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.

Do Thiopurines Reduce the Risk of Surgery in Elderly Onset Inflammatory Bowel Disease? A 20-Year National Population-Based Cohort Study.

BACKGROUND: Evidence that thiopurines impact on the risk of surgery in elderly onset inflammatory bowel disease (EO-IBD) is lacking. We aimed to compare the rates of surgery in EO-IBD (>60 years at diagnosis) with adult-onset IBD (18-59 yrs), and examine the impact of thiopurines on surgical risk in EO-IBD. METHODS: Using a U.K. database between 1990 and 2010, we compared rates of surgery between adult-onset IBD and EO-IBD using survival analysis. Ulcerative colitis (UC) and Crohn's disease (CD) were analyzed separately. Cox proportional hazard modeling was used to determine the adjusted relative risk of surgery. We further assessed the impact of duration of thiopurine treatment on risk of surgery. RESULTS: We identified 2758 of 9515 patients with UC and 1349 of 6490 patients with CD, with EO-IBD. Cumulative 1, 5, and 10 years risk of colectomy was similar in EO-UC (2.2, 4.5, and 5.8%, respectively) and AO-UC (2.2, 5.0, and 7.3%, respectively; P = 0.15). Cumulative 1, 5, and 10 years risk of first intestinal surgery was lower in EO-CD (9.5, 14.6, and 17.9%, respectively) than AO-CD (12.2, 19.0, and 24.4%, respectively; P < 0.001). Early steroid use, steroid dependency, and thiopurine use was associated with higher risk of colectomy in EO-UC. Among EO-UC receiving thiopurines for >12 months, there was a 70% reduction in risk of colectomy (hazard ratio. 0.30; 95% confidence interval, 0.15-0.58). Thiopurines were not associated with a reduced risk of surgery in EO-CD. CONCLUSIONS: Risk of colectomy in EO-UC does not differ from AO-UC, but the risk of surgery in EO-CD is significantly lower than in AO-CD. Sustained thiopurine use of 12 months or more duration in EO-UC reduces the risk colectomy, but does not impact on the risk of surgery in EO-CD. These findings are important given the greater risk of thiopurine-associated lymphoma in the elderly.

Inflammatory bowel disease detection and monitoring by measuring biomarkers in non-invasively collected colorectal mucus.

BACKGROUND AND AIM: Non-invasive detection and monitoring of inflammatory bowel disease (IBD) is an important clinical challenge. Stool calprotectin is the most popular among available options, but the necessity of stool collection limits its acceptability. This study aimed to evaluate biomarker measurement in non-invasively collected colorectal mucus as a new tool for IBD detection and activity monitoring. METHODS: Calprotectin, eosinophil-derived neurotoxin (EDN), and protein S100A12 were measured in colorectal mucus self-collected following defecation by 58 patients with IBD (before therapy), 50 patients with irritable bowel syndrome, and 33 healthy volunteers. Patients with IBD also collected samples at days 10, 20, and 30 of treatment for disease activity monitoring. RESULTS: Protein biomarker levels were significantly (P < 0.001) higher in IBD patients than in irritable bowel syndrome and control groups. Calprotectin and EDN effectively detected IBD with a respective sensitivity and specificity of 0.76 and 0.92 for calprotectin and 0.83 and 0.94 for EDN. S100A12 was less sensitive. Calprotectin and EDN results were combined in a new test (CALEDN) that had a sensitivity of 0.91 and a specificity of 0.89. Repeated biomarker measurement during IBD treatment demonstrated a steady decline of calprotectin and EDN levels as well as CALEDN values in patients responding to applied therapy and lack of this pattern in non-responders. CONCLUSIONS: Measuring calprotectin and EDN in non-invasively collected colorectal mucus presents a simple and efficient method for IBD detection and monitoring. Excellent performance of EDN for this purpose is reported for the first time. Combining calprotectin and EDN in one test improves IBD detection sensitivity.

Emerging trends and risk factors for perianal surgery in Crohn's disease: a 20-year national population-based cohort study.

