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.

Gastric Cancer Screening in Common Variable Immunodeficiency.

Individuals with common variable immunodeficiency (CVID) have an increased risk of gastric cancer, and gastrointestinal lymphoma, yet screening for premalignant gastric lesions is rarely offered routinely to these patients. Proposed screening protocols are not widely accepted and are based on gastric cancer risk factors that are not applicable to all CVID patients. Fifty-two CVID patients were recruited for screening gastroscopy irrespective of symptoms or blood results and were compared to 40 controls presenting for gastroscopy for other clinical indications. Overall, 34% of CVID patients had intestinal metaplasia (IM), atrophic gastritis or moderate to severe non-atrophic gastritis, which can increase the risk of gastric cancer, compared to 7.5% of controls (p < 0.01). Focal nodular lymphoid hyperplasia, a precursor lesion for gastrointestinal lymphoma, was seen in eight CVID patients (16%), one of whom was diagnosed with gastrointestinal lymphoma on the same endoscopy. High-risk gastric pathology was associated with increased time since diagnosis of CVID, smoking, Helicobacter pylori, a low-serum pepsinogen I concentration, and diarrhea, but not pepsinogen I/II ratio, iron studies, vitamin B12 levels or upper gastrointestinal symptoms. There was a lower rate of detection of IM when fewer biopsies were taken, and IM and gastric atrophy were rarely predicted by the endoscopist macroscopically, highlighting the need for standardized biopsy protocols. The prevalence of premalignant gastric lesions in patients with CVID highlights the need for routine gastric screening. We propose a novel gastric screening protocol to detect early premalignant lesions and reduce the risk of gastric cancer and gastric lymphoma in these patients.

Hygiene Hypothesis: Is the Evidence the Same All Over the World?

BACKGROUND: The hygiene hypothesis refers to where modern living conditions are responsible for the increasing incidences of immune-related diseases including the development of inflammatory bowel diseases (IBD). Improved hygiene may result in decreased enteric microbiota diversity and dysbiosis, which may be responsible for the development of IBD. KEY MESSAGES: The rising incidence of IBD is well documented in developing regions of the world, in accordance with the hygiene hypothesis. What is unknown, however, is whether the hygiene hypothesis is applicable all over the world. Hygiene cannot be easily measured and proxy markers need to be used. These include regional data such as a country's gross domestic product or an individual's affluence or exposure to infection risk factors. A comparative case-control study of Caucasian Australian IBD subjects versus migrants from the Middle East to Australia identified that environmental risk factors are different in the 2 populations. Among Australian Caucasians, hygiene-related environmental risk factors are no longer relevant in the development of IBD. Given the country's high affluence, there has been high hygienic standard for several generations. However, migrants from less affluent countries exposed to hygiene-related environmental factors are at increased risks of developing IBD, especially in the second generation migrants born in the affluent country. Divergent risk factors include the use of antibiotics in childhood increasing the risk of IBD in developed societies but being a risk factor for developing IBD in migrants. In India, risk factors associated with infections were found to be positively associated with the development of ulcerative colitis, rather than protective. CONCLUSIONS: The hygiene hypothesis is not applicable to all populations worldwide, being most relevant in societies undergoing increasing affluence or following migration from less to more affluent countries. This review examines data from around the world that link the hygiene hypothesis with the development of IBD and in particular the divergent results arising from data from affluent countries versus less-affluent countries.

Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific.

