Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic.

OBJECTIVE: Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD. DESIGN: Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study. RESULTS: Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups. CONCLUSIONS: Following a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Stoma Formation in Crohn's Disease and the Likelihood of Antidepressant Use: A Population-Based Cohort Study.

BACKGROUND & AIMS: The impact of a temporary or permanent stoma on mental health in Crohn's Disease (CD) is unknown. The aim was to examine the association between intestinal surgery and stoma formation and subsequent antidepressant medication (ADM) use. METHODS: Using the Clinical Practice Research Datalink, we identified individuals with CD who underwent intestinal surgery between 1998-2018. We excluded individuals with a prescription for an ADM in the 6 months before surgery. Individuals were stratified into three groups: no stoma, temporary stoma, and permanent stoma. We used Kaplan-Meier curves to examine initiation of ADM after intestinal surgery and Cox regression to identify risk factors for ADM use after intestinal surgery. RESULTS: We identified 1,272 cases of CD undergoing their first intestinal surgery. Of these, 871 (68.5%) had no stoma, 191 (15.0%) had a temporary stoma and 210 (16.5%) had a permanent stoma. The 10-year cumulative incidence of ADM use was 26.4%, 33.4% and 37.3% respectively. Individuals with a permanent stoma were 71% more likely to receive an ADM than those with no stoma (HR 1.71, 95% CI 1.20-2.44). Individuals with a temporary stoma reversed within 12 months had a similar likelihood of ADM use to those without stoma formation (HR 0.99, 95% CI 0.64-1.53) whereas temporary stoma formation with late reversal after 12 months was associated with significantly greater likelihood of ADM use (HR 1.85, 95% CI 1.15-2.96). CONCLUSIONS: Permanent stomas and temporary stomas with late reversal surgery are associated with increased ADM use after intestinal surgery, likely associated with increased anxiety and depression.

Depression in individuals who subsequently develop inflammatory bowel disease: a population-based nested case-control study.

OBJECTIVE: Depression is a potential risk factor for developing IBD. This association may be related to GI symptoms occurring before diagnosis. We aimed to determine whether depression, adjusted for pre-existing GI symptoms, is associated with subsequent IBD. DESIGN: We conducted a nested case-control study using the Clinical Practice Research Datalink identifying incident cases of UC and Crohn's disease (CD) from 1998 to 2016. Controls without IBD were matched for age and sex. We measured exposure to prevalent depression 4.5-5.5 years before IBD diagnosis. We created two sub-groups with prevalent depression based on whether individuals had reported GI symptoms before the onset of depression. We used conditional logistic regression to derive ORs for the risk of IBD depending on depression status. RESULTS: We identified 10 829 UC cases, 4531 CD cases and 15 360 controls. There was an excess of prevalent depression 5 years before IBD diagnosis relative to controls (UC: 3.7% vs 2.7%, CD 3.7% vs 2.9%). Individuals with GI symptoms prior to the diagnosis of depression had increased adjusted risks of developing UC and CD compared with those without depression (UC: OR 1.47, 95% CI 1.21 to 1.79; CD: OR 1.41, 95% CI 1.04 to 1.92). Individuals with depression alone had similar risks of UC and CD to those without depression (UC: OR 1.13, 95% CI 0.99 to 1.29; CD: OR 1.12, 95% CI 0.91 to 1.38). CONCLUSIONS: Depression, in the absence of prior GI symptoms, is not associated with subsequent development of IBD. However, depression with GI symptoms should prompt investigation for IBD.

Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD.

OBJECTIVE: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine. DESIGN: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4ß7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine. RESULTS: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine. CONCLUSION: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab.

OBJECTIVE: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections. DESIGN: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4ß7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020. RESULTS: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001). CONCLUSIONS: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Adaptations to the British Society of Gastroenterology guidelines on the management of acute severe UC in the context of the COVID-19 pandemic: a RAND appropriateness panel.

