Longitudinal Fecal Calprotectin Profiles Characterize Disease Course Heterogeneity in Crohn's Disease.

BACKGROUND AND AIMS: The progressive nature of Crohn's disease is highly variable and hard to predict. In addition, symptoms correlate poorly with mucosal inflammation. There is therefore an urgent need to better characterize the heterogeneity of disease trajectories in Crohn's disease by utilizing objective markers of inflammation. We aimed to better understand this heterogeneity by clustering Crohn's disease patients with similar longitudinal fecal calprotectin profiles. METHODS: We performed a retrospective cohort study at the Edinburgh IBD Unit, a tertiary referral center, and used latent class mixed models to cluster Crohn's disease subjects using fecal calprotectin observed within 5 years of diagnosis. Information criteria, alluvial plots, and cluster trajectories were used to decide the optimal number of clusters. Chi-square test, Fisher's exact test, and analysis of variance were used to test for associations with variables commonly assessed at diagnosis. RESULTS: Our study cohort comprised 356 patients with newly diagnosed Crohn's disease and 2856 fecal calprotectin measurements taken within 5 years of diagnosis (median 7 per subject). Four distinct clusters were identified by characteristic calprotectin profiles: a cluster with consistently high fecal calprotectin and 3 clusters characterized by different downward longitudinal trends. Cluster membership was significantly associated with smoking (P = .015), upper gastrointestinal involvement (P < .001), and early biologic therapy (P < .001). CONCLUSIONS: Our analysis demonstrates a novel approach to characterizing the heterogeneity of Crohn's disease by using fecal calprotectin. The group profiles do not simply reflect different treatment regimens and do not mirror classical disease progression endpoints.

Normalization of Fecal Calprotectin Within 12 Months of Diagnosis Is Associated With Reduced Risk of Disease Progression in Patients With Crohn's Disease.

BACKGROUND & AIMS: The level of fecal calprotectin (FC) correlates with endoscopic evidence of inflammation in Crohn's disease (CD). A treat-to-target algorithm for patients with CD, that incorporates FC, outperforms a treatment strategy based on symptoms alone in the induction of mucosal healing at 12 months. We investigated whether normalization of FC within 12 months of diagnosis of CD is associated with a reduction in disease progression. METHODS: We performed a retrospective cohort study at a tertiary IBD centre in the United Kingdom. We identified all incident cases of CD diagnosed from 2005 through 2017. Patients with a FC measurement ≥250 µg/g at diagnosis who also had at least 1 follow-up FC measurement within the first 12 months of diagnosis and >12 months of follow up were included. The last FC measurement within 12 months of diagnosis was used to determine normalization (cut-off <250 µg/g). The primary endpoint was time to first disease progression (composite of progression in Montreal disease behavior B1 to B2/3, B2 to B3, or new perianal disease; CD-related surgery; or CD-related hospitalization). Cox proportional hazards regression analysis was used to determine independent factors associated with time to first disease progression. RESULTS: A total of 375 patients out of 1389 incident cases were included, with a median follow up of 5.3 years (interquartile range, 3.1-7.4 years). Normalization of FC within 12 months of diagnosis was confirmed in 43.5% of patients. Patients with normalized levels of FC had a significantly lower risk of composite disease progression (hazard ratio [HR], 0.36; 95% CI, 0.24-0.53; P < .001). They also had a lower risk of reaching any of the separate progression endpoints (progression in Montreal behavior or new perianal disease HR, 0.22; 95% CI, 0.11-0.45; P < .001; hospitalization HR, 0.33; 95% CI, 0.21-0.53; P <.001; surgery HR, 0.39; 95% CI, 0.19-0.78; P = .008) CONCLUSIONS: Normalization of FC within 12 months of diagnosis is associated with a reduced risk of progression of CD.

Analysis of colectomy rates for ulcerative colitis in pre- and postbiological eras in Lothian, Scotland.