OBJECTIVE: The rising incidence of inflammatory bowel disease in Asia supports the importance of environmental risk factors in disease aetiology. This prospective population-based case-control study in Asia-Pacific examined risk factors prior to patients developing IBD. DESIGN: 442 incident cases (186 Crohn's disease (CD); 256 UC; 374 Asians) diagnosed between 2011 and 2013 from eight countries in Asia and Australia and 940 controls (frequency-matched by sex, age and geographical location; 789 Asians) completed an environmental factor questionnaire at diagnosis. Unconditional logistic regression models were used to estimate adjusted ORs (aOR) and 95% CIs. RESULTS: In multivariate model, being breast fed >12 months (aOR 0.10; 95% CI 0.04 to 0.30), antibiotic use (aOR 0.19; 0.07 to 0.52), having dogs (aOR 0.54; 0.35 to 0.83), daily tea consumption (aOR 0.62; 0.43 to 0.91) and daily physical activity (aOR 0.58; 0.35 to 0.96) decreased the odds for CD in Asians. In UC, being breast fed >12 months (aOR 0.16; 0.08 to 0.31), antibiotic use (aOR 0.48; 0.27 to 0.87), daily tea (aOR 0.63; 0.46 to 0.86) or coffee consumption (aOR 0.51; 0.36 to 0.72), presence of hot water tap (aOR 0.65; 0.46 to 0.91) and flush toilet in childhood (aOR 0.71; 0.51 to 0.98) were protective for UC development whereas ex-smoking (aOR 2.02; 1.22 to 3.35) increased the risk of UC. CONCLUSIONS: This first population-based study of IBD risk factors in Asia-Pacific supports the importance of childhood immunological, hygiene and dietary factors in the development of IBD, suggesting that markers of altered intestinal microbiota may modulate risk of IBD later in life.

Inflammatory Bowel Disease Environmental Risk Factors: A Population-Based Case-Control Study of Middle Eastern Migration to Australia.

BACKGROUND & AIMS: The incidences of the inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis (UC) are increasing, indicating gene-environment interactions. Migrants from low-IBD-prevalence countries to a high-prevalence country may help identify the relative contribution of environmental risk factors compared with native Caucasians. METHODS: This prospective case-control study evaluated IBD environmental risk factors of Middle Eastern migrants (MEM) in Australia compared with matched Caucasian IBD subjects, MEM controls, Caucasian controls, and controls in the Middle East using adjusted odds ratios (aOR). RESULTS: A total of 795 subjects were recruited: 154 MEM cases (75 CD; 79 UC), 153 MEM controls, 162 Caucasian cases (85 CD; 77 UC), 173 Caucasian controls, and 153 controls in Lebanon. Smoking increased CD risk in MEM and Caucasians and reduced UC risk in Caucasians (aOR, 0.77; 95% CI, 0.41-0.98) but not MEM (aOR, 1.45; 95% CI, 0.80-2.62). Antibiotic use reduced the risk of MEM CD (aOR, 0.27; 95% CI, 0.11-0.67) and UC (aOR, 0.38; 95% CI, 0.18-0.80), but increased the risk in Caucasians (CD: aOR, 5.24; 95% CI, 2.13-12.90; and UC: aOR, 6.82; 95% CI, 2.67-17.38). Most hygiene markers (rural dwelling, pet ownership, pet feeding, and farm animal contact) reduced CD and UC risk in MEM (P < .05). In contrast, in Caucasians these hygiene markers lacked significance. Other significant risk factors include IBD family history, appendectomy, tonsillectomy, and breastfeeding. CONCLUSIONS: Differential IBD environmental risk factors exist between migrants and native Caucasians, indicating a dynamic interplay between environmental factors and IBD risk for immigrants that is distinct to those factors most relevant in native Caucasians.

Meta-analysis: Persistence of advanced therapies in the treatment of inflammatory bowel disease.