OBJECTIVE: Management of acute severe UC (ASUC) during the novel COVID-19 pandemic presents significant dilemmas. We aimed to provide COVID-19-specific guidance using current British Society of Gastroenterology (BSG) guidelines as a reference point. DESIGN: We convened a RAND appropriateness panel comprising 14 gastroenterologists and an IBD nurse consultant supplemented by surgical and COVID-19 experts. Panellists rated the appropriateness of interventions for ASUC in the context of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Median scores and disagreement index (DI) were calculated. Results were discussed at a moderated meeting prior to a second survey. RESULTS: Panellists recommended that patients with ASUC should be isolated throughout their hospital stay and should have a SARS-CoV-2 swab performed on admission. Patients with a positive swab should be discussed with COVID-19 specialists. As per BSG guidance, intravenous hydrocortisone was considered appropriate as initial management; only in patients with COVID-19 pneumonia was its use deemed uncertain. In patients requiring rescue therapy, infliximab with continuing steroids was recommended. Delaying colectomy because of COVID-19 was deemed inappropriate. Steroid tapering as per BSG guidance was deemed appropriate for all patients apart from those with COVID-19 pneumonia in whom a 4-6 week taper was preferred. Post-ASUC maintenance therapy was dependent on SARS-CoV-2 status but, in general, biologics were more likely to be deemed appropriate than azathioprine or tofacitinib. Panellists deemed prophylactic anticoagulation postdischarge to be appropriate in patients with a positive SARS-CoV-2 swab. CONCLUSION: We have suggested COVID-19-specific adaptations to the BSG ASUC guideline using a RAND panel.

British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic.

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Smoking Status at Diagnosis and Subsequent Smoking Cessation: Associations With Corticosteroid Use and Intestinal Resection in Crohn's Disease.

BACKGROUND: The impact of smoking at diagnosis and subsequent smoking cessation on clinical outcomes in Crohn's disease (CD) has not been evaluated in a population-based cohort. METHODS: Using a nationally representative clinical research database, we identified incident cases of CD between 2005 and 2014. We compared the following outcomes: overall corticosteroid (CS) use; flares requiring CS; CS dependency and intestinal surgery between smokers and non-smokers at time of CD diagnosis. Differences in these outcomes were also compared between persistent smokers and smokers who quit within 2 years of diagnosis. RESULTS: We identified 3553 patients with a new CD diagnosis over the study period of whom 1121 (32%) were smokers. Smokers at CD diagnosis had significantly higher CS-use (56 versus 47%, p < 0.0001), proportionally more CS flares (>1 CS flare/year: 9 versus 6%, p < 0.0001), and higher CS dependency (27 versus 21%, p < 0.0001) than non-smokers. Regression analysis identified smoking at diagnosis to be associated with a higher risk of intestinal surgery (HR 1.64, 95% CI 1.16-2.52). There was a significantly higher proportion of 'quitters' who remained steroid-free through follow-up in comparison to 'persistent smokers' (45.4 versus 37.5%, respectively, p = 0.02). 'Quitters' also had lower rates of CS dependency compared to 'persistent smokers' (24 versus 33%, p = 0.008). CONCLUSIONS: Smokers at CD diagnosis have higher CS-use, CS dependency and higher risk of intestinal surgery. Quitting smoking appears to have beneficial effects on disease related outcomes, including reducing CS dependency highlighting the importance of offering early smoking cessation support.

Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1-5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.

Diagnosis and outcome of Clostridium difficile infection by toxin enzyme immunoassay and polymerase chain reaction in an island population.