BACKGROUND: Little is known about the rates of perianal surgery (PAS) in Crohn's disease (CD). Our aim was to determine trends in PAS, the timing of surgery relative to the diagnosis of CD and to identify subgroups at risk of PAS. MATERIALS AND METHODS: We identified 9391 incident cases of CD between 1989 and 2009. We defined three eras: era 1 (1989-1995), era 2 (1996-2002) and era 3 (2003-2009), and determined trends in procedure type and the time to first PAS relative to the date of diagnosis. We used Kaplan-Meier analysis to calculate the rate of first PAS and performed Cox regression to determine subgroups at risk of PAS. RESULTS: Among the 9391 incident cases of CD, 405 (4.3%) underwent PAS. The overall rate of PAS was 5.5% [95% confidence interval (CI): 4.9-6.2%] 10 years after diagnosis. 34% (n=137) of all patients undergoing PAS had surgery in the 5 years before CD diagnosis. Abscess drainage increased from 34 to 58%, whereas proctectomy decreased from 16 to 6% between eras 1 and 3, respectively. Men [hazard rate (HR) 1.51, 95% CI: 1.24-1.84], those aged 17-40 years (HR 1.69, 95% CI: 1.09-2.02 vs. those aged >40 years) and those with a history of previous intestinal resection (HR 28.5, 95% CI: 22.2-36.5) were more likely to have PAS. CONCLUSION: Around one-third of patients have a PAS in the 5 years preceding their diagnosis of CD. Surgical practice has changed over 20 years, with a decrease in proctectomy and a concurrent increase in abscess drainage that is likely to reflect improvements in therapeutic practice.

Assessment of cytology and mucin 2 in colorectal mucus collected from patients with inflammatory bowel disease: Results of a pilot trial.

BACKGROUND AND AIM: Non-invasive diagnosis of colorectal disease remains problematic, fecal biomarkers presenting the only current option. Colorectal mucus is the diagnostically informative element of stool samples, but its separation from stool is difficult. We aimed to: (i) test a novel method of non-invasive colorectal mucus sampling in a pilot clinical trial; (ii) evaluate sampling method acceptance by study participants; (iii) characterize the collected material cytologically; and (iv) assess feasibility of quantitative protein analysis in the samples. METHODS: A total of 141 patients with IBD (58), IBS (50), and healthy controls (33) participated in the study. Samples rich in colorectal mucus were self-collected by swabbing the anal area immediately following defecation. Collected samples were examined cytologically and subjected to quantitative analysis for total protein and mucin 2 (MUC2). RESULTS: The novel sampling technique was assessed as "good" or "adequate" by 96% of study participants. A total of 55% of the collected samples were free of fecal contamination. Cytology showed large numbers of well preserved inflammatory cells in IBD cases. Total protein values varied in all groups, being affected by fecal contamination. MUC2 levels were similar among all IBD-free individuals (control and IBS groups) and elevated in IBD patients (p < 0.001). MUC2 measurement applied as a test for IBD detection provided sensitivity = 72.4% and specificity = 86.7%. CONCLUSIONS: A novel non-invasive method for collecting human colorectal mucus has been successfully tested. The method was very well accepted by trial participants. The results have proven high quality of collected samples for both cytological investigation and diagnostic biomarker analysis.

Colorectal mucus non-invasively collected from patients with inflammatory bowel disease and its suitability for diagnostic cytology.

Colorectal mucus is a key component of the protective gut barrier which is altered in inflammatory bowel disease (IBD). We aimed to cytologically characterize colorectal mucus non-invasively collected from IBD patients using our new sampling technique. Colorectal mucus was self-collected by 58 IBD patients comprising 31 ulcerative colitis (UC) and 27 Crohn's disease (CD) cases. The samples were examined cytologically, and immunocytochemically. Large numbers of well-preserved granulocytes were typically detected (neutrophils undergoing degradation were observed as well). Plasma cells and erythrophagocytosis were present in 18.2% and 29.1% of cases, respectively, predominantly in patients with UC and distal CD. Immunocytochemical visualization of calprotectin in neutrophils, eosinophil-derived neurotoxin in eosinophils and tumour necrosis factor-α in macrophages was also achieved. Correct cytological diagnosis was made in 61.8% of analysed IBD cases. Our new method of colorectal mucus sampling provides highly informative material for cytology. Findings of the presence of plasmocytes and erythrophagocytosis in colorectal mucus are unique and may reflect previously unknown mechanisms of IBD pathogenesis. Immunocytochemical detection of inflammation biomarkers demonstrates the suitability of this material for biomarker quantification. These promising results suggest a potential role for colorectal mucus cytology in the non-invasive diagnosis of IBD.