BACKGROUND: The expanding options in advanced therapies for ulcerative colitis (UC) and Crohn's disease (CD) present challenges in treatment selection. Persistence analysis assesses drug durability in real-world settings, acting as a surrogate marker for medication efficacy and tolerance. Unlike traditional comparative studies, persistence analysis provides insights extending beyond the initial year of treatment. AIM: To provide real-world evidence on treatment effectiveness, tolerability and preferences of physicians and patients regarding various advanced therapies for IBD. METHODS: We conducted a systematic review of observational studies up to March 2023 assessing advanced therapies' persistence in UC and CD. Advanced therapies under examination included infliximab, adalimumab, vedolizumab, ustekinumab, golimumab, certolizumab and tofacitinib. We pooled the persistence of each agent and conducted a meta-analysis to compare the persistence of newer agents with traditional TNF inhibitors (TNFi)-specifically infliximab and adalimumab. RESULTS: Among 63 observational studies, vedolizumab had the highest 1-year persistence in UC (73.8%, 95% CI: 70.0%-77.6%) and ustekinumab in CD (77.5%, 95% CI: 72.9%-82.1%). Compared to TNFi, vedolizumab demonstrated increased persistence with a relative risk (RR) of 1.30 (95% CI: 1.19-1.41) for UC and 1.14 (95% CI: 1.09-1.20) for CD at 1 year, while ustekinumab demonstrated a RR of 1.15 (95% CI: 1.07-1.23) for CD at 1 year. Vedolizumab exhibited sustained increased persistence in UC over 2 years compared to TNFi (RR: 1.33, 95% CI 1.14-1.54). CONCLUSION: This meta-analysis highlights the superior persistence of ustekinumab and vedolizumab over TNFi, and offers valuable insights for clinicians navigating the challenging landscape of UC and CD therapeutic choices.

Capsule endoscopy retention in the upper esophagus: A comprehensive literature review.

Capsule endoscopy is the first-line investigation for small bowel disorders. Capsule retention in the small bowel is the most common adverse event. Retention has also been reported in the upper esophagus; however, guidance for diagnosis and management is lacking. This review aims to summarize the diagnostic workup and management of this complication. We conducted a systematic literature review by searching 5 databases; relevant keywords and MeSH terms were used. Exclusion criteria included publications of non-adult patients in non-English languages. Data from eligible studies were analyzed using IBM SPSS 29. Twelve case reports were found (9 males, median age of 76 years); 10 capsule retentions in Zenker's diverticulum and 2 in the cricopharyngeus. Most patients were asymptomatic before capsule endoscopy. Capsule retention was symptomatic in half of the patients (6/12). A neck X-ray confirmed the diagnosis in all patients. Endoscopic capsule retrieval was achieved by different tools (9/12) (Roth's net was the most used tool, 6 patients); retrieval required rigid endoscopy in a few cases (3/12). Endoscopic capsule re-insertion was successful; using an overtube to bypass the upper esophagus was the safest method. In conclusion, capsule retention in the upper esophagus is uncommon yet exposes patients to the risk of unnecessary procedures. Symptoms of swallowing and medium-to-large size Zenker's diverticulum should be considered contra-indications for capsule endoscopy. Neck and chest X-rays are required for elderly patients who do not pass the capsule 2 weeks after ingestion. Endoscopic retrieval using Roth's net and re-insertion through an overtube should be considered first-line management.

Comparing persistence of new biologics to conventional anti-TNF alphas in adult patients with inflammatory bowel disease: a systematic review and meta-analysis protocol.

BACKGROUND: Biological therapy is a cornerstone of managing moderate-to-severe inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD). New biologics have been evolving over the past 20 years and selection of an agent remains challenging.Drug persistence measures the duration of time from initiation to discontinuation of a therapy, which can be a surrogate marker of drug tolerance and efficacy. OBJECTIVES: The study aimed to compare drug persistence of new generation biologics for the treatment of UC and CD (vedolizumab, ustekinumab, certolizumab, tofacitinib, natalizumab and golimumab) with conventional anti-tumor necroisis factor alphas (anti-TNF alphas) (adalimumab and infliximab) in adult patients with IBD. Results of the study may provide guidance on the preferred first and subsequent lines of biological treatments in patients with IBD. METHODS AND ANALYSIS: Search via electronic databases including EMBASE, MEDLINE, PubMed and clinical trial databases will be conducted on 10 March 2023 with eligible studies included from inception of 2017 to 2023. The primary outcomes are 1-year persistence of individual biologics with comparison of new biologics versus conventional anti-TNF alphas. A meta-analysis will be conducted using Review Manager V.5 and outcome will be presented as relative risk. Heterogeneity will be assessed with forest plot, χ2 and I2, followed with sensitivity analysis and subgroup analysis. Finally, the Grading of Recommendations Assessment, Development and Evaluation system will be used to assess the quality of evidence. ETHICS AND DISSEMINATION: Ethical approval is not required as no private information of participants will be used. Results of the present study will be disseminated in a peer-reviewed journal or conference presentation. PROSPERO REGISTRATION NUMBER: CRD42023392236.

