antimicrobial antibodies was higher in patients with severe recurrence (Rutgeert's i3-i4) at 18 months, adjusted for clinical risk factors (odds ratio 1.16, 95% confidence interval 1.01-1.34, P = 0.039). Smoking affected antibody status. CONCLUSIONS: Anti-Fla-X and presence of all anti-bacterial antibodies identifies patients at higher risk of early postoperative Crohn's disease recurrence. Serologic screening pre-operatively may help identify patients at increased risk of recurrence.