Biological Agents in the Treatment of Crohn's Disease: A Propensity Score-Matched Analysis From the Prospective Persistence Australian National IBD Cohort (PANIC3) Study.

INTRODUCTION: Comparative effectiveness research provides data on the relative benefits and risks between treatments. In Crohn's disease (CD), however, there are few head-to-head studies comparing advanced therapies and none with long-term follow-up. Real-world effectiveness, defined by treatment persistence, obtained from prospective population-based patient cohorts, may help determine the best sequencing and positioning of biological agents. METHODS: We analyzed the prospectively collected population-based Australian national Pharmaceutical Benefits Scheme dispensing data registry (2005-2019) for CD. There is no mandated biological agent prescribing order, and all citizens and permanent residents are eligible for treatment irrespective of insurance status. Propensity score matching was performed to reduce selection bias. RESULTS: There were 2,029 lines of therapy in 1,446 patients (median age 43 years, interquartile range 34-58, 44% male patients) over the 15-year period with 5,618 patient-years of follow-up. Per line of therapy, 915/2,029 (45.1%) patients used adalimumab, 722/2,029 (35.6%) used infliximab, 155/2,029 (7.6%) used vedolizumab, and 237/2,029 (11.7%) used ustekinumab. When used in biological agent-naive patients, there was no difference in persistence between any agent ( P > 0.05). Used after first line in biological agent-experienced CD, ustekinumab had significantly better persistence than non-ustekinumab biological agents ( P = 0.0018), vs anti-tumor necrosis factor (TNF) alpha therapy ( P = 0.006) or vedolizumab ( P < 0.001). Ustekinumab persistence was unaffected by prior biological agent exposure ( P = 0.51). After anti-TNF use, ustekinumab had superior persistence to an alternative anti-TNF agent ( P = 0.033) and to vedolizumab ( P = 0.026). Using a propensity score-matched analysis adjusted for age, immunomodulator use, and bio-exposed status, ustekinumab had superior persistence to anti-TNF ( P = 0.01). Multivariate predictors of worse persistence were the use of a non-ustekinumab biological agent (adjusted hazard ratio 2.10, P < 0.001), and bio-experienced status (adjusted hazard ratio 1.23, P < 0.001). DISCUSSION: This large national prospective database with nonhierarchical prescribing of biological agents did not identify superior persistence of any agent in bio-naive CD. However, for patients with bio-experienced CD, persistence was greater with ustekinumab.

Knowledge and attitudes towards the use of histological assessments in ulcerative colitis by gastroenterologists vs pathologists.

BACKGROUND: Histological remission is increasingly accepted as a treatment endpoint in the management of ulcerative colitis (UC). However, the knowledge of histology guidelines and the attitudes towards their use in clinical practice by gastroenterologists and pathologists is unknown. AIM: To evaluate the knowledge of histology guidelines and attitudes towards the use of histology in UC by gastroenterologists and pathologists. METHODS: A prospective, cross-sectional nationwide survey of gastroenterologists and pathologists who analyse UC specimens was conducted. The survey consisted of 34 questions to assess gastroenterologists' and pathologists' knowledge (score out of 19) and attitudes towards histological assessment in UC. Survey questions were formulated using the European Crohn's and Colitis position paper on histopathology and the British Society of Gastroenterology biopsy reporting guidelines. It included knowledge of histological assessment of disease activity and dysplasia, knowledge of histological scoring systems for ulcerative colitis, uptake of histology scoring systems in routine practice, attitudes towards the role of histological activity, and the use of histological activity in clinical scenarios. RESULTS: Of 89 responders (77 gastroenterologists, 12 pathologists), there was almost universal acceptance that histological assessment should form part of UC evaluation [95% gastroenterologists, 92% pathologists]. However, gastroenterologists reported that 92% of their pathologists do not use a histological scoring system. Utilisation of a formal histological scoring system was preferred by 77% of gastroenterologists and 58% of pathologists. Both groups lacked awareness of the Geboes Score, Nancy Index and Robarts Histopathological Index scoring systems with 91%, 87%, and 92% of gastroenterologists respectively; and 83%, 83%, and 92% pathologists respectively, being uncertain of scoring systems' remission definitions. Histology knowledge score was not significantly different between gastroenterologists and pathologists [9/19 (IQR: 8-11) vs 8/19 (IQR: 7-10), P = 0.54]. Higher knowledge scores were predicted by hospital attending gastroenterologists (P = 0.004), participation in inflammatory bowel disease (IBD) multidisciplinary teams (P = 0.009), and self-declared IBD sub-specialist (P = 0.03). CONCLUSION: Histological remission is a recognised target for both gastroenterologists and pathologists. Despite this, knowledge of histological scoring systems and their utilisation is poor.