AIM: Biological treatment is effective in maintaining remission in ulcerative colitis (UC), although the effect on colectomy rates remains unclear. In the UK the use of antitumour necrosis factor and anti-α4ß7 treatments for maintenance therapy in UC was restricted until 2015. The aim of this study was to describe the impact that this change in the prescribing of biologicals had on colectomy rates for UC. METHOD: All patients (adult and paediatric) with a diagnosis of UC who received maintenance biological treatment and/or underwent a colectomy in Lothian, Scotland between 2005 and 2018 were identified. Linear and segmental regression analyses were used to identify the annual percentage change (APC) and temporal trends (statistical joinpoints) in biological prescription and colectomy rates. RESULTS: Rates of initiation of maintenance biological therapy increased from 0.05 per 100 UC patients in 2005 to 1.26 in 2018 (p < 0.001). Colectomy rates per 100 UC patients fell from 1.47 colectomies in 2005 to 0.44 in 2018 (p < 0.001). The APC for colectomy decreased by 4.1% per year between 2005 and 2014 and by 18.9% between 2014 and 2018. Temporal trend analysis (2005-2018) identified a significant joinpoint in colectomy rates in 2014 (p = 0.019). CONCLUSION: The use of maintenance biological therapy increased sharply following the change in guidance. This has been paralleled by a significant reduction in the rates of colectomy over the same time period.

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.

Paediatric Patients (Less Than Age of 17 Years) Account for Less Than 1.5% of All Prevalent Inflammatory Bowel Disease Cases.

The prevalence of inflammatory bowel disease (IBD) continues to rise globally; however, the true proportion of paediatric IBD patients remains unknown. We conducted an all-age, multiparameter, population-based search using capture-recapture methodology to identify all IBD cases to August 31, 2018 within Lothian, a defined health board and the largest of the 3 within South-East Scotland. Individual case note validation was performed for all 24,601 possible IBD cases according to internationally recognised diagnostic and age criteria. Of 7035 confirmed point-prevalent patients, 560 were classified as A1 age phenotype at diagnosis, constituting just 8% of all cases. Ninety-nine patients were less than 17 years of age on August 31, 2018, constituting only 1.4% of all point-prevalent cases. These results demonstrate the true contemporary proportion of prevalent paediatric IBD patients is strikingly low, reflecting compounding prevalence in adult practice and the near-normal life expectancy of this chronic, incurable condition.

IBD prevalence in Lothian, Scotland, derived by capture-recapture methodology.

OBJECTIVE: IBD prevalence is estimated to be rising, but no detailed, recent UK data are available. The last reported prevalence estimate in the UK was 0.40% in 2003. We aimed to establish the current, and project future, prevalence in Lothian, Scotland. DESIGN: We conducted an all-age multiparameter search strategy using inpatient IBD international classification of disease (ICD-10) coding (K50/51)(1997-2018), IBD pathology coding (1990-2018), primary and secondary care prescribing data (2009-2018) and a paediatric registry, (1997-2018) to identify 'possible' IBD cases up to 31/08/2018. Diagnoses were manually confirmed through electronic health record review as per Lennard-Jones/Porto criteria. Autoregressive integrated moving average (ARIMA) regression was applied to forecast prevalence to 01/08/2028. RESULTS: In total, 24 601 possible IBD cases were identified of which 10 499 were true positives. The point prevalence for IBD in Lothian on 31/08/2018 was 784/100 000 (UC 432/100 000, Crohn's disease 284/100 000 and IBD unclassified (IBDU) 68/100 000). Capture-recapture methods identified an additional 427 'missed' cases (95% CI 383 to 477) resulting in a 'true' prevalence of 832/100 000 (95% CI 827 to 837).Prevalence increased by 4.3% per year between 2008 and 2018 (95% CI +3.7 to +4.9%, p<0.0001). ARIMA modelling projected a point prevalence on 01/08/2028 of 1.02% (95% CI 0.97% to 1.07%) that will affect an estimated 1.53% (95% CI 1.37% to 1.69%) of those >80 years of age. CONCLUSIONS: We report a rigorously validated IBD cohort with all-age point prevalence on 31/08/2018 of 1 in 125, one of the highest worldwide.