Vedolizumab has longer persistence than infliximab as a first-line biological agent but not as a second-line biological agent in moderate-to-severe ulcerative colitis: real-world registry data from the Persistence Australian National IBD Cohort (PANIC) study.

Background: The choice between infliximab (IFX) and vedolizumab (VED) as a first-line biological agent in moderate-to-severe ulcerative colitis (UC) can be difficult. Second-line vedolizumab (VED) efficacy may decline following prior infliximab (IFX) treatment failure in UC patients. However, it is not known whether second-line IFX efficacy declines after failure of first-line VED. Aims: We aimed to compare first-line and second-line persistence of IFX and VED, in particular whether second-line IFX persistence declines after failure of first-line VED. Methods: Persistence of IFX and VED was analysed from the Australian Pharmaceutical Benefits Scheme registry data as either first- or second-line treatment in UC. Propensity score matching (1:1) was conducted in the comparison of first-line treatments. Cox proportional hazard regression analysis was used to identify significant predictors and expressed as a hazard ratio (HR and 95% CI). Results: There were 420 subjects with moderate-to-severe UC who received either first-line IFX (n = 251) or VED (n = 169), with 774 patient-years of follow-up. First-line VED had significantly longer persistence than first-line IFX (>50.2 versus 22.2 months, p = 0.001). Fifty-three subjects failed first-line IFX and swapped to second-line VED (IFX→VED group). Twenty-two subjects failed first-line VED group and swapped to second-line IFX (VED→IFX group). First-line VED persistence was significantly longer than second-line VED (>50.2 versus 32.0 months, p = 0.03), but first-line IFX persistence was not statistically significantly different to second-line IFX (27.6 months versus > 38.6 months, p = 0.30). Immunomodulator co-therapy was significantly associated with a lower risk of nonpersistence of first-line VED (HR: 0.55, 95% CI: 0.33-0.89, p = 0.02) and IFX (HR: 0.63,95%CI: 0.33-0.92, p = 0.02). Conclusion: VED had a significantly longer persistence than IFX as first-line biological agent but does not disadvantage second-line IFX use in moderate-to-severe UC. VED after IFX is associated with significantly poorer persistence. VED, therefore, should be considered as the first-line biological agent of choice in UC.

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.

The association between new generation oral contraceptive pill and the development of inflammatory bowel diseases.

BACKGROUND/AIMS: To examine the association between use of oral contraceptive pills (OCPs) and the risk of developing inflammatory bowel diseases (IBD), in a modern cohort. METHODS: A prospective nested case-control study across sites in the Asia-Pacific region was conducted; involving female IBD cases and asymptomatic controls. Subjects completed a questionnaire addressing questions related to OCP use. Primary outcome was the risk of development of IBD of those exposed to OCP versus non-exposure. Secondary outcomes were development of Crohn's disease (CD) versus ulcerative colitis (UC), and whether age of first use of OCP use may be associated with risk of IBD. RESULTS: Three hundred and forty-eight female IBD cases (41% CD, median age: 43 years) and 590 female age-matched controls were recruited. No significant association was found between OCP use and the risk of IBD (odds ratio [OR], 1.65; 95% confidence interval, 0.77-3.13; P=0.22), CD (OR, 1.55) or UC (OR, 1.01). The lack of association persisted when results were adjusted for age and smoking. IBD cases commenced OCP use at a younger age than controls (18 years vs. 20 years, P=0.049). CONCLUSIONS: In this large cohort of subjects from the Asia-Pacific region, we found a modest but not significantly increased risk of developing IBD amongst OCP users.