The diagnostic yield of pan-enteric capsule endoscopy in inflammatory bowel disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: Capsule endoscopy (CE) is a non-invasive diagnostic modality enabling real time video imaging of the gastrointestinal (GI) mucosa. Pan-enteric capsule endoscopy (PCE) is now able to thoroughly assess the entire GI tract, including for inflammatory bowel disease (IBD). Our aim was to evaluate the diagnostic accuracy of PCEs in IBD. METHODS: We comprehensively searched electronic databases (MEDLINE, SCOPUS, EMBASE, and Cochrane Central Register of Controlled Trials) for studies comparing the diagnostic accuracy of PCE with endoscopic evaluation, intestinal ultrasound or magnetic resonance enterography (MRE). Data were analyzed by calculating forest plots and the use of the I2 statistic for heterogeneity. RESULTS: Fourteen studies were identified, with seven studies evaluating PCE diagnostic yield in Crohn's disease (CD) and seven studies in ulcerative colitis (UC). In CD, there was a trend to superiority of PCE over MRE and colonoscopy with a pooled odds ratio (OR) of 1.25 (95% CI, 0.85-1.86%) for the detection of CD. This translates to an increased diagnostic yield of 5% and 7% for PCE compared with MRE and colonoscopy, respectively. PCEs had a diagnostic sensitivity for the detection of UC of 93.8% (95% CI, 87.6-97.0%) and a specificity of 69.8% (95% CI, 38.2-89.6%). CONCLUSION: PCEs have a comparable diagnostic yield to colonoscopy and MRE in Crohn's disease. The major difficulty remains standardization of PCE scoring systems and the lack of transmural assessment. In UC, PCE has an excellent diagnostic sensitivity and positive predictive value, but there are limitations to its use including the lack of histologic assessment and poor specificity.

Higher infliximab and adalimumab trough levels are associated with fistula healing in patients with fistulising perianal Crohn's disease.

BACKGROUND: Tumor necrosis factor-alpha inhibitors, including infliximab and adalimumab, are effective medical treatments for perianal fistulising Crohn's disease (CD), but not all patients achieve fistula healing. AIM: To determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels. METHODS: In this multicentre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia, we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment. Data collected included demographics, serum infliximab and adalimumab trough levels (mg/L) within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy. The primary outcome was fistula healing, defined as cessation in fistula drainage. The secondary outcome was fistula closure, defined as healing and closure of all external fistula openings. Differences between patients who did or did not achieve fistula healing were compared using the chi-square test, t test or Mann-Whitney U test. RESULTS: One hundred and fourteen patients (66 infliximab, 48 adalimumab) were included. Forty-eight (72.7%) patients on maintenance infliximab achieved fistula healing and 18 (27.3%) achieved fistula closure. Thirty-seven (77%) patients on maintenance adalimumab achieved fistula healing and 17 (35.4%) achieved fistula closure. Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than patients who did not [infliximab: 6.4 (3.8-9.5) vs 3.0 (0.3-6.2) mg/L, P = 0.003; adalimumab: 9.2 (6.5-12.0) vs 5.4 (2.5-8.3) mg/L, P = 0.004]. For patients on infliximab, fistula healing was associated with lower rates of detectable anti-infliximab antibodies and younger age. For patients on adalimumab, fistula healing was associated with higher rates of combination therapy with an immunomodulator. Serum trough levels for patients with and without fistula closure were not significantly different for infliximab [6.9 (4.3-10.2) vs 5.5 (2.5-8.3) mg/L, P = 0.105] or adalimumab [10.0 (6.6-12.0) vs 7.8 (4.2-10.0) mg/L, P = 0.083]. CONCLUSION: Higher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.