Association Between Level of Fecal Calprotectin and Progression of Crohn's Disease.

BACKGROUND & AIMS: Mucosal healing is associated with improved outcomes in patients with Crohn's disease (CD), but assessment typically requires ileocolonoscopy. Calprotectin can be measured in fecal samples to determine luminal disease activity in place of endoscopy-this measurement is an important component of the treat-to-target strategy. We investigated whether levels of fecal calprotectin are associated with subsequent CD progression. METHODS: We performed a retrospective study of 918 patients with CD (4218 patient-years of follow-up evaluation; median, 50.6 mo; interquartile range [IQR], 32.8-76.0 mo) managed at a tertiary medical center in Edinburgh, United Kingdom, from 2003 through 2015. Patients were included if they had 1 or more fecal calprotectin measurements made 3 months or more after their diagnosis. We collected clinical data and fecal calprotectin measurements and analyzed these data to identify factors associated with a composite outcome of progression in Montreal behavior, hospitalization, and resection. RESULTS: An increased level of fecal calprotectin at the index visit was associated with subsequent progression of CD, independent of symptoms or disease location. The median level of fecal calprotectin at the index visit was 432 µg/g (IQR, 1365-998 µg/g) in patients who reached the composite end point vs 180 µg/g (IQR, 50-665 µg/g) in patients who did not. In multivariable analysis, a cut-off value of 115 µg/g calprotectin identified patients who met the end point with a hazard ratio of 2.4 (95% CI, 1.8-3.1; P < .0001). CONCLUSIONS: In a retrospective analysis of patients with CD, we found that measurements of fecal calprotectin made during routine monitoring can identify patients at risk for disease progression, independent of symptoms or disease location. It is therefore important to screen asymptomatic patients for mucosal inflammation and pursue complete resolution of inflammation.

Mbd2 enables tumourigenesis within the intestine while preventing tumour-promoting inflammation.

Epigenetic regulation plays a key role in the link between inflammation and cancer. Here we examine Mbd2, which mediates epigenetic transcriptional silencing by binding to methylated DNA. In separate studies the Mbd2-/- mouse has been shown (1) to be resistant to intestinal tumourigenesis and (2) to have an enhanced inflammatory/immune response, observations that are inconsistent with the links between inflammation and cancer. To clarify its role in tumourigenesis and inflammation, we used constitutive and conditional models of Mbd2 deletion to explore its epithelial and non-epithelial roles in the intestine. Using a conditional model, we found that suppression of intestinal tumourigenesis is due primarily to the absence of Mbd2 within the epithelia. Next, we demonstrated, using the DSS colitis model, that non-epithelial roles of Mbd2 are key in preventing the transition from acute to tumour-promoting chronic inflammation. Combining models revealed that prior to inflammation the altered Mbd2-/- immune response plays a role in intestinal tumour suppression. However, following inflammation the intestine converts from tumour suppressive to tumour promoting. To summarise, in the intestine the normal function of Mbd2 is exploited by cancer cells to enable tumourigenesis, while in the immune system it plays a key role in preventing tumour-enabling inflammation. Which role is dominant depends on the inflammation status of the intestine. As environmental interactions within the intestine can alter DNA methylation patterns, we propose that Mbd2 plays a key role in determining whether these interactions are anti- or pro-tumourigenic and this makes it a useful new epigenetic model for inflammation-associated carcinogenesis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Surgical management of the diabetic foot: The current evidence.

