Ten missteps in the management of inflammatory bowel disease in Asia: An expert report by the Asian Pacific Association of Gastroenterology Working Group on Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is rapidly emerging in the Asia Pacific region. However, there are many challenges in the diagnosis and management of this condition. The Asian Pacific Association of Gastroenterology (APAGE) Working Group on IBD conducted a round table meeting to identify 10 common mistakes in the management of IBD in Asia. To summarize, many physicians still over rely on a definitive histological diagnosis before starting treatment and do not fully establish disease extent such as perianal and proximal gastrointestinal involvement in Crohn's disease (CD) or extent of involvement in ulcerative colitis (UC). It is also essential to actively look for evidence of extra-intestinal manifestations, which may influence choice of therapy. In terms of conventional therapy, underuse of topical 5 aminosalicylates (5-ASAs) in UC and inappropriate dosing of corticosteroids are also important considerations. Acute severe UC remains a life-threatening condition and delay in starting rescue therapy after inadequate response to intravenous steroids is still common. Anti-tumor necrosis factors should be considered first line in all cases of complex perianal fistulizing CD. Most patients with IBD are on potent immunosuppressive therapy and should be screened for latent infections and offered vaccinations according to guidelines. Under-recognition and management of significant complications such as anemia, osteoporosis, malnutrition, and thromboembolism should also be addressed. Colonoscopy is still not properly performed for dysplasia/cancer surveillance and for evaluating post-op recurrence of CD. Another common misstep is inappropriate withdrawal of medications during pregnancy leading to increased complications for the mother and the newborn.

Academy of Medicine, Singapore clinical guideline on endoscopic surveillance and management of gastric premalignant lesions.

Gastric cancer (GC) has a good prognosis, if detected at an early stage. The intestinal subtype of GC follows a stepwise progression to carcinoma, which is treatable with early detection and intervention using high-quality endoscopy. Premalignant lesions and gastric epithelial polyps are commonly encountered in clinical practice. Surveillance of patients with premalignant gastric lesions may aid in early diagnosis of GC, and thus improve chances of survival. An expert professional workgroup was formed to summarise the current evidence and provide recommendations on the management of patients with gastric premalignant lesions in Singapore. Twenty-five recommendations were made to address screening and surveillance, strategies for detection and management of gastric premalignant lesions, management of gastric epithelial polyps, and pathological reporting of gastric premalignant lesions.

Academy of Medicine, Singapore clinical guideline on the use of sedation by non-anaesthesiologists during gastrointestinal endoscopy in the hospital setting.

INTRODUCTION: In Singapore, non-anaesthesiologists generally administer sedation during gastrointestinal endoscopy. The drugs used for sedation in hospital endoscopy centres now include propofol in addition to benzodiazepines and opiates. The requirements for peri-procedural monitoring and discharge protocols have also evolved. There is a need to develop an evidence-based clinical guideline on the safe and effective use of sedation by non-anaesthesiologists during gastrointestinal endoscopy in the hospital setting. METHODS: The Academy of Medicine, Singapore appointed an expert workgroup comprising 18 gastroenterologists, general surgeons and anaesthesiologists to develop guidelines on the use of sedation during gastrointestinal endoscopy. The workgroup formulated clinical questions related to different aspects of endoscopic sedation, conducted a relevant literature search, adopted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology and developed recommendations by consensus using a modified Delphi process. RESULTS: The workgroup made 16 recommendations encompassing 7 areas: (1) purpose of sedation, benefits and disadvantages of sedation during gastrointestinal endoscopy; (2) pre-procedural assessment, preparation and consent taking for sedation; (3) Efficacy and safety of drugs used in sedation; (4) the role of anaesthesiologist administered sedation during gastrointestinal endoscopy; (5) performance of sedation; (6) post-sedation care and discharge after sedation; and (7) training in sedation for gastrointestinal endoscopy for non-anaesthesiologists. CONCLUSION: These recommendations serve to guide clinical practice during sedation for gastrointestinal endoscopy by non-anaesthesiologists in the hospital setting.

Severity of gastric intestinal metaplasia predicts the risk of gastric cancer: a prospective multicentre cohort study (GCEP).