Assisted Reproductive Technology in Crohn's Disease and Ulcerative Colitis: A Systematic Review and Meta-Analysis.

INTRODUCTION: Infertility may occur in women with Crohn's disease (CD) and ulcerative colitis (UC), especially after surgery such as ileal pouch-anal anastomosis (IPAA). Assisted reproductive technology (ART) may be an option, but the safety and efficacy in this setting has been based on small cohorts to date. We performed a systematic review and meta-analysis to address this data gap. METHODS: A systematic review and random-effects meta-analysis was performed until May 2020. The primary outcomes were pregnancy and live birth rates per cycle of ART. RESULTS: Eleven studies met inclusion criteria for the systematic review and 4 for the meta-analysis. Compared with the general population, women with CD (with and without previous surgery) had no difference in pregnancy rates (odds ratio [OR] = 0.69, 95% confidence interval [CI]: 0.45-1.05) but had reduced live births (OR = 0.67, 95% CI: 0.53-0.85) per cycle of ART. ART live birth rates are not reduced in women with medically managed CD; however, they are 49%-71% lower after CD-related surgery. Women with UC had no difference in both pregnancy rates (OR = 0.99, 95% CI: 0.63-1.55) and live birth rates (OR = 0.88, 95% CI: 0.67-1.17); however, live birth rates were reduced after IPAA failure (hazard ratio = 0.36, 95% CI: 0.14-0.92). Two studies did not identify any significant safety signals. DISCUSSION: ART is safe and effective in patients with UC and medically managed CD, with pregnancy and live birth rates similar to that of the general population. However, within the limitations of the available literature, current data suggest that efficacy is reduced in women with CD-related surgery and IPAA failure. Greater gastroenterologist awareness of ART is needed to facilitate timely fertility therapy referral when indicated, particularly in CD.

Superior treatment persistence with ustekinumab in Crohn's disease and vedolizumab in ulcerative colitis compared with anti-TNF biological agents: real-world registry data from the Persistence Australian National IBD Cohort (PANIC) study.

BACKGROUND: Medication persistence contributes real-world evidence about treatment effectiveness, tolerability and prescriber and patient acceptability. AIMS: To evaluate persistence of biological agents in Crohn's disease (CD) and ulcerative colitis (UC) and the effects of immunomodulator use and treatment lines. METHODS: Retrospective national population-based data on treatment persistence for adalimumab, infliximab vedolizumab and ustekinumab for CD and UC were analysed from the Australian Pharmaceutical Benefits Scheme using Kaplan-Meier analysis and Cox proportional hazards models. RESULTS: There were 2499 patients included with 8219 person-years of follow-up. In CD patients ustekinumab had increased persistence compared to anti-TNF agents (HR: 1.79, 95%CI: 1.32-2.38, P < 0.01). Twelve-month CD persistence rates were ustekinumab 80.0%, vedolizumab 73.5%, infliximab 68.1% and adalimumab 64.2% (P = 0.01). In moderate-severe UC vedolizumab had increased persistence compared to anti-TNF agents (HR: 1.67, 95% CI: 1.27-2.18 P < 0.001). Twelve-month UC persistence rates were vedolizumab 73.4%, infliximab 61.1% and adalimumab 45.5% (P < 0.001). Immunomodulator co-therapy did not significantly increase persistence in non-anti-TNF therapy (P > 0.05). Thiopurines increased persistence of anti-TNF agents in CD (P < 0.001) and UC (P = 0.03). Methotrexate co-therapy increased persistence of anti-TNF agents in CD (P = 0.001) only. First-line therapy was superior to non-first line in persistence (P < 0.001). In fistulising CD, the persistence of infliximab and adalimumab was not significantly different (P = 0.11). CONCLUSION: Persistence was highest in ustekinumab in CD and vedolizumab in UC. Factors which increased the persistence of biological agents are first-line therapy, and immunomodulator co-therapy in anti-TNF agent use.

Review of pregnancy in Crohn's disease and ulcerative colitis.