Safety of proton pump inhibitors and risk of gastric cancers: review of literature and pathophysiological mechanisms.

INTRODUCTION: Despite being an overall safe drug, several long-term adverse effects are associated with proton pump inhibitors (PPIs). The link between PPI use and gastric neuroendocrine tumors (NETs), gastric adenocarcinomas and Barrett's esophagus progression gastric cancers has been investigated due to PPI-induced hypergastrinemia. AREAS COVERED: The pathophysiological mechanisms underlying PPI exposure and gastric NETs, gastric adenocarcinomas and Barrett's esophagus progression are discussed. The quality of randomized control studies, cohort studies and case reports investigating the link between gastric cancers and PPIs are examined. Recommendations for clinicians are provided. EXPERT OPINION: PPIs cause a hypergastrinemic state, increasing enterochromaffin-like cell dysplasia and risk of gastric NET development, increasing gastritis severity in the context of Helicobacter pylori infection, and progression of carcinogenesis in a certain predisposed subset of Barrett's esophagus patients. There are case reports of PPI-induced gastric NETs and adenocarcinomas as consequences of these effects. In pernicious anemia and chronic gastritis, clinicians should be aware of potential increased risk of gastric NET development with chronic PPI use in these patients. Eradication status of H. pylori prior to commencing long-term PPI therapy should be established to reduce the risk of severe atrophic gastritis and development of gastric dysplasia.

Epidemiological studies of migration and environmental risk factors in the inflammatory bowel diseases.

Inflammatory bowel diseases (IBD) are idiopathic chronic diseases of the gastrointestinal tract well known to be associated with both genetic and environmental risk factors. Permissive genotypes may manifest into clinical phenotypes under certain environmental influences and these may be best studied from migratory studies. Exploring differences between first and second generation migrants may further highlight the contribution of environmental factors towards the development of IBD. There are few opportunities that have been offered so far. We aim to review the available migration studies on IBD, evaluate the known environmental factors associated with IBD, and explore modern migration patterns to identify new opportunities and candidate migrant groups in IBD migration research.

Prospective validation study of the International Classification of Functioning, Disability and Health score in Crohn's disease and ulcerative colitis.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) may result in disability. We aim to validate a novel scoring system for the IBD disability index (IBD-DI), and identify predictors of disability and its correlation with work absenteeism. METHODS: This prospective IBD ambulatory clinic cohort study measured IBD-DI, Crohn's Disease Activity Index (CDAI) for Crohn's disease (CD) or partial Mayo score (pMayo) for ulcerative colitis (UC), IBDQ quality-of-life, and Work Productivity and Activity Impairment. Negative IBD-DI represented greater disability. Validation tests were performed and predictors and extent of work absenteeism were determined. RESULTS: 166 consecutive subjects were recruited (75 CD, 41 UC, 50 controls). IBD-DI correlated with CDAI (r=-0.77, P<0.001), pMayo (r=-0.82, P<0.001) and IBDQ (r=0.86, P<0.001). IBD-DI differentiated CD, and UC from controls (medians -7, -4, +10; P<0.001) with a score of >3.5 identifying controls with 94% sensitivity and 83% specificity (area-under-curve 0.92). Stable patients had unchanged IBD-DI (P=ns) but not in those who relapsed (P<0.001). Intraclass correlation was 0.89 and Cronbach's alpha of internal consistency was 0.94. Diagnosis age, sex, phenotype, perianal disease, prior surgery, steroid-use and disease duration did not influence the IBD-DI but active use of biological agents significantly reduced disability (P=0.03). 21.6% of IBD patients had moderate-severe disability equating to missing >25% of work hours in the previous week. Multivariate analysis identified that only IBD-DI to be predictive of unemployment status (OR: 0.94; 95% CI: 0.89-0.99). CONCLUSIONS: The IBD-DI is a valid tool measuring disability in both CD and UC and correlates with workforce participation. It is a potential useful tool in the assessment of participation restriction and activity limitation. TRIAL REGISTRATION: ACTRN12613000903785.