OBJECTIVE: To investigate the incidence of gastric cancer (GC) attributed to gastric intestinal metaplasia (IM), and validate the Operative Link on Gastric Intestinal Metaplasia (OLGIM) for targeted endoscopic surveillance in regions with low-intermediate incidence of GC. METHODS: A prospective, longitudinal and multicentre study was carried out in Singapore. The study participants comprised 2980 patients undergoing screening gastroscopy with standardised gastric mucosal sampling, from January 2004 and December 2010, with scheduled surveillance endoscopies at year 3 and 5. Participants were also matched against the National Registry of Diseases Office for missed diagnoses of early gastric neoplasia (EGN). RESULTS: There were 21 participants diagnosed with EGN. IM was a significant risk factor for EGN (adjusted-HR 5.36; 95% CI 1.51 to 19.0; p<0.01). The age-adjusted EGN incidence rates for patients with and without IM were 133.9 and 12.5 per 100 000 person-years. Participants with OLGIM stages III-IV were at greatest risk (adjusted-HR 20.7; 95% CI 5.04 to 85.6; p<0.01). More than half of the EGNs (n=4/7) attributed to baseline OLGIM III-IV developed within 2 years (range: 12.7-44.8 months). Serum trefoil factor 3 distinguishes (Area Under the Receiver Operating Characteristics 0.749) patients with OLGIM III-IV if they are negative for H. pylori. Participants with OLGIM II were also at significant risk of EGN (adjusted-HR 7.34; 95% CI 1.60 to 33.7; p=0.02). A significant smoking history further increases the risk of EGN among patients with OLGIM stages II-IV. CONCLUSIONS: We suggest a risk-stratified approach and recommend that high-risk patients (OLGIM III-IV) have endoscopic surveillance in 2 years, intermediate-risk patients (OLGIM II) in 5 years.

Author Correction: Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Asian Pacific Association of Gastroenterology (APAGE) Inflammatory Bowel Disease (IBD) Working Party guidelines on IBD management during the COVID-19 pandemic.

The COVID-19 pandemic, secondary to SARS-CoV-2, has resulted in high mortality and morbidity worldwide. As inflammatory bowel disease (IBD) is a chronic disease, and most patients are on long-term immunosuppressive agents, there is understandable concern, particularly in terms of therapy. In view of this, experts in IBD across the Asia Pacific region were invited to put together recommendations based on their experience and the currently available data. In general, most IBD therapies (with a few exceptions) can be continued safely, and the general consensus is that maintaining disease control should remain the main principle of management. In addition, social distancing measures and the appropriate use of personal protective equipment should be strictly adhered to. During the current pandemic, face-to-face clinic follow ups and non-urgent procedures should be kept to a minimum.

An intronic FTO variant rs16952570 confers protection against thiopurine-induced myelotoxicities in multiethnic Asian IBD patients.

Thiopurines are used in the treatment of inflammatory bowel disease (IBD) but remain clinically challenging to manage due to wide interpatient variability in clinical outcomes and adverse events. Apart from genetic variants in thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) genes, polymorphisms in FTO alpha-ketoglutarate dependent dioxygenase (FTO) were found predictive of thiopurine-induced leukopenia, albeit with conflicting results. To clarify the role of FTO variants in a multiethnic Asian IBD cohort, we recruited 149 patients on thiopurine-based therapy and genotyped two FTO variants p.Ala134Thr (rs79206939) and rs16952570 T > C using Sanger sequencing. FTO p.Ala134Thr (rs79206939) was non-polymorphic and absent whereas intronic rs16952570 T > C was equally prevalent in Chinese (22%) and Indians (18%) and higher in Malays (28%). Higher nadir white blood cell (WBC) and absolute neutrophil count (ANC) levels were observed in patients harboring FTO rs16952570 CC genotypes compared with TT carriers at 4, 8, and 12 weeks after start of thiopurine therapy (P < 0.05). A similar trend was observed in patients carrying the previously well-characterized NUDT15 rs116855232 wild-type CC genotypes. Further in silico analysis suggests that FTO variants linked to rs16952570, particularly rs74018601, may play a regulatory role in altering the FTO expression. The findings from this study indicate a novel protective association with the FTO variant rs16952570 CC genotype and hematological parameters.

Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia.

The Asia-Pacific Working Group on inflammatory bowel disease (IBD) was established in Cebu, Philippines, under the auspices of the Asian Pacific Association of Gastroenterology with the goal of improving IBD care in Asia. This consensus is carried out in collaboration with Asian Organization for Crohn's and Colitis. With biologic agents and biosimilars becoming more established, it is necessary to conduct a review on existing literature and establish a consensus on when and how to introduce biologic agents and biosimilars in the conjunction with conventional treatments for ulcerative colitis (UC) and Crohn's disease (CD) in Asia. These statements also address how pharmacogenetics influence the treatments of UC and CD and provide guidance on response monitoring and strategies to restore loss of response. Finally, the review includes statements on how to manage treatment alongside possible hepatitis B and tuberculosis infections, both common in Asia. These statements have been prepared and voted upon by members of IBD workgroup employing the modified Delphi process. These statements do not intend to be all-encompassing and future revisions are likely as new data continue to emerge.

Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia.

The Asia-Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, under the auspices of the Asia-Pacific Association of Gastroenterology with the goal of improving inflammatory bowel disease care in Asia. This consensus is carried out in collaboration with Asian Organization for Crohn's and Colitis. With biologic agents and biosimilars becoming more established, it is necessary to conduct a review on existing literature and establish a consensus on when and how to introduce biologic agents and biosimilars in conjunction with conventional treatments for ulcerative colitis and Crohn's disease in Asia. These statements also address how pharmacogenetics influences the treatments of ulcerative colitis and Crohn's disease and provides guidance on response monitoring and strategies to restore loss of response. Finally, the review includes statements on how to manage treatment alongside possible hepatitis B and tuberculosis infections, both common in Asia. These statements have been prepared and voted upon by members of inflammatory bowel disease workgroup employing the modified Delphi process. These statements do not intend to be all-encompassing, and future revisions are likely as new data continue to emerge.

Population Density and Risk of Inflammatory Bowel Disease: A Prospective Population-Based Study in 13 Countries or Regions in Asia-Pacific.

INTRODUCTION: Living in an urban environment may increase the risk of developing inflammatory bowel disease (IBD). It is unclear if this observation is seen globally. We conducted a population-based study to assess the relationship between urbanization and incidence of IBD in the Asia-Pacific region. METHODS: Newly diagnosed IBD cases between 2011 and 2013 from 13 countries or regions in Asia-Pacific were included. Incidence was calculated with 95% confidence interval (CI) and pooled using random-effects model. Meta-regression analysis was used to assess incidence rates and their association with population density, latitude, and longitude. RESULTS: We identified 1175 ulcerative colitis (UC), 656 Crohn's disease (CD), and 37 IBD undetermined (IBD-U). Mean annual IBD incidence per 100 000 was 1.50 (95% CI: 1.43-1.57). India (9.31; 95% CI: 8.38-10.31) and China (3.64; 95% CI, 2.97-4.42) had the highest IBD incidence in Asia. Incidence of overall IBD (incidence rate ratio [IRR]: 2.19; 95% CI: 1.01-4.76]) and CD (IRR: 3.28; 95% CI: 1.83-9.12) was higher across 19 areas of Asia with a higher population density. In China, incidence of IBD (IRR: 2.37; 95% CI: 1.10-5.16) and UC (IRR: 2.63; 95% CI: 1.2-5.8) was positively associated with gross domestic product. A south-to-north disease gradient (IRR: 0.94; 95% CI: 0.91-0.98) was observed for IBD incidence and a west-to-east gradient (IRR: 1.14; 95% CI: 1.05-1.24) was observed for CD incidence in China. This study received IRB approval. CONCLUSIONS: Regions in Asia with a high population density had a higher CD and UC incidence. Coastal areas within China had higher IBD incidence. With increasing urbanization and a shift from rural areas to cities, disease incidence may continue to climb in Asia.

A review of vedolizumab and ustekinumab for the treatment of inflammatory bowel diseases.