The prevalence of diabetes mellitus and its associated complications, particularly diabetic foot pathologies, poses significant healthcare challenges and economic burdens globally. This review synthesises current evidence on the surgical management of the diabetic foot, focusing on the interplay between neuropathy, ischemia, and infection that commonly culminates in ulcers, infections, and, in severe cases, amputations. The escalating incidence of diabetes mellitus underscores the urgency for effective management strategies, as diabetic foot complications are a leading cause of hospital admissions among diabetic patients, significantly impacting morbidity and mortality rates. This review explores the pathophysiological mechanisms underlying diabetic foot complications and further examines diabetic foot ulcers, infections, and skeletal pathologies such as Charcot arthropathy, emphasising the critical role of early diagnosis, comprehensive management strategies, and interdisciplinary care in mitigating adverse outcomes. In addressing surgical interventions, this review evaluates conservative surgeries, amputations, and reconstructive procedures, highlighting the importance of tailored approaches based on individual patient profiles and the specific characteristics of foot pathologies. The integration of advanced diagnostic tools, novel surgical techniques, and postoperative care, including offloading and infection control, are discussed in the context of optimising healing and preserving limb function.

Validation of the ACE [Albumin, CRP, and Endoscopy] Index in Acute Colitis: Analysis of the CONSTRUCT dataset.

BACKGROUND AND AIMS: In 2020 we reported the ACE Index in acute colitis which used biochemical and endoscopic parameters to predict steroid non-response on admission in patients with acute ulcerative colitis [UC]. We aimed to validate the ACE Index in an independent cohort. METHODS: The validation cohort comprised patients screened as eligible for inclusion in the CONSTRUCT study, a prospective, randomized, placebo-controlled trial which compared the effectiveness of treatment with infliximab vs ciclosporin in patients admitted with acute UC. The CONSTRUCT cohort database was reviewed at The Edinburgh IBD Unit and the same biochemical and endoscopic variables and cut-off values as those in the derivation cohort were applied to the validation cohort. RESULTS: In total, 800 patients were identified; 62.5% [55/88] of patients with a maximum ACE Index of 3 did not respond to intravenous [IV] steroids (positive predictive value [PPV] 62.5%, negative predictive value [NPV] 79.8%). Furthermore, 79.8% [158/198] of patients with an ACE Index of 0 responded to IV steroids [PPV 79.8%, NPV 62.5%]. Receiver operator characteristic [ROC] curve analysis produced an area under the curve [AUC] of 0.663 [p < 0.001]. CONCLUSIONS: We have now reported and externally validated the ACE Index in acute colitis in a combined cohort of over 1000 patients from across the UK. The ACE Index may be used in conjunction with clinical judgement to help identify patients admitted with active UC who are at high risk of not responding to IV steroids. Further studies are required to improve objectivity and accuracy of assessment.

Long-term outcomes and predictors of vedolizumab persistence in ulcerative colitis.

Background: Long-term vedolizumab (VDZ) outcomes in real-world cohorts have been largely limited to 1-year follow-up, with few bio-naïve patients or objective markers of inflammation assessed. Objectives: We aimed to assess factors affecting VDZ persistence including clinical, biochemical and faecal biomarker remission at 1, 3 and 5 years. Design: We performed a retrospective, observational, cohort study. Methods: All adult inflammatory bowel disease (IBD) patients who had received VDZ induction for ulcerative colitis (UC)/IBD-unclassified (IBDU) were included. Baseline phenotype and follow-up data were collected via a review of electronic medical records. Results: We included 290 patients [UC n = 271 (93.4%), IBDU n = 19 (6.6%)] with a median time on VDZ of 27.6 months (interquartile range: 14.4-43.2). At the end of follow-up, a total of 157/290 (54.1%) patients remained on VDZ. The median time to discontinuation was 14.1 months (7.0-23.3). Previous exposure to ⩾1 advanced therapy, steroid use at baseline and disease extension (E3 and E2 versus E1) were independent predictors for worse VDZ persistence. Clinical remission (partial Mayo < 2) was 75.7% (171/226), 72.4% (157/217) and 70.2% (127/181) at years 1, 3 and 5, respectively. Steroid use during maintenance VDZ therapy occurred in 31.7% (92/290), hospitalization in 15.5% (45/290) and surgery in 3.4% (10/291). The rate of serious adverse events was 1.2 per 100 patient-years of follow-up. Conclusion: VDZ effectiveness appears enduring with favourable long-term safety profile. VDZ persistence was influenced by previous exposure to biologics/small molecules, disease distribution and steroid use at baseline in our study.