Inflammatory bowel disease (IBD) frequently affects women of childbearing age and can have implications in pregnancy. Most women with IBD have comparable fertility with women in the general population. Fertility is reduced in women with active disease or previous ileal-pouch-anal anastomosis (IPAA) surgery and is temporarily reduced in men taking sulfasalazine. Women with IBD have an increased risk of preterm delivery, low birth weight, small-for-gestational-age infants and Cesarean section (CS) delivery, however, no increased risk of congenital abnormalities. These adverse outcomes are particularly prevalent for women with active IBD compared with those with quiescent disease. Conception should occur during disease remission to optimize maternal and fetal outcomes and reduce the risk of disease exacerbations during pregnancy. Pre-conception counseling is therefore pertinent to provide patient education, medication review for risk of teratogenicity and objective disease assessment. Most medications are safe during pregnancy and breastfeeding, with the exception of methotrexate, ciclosporin, allopurinol and tofacitinib. Delivery modality should be guided by obstetric factors in most cases; however, CS is recommended for women with active perianal disease and can be considered for women with inactive perianal disease or IPAA. In conclusion, most women with IBD have uncomplicated pregnancies. Active IBD is the predominant predictor of poor outcomes and disease exacerbations; therefore, maintenance of disease remission during and before pregnancy is crucial.

Australia IBD Microbiome (AIM) Study: protocol for a multicentre longitudinal prospective cohort study.

INTRODUCTION: Crohn's disease and ulcerative colitis are common chronic idiopathic inflammatory bowel diseases (IBD), which cause considerable morbidity. Although the precise mechanisms of disease remain unclear, evidence implicates a strong multidirectional interplay between diet, environmental factors, genetic determinants/immune perturbations and the gut microbiota. IBD can be brought into remission using a number of medications, which act by suppressing the immune response. However, none of the available medications address any of the underlying potential mechanisms. As we understand more about how the microbiota drives inflammation, much interest has focused on identifying microbial signals/triggers in the search for effective therapeutic targets. We describe the establishment of the Australian IBD Microbiota (AIM) Study, Australia's first longitudinal IBD bioresource, which will identify and correlate longitudinal microbial and metagenomics signals to disease activity as evaluated by validated clinical instruments, patient-reported surveys, as well as biomarkers. The AIM Study will also gather extensive demographic, clinical, lifestyle and dietary data known to influence microbial composition in order to generate a more complete understanding of the interplay between patients with IBD and their microbiota. METHODS: The AIM Study is an Australian multicentre longitudinal prospective cohort study, which will enrol 1000 participants; 500 patients with IBD and 500 healthy controls over a 5-year period. Assessment occurs at 3 monthly intervals over a 24-month period. At each assessment oral and faecal samples are self-collected along with patient-reported outcome measures, with clinical data also collected at baseline, 12 and 24 months. Intestinal tissue will be sampled whenever a colonoscopy is performed. Dietary intake, general health and psychological state will be assessed using validated self-report questionnaires. Samples will undergo metagenomic, transcriptomic, proteomic, metabolomic and culturomic analyses. Omics data will be integrated with clinical data to identify predictive biomarkers of response to therapy, disease behaviour and environmental factors in patients with IBD. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the South Eastern Sydney Local Health District Research Ethics Committee (HREC 2019/ETH11443). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12619000911190.

Use of medications during pregnancy and breastfeeding for Crohn's disease and ulcerative colitis.

Introduction: The peak age of diagnosis of inflammatory bowel disease (IBD) occurs during childbearing years, therefore management of IBD during pregnancy is a frequent occurrence. Maintenance of disease remission is crucial to optimize pregnancy outcomes, and potential maternal or fetal toxicity from medications must be balanced against the risks of untreated IBD.Areas covered: This review summarizes the literature on safety and use of medications for IBD during pregnancy and lactation.Expert opinion: 5-aminosalicylates, corticosteroids and thiopurines are safe for use during pregnancy, while methotrexate and tofacitinib should only be used with extreme caution. Anti-TNF agents (except certolizumab), vedolizumab, ustekinumab and tofacitinib readily traverse the placenta via active transport, therefore theoretically may affect fetal development. Certolizumab only undergoes passive transfer across the placenta, thus has markedly lower cord blood levels making it likely the safest biologic agent for infants. There is reasonable evidence to support the safety of anti-TNF monotherapy and combination therapy during pregnancy and lactation. Vedolizumab and ustekinumab are also thought to be safe in pregnancy and lactation, while tofacitinib is generally avoided due to teratogenic effects in animal studies.