Recent advancement in the understanding of the pathophysiology of inflammatory bowel disease has seen an expansion in therapeutic options. Vedolizumab, a selective α4ß7 inhibitor, and ustekinumab, an IL 12/23 p40 inhibitor, have provided the much-awaited out-of-class alternatives for patients who have failed or who are intolerant to anti-Tumor Necrosis Factor (TNF) therapy. However, questions remain as to how we may best use these novel therapeutic agents. We evaluate the evidence available from randomized controlled trials and postmarketing cohort studies and discuss their safety, efficacy, and limitations, in relation to anti-TNF therapy, in optimizing the treatment outcomes.

Mycobacterium abscessus Infection During Ustekinumab Treatment in Crohn's Disease: A Case Report and Review of the Literature.

The introduction of ustekinumab, an interleukin [IL]12/23 p40 inhibitor, to the therapeutic armamentarium of Crohn's disease has provided a much needed treatment option for patients who have failed conventional biologics with anti-tumour necrosis factor [TNF] and anti-integrin agents. Despite targeting two major cytokine pathways, the side effect profile of ustekinumab appears to be favourable in clinical trials. In particular, the risk of tuberculosis infection was observed to be lower than in patients who have received anti-TNF agents. The risk of non-tuberculosis mycobacterium infection, however, remains unknown. Here, we report the first case of a patient with Crohn's disease who developed Mycobacterium abscessus infection while on ustekinumab treatment.

Consensus and contentious statements on the use of probiotics in clinical practice: A south east Asian gastro-neuro motility association working team report.

The concept of consuming microorganisms in the treatment of a medical condition and in health maintenance has gained much attraction, giving rise to an abundance of medical claims and of health supplements. This study identified relevant clinical questions on the therapeutic use of probiotics and reviewed the literature in irritable bowel syndrome, inflammatory bowel disease, impaired intestinal immunity, liver disease, intestinal infections, and common childhood digestive disorders. Statements were developed to address these clinical questions. A panel of experienced clinicians was tasked to critically evaluate and debate the available data. Both consensus and contentious statements are presented to provide to clinicians a perspective on the potential of probiotics and importantly their limitations.

Genomic and Epigenomic Profiling of High-Risk Intestinal Metaplasia Reveals Molecular Determinants of Progression to Gastric Cancer.

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We performed (epi)genomic profiling of 138 IMs from 148 cancer-free patients, recruited through a 10-year prospective study. Compared with GCs, IMs exhibit low mutational burdens, recurrent mutations in certain tumor suppressors (FBXW7) but not others (TP53, ARID1A), chromosome 8q amplification, and shortened telomeres. Sequencing identified more IM patients with active Helicobacter pylori infection compared with histopathology (11%-27%). Several IMs exhibited hypermethylation at DNA methylation valleys; however, IMs generally lack intragenic hypomethylation signatures of advanced malignancy. IM patients with shortened telomeres and chromosomal alterations were associated with subsequent dysplasia or GC; conversely patients exhibiting normal-like epigenomic patterns were associated with regression.

Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention.

Chemoprevention-the use of medication to prevent cancer-can be augmented by the consumption of produce enriched with natural metabolites. However, chemopreventive metabolites are typically inactive and have low bioavailability and poor host absorption. Here, we show that engineered commensal microbes can prevent carcinogenesis and promote the regression of colorectal cancer through a cruciferous vegetable diet. The engineered commensal Escherichia coli bound specifically to the heparan sulphate proteoglycan on colorectal cancer cells and secreted the enzyme myrosinase to transform host-ingested glucosinolates-natural components of cruciferous vegetables-to sulphoraphane, an organic small molecule with known anticancer activity. The engineered microbes coupled with glucosinolates resulted in >95% proliferation inhibition of murine, human and colorectal adenocarcinoma cell lines in vitro. We also show that murine models of colorectal carcinoma fed with the engineered microbes and the cruciferous vegetable diet displayed significant tumour regression and reduced tumour occurrence.

Predictive role of NUDT15 variants on thiopurine-induced myelotoxicity in Asian inflammatory bowel disease patients.

