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.

Approximately 1 in 10 ambulatory inflammatory bowel disease patients are at risk of malnutrition: A prospective Singapore cohort.

OBJECTIVES: Prevalence of malnutrition among ambulatory inflammatory bowel disease (IBD) patients in Singapore is unknown. We aimed to evaluate the prevalence of ambulatory IBD patients at risk of malnutrition (ARMN) using Malnutrition Universal Screening Tool (MUST) and its clinical outcomes. METHODS: IBD patients were recruited from March to June 2018 and followed up for 6 months. ARMN patients were defined as having a MUST score of 2 or more compared with those not at risk (non-ARMN). RESULTS: Altogether 217 patients were recruited, including 128 (59.0%) with ulcerative colitis (UC) and 89 (41.0%) with Crohn's disease (CD). The mean body mass index (BMI) was 23.5 ± 4.5 kg/m2 ; 35 (16.1%) patients were on biologics, and 52 (24.0%) were on steroids. Among them 25 (11.5%) patients were ARMN, with a predominance of UC (n = 15, 60.0%). The majority of ARMN patients were underweight (n = 23, 92.0%) while 114 (59.4%) non-ARMN patients were overweight. ARMN patients had a significantly lower albumin (38.3 g/L vs 41.9 g/L) and a significantly increased proportion of patients with C-reactive protein ≥5 mg/L (36.0% vs 19.3%). There was a trend towards longer hospital stay among ARMN patients, although this was not statistically significant. Use of biologics or immunomodulators and albumin levels were associated with being ARMN. CONCLUSION: Using MUST, 11.5% of our ambulatory IBD patients in Singapore were identified to be ARMN. Among ARMN patients, a trend was demonstrated towards a longer hospital stays for admitted patients. This underscores the need to actively screen ambulatory IBD patients for malnutrition.

Practice pattern variability among gastroenterologists in colorectal cancer surveillance and management of colorectal dysplasia in inflammatory bowel disease.

OBJECTIVE: There is debate on the best method of colorectal cancer (CRC) surveillance in inflammatory bowel disease (IBD). We aimed to examine how gastroenterologists around the world practice CRC surveillance and manage dysplastic lesions in IBD. METHODS: A 22-question survey was emailed to gastroenterologists from 34 countries. It included questions on resources for, frequency and mode of CRC surveillance, and management of colorectal dysplasia. Fisher's exact test and logistic regression were used to evaluate the differences among respondents in various domains. RESULTS: There were 217 eligible responses, with most gastroenterologists working in public hospitals (76%), and treating >10 patients with IBD weekly (71%). High-definition white light endoscopy (HDWLE) was available in 93.1% of the centers. The preferred mode of surveillance was HDWLE with dye-spray chromoendoscopy and targeted biopsies (41.2%). Fewer than 50% of physicians reported using chromoendoscopy in >50% of cases, citing time as the limiting factor (73.7%). Of these gastroenterologists 63% infrequently (<25% of cases) performed random biopsies during chromoendoscopy. They would attempt endoscopic mucosal resection for polypoid lesions >10 mm (67.2%), including >20 mm lesions with low grade dysplasia (49.8%), and non-polypoid lesions >10 mm without dysplasia (56.9%). For non-polypoid lesions >20 mm with low- and high-grade dysplasia, referral to expert endoscopists was the preferred option. CONCLUSION: The preferred method of CRC surveillance was HDWLE with chromoendoscopy and targeted biopsies. Random biopsies were infrequently performed. The uptake of chromoendoscopy for surveillance in practice was low. Physicians varied in their approach in removing endoscopically resectable dysplastic lesions.

Vaccinations and inflammatory bowel disease - a systematic review.