BACKGROUND AND AIM: Clostridium difficile infection (CDI) is a potentially life-threatening cause of diarrhea. Correct laboratory diagnosis is essential to differentiate CDI from other causes of diarrhea. A positive fecal C. difficile toxin (CDT) is the best indicator of CDI, but the significance of a positive fecal nucleic acid amplification test (NAAT) remains unclear. Our aim was to elucidate the significance of CDI diagnostics in patients in Jersey. METHODS: A retrospective, 5-year study was conducted at an island district general hospital of patients who developed CDI. Patients were grouped according to CDT and NAAT status and their association with outcome (indicators of severity and 30-day case-fatality rate) compared. RESULTS: A total of 207 specimens were toxin positive, 92 NAAT positive and toxin negative, and 39 had a stool sample negative by both toxin and NAAT testing. A positive toxin stool sample was associated with both significantly higher white cell count (14.5 × 109 /L vs 11.3 × 109 /L, P = 0.003) and C-reactive protein (114.7 mg/dL vs 82.9 mg/dL, P = 0.001), but NAAT positivity was not (P = 0.269, 0.728). A positive CDT assay was a significant independent predictor of death (odds ratio [OR]: 1.89 [95% CI: 1.04-3.43], P = 0.046), but a positive NAAT in CDT negative samples was not (OR: 1.02 [95% CI: 0.34-3.12], P = 1.0). CONCLUSIONS: The findings of this study, derived from evolving clinical practice, provide greater clarity in the interpretation of CDI diagnostics. In CDT-negative disease, a positive NAAT neither predicts disease severity nor mortality. NAAT-positive and toxin-negative patients require instigation of infection control measures, but the need for specific treatment remains unclear.

Patients with Endoscopically Visible Polypoid Adenomatous Lesions Within the Extent of Ulcerative Colitis Have an Increased Risk of Colorectal Cancer Despite Endoscopic Resection.

OBJECTIVES: Ulcerative colitis (UC) is associated with an increased risk of colorectal cancer (CRC). Few studies have looked at long-term outcomes of endoscopically visible adenomatous lesions removed by endoscopic resection in these patients. We aimed to assess the risk of developing CRC in UC patients with adenomatous lesions that develop within the segment of colitis compared to the remainder of an ulcerative colitis cohort. METHODS: We identified patients with a confirmed histological diagnosis of UC from 1991 to 2004 and noted outcomes till June 2011. The Kaplan-Meier method was used to estimate cumulative probability of subsequent CRC. Factors associated with risk of CRC were assessed in a Cox proportional hazards model. RESULTS: Twenty-nine of 301 patients with UC had adenomatous lesions noted within the segment of colitis. The crude incidence rate of developing colon cancer in patients with UC was 2.45 (95 % CI 1.06-4.83) per 1000 PYD and in those with UC and polypoid adenomas within the extent of inflammation was 11.07 (95 % CI 3.59-25.83) per 1000 PYD. Adjusted hazards ratio of developing CRC on follow-up in UC patients with polypoid dysplastic adenomatous lesions within the extent of inflammation was 4.0 (95 % CI 1.3-12.4). CONCLUSIONS: The risk of developing CRC is significantly higher in UC patients with polypoid adenomatous lesions, within the extent of inflammation, despite endoscopic resection. Patients and physicians should take the increased risk into consideration during follow-up of these patients.

Small intestinal contrast ultrasonography for the detection of small bowel complications in Crohn's disease: correlation with intraoperative findings and magnetic resonance enterography.

