Prevalence and duration of gastrointestinal symptoms before diagnosis of Inflammatory Bowel Disease and predictors of timely specialist review: a population-based study.

BACKGROUND AND AIMS: Lack of timely referral and significant waits for specialist review amongst individuals with unresolved gastrointestinal (GI) symptoms can result in delayed diagnosis of Inflammatory Bowel Disease (IBD). AIMS: To determine the frequency and duration of GI symptoms and predictors of timely specialist review before the diagnosis of both Crohn's Disease (CD) and ulcerative colitis (UC). METHODS: Case-control study of IBD matched 1:4 for age and sex to controls without IBD using the Clinical Practice Research Datalink from 1998-2016. RESULTS: We identified 19,555 cases of IBD, and 78,114 controls. 1 in 4 cases of IBD reported gastrointestinal symptoms to their primary care physician more than 6 months before receiving a diagnosis. There is a significant excess prevalence of GI symptoms in each of the 10 years before IBD diagnosis. GI symptoms were reported by 9.6% and 10.4% at 5 years before CD and UC diagnosis respectively compared to 5.8% of controls. Amongst patients later diagnosed with IBD, <50% received specialist review within 18 months from presenting with chronic GI symptoms. Patients with a previous diagnosis of irritable bowel syndrome or depression were less likely to receive timely specialist review (IBS: HR=0.77, 95%CI 0.60-0.99, depression: HR=0.77, 95%CI 0.60-0.98). CONCLUSIONS: There is an excess of GI symptoms 5 years before diagnosis of IBD compared to the background population which are likely attributable to undiagnosed disease. Previous diagnoses of IBS and depression are associated with delays in specialist review. Enhanced pathways are needed to accelerate specialist referral and timely IBD diagnosis.

Systematic review with meta-analysis: the impact of a depressive state on disease course in adult inflammatory bowel disease.

BACKGROUND: Despite a higher prevalence of psychosocial morbidity in Inflammatory Bowel Disease (IBD), the association between depressive state and disease course in IBD is poorly understood. AIM: To investigate the impact of depressive state on disease course in IBD. METHODS: We conducted a systematic review in MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and PsychINFO for prospective studies evaluating the impact of baseline depressive state on subsequent disease course in adult IBD. RESULTS: Eleven studies matched our entry criteria, representing 3194 patients with IBD. Three reported on patients with ulcerative colitis (UC), four included patients with Crohn's disease (CD) exclusively, and four studies included both UC and CD. Five studies reported an association between depressive state and disease course. None of the UC-specific studies found any association. In three of four CD-specific studies, a relationship between depressive state and worsening disease course was found. In four of five studies including patients in remission at baseline, no association between depressive state and disease course was found. Pooled analysis of IBD studies with patients in clinical remission at baseline identified no association between depressive state and disease course (HR 1.04, 95%CI: 0.97-1.12). CONCLUSION: There is limited evidence to support an association between depressive state and subsequent deterioration in disease course in IBD, but what data that exist are more supportive of an association with CD than UC. Baseline disease activity may be an important factor in this relationship. Further studies are needed to understand the relationship between mental health and outcomes in IBD.

Steroid dependency and trends in prescribing for inflammatory bowel disease - a 20-year national population-based study.

BACKGROUND: It is unclear whether adherence to prescribing standards has been achieved in inflammatory bowel disease (IBD). AIM: To determine how prescribing of 5-aminosalicylates (5-ASAs), steroids and thiopurines has changed in response to emerging evidence. METHODS: We examined trends in oral and topical therapies in 23 509 incident IBD cases (6997 with Crohn's disease and 16 512 with ulcerative colitis) using a nationally representative sample between 1990 and 2010. We created five eras according to the year of diagnosis: era 1 (1990-1993), era 2 (1994-1997), era 3 (1998-2001), era 4 (2002-2005) and era 5 (2006-2010). We calculated the proportion of patients treated with prolonged 5-ASAs (>12 months) and steroid dependency, defined as prolonged steroids (>3 months) or recurrent (restarting within 3 months) steroid exposure. We calculated the cumulative probability of receiving each medication using survival analysis. RESULTS: Half of the Crohn's disease patients were prescribed prolonged oral 5-ASAs during the study, although this decreased between era 3 and 5 from 61.8% to 56.4% (P = 0.002). Thiopurine use increased from 14.0% to 47.1% (P < 0.001) between era 1 and 5. This coincided with a decrease in steroid dependency from 36.5% to 26.8% (P < 0.001) between era 1 and 2 and era 4 and 5 respectively. In ulcerative colitis, 49% of patients were maintained on prolonged oral 5-ASAs. Despite increasing thiopurine use, repeated steroid exposure increased from 15.3% to 17.8% (P = 0.02) between era 1 and 2 and era 4 and 5 respectively. CONCLUSIONS: Prescribing in clinical practice insufficiently mirrors the evidence base. Physicians should direct management towards reducing steroid dependency and optimising 5-ASA use in patients with IBD.

Impact of early thiopurines on surgery in 2770 children and young people diagnosed with inflammatory bowel disease: a national population-based study.