Vedolizumab long-term use in ulcerative colitis What was this study done? • Vedolizumab efficacy and safety in ulcerative colitis have been firmly established by existing evidence. • Long-term data from the GEMINI trial further corroborate the favourable safety profile over an extended duration but there is little data on long-term vedolizumab use over 1 year. What did the researches do? • We performed a retrospective, observational, cohort study. All adult IBD patients who ever received vedolizumab induction from November 2014 to December 2021 for ulcerative colitis/IBDU were included. What did the researchers find? • This real-world study demonstrates that vedolizumab persistence exceeds 80% at 1 year and remains nearly 50% at 5 years with no new safety signals. • Worse vedolizumab persistence is associated with prior exposure to biologics/small molecules, more extensive disease involvement and steroid use at vedolizumab initiation. What do the findings mean? • These findings have important implications for drug positioning and sequencing, as well as for optimizing outcomes when vedolizumab is utilized as first-line therapy. Furthermore, it also emphasizes the long-term safety profile.

Mechanism of association between BMI and dysfunction of the gastro-oesophageal barrier in patients with normal endoscopy.

INTRODUCTION: The association between body mass index (BMI) and gastro-oesophageal pressure gradient (GOPG) is incompletely understood. We examined the association between BMI and gastro-oesophageal (GO) barrier function and the effect of mechanically increasing intra-abdominal pressure on GO physiology. METHODS: (A) 103 dyspeptic patients with normal endoscopy underwent 24 h pH-metry and upper gastrointestinal manometry. Relationships between BMI and acid reflux, intragastric pressure (IGP), GOPG and lower oesophageal sphincter (LOS) pressure were calculated using bivariate correlations. (B) In 18 healthy volunteers, the effects of increasing IGP by abdominal belt on GO manometry were studied. RESULTS: (A) There was a linear correlation between BMI and oesophageal acid exposure in erect (R=0.35, p<0.001) and supine (R=0.40, p<0.001) positions. BMI was strongly associated with IGP (inspiration: R=0.66, p<0.001; expiration: R=0.78, p<0.001) and inspiratory GOPG (R=0.50, p<0.001). There were a positive correlation between BMI and inspiratory LOS pressure relative to atmospheric pressure (R=0.29, p=0.016) and a negative correlation with LOS pressure relative to IGP on expiration (R=-0.25, p=0.018). Logistic regression models using all significant manometric variables and relevant interactions revealed marked decline in the magnitude and significance of relationship between BMI and oesophageal acid exposure in supine (from OR 1.12 (95% CI 1.03 to 1.22), p=0.009, to 1.00 (0.86 to 1.17), p=0.999) and upright positions (from 1.11 (1.02 to 1.20), p=0.020, to 1.03 (0.89 to 1.18), p=0.717). (B) Application of the constricting abdominal belt produced similar manometric changes to those associated with increased BMI. However, the belt did not reproduce the reduced LOS pressure relative to IGP. CONCLUSION: The association between reflux and BMI may be largely explained by effects of increased intra-abdominal pressure. However, the reduced LOS pressure associated with BMI may be mediated by another mechanism or effects of chronic rather than acute elevation of intra-abdominal pressure.

Macrophages in intestinal homeostasis and inflammatory bowel disease.

Macrophages are essential for the maintenance of intestinal homeostasis, yet appear to be drivers of inflammation in the context of inflammatory bowel disease (IBD). How these peacekeepers become powerful aggressors in IBD is still unclear, but technological advances have revolutionized our understanding of many facets of their biology. In this Review, we discuss the progress made in understanding the heterogeneity of intestinal macrophages, the functions they perform in gut health and how the environment and origin can control the differentiation and longevity of these cells. We describe how these processes might change in the context of chronic inflammation and how aberrant macrophage behaviour contributes to IBD pathology, and discuss how therapeutic approaches might target dysregulated macrophages to dampen inflammation and promote mucosal healing. Finally, we set out key areas in the field of intestinal macrophage biology for which further investigation is warranted.