BACKGROUND: Genetic variants of TPMT and NUDT15 have been reported to predict the inter-patient variability in response and toxicity profiles of patients receiving thiopurine therapy. However, the clinical utility of TPMT genotyping in guiding thiopurine doses has been questionable, in part due to underlying differences in the prevalence of TPMT variants in both Caucasian and Asian populations. Several NUDT15 variants have been associated with thiopurine-induced leukopenia, particularly in Asian cohorts. So far, none have been reported in a multiethnic Asian population. AIM: To investigate the associations between TPMT and NUDT15 variants with thiopurine-induced myelotoxicity in 129 Asian inflammatory bowel disease patients. MATERIALS & METHODS: Pyrosequencing was performed to screen for TPMT and NUDT15 variants. Intracellular steady-state metabolite concentrations were quantified using liquid chromatography-tandem mass spectrometry. RESULTS: Significant declines in nadir white blood cell, absolute neutrophil count and platelet counts were observed with increasing copy numbers of the risk T allele at NUDT15 c.415C>T locus (overall p < 0.05) within 4, 8 and 12 weeks and 6 months after thiopurine initiation. Patients with low and intermediate NUDT15 activity, as inferred from haplotype pairs, had significantly higher risks of leukopenia (p = 0.000253) and neutropenia (p = 0.002) compared with patients with normal NUDT15 activity. CONCLUSION: These findings highlight the critical relevance of NUDT15 pharmacogenetics in predicting for thiopurine-induced myelotoxicity and confirm the lack of significance of TPMT variants in Asian inflammatory bowel disease patients.

Asia Pacific Consensus Statements on Crohn's disease. Part 1: Definition, diagnosis, and epidemiology: (Asia Pacific Crohn's Disease Consensus--Part 1).

Inflammatory bowel disease (IBD) was previously thought to be rare in Asia, but emerging data indicate rising incidence and prevalence of IBD in the region. The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology with the goal of developing best management practices, coordinating research, and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis, and management of Crohn's disease. The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses, and treatment availability. It does not intend to be all comprehensive and future revisions are likely to be required in this ever-changing field.

Asia-Pacific consensus statements on Crohn's disease. Part 2: Management.

The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology (APAGE) with the goal of developing best management practices, coordinating research and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis (UC) with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis and management of Crohn's disease (CD). The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses and treatment availability. It does not intend to be all-comprehensive and future revisions are likely to be required in this ever-changing field.

Early Course of Inflammatory Bowel Disease in a Population-Based Inception Cohort Study From 8 Countries in Asia and Australia.

BACKGROUND & AIMS: The incidence of inflammatory bowel disease (IBD) is increasing in Asia, but little is known about disease progression in this region. The Asia-Pacific Crohn's and Colitis Epidemiology Study was initiated in 2011, enrolling subjects from 8 countries in Asia (China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore, and Thailand) and Australia. We present data from this ongoing study. METHODS: We collected data on 413 patients diagnosed with IBD (222 with ulcerative colitis [UC], 181 with Crohn's disease [CD], 10 with IBD unclassified; median age, 37 y) from 2011 through 2013. We analyzed the disease course and severity and mortality. Risks for medical and surgical therapies were assessed using Kaplan-Meier analysis. RESULTS: The cumulative probability that CD would change from inflammatory to stricturing or penetrating disease was 19.6%. The cumulative probabilities for use of immunosuppressants or anti-tumor necrosis factor agents were 58.9% and 12.0% for patients with CD, and 12.7% and 0.9% for patients with UC, respectively. Perianal CD was associated with an increased risk of anti-tumor necrosis factor therapy within 1 year of its diagnosis (hazard ratio, 2.97; 95% confidence interval, 1.09-8.09). The cumulative probabilities for surgery 1 year after diagnosis were 9.1% for patients with CD and 0.9% for patients with UC. Patients with CD and penetrating disease had a 7-fold increase for risk of surgery, compared with patients with inflammatory disease (hazard ratio, 7.67; 95% confidence interval, 3.93-14.96). The overall mortality for patients with IBD was 0.7%. CONCLUSIONS: In a prospective population-based study, we found that the early course of disease in patients with IBD in Asia was comparable with that of the West. Patients with CD frequently progress to complicated disease and have accelerated use of immunosuppressants. Few patients with early stage UC undergo surgery in Asia. Increasing our understanding of IBD progression in different populations can help optimize therapy and improve outcomes.