INTRODUCTION: Patients with inflammatory bowel disease(IBD) are at risk of infections, many of which are preventable with vaccinations. We performed a systematic review on various aspects of vaccination in IBD. METHODS: We searched PubMed, and EMBASE databases, through 31 January 2021. Primary outcomes included vaccination rates, predictors of vaccination, reasons of vaccination hesitancy and acceptance, and outcomes of intervention. Findings were presented with medians, ranges, and narrative synthesis. RESULTS: We included 33 observational studies comprising 146,918 patients and 681 physicians. The median vaccination rates of influenza, pneumococcal pneumonia, and hepatitis B vaccines were 42%(IQR, 28%-61.5%), 20%(IQR, 9%-38.5%), and 48%(IQR, 29%-53%), respectively. Uses of immunosuppressant, older age and physician recommendations have positive influence on vaccination rate. Lack of vaccine-related knowledge and awareness of need for vaccination are main reasons of vaccine hesitancy among patients and physicians. There was disagreement between gastroenterologists and primary-care physicians on whose responsibility to offer vaccination. Education was the sole intervention identified, with variable success. CONCLUSION: This systematic review demonstrates that the vaccination rates of IBD patients, similar to other chronic diseases, are suboptimal. Lack of vaccine-related knowledge and awareness of the need for vaccination are main reasons of vaccine hesitancy amongst patients and physicians. Education, though effective, was the only available intervention identified. Gastroenterologist could take the lead in educating, and initiating vaccination among IBD patients.

Smoking May Reduce the Effectiveness of Anti-TNF Therapies to Induce Clinical Response and Remission in Crohn's Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Cigarette smoking worsens prognosis of Crohn's disease [CD]. We conducted a systematic review and meta-analysis to examine the association between smoking and induction of clinical response or remission with anti-tumour necrosis factor [TNF] therapy. METHODS: MEDLINE, EMBASE, PubMed, and Cochrane CENTRAL [June 2019] were searched for studies reporting the effect of smoking on short-term clinical response and remission to anti-TNF therapy [≤16 weeks following the first treatment] in patients with CD. Risk ratios [RR] with 95% confidence intervals [CI] were calculated using random-effects models. RESULTS: Eighteen observational studies and three randomised controlled trials [RCT] were included. Current smokers and non-smokers [never or former] had similar rates of clinical response [observational studies RR: 0.96; 95% CI: 0.88, 1.05; RCTs RR: 1.09; 95% CI: 0.84, 1.41]. When restricted to studies clearly defining the smoking exposure, smokers treated with anti-TNF were less likely to achieve clinical response than non-smokers [smokers defined as having ≥5 cigarettes/day for ≥6 months RR: 0.63; 95% CI: 0.48, 0.83; lifetime never smokers vs ever smokers excluding former smokers RR: 0.81; 95% CI: 0.71, 0.93]. Current smokers were also less likely to achieve clinical remission in observational studies [RR: 0.75; 95% CI: 0.57, 0.98], though this association was not seen in RCTs [RR: 1.04; 95% CI: 0.89, 1.21]. CONCLUSIONS: Smoking is significantly associated with a reduction in the ability of infliximab or adalimumab to induce short-term clinical response and remission when pooling studies where smoking status was clearly defined. When patients with CD are treated with highly effective therapy, including anti-TNF agents, concurrent smoking cessation may improve clinical outcomes.

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.

Pre-operative Exposure to Ustekinumab: A Risk Factor for Postoperative Complications in Crohn's Disease (CD)?

Crohn's disease (CD) is a chronic inflammatory condition of the intestinal tract that is characterised by a relapsing and remitting course. Despite advancements in therapeutic options for CD, a substantial number of patients still require surgery for medically refractory disease or disease-related complications. Given the widespread adoption of biologic therapies for the management of patients with moderate-to-severe CD, a high number of patients are likely to be on biologic therapy at the time of needing intestinal surgery: the safety of biologics in perioperative setting is of great interest. While more clinical data are available for TNF antagonists and vedolizumab, the safety data for ustekinumab, an IL 12/23 inhibitor, is lacking. Here, we review the available data from published literature on the postoperative outcomes for CD patients exposed to ustekinumab perioperatively.

The Role of Bowel Ultrasound in Detecting Subclinical Inflammation in Pregnant Women with Crohn's Disease.