Multiple infliximab biosimilar switches appear to be safe and effective in a real-world inflammatory bowel disease cohort.

BACKGROUND: Switching from originator infliximab (IFX) to biosimilar IFX is effective and safe. However, data on multiple switching are scarce. The Edinburgh inflammatory bowel disease (IBD) unit has undertaken three switch programmes: (1) Remicade to CT-P13 (2016), (2) CT-P13 to SB2 (2020), and (3) SB2 to CT-P13 (2021). OBJECTIVE: The primary endpoint of this study was to assess CT-P13 persistence following switch from SB2. Secondary endpoints included persistence stratified by the number of biosimilar switches (single, double and triple), effectiveness and safety. METHODS: We performed a prospective, observational, cohort study. All adult IBD patients on IFX biosimilar SB2 underwent an elective switch to CT-P13. Patients were reviewed in a virtual biologic clinic with protocol driven collection of clinical disease activity, C-reactive protein (CRP), faecal calprotectin (FC), IFX trough/antibody levels, and drug survival. RESULTS: 297 patients (CD n = 196 [66%], ulcerative colitis/inflammatory bowel disease unclassified n = 101, [34%]) were switched (followed-up: 7.5 months [6.8-8.1]). This was the third, second and first IFX switch for 67/297 (22.5%), 138/297 (46.5%) and 92/297 (31%) of the cohort respectively. 90.6% of patients remained on IFX during follow-up. The number of switches was not independently associated with IFX persistence after adjusting for confounders. Clinical (p = 0.77), biochemical (CRP ≤5 mg/ml; p = 0.75) and faecal biomarker (FC<250 µg/g; p = 0.63) remission were comparable at baseline, week 12 and week 24. CONCLUSION: Multiple successive switches from IFX originator to biosimilars are effective and safe in patients with IBD, irrespective of the number of IFX switches.

Real-World Cohort Study on the Effectiveness and Safety of Filgotinib Use in Ulcerative Colitis.

BACKGROUND: Filgotinib is a small molecule with preferential inhibition of Janus kinase type 1, approved for the treatment of ulcerative colitis in Scotland in May 2022. We present the first real world experience on its use in clinical practice. METHODS: In this retrospective, observational, cohort study we assessed patients with active ulcerative colitis who received filgotinib in NHS Lothian, Scotland. Baseline demographic, phenotype and follow-up data were collected via review of electronic medical records. RESULTS: We included 91 patients with median treatment duration of 39 weeks (IQR 23-49). Among the cohort, 67% (61/91) were biologic and small molecule naïve, whilst 20.9% (19/91) had failed one and 12.1% (11/91) ≥2 classes of advanced therapy. Of the biologic and small molecule naïve patients, 18% (11/61) were also thiopurine naïve. Clinical remission (partial Mayo score <2) was achieved in 71.9% (41/57) and 76.4% (42/55) of patients at weeks 12 and 24 respectively. Biochemical remission (CRP≤5mg/L) was achieved in 87.3% (62/71) at week 12 and 88.9% (40/45) at week 24. Faecal biomarker (calprotectin <250µg/g) remission was achieved in 82.8% (48/58) at week 12 and 79.5% (35/44) at week 24.At the end of follow-up, median 42 weeks (IQR 27-50), 82.4% (75/91) of patients remained on filgotinib. Severe adverse events leading to drug discontinuation occurred in 2.2% (2/91) and there were 8.8% (8/91) moderate adverse events that required temporary discontinuation. CONCLUSION: These are the first reported data on the real-world efficacy and safety of filgotinib in ulcerative colitis. Our findings demonstrate that filgotinib is an effective and low risk treatment option for these patients.