Differences in intestinal metaplasia in Barrett's esophagus patients in an ethnically diverse south London population.

Barrett's esophagus (BE) is the replacement of any portion of the normal distal squamous epithelial mucosa by metaplastic columnar epithelium and is the only known precursor for esophageal adenocarcinoma. We undertook a study to identify ethnic differences for the presence of intestinal metaplasia (IM) in BE in patients in an ethnically diverse south London population. Retrospective analysis was done using the endoscopy database of St George's Hospital NHS Trust, which serves a large ethnically diverse London population. Gastroscopy records between 2009 and 2012 were retrieved, and patients with an endoscopic diagnosis of BE were identified. Patients of Indian subcontinent Asian origin (ISCA) were further identified. The presence of IM was retrieved from hospital pathology databases and was the primary outcome measured. Multivariate logistic regression analysis was performed to determine the odds of having IM by ethnic origin. ISCAs were 70% less likely to have IM compared to non-ISCAs (OR 0.32, 95% CI: 0.16-0.61, p = 0.001). This is the first study to identify differences in histological findings in ISCAs with BE living in the UK. Our findings may be useful for the future risk stratification of BE patients. Identification of environmental factors responsible for this difference would be of great therapeutic value.

Impact of timing and duration of thiopurine treatment on first perianal surgery in Crohn's disease: UK population-based study (1995-2009).

BACKGROUND: The impact of thiopurine (TP) use on perianal surgery is uncertain. Our aim was to determine trends in perianal surgery and the impact of timing and duration of TPs on the risk of first perianal surgery. METHODS: We identified a population-based cohort of incident cases of Crohn's disease between 1995 and 2009. We used Kaplan-Meier analysis to determine trends in TP usage and first perianal surgery by era of diagnosis: era 1 (1995-2002) and era 2 (2003-2009). We quantified the impact of duration and timing of TPs on the risk of perianal surgery using a Cox regression model. RESULTS: We identified a cohort of 5235 incident cases of Crohn's disease. The 5-year cumulative probability of first perianal surgery decreased from 2.7% to 1.7% between era 1 and era 2, respectively (P = 0.03). TP use for greater than 18 months was associated with a 40% risk reduction for first perianal surgery (hazard ratio: 0.60, 95% confidence interval: 0.39-0.95) and 49% if TPs were used for 2 years or more (hazard ratio: 0.51, 95% confidence interval: 0.32-0.99). There was no demonstrable additional benefit from early TP use within the first year after diagnosis (hazard ratio: 0.85, 95% confidence interval: 0.52-1.40, P = 0.53). CONCLUSIONS: Over the past 15 years, TP use has increased by 50%, whereas perianal surgery rates have decreased by 37% among UK population with Crohn's disease. Sustained use for 18 months was associated with a reduced risk of perianal surgery by almost a half in the first 5 years after diagnosis.

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 impact of thiopurines on surgical outcomes in inflammatory bowel disease: do they make a difference?

Ulcerative colitis and Crohn's disease together are known as inflammatory bowel disease (IBD). Surgery is considered for more severe disease and is a dreaded consequence for patients. Thiopurines have proven efficacy in the induction and maintenance of remission of IBD, but the long-term need for surgery remains uncertain with conflicting results from the available studies. The timing and duration of thiopurines also appears to play a pivotal role in the management of these conditions and may also affect the need for surgery. Data from Denmark, Canada, Hungary and the UK appear to suggest a reduction in surgery rates prior to the introduction of anti-tumor necrosis factor (TNF) therapy. The authors aim to review the more recent literature evaluating the surgery rates in IBD and changes in disease trends over time. We ask whether increasing thiopurine prescribing has had an effect on the surgery rates in the era of biologic therapy and whether more aggressive treatment approaches have altered the natural history of IBD.