BACKGROUND AND AIMS: Maintaining disease remission improves outcomes for pregnant women with Crohn's disease (CD). As symptoms may correlate poorly with disease activity in the gravid state, we investigated the utility of bowel sonography during pregnancy to assess disease activity. METHODS: We conducted a prospective observational cohort study of pregnant women with CD undergoing bowel sonography between July 1, 2012, and December 1, 2016. Clinically active disease was defined using standardized clinical indices (Harvey Bradshaw Index >4 for active disease). Sonographic findings were graded as inactive (normal, mild) or active (moderate, severe) by expert radiologists. RESULTS: There were 91 pregnancies in 82 CD patients. Symptoms were present in 12 pregnancies; however, eight (67%) had sonographic findings of inactive disease, and escalation of therapy was not initiated. Conversely, sonographically active disease in seven asymptomatic pregnancies resulted in four women escalating therapy. The remaining three women declined escalation of therapy, one had a miscarriage, and the other two women had persistently active disease on sonography and endoscopy at one-year postpartum. CONCLUSIONS: Bowel ultrasound may detect subclinical inflammation in asymptomatic pregnant women with CD and stratify CD activity in symptomatic patients. Therefore, bowel sonography should be considered as a useful adjunct for the assessment of the pregnant woman with Crohn's disease.

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.

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.

A Global Survey of Gastroenterologists' Travel Advice to Patients with Inflammatory Bowel Disease on Immunosuppressive Agents and Management of Those Visiting Tuberculosis-Endemic Areas.

BACKGROUND: With increasing use of biological therapies and immunosuppressive agents, patients with inflammatory bowel disease[IBD] have improved clinical outcome and international travel in this group is becoming common. Adequate pre-travel advice is important. We aim to determine the proportion of gastroenterologists who provided pre-travel advice, and to assess their management strategies for patients on biological therapies visiting tuberculosis[TB]-endemic areas. METHODS: A 57-question survey was distributed to IBD physicians in 23 countries. We collected physicians' demographics, and using a standardized Likert scale, assessed physicians' agreement with stated treatment choices. RESULTS: A total of 305 gastroenterologists met inclusion criteria. Overall, 52% would discuss travel-related issues: travellers' diarrhoea [TD], travel-specific vaccines, medical care and health insurance abroad, and TB. They were more likely to advise patients not to travel to TB-endemic area if on both anti-tumour necrosis factor [TNF] and azathioprine, than if on vedolizumab and azathioprine [47% vs 17.6%, p < 0.01]. More IBD physicians agreed with vedolizumab monotherapy vs anti-TNF monotherapy [29.9% vs 23%, p < 0.01]. Two-thirds would continue all IBD treatments and not cease any medications. Chest X-ray and interferon-gamma-release assay were the preferred methods to assess for active and latent TB infection. Knowledge on vaccines among IBD physicians was inadequate (survey mean [SD] scores 10.76 [±6.8]). However, they were more familiar with the societal guidelines on management of venous thromboembolism and TD (mean scores 14.9 [±5.3] and 11.9 [±3.9] respectively). CONCLUSION: Half of IBD specialists would provide pre-travel advice to IBD patients and two-thirds would advise continuing all IBD medications even when travelling to TB-endemic areas. More education on vaccinations would be particularly helpful for IBD physicians.

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.

Preoperative Ustekinumab Treatment Is Not Associated With Increased Postoperative Complications in Crohn's Disease: A Canadian Multi-Centre Observational Cohort Study.

BACKGROUND: Ustekinumab (UST), an anti-IL12/23 inhibitor is indicated for moderate-to-severe Crohn's disease (CD). However, it is unclear if patients treated with UST are at increased risk for postoperative complications. AIM: To evaluate the postoperative safety outcomes in UST-treated CD patients. METHODS: A multicentre cohort study of UST-treated CD patients at two tertiary care centres (University of Calgary, University of Alberta, Canada) undergoing abdominal surgery between 2009 and 2016 was performed. Postoperative outcomes were compared against a control cohort of anti-TNF-treated patients over the same time-period. The primary outcome was occurrence of postoperative complications up to six months postoperatively, stratified by timing (early <30 days vs. late complications ≥30 days). RESULTS: Twenty UST-treated patients and 40 anti-TNF-treated patients were included with a median preoperative treatment exposure of 6.5 months and 18 months, respectively (p=0.01). Bowel obstruction was the most common surgical indication in both cohorts. UST-treated patients were more likely to require an ostomy (70.0% vs. 12.5%, p<0.001) and be on combination therapy with either systemic corticosteroids or concurrent immunomodulators (azathioprine or methotrexate) (25.0% vs. 2.5%, p=0.01). Despite the increased concomitant use of immunosuppression in the UST-treated cohort, there were no significant differences in early or late postoperative wound infections (1/20 in UST-cohort, 2/40 in anti-TNF cohort, p=1.00), anastomotic leak (0/20 in UST-cohort, 3/40 in anti-TNF cohort, p=0.54), or postoperative ileus/obstruction (3/20 in UST-cohort, 4/40 in anti-TNF cohort, p=0.67). CONCLUSIONS: CD patients receiving preoperative UST did not experience an increase in postoperative complications, despite increased use of concurrent immunosuppression.