Rates, predictive factors and effectiveness of ustekinumab intensification to 4- or 6-weekly intervals in Crohn's disease.

BACKGROUND: The UNITI trial reports efficacy of ustekinumab (UST) dose intensification in Crohn's disease (CD) from 12- to 8-weekly, but not 4-weekly. We aimed 1) to assess the cumulative incidence of UST dose intensification to 4- or 6-weekly, 2) to identify factors associated with dose intensification, and 3) to assess the effectiveness of this strategy. METHODS: We performed a retrospective, observational cohort study in NHS Lothian including all UST treated CD patients (2015-2020). RESULTS: 163 CD patients were treated with UST (median follow-up: 20.3 months [13.4-38.4]), of whom 55 (33.7%) underwent dose intensification to 4-weekly (n = 50, 30.7%) or 6-weekly (n = 5, 3.1%). After 1 year 29.9% were dose intensified. Prior exposure to both anti-TNF and vedolizumab (HR 9.5; 1.3-70.9), and concomitant steroid use at UST start (HR 1.8; 1.0-3.1) were associated with dose intensification. Following dose intensification, 62.6% patients (29/55) remained on UST beyond 1 year. Corticosteroid-free clinical remission was achieved in 27% at week 16 and 29.6% at last follow-up. CONCLUSION: One third of CD patients treated with UST underwent dose intensification to a 4- or 6-weekly interval within the first year. Patients who failed both anti-TNF and vedolizumab, or required steroids at initiation were more likely to dose intensify.

CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury.

The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages are the predominant immune cell in the salivary glands and are attractive therapeutic targets due to their unrivaled capacity to drive tissue repair. Yet, the nature and role of macrophages in salivary gland homeostasis and how they may contribute to tissue repair after injury are not well understood. Here, we show that at least two phenotypically and transcriptionally distinct CX3CR1+ macrophage populations are present in the adult salivary gland, which occupy anatomically distinct niches. CD11c+CD206-CD163- macrophages typically associate with gland epithelium, whereas CD11c-CD206+CD163+ macrophages associate with blood vessels and nerves. Using a suite of complementary fate mapping systems, we show that there are highly dynamic changes in the ontogeny and composition of salivary gland macrophages with age. Using an in vivo model of radiation-induced salivary gland injury combined with genetic or antibody-mediated depletion of macrophages, we demonstrate an essential role for macrophages in clearance of cells with DNA damage. Furthermore, we show that epithelial-associated macrophages are indispensable for effective tissue repair and gland function after radiation-induced injury, with their depletion resulting in reduced saliva production. Our data, therefore, provide a strong case for exploring the therapeutic potential of manipulating macrophages to promote tissue repair and thus minimize salivary gland dysfunction after radiotherapy.

BMI is superior to symptoms in predicting response to proton pump inhibitor: randomised trial in patients with upper gastrointestinal symptoms and normal endoscopy.

OBJECTIVES: In most patients undergoing endoscopy for upper gastrointestinal (GI) symptoms in the Western world, no macroscopic abnormality or evidence of Helicobacter pylori infection is identified. Following this negative investigation, proton pump inhibitor (PPI) therapy is usually prescribed. The aim of this study was to assess the value of such treatment compared with placebo and to identify predictors of response. DESIGN: Prospective parallel randomised study. SETTING: Dyspepsia Research Clinic. PARTICIPANT: 105 patients (49 men, median age 44 years, IQR 22) with normal endoscopy and H pylori negative with ongoing upper GI symptoms following 2-week run-in period. Intervention Full demographic symptom severity and characteristics were assessed and 24 h oesophageal pH metry and oesophageal manometry were performed prior to randomisation to 2 weeks of treatment with lansoprazole 30 mg/day or placebo (2:1), with reassessment of symptom severity during the second week of treatment. PRIMARY OUTCOME: 50% reduction in Glasgow Dyspepsia Severity Score (GDSS). RESULTS: According to intention to treat analysis, the response was 35.7% for the active group and 5.7% for the placebo group (p < 0001). The only non-invasive independent predictor of response to PPI in multivariable analysis was the patient's body mass index (BMI) (p = 0.003). The association of BMI with response to PPI was apparent across the full range of quartiles (p values for trend=0.01). BMI had a similar predictive value to either 24 h oesophageal pH metry or manometry. Predominant symptom and symptom subgroups were unhelpful in predicting the response to PPI. Including all pretreatment assessments, only BMI (p < 0.05) and lower oesophageal sphincter pressure (p < 0.05) were independent predictors of response. CONCLUSION: The response to PPI therapy is likely to be related to underlying acid reflux. The strong predictive value of BMI is probably due to its association with underlying reflux disease and the fact that it is a more objective and reproducible measure than symptom characteristics. It is recommended that BMI should be measured in patients with upper GI symptoms. Trial Registration Number ISRCTN 32863375.