High prevalence of Crohn disease and ulcerative colitis among older people in Sydney.

OBJECTIVES: To determine the age-standardised prevalence of inflammatory bowel disease (IBD) in a metropolitan area of Sydney, with a focus on its prevalence among older people. DESIGN, SETTING: Population-based epidemiological study of people with IBD in the City of Canada Bay, a local government area in the inner west of Sydney, during 1 March 2016 - 10 November 2016. PARTICIPANTS: Patients diagnosed with confirmed IBD according to the Copenhagen or revised Porto criteria. MAIN OUTCOME MEASURES: Crude prevalence of IBD, including Crohn disease and ulcerative colitis; age-standardised prevalence of IBD, based on the World Health Organization standard population; prevalence rates among people aged 65 years or more. RESULTS: The median age of 364 people with IBD was 47 years (IQR, 34-62 years); 185 were women (50.8%). The crude IBD prevalence rate was 414 cases (95% CI, 371-456 cases) per 100 000 population; the age-standardised rate was 348 cases (95% CI, 312-385 cases) per 100 000 population. The age-standardised rate for Crohn disease was 166 cases (95% CI, 141-192 cases) per 100 000 population; for ulcerative colitis, 148 cases (95% CI, 124-171 cases) per 100 000 population. The IBD prevalence rate in people aged 65 years or more was 612 cases (95% CI, 564-660 cases) per 100 000, and for those aged 85 years or more, 891 cases (95% CI, 833-949 cases) per 100 000; for people under 65, the rate was 380 cases (95% CI, 342-418 cases) per 100 000. CONCLUSIONS: We found that the prevalence of confirmed IBD in a metropolitan sample was highest among older people. Challenges for managing older patients with IBD include higher rates of comorbid conditions, polypharmacy, and cognitive decline, and the immunosuppressive nature of standard therapies for IBD.

Defined microbiota transplant restores Th17/RORγt+ regulatory T cell balance in mice colonized with inflammatory bowel disease microbiotas.

The building evidence for the contribution of microbiota to human disease has spurred an effort to develop therapies that target the gut microbiota. This is particularly evident in inflammatory bowel diseases (IBDs), where clinical trials of fecal microbiota transplantation have shown some efficacy. To aid the development of novel microbiota-targeted therapies and to better understand the biology underpinning such treatments, we have used gnotobiotic mice to model microbiota manipulations in the context of microbiotas from humans with inflammatory bowel disease. Mice colonized with IBD donor-derived microbiotas exhibit a stereotypical set of phenotypes, characterized by abundant mucosal Th17 cells, a deficit in the tolerogenic RORγt+ regulatory T (Treg) cell subset, and susceptibility to disease in colitis models. Transplanting healthy donor-derived microbiotas into mice colonized with human IBD microbiotas led to induction of RORγt+ Treg cells, which was associated with an increase in the density of the microbiotas following transplant. Microbiota transplant reduced gut Th17 cells in mice colonized with a microbiota from a donor with Crohn's disease. By culturing strains from this microbiota and screening them in vivo, we identified a specific strain that potently induces Th17 cells. Microbiota transplants reduced the relative abundance of this strain in the gut microbiota, which was correlated with a reduction in Th17 cells and protection from colitis.

Gastroenterologists' preference and risk perception on the use of immunomodulators and biological therapies in elderly patients with ulcerative colitis: an international survey.