Symptoms of anxiety and depression are independently associated with inflammatory bowel disease-related disability.

BACKGROUND: Inflammatory bowel disease (IBD) frequently results in disability. The relevance of psychological effects in causing disability, and whether disability occurs similarly in non-Western cohorts is as yet unknown. AIM: We assessed the relationship between symptoms of anxiety and depression, quality of life and disability in a Singaporean IBD cohort and their predictors. METHODS: Cross-sectional study. We assessed consecutive IBD subjects' IBD-Disability Index (IBD-DI), Hospital Anxiety and Depression Scale (HADS), and IBD questionnaire (IBDQ). Clinical and demographic variables were collected. Non-parametric statistical analyses were performed. Independent predictors of disability were identified through multivariate logistic regression. RESULTS: 200 consecutive subjects were recruited (males: 69%; median age: 43.8 (±15.4) years; 95 had Crohn's disease (CD), 105 had ulcerative colitis (UC); median IBD duration: 10.8 (±9.0) years.) 27% of the cohort had anxiety and/or depression, which worsened disability (IBD-DI: -9 (±14) with anxiety vs 6 (±13) without anxiety, P<0.001; -12 (±16) with depression vs 5 (±13) without depression, P<0.001). Age at diagnosis, use of prednisolone, stricturing CD and active IBD were significant predictors of disability. IBDQ strongly correlated with IBD-DI(rs=0.82, P<0.01). CONCLUSION: Symptoms of anxiety and depression were common in this Asian cohort of IBD and were strongly associated with IBD-related disability. Recognizing psychological issues contributing to disability in IBD is important to ensure holistic care and appropriate treatment.

Perceptions of non-alcoholic fatty liver disease - an Asian community-based study.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is closely related to metabolic syndrome and its risk factors. Worldwide, epidemiological studies have reported NAFLD prevalence rates of 5% to 30% depending on geographical variations. While epidemiological data suggest a progressively increasing prevalence of metabolic risk factors in Singapore, there are limited data about NAFLD per se in the community. We aim to explore the prevalence and perceptions of NAFLD in Singapore. METHODS: Attendees at a gastroenterology public forum were enrolled in a cross-sectional observational study evaluating demographic, anthropometric and clinical information. The diagnosis of NAFLD was based on sonographic criteria. Metabolic syndrome was defined according to International Diabetes Federation guidelines. Perceptions of NAFLD were explored using a self-administered survey questionnaire. RESULTS: A total of 227 subjects were recruited, with NAFLD being diagnosed in 40% of the cohort. Relative to those without NAFLD, subjects with NAFLD had higher male preponderance, older age, higher body mass index, waist circumference and more metabolic syndrome (all P < 0.05). Although 71.2% subjects had heard about NAFLD before, only 25.4% of them felt that they were at risk of NAFLD. Comparable responses were observed in subjects with no metabolic risk factors relative to subjects with one or more metabolic risk factors (P > 0.05). Of note, 75.6% of subjects with one or more metabolic risk factors did not think that they were at risk of NAFLD. CONCLUSION: Our study suggests a significant local prevalence of NAFLD in the community including non-obese individuals. Considering the tendency to underestimate risk of NAFLD, enhanced public education about NAFLD is warranted to improve understanding.