Polychlorinated biphenyl (PCB) concentrations and profiles in marine mammals from the North Atlantic Ocean.

Polychlorinated biphenyls (PCBs) can provide crucial information into the bioaccumulation and biomagnification of POPs in marine mammals. Muscle tissue samples were obtained for detailed PCB congener specific analysis of all 209 PCBs in 11 species of marine mammals stranded across the coast of the UK between 2010 and 2013. At least 145 PCB congeners were found in each individual. The highest concentrations of PCBs were recorded in a killer whale (318 mg/kg lipid) and the highest toxic equivalent in a Risso's dolphin (1687 pg/g TEQ2005 wet). Concentrations of PCBs in the majority of samples exceeded toxic thresholds (9 mg/kg lipid) for marine mammals, highlighting the health risk they face from PCB exposure. Many PCB profiles did not fit typical 'Aroclor' signatures, but instead indicated patterns of congeners that are resistant to biotransformation and elimination. However, this study identified a novel PCB signature in a sei whale that has not yet been previously observed in marine mammals. The whale had a PCB profile that included lighter and inadvertent PCB congeners such as PCB 11, suggesting that the main source of exposure was through atmospheric deposition, rather than terrestrial discharges. Seven subsamples were chosen for chiral analysis of PCB 95, 136 and 149. The enantiomer fractions (EFs) of C-PCBs 95 and 149 were non racemic suggesting there may be enantiomer selective metabolism in marine mammals. Although there has been a shift in the literature towards emerging pollutants, this study acts as a stark reminder that PCBs continue to pose a significant risk to wildlife.

Incidence of collagenous colitis in NHS Lothian: a population-based study.

Objective: Increases in incidence of collagenous colitis (CC) have been documented across Europe; however, previous data from NHS Lothian (1998-2003) demonstrated this to be a low-prevalence area. We aimed to assess incidence of CC in NHS Lothian over time by comparing a more recent cohort (2013-2018) with our existing cohort. Methods: All histologically confirmed diagnoses of CC between 2013 and 2018 were obtained from the NHS Lothian colorectal pathology department (Western General Hospital, Edinburgh). Case record review was performed to obtain relevant demographic and clinical data. Data were also collected regarding the availability of colonoscopy in NHS Lothian. Results: 224 cases of CC were diagnosed between 2013 and 2018, compared with 25 between 1998 and 2003. Mean annual incidence rose from 0.5/100 000 population to 4.3/100 000 population. Incidence in females ≥60 years old rose from 2.3/100 000 population to 22.4/100 000 population (p<0.001). The total number of colonoscopies performed increased by 179.1% from 15 262 (1998-2003) to 42 600 (2013-2018), with the number of CC cases per 1000 colonoscopies performed rising from 1.7 to 5.3 (p<0.001). Conclusion: We describe the increasing incidence of CC in Southeast Scotland, with temporal trends comparable to other European countries. The increase is particularly marked in older females and parallels increasing numbers of colonoscopies being performed.