BACKGROUND: The role of early thiopurine treatment in inflammatory bowel disease (IBD) is unproven. AIM: To quantify the impact of timing and duration of thiopurines on the risk of first surgery in children and young people with IBD using a population-based cohort. METHODS: We constructed an incident cohort of children and young people aged <25 years, diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) from 1990 to 2009. We used Cox proportional hazards modelling to determine the impact of early thiopurine use, commenced within a year of diagnosis on risk of first surgery. RESULTS: We identified 1595 and 1175 incident cases of CD and UC respectively with a mean length of follow-up of 4.3 years/person. There were 216 (13.5%) and 73 (6.2%) surgeries for CD and UC patients between 1990 and 2009 respectively. In CD among thiopurine users, the absolute risk of surgery at 5 years for early thiopurine use vs. late was 15.3% (95% CI: 10.5-22.1) vs. 22.1% (95% CI: 18.1-26.9) respectively. After adjustment, the early use of thiopurines was associated with a reduction in risk of first surgery of 39% (HR 0.61, 95% CI: 0.41-0.91) over the 20-year study period. In UC, early thiopurine use offered no additional benefit. CONCLUSIONS: In Crohn's disease, early treatment with thiopurines in children and young people is associated with an appreciable reduction in the risk of surgery, but early treatment does not reduce surgical risk in UC.

The impact of timing and duration of thiopurine treatment on colectomy in ulcerative colitis: a national population-based study of incident cases between 1989-2009.

BACKGROUND: The role of thiopurines in altering the risk of colectomy in ulcerative colitis (UC) remains unclear. AIMS: To examine predictors of colectomy in UC and determine the impact of thiopurines on the risk of colectomy. METHODS: We constructed a population-based cohort of incident cases of UC in the United Kingdom between 1989 and 2009. We determined trends in thiopurine usage and colectomy for three defined cohorts: era 1 (1989-1995), era 2 (1996-2002), era 3 (2003-2009). We used Cox regression to determine predictors of colectomy and quantified the impact of duration and timing of thiopurine use on the risk of colectomy. RESULTS: We identified 8673 incident cases of UC. 5-year colectomy rates increased from 4.2%, 5.1% to 6.9% (P = 0.001) for era 1, era 2 and era 3, respectively, despite increasing thiopurine use. This was not significant after adjustment for predictors of colectomy (P = 0.06). There was a higher risk of colectomy in men (HR 1.44, 95% CI: 1.19-1.73), those diagnosed at an early age (HR 1.35, 95% CI: 1.04-1.75; 16-24 vs. 25-64) and early steroid users (HR 1.94, 95% CI: 1.59-2.37). 5-ASA users were less likely to require a colectomy (HR 0.35, 95% CI: 0.28-0.44). Amongst thiopurine users, those treated for greater than 12 months had a 71% reduction in risk of colectomy (HR 0.29, 95% CI: 0.21-0.40). Early thiopurines offered no additional benefit. CONCLUSIONS: Thiopurine exposure for greater than 12 months reduces the likelihood of colectomy by 71%. Young men and those requiring steroids within 3 months of diagnosis are at greatest risk of colectomy, and most likely to benefit from sustained thiopurine use.

Temporal trends in imaging and associated radiation exposure in inflammatory bowel disease.

OBJECTIVES: Increasing use of diagnostic imaging in inflammatory bowel disease (IBD) has led to concerns about the malignant potential of ionising radiation in a cohort that have an increased lifetime risk of gastrointestinal malignancy. The aim was to quantify radiation exposure in IBD patients referred from primary care, determine predictors of high exposure and evaluate temporal trends in diagnostic imaging over a 20-year period. METHODS: This was a retrospective cohort study whereby IBD patients were recruited from the outpatient clinic and evaluated retrospectively. The total cumulative effective dose (CED) received from tests was calculated for each subject. Cox regression was performed to assess factors associated with potentially harmful levels of ionising radiation defined as total CED > 50 milli-sieverts (mSv; equivalent to five CT abdomen scans). RESULTS: The cohort included 415 patients. Median total CED was 7.2 mSv (IQR: 3.0-22.7) in Crohn's disease and 2.8 mSv (IQR: 0.8-8.9) in ulcerative colitis patients, respectively. A total of 32 patients (8%) received a CED > 50 mSv. A history of IBD-related surgery was associated with high exposure (HR 7.7). During the study period, usage of abdominal CT increased by 310%. CONCLUSION: Approximately 1 in 13 patients in the study cohort were exposed to potentially harmful levels of ionising radiation. Strategies to minimise exposure to diagnostic medical radiation in IBD patients are required.

Genital lymphoedema due to ano-genital granulomatosis.

A 21-year-old man presented to genitourinary (GU) medicine physicians with (initially) painful penile and scrotal swelling. A diagnosis of ano-genital granulomatosis was confirmed on histological analysis of penile skin. Enquiring about systemic symptoms resulted in the additional diagnosis of gastrointestinal Crohn's disease. The patient is now receiving immunosuppressive therapy to treat both conditions.

Assessment of administrative data for evaluating the shifting acquisition of Clostridium difficile infection in England.

BACKGROUND: Little is known about the acquisition of Clostridium difficile infection (CDI) and whether it represents hospital- or community-acquired infection. AIM: To test the feasibility and value of using national hospital admissions data from Hospital Episode Statistics to examine trends in CDI in England. METHODS: Hospital Episode Statistics from the period 1997/98 to 2009/10 were used. Time trends were analysed using two different denominators of hospital activity: total admissions and total bed-days