BACKGROUND AND AIMS: In evaluating small bowel Crohn's disease (CD), small intestine contrast-enhanced ultrasonography (SICUS) is emerging as an alternative to magnetic resonance enterography (MRE). This retrospective study compared the diagnostic accuracy of SICUS and MRE with surgical findings, and their level of agreement. METHODS: We identified a cohort of CD patients investigated by either SICUS and/or MRE that subsequently required resective bowel surgery within 6 months. The accuracy and agreement of SICUS and MRE to detect small bowel complications were compared with intraoperative findings using kappa coefficient (κ). Agreement between SICUS and MRE in those undergoing both modalities was also assessed. RESULTS: A total of 67 patients were evaluated; 25 underwent SICUS and 17 underwent MRE prior to surgery. Another 25 patients underwent both SICUS and MRE. When compared with intraoperative findings, the sensitivity of SICUS and MRE was 87.5% and 100%, respectively, in detecting strictures, 87.7% and 66.7% for fistulae, 100% for both in identifying abscesses, 100% and 66.7% for bowel dilatation, and 94.7% and 81.8% in defining bowel wall thickening. When correlating SICUS and MRE with surgery, there was a high level of agreement in localizing strictures (κ = 0.75, 0.88, respectively), fistulae (κ = 0.82, 0.79) and abscesses (κ = 0.87, 0.77). Concordance between SICUS and MRE was substantial or almost complete in identifying stricturing disease (κ = 0.84), their number and location (κ = 0.85), fistulae (κ = 0.65), and mucosal thickening (κ = 0.61). CONCLUSION: SICUS accurately identified small bowel complications and correlated well with MRE and intraoperative findings. SICUS offers an alternative in the preoperative assessment of CD.

The role of thiopurines in reducing the need for surgical resection in Crohn's disease: a systematic review and meta-analysis.

OBJECTIVES: The thiopurine (TP) analogs azathioprine and mercaptopurine have proven efficacy in inducing and maintaining clinical remission in Crohn's disease (CD). Their impact on the long-term need for surgery is uncertain since studies have reported conflicting results. The aim of this systematic review was to summarize and evaluate evidence of the published literature regarding those studies assessing the impact of TPs on the risk of first surgical resection in CD. METHODS: We searched Medline, EMBASE, CINAHL, and hand searched reference lists of identified articles, without language restrictions in August 2013. RESULTS: Seventeen retrospective observational studies (eight population based, three multicenter, and six referral center) representing 21,632 participants met our inclusion criteria. Of these 10 studies involving 12,586 participants provided data on the hazard ratio (HR) and 95% confidence intervals (CIs) evaluating use of TPs and surgical risk. The combined pooled HR of first intestinal resection with TP use was 0.59 (95% CI 0.48-0.73). CONCLUSIONS: TP use is associated with a 40% lowered risk of surgical resection in patients with CD. Despite significant reductions in rates of surgical resection in patients with CD over the last 5 decades and increasing use of TPs, a large proportion of patients with CD still require resectional surgery.

The impact of timing and duration of thiopurine treatment on first intestinal resection in Crohn's disease: national UK population-based study 1989-2010.

OBJECTIVES: The efficacy of thiopurines (TPs) in altering the risk of surgery in Crohn's disease (CD) remains controversial. We evaluated the impact of TP therapy, optimal timing, and duration of TP therapy on first intestinal resection rates using a population-based cohort. METHODS: We constructed a population-based cohort of incident cases of CD between 1989 and 2005. We used the Kaplan-Meier analysis to calculate time trends in TP use and first intestinal resection in three groups defined by time period of diagnosis: 1989-1993, 1994-1999, and 2000-2005 groups A, B, and C, respectively. We quantified impact of duration and timing of TP treatment on likelihood of surgery using Cox regression and propensity score matching. RESULTS: We identified 5,640 eligible patients with CD. The 5-year cumulative probability of TP use increased from 12, 18, to 25% ( P<0.0001) while probability of first intestinal resection decreased from 15, 12 to 9% (P<0.001) in groups A, B, and C, respectively. Patients treated with at least 6 months of TP therapy had a 44% reduction in the risk of surgery (hazards ratio (HR): 0.56; 95% confidence interval (CI): 0.37-0.85) and those receiving at least 12 months of TP therapy had a 69% reduction in the risk of surgery (HR: 0.31; 95% CI: 0.22-0.44). Early treatment (<12 months from diagnosis) vs. late treatment with TP showed no additional benefit in reducing risk of surgery (HR: 0.41; 95% CI: 0.27-0.61 vs. 0.21; 95% CI: 0.13-0.34). CONCLUSIONS: Over the past 20 years, TP use has doubled, whereas intestinal surgery has fallen by one-third among the UK population of Crohn's patients. Prolonged exposure is associated with a reduced likelihood of surgery whereby more than 12 months TP therapy reduces the risk of first intestinal surgery two-fold; however, early initiation of TP treatment offered no apparent additional benefit.