BACKGROUND AND AIMS: Comorbidities, polypharmacy, malignancies, and infections complicate management of elderly patients with inflammatory bowel diseases (IBD). This study assessed gastroenterologists' preference in the prescription of medications or surgery to elderly patients with IBD, and the factors associated with their choices. METHODS: An international case-based survey was conducted that presented three cases of steroid-dependent ulcerative colitis assessing young-age versus elderly-age patients, with and without comorbidity. Physician characteristics and practice demographics were collected. Factors associated with selection of different choices of therapy were determined by logistic regression analysis. RESULTS: A total of 424 respondents from 41 countries were included. Vedolizumab (53.2%) and thiopurines (19.4%) were the top treatment preferences for moderate-to-severe ulcerative colitis (P < 0.0001). Comorbidity and older age were independently associated with more frequent use of vedolizumab (P < 0.0001), and less frequent use of immunomodulators and anti-tumour necrosis factor (TNF; P < 0.0001). Comorbidity was the only independent predictor for selecting colectomy (P < 0.0001). A history of lymphoma (94%) and opportunistic infection (78.3%) were the most frequent conditions precluding the use of thiopurine and anti-TNF in elderly patients with IBD. Only 6.1% of respondents considered patient age a limit for vedolizumab, while 37.9% considered age as a limiting factor in prescribing thiopurines (P < 0.001). Geographical heterogeneity was identified with significantly more physicians from Oceania and North America favouring the use of vedolizumab. CONCLUSION: Vedolizumab was the preferred first-line agent in the treatment of elderly patients with IBD with steroid-dependent moderate-to-severe ulcerative colitis. Older age and presence of comorbidity influenced the selection of medication. Comorbidity was the main predictor of colectomy. Geographical heterogeneity in prescribing habits may relate to medication reimbursement in individual countries.

Epidemiology of inflammatory bowel disease in South America: A systematic review.

BACKGROUND: The worldwide epidemiology of inflammatory bowel disease (IBD) is rapidly changing. Increasing Crohn's disease (CD) and ulcerative colitis (UC) incidence and prevalence have been recorded in developing regions such as Asia, Africa and Eastern Europe where it was previously thought to be uncommon. Whether this is also the case in South America is not well known. Demonstration that developing regions worldwide have increasing IBD incidence would indicate that environmental change plays a significant role in the development of IBD. AIM: To report the incidence, prevalence and disease characteristics of CD and UC within the South American continent. METHODS: A systematic review was conducted by searching published studies in major international and regional databases (MEDLINE, EMBASE and Scopus) between January 1990 and December 2018. Outcomes considered were incidence, prevalence, phenotype, environmental and genetic factors, ethnicity and gender. A pair of independent reviewers screened and reviewed all identified articles. RESULTS: One hundred and sixty two citations were initially retrieved with 18 studies included in this systematic review. The majority of included studies were from Brazil (n =13, 72%). The incidence of UC ranged from 4.3-5.3/100000 person-years whilst the incidence of CD ranged from 0.74-3.5/100000 person-years. Prevalence ranged from 15.0-24.1/100000 inhabitants for UC and from 2.4-14.1/100000 inhabitants for CD. The incidence and prevalence of both UC and CD has increased significantly in Brazil over the past 21 years. Pancolitis was the most common disease distribution in patients with UC whilst colonic involvement was the most common distribution in CD. People residing in urban areas were at higher risk of developing both CD and UC. CONCLUSION: The IBD burden in South America is increasing at a rate possibly even greater than other developing regions around the world. There is a paucity of high-quality epidemiological studies and further robust and representative data are required to further explore modifiable risk factors and disease phenotypes.

Emergent colectomy rates decreased while elective ileal pouch rates were stable over time: a nationwide inpatient sample study.

PURPOSE: Despite advances in biologic therapy, approximately 10-15% of ulcerative colitis (UC) patients require surgery. We aimed to (1) examine the rates of emergent colectomy and elective ileal pouch anal anastomosis (IPAA) over time among UC patients in the USA and (2) investigate disparities in surgery rates by patient demographics. METHODS: Data from the Nationwide Inpatient Sample (NIS) from 2000 to 2014 were analyzed. Inclusion criteria were admissions with a primary UC ICD-9-CM diagnosis code and age > 18. Emergent cases were defined as those admitted through the emergency room with an outcome ICD-9-CM code for subtotal colectomy. Elective IPAA cases were defined with an outcome ICD-9-CM code for IPAA, used as a surrogate measure of colectomy. Patient and hospital-level demographics were analyzed. Temporal trends of colectomy were analyzed utilizing joinpoint-regression analysis with calculation of annual percentage change (APC). RESULTS: A total of 470,708 admissions were included over the 14-year period. Emergent colectomy rate significantly declined (APC - 7.35%, p = 0.0002), while the rate of elective IPAA remained stable (APC - 0.21%, p = 0.8). Emergent colectomy rates declined similarly across all demographics, though not as marked among patients age 50 and older and Medicare patients. Elective IPAA rates were significantly lower among blacks and patients with public insurance. CONCLUSIONS: There has been a significant decline in emergent UC colectomy rates in the USA; however, the overall need for surgery appears unchanged given stable IPAA rates. This suggests a limited impact on overall surgery rates with a shift from emergent to elective procedures.