Factors associated with vitamin D deficiency in a multicultural inflammatory bowel disease cohort.

OBJECTIVE: The aim of this study was to determine the prevalence of vitamin D deficiency in a multicultural inflammatory bowel disease (IBD) cohort and determine predictors of deficiency including ethnicity. DESIGN: Patients with IBD were recruited into a dedicated database over a 6-month period and evaluated retrospectively. SETTING: Department of Gastroenterology, St George's University Hospital, London, UK. OUTCOMES MEASURED: Clinical data including demographics, ethnic group, disease phenotype by the Montreal classification, vitamin D level and season tested were recorded from clinical and electronic medical records. Vitamin D levels were classified as normal (≥50 nmol/l) and deficient (<50 nmol/l). RESULTS: 168 patients had a vitamin D level measured subsequent to diagnosis. There was no significant difference in the median vitamin D level between patients with Crohn's disease (CD) and ulcerative colitis (UC) (39 nmol/l (IQR 23-56) vs 28 nmol/l (IQR 17-51), p=0.35). Overall the median vitamin D level was significantly lower in non-Caucasians (Asian and Black) versus Caucasians (28 nmol/l (IQR 17-41) vs 41 nmol/l (IQR 25-63), p<0.0001). Multiple regression analysis revealed IBD related surgery (OR 2.9) and ethnicity (OR 6.0 non-Caucasian vs Caucasian) in CD and ethnicity (OR 5.0 non-Caucasian vs Caucasian) in UC were independently associated with vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency is common in IBD patients; therefore, we suggest monitoring of vitamin D levels and correction with supplements especially in non-Caucasians and those with a history of IBD related surgery.

The influence of swelling and matrix degradation on the microstructural integrity of tendon.

Tendon is multi-level fibre composite material, responsible for the transmission of forces from muscles to the skeleton. It is composed of a hierarchical arrangement of collagenous units surrounded by a proteoglycan-rich matrix, arranged to support strain transfer, and thus contribute to the mechanical behaviour of tendon. This study examines the effect of swelling and enzymatic degradation on structural integrity at different levels of the tendon hierarchy. Biochemical and microstructural analysis are used to examine the effects of incubation on the composition and swelling of the matrix, prior to a mechanical characterisation of sample integrity. Results indicated significant swelling of tendon fibrils and interfibrillar matrix after incubation in phosphate buffered saline, leading to a reduction in ultimate tensile load, with failure initiated between fibrils and sub-fibrils. In contrast, incubation with the enzyme chondroitinase ABC resulted in a total removal of glycosaminoglycan from the samples, and a subsequent reduction in the extent of swelling. These fascicles also demonstrated an increase in failure loads, with failure predominating between fibres. The findings from this work confirm the importance of the non-collagenous matrix components in controlling strain transfer within tendon structures. It also highlights the necessity to maintain samples within a suitable and controlled environment prior to testing.

The influence of noncollagenous matrix components on the micromechanical environment of tendon fascicles.

Tendon is composed of type I collagen fibers, interspersed with proteoglycan matrix and cells. Glycosaminoglycans may play a role in maintaining the structural integrity of tendon, preventing excessive shearing between collagen components. This study tests the hypothesis that tendon extension mechanisms can be altered by modifying the composition of noncollagenous matrix. Tendon explants were treated with phosphate buffered saline (PBS) or PBS + 0.5 U ml(-1) chondroitinase ABC. Structural changes were examined using TEM and biochemical analysis, while strain response was examined using confocal microscopy and gross mechanical characterization. Chondroitinase ABC removed 90% of glycosaminoglycans from the matrix. Results demonstrated significant swelling of fibrils and surrounding matrix when incubated in either solution. In response to applied strain, PBS incubated samples demonstrated significantly less sliding between adjacent fibers than nonincubated, and a 33% reduction in maximum force. By contrast, fascicles incubated in chondroitinase ABC demonstrated a similar strain response to nonincubated. Data indicate that collagen-proteoglycan binding characteristics can be influenced by incubation and this, in turn, can influence the preferred extension mechanisms adopted by fascicles. This highlights the importance of maintaining fascicles within their natural environment to prevent structural or mechanical changes prior to subsequent analysis.