Chronic abdominal pain in inflammatory bowel disease: a practical guide.

Pain is common in inflammatory bowel disease (IBD), yet many patients feel their pain is not addressed by healthcare professionals. Listening to a patient's concerns about pain, assessing symptoms and acknowledging the impact these have on daily life remain crucial steps in addressing pain in IBD. While acute pain may be effectively controlled by pain medication, chronic pain is more complex and often pharmacological therapies, particularly opioids, are ineffective. Low-dose tricyclic antidepressants and psychological approaches, including cognitive-behavioural therapy, have shown some promise in offering effective pain management while lifestyle changes such as a trial of low-fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet in those with overlapping irritable bowel syndrome may also reduce pain. Patients benefit from a long-term, trusting relationship with their healthcare professional to allow a holistic approach combining pharmacological, psychological, lifestyle and dietary approaches to chronic pain. We present a practical review to facilitate management of chronic abdominal pain in IBD.

Using clinical cases to guide healthcare.

Evidence-based practice (EBP) has been the gold standard in healthcare for nearly three centuries and aims to assist physicians in providing the safest and most effective healthcare for their patients. The well-established hierarchy of evidence lists systematic reviews and meta-analyses at the top however these methodologies are not always appropriate or possible and in these instances case-control studies, case series and case reports are utilised to support EBP. Case-control studies allow simultaneous study of multiple risk factors and can be performed rapidly and relatively cheaply. A recent example was during the Coronavirus pandemic where case-control studies were used to assess the efficacy of personal protective equipment for healthcare workers. Case series and case reports also play a role in EBP and are particularly useful to study rare diseases such as inflammatory bowel disease in transgender and gender non-conforming individuals. They are also vital in generating and disseminating early signals and encouraging further research. Whilst these methodologies have weaknesses, particularly with regards to bias and loss of patient confidentiality for rare pathologies, they have an important part to play in EBP and when appropriately utilised can significantly impact upon clinical practice.

Biomarkers in inflammatory bowel disease: a practical guide.

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD), is a costly condition in terms of morbidity and healthcare utilization, with an increasing prevalence now approaching 1% in the Western world. Endoscopic assessment of IBD remains the gold standard for diagnosis, evaluation of treatment response and determination of post-operative recurrence, but is expensive and invasive. Biomarkers can facilitate non-invasive disease assessment, with C-reactive protein and faecal calprotectin as the most widely available biomarkers in current clinical practice. This narrative review summarizes the evidence for their use in both UC and CD and offers practical guidance for healthcare providers taking into account the limitations of biomarker interpretation. We present evidence for the future use of novel biomarkers in IBD and discuss how biomarker discovery could deliver the goal of precision medicine in IBD.

Biomarkers in inflammatory bowel disease: a practical guide Inflammatory bowel disease (IBD) is a term used to describe two conditions, ulcerative colitis (UC) and Crohn's disease (CD). These two diseases cause inflammation of the bowel, which can lead to diarrhoea, abdominal pain and bleeding from the back passage. The best way of assessing how active a patient's IBD is, is by performing a camera test called a colonoscopy. However, having a colonoscopy is inconvenient, comes with some risks to the patient, and uses a lot of healthcare resources. 'Biomarkers' are proteins detectable in body fluids (such as blood, poo and urine) which can give information to medical staff about how active a patient's disease is, without the need for colonoscopy. In this article, we give guidance about how best to use these tests, and when they might not be so useful. We also discuss new biomarkers and ways in which they could be used in the future to predict which treatments patients might respond to best.