Safety of drugs used for the treatment of Crohn's disease.

INTRODUCTION: Medications in treating Crohn's disease (CD) have evolved over the last two decades, particularly with the use of biologic agents. There are, however, concerns about the safety and adverse events associated with these medications. The authors review the safety profile of immunosuppressive medications used in Crohn's disease in adult patients. AREAS COVERED: The authors performed a literature search until October 2018 to examine safety data on thiopurines, methotrexate, anti-TNFα agents, vedolizumab and ustekinumab. The authors focused on 'trial' and 'real-world' data for the biologic agents. Safety in pregnancy and the elderly are also presented. EXPERT OPINION: Available data in CD suggest that immunosuppressive medications are relatively safe, although there are concerns about an elevated risk of serious infections, skin cancer and lymphoma particularly with thiopurines and anti-TNFα agents. Data on vedolizumab and ustekinumab suggest these newer biologic agents are well tolerated; however, longer term data in CD are required to identify risks with extended use. Apart from methotrexate, there appear to be no adverse congenital outcomes with exposure of drugs during pregnancy.

Specific Bacteria and Metabolites Associated With Response to Fecal Microbiota Transplantation in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) can induce remission in patients with ulcerative colitis (UC). In a randomized controlled trial of FMT in patients with active UC, we aimed to identify bacterial taxonomic and functional factors associated with response to therapy. METHODS: We performed a double-blind trial of 81 patients with active UC randomly assigned to groups that received an initial colonoscopic infusion and then intensive multidonor FMT or placebo enemas, 5 d/wk for 8 weeks. Patients in the FMT group received blended homogenized stool from 3-7 unrelated donors. Patients in the placebo group were eligible to receive open-label FMT after the double-blind study period. We collected 314 fecal samples from the patients at screening, every 4 weeks during treatment, and 8 weeks after the blinded or open-label FMT therapy. We also collected 160 large-bowel biopsy samples from the patients at study entry, at completion of 8 weeks of blinded therapy, and at the end of open-label FMT, if applicable. We analyzed 105 fecal samples from the 14 individual donors (n = 55), who in turn contributed to 21 multidonor batches (n = 50). Bacteria in colonic and fecal samples were analyzed by both 16S ribosomal RNA gene and transcript amplicon sequencing; 285 fecal samples were analyzed by shotgun metagenomics, and 60 fecal samples were analyzed for metabolome features. RESULTS: FMT increased microbial diversity and altered composition, based on analyses of colon and fecal samples collected before vs after FMT. Diversity was greater in fecal and colon samples collected before and after FMT treatment from patients who achieved remission compared with patients who did not. Patients in remission after FMT had enrichment of Eubacterium hallii and Roseburia inulivorans compared with patients who did not achieve remission after FMT and had increased levels of short-chain fatty acid biosynthesis and secondary bile acids. Patients who did not achieve remission had enrichment of Fusobacterium gonidiaformans, Sutterella wadsworthensis, and Escherichia species and increased levels of heme and lipopolysaccharide biosynthesis. Bacteroides in donor stool were associated with remission in patients receiving FMT, and Streptococcus species in donor stool was associated with no response to FMT. CONCLUSIONS: In an analysis of fecal and colonic mucosa samples from patients receiving FMT for active UC and stool samples from donors, we associated specific bacteria and metabolic pathways with induction of remission. These findings may be of value in the design of microbe-based therapies for UC. ClinicalTrials.gov, Number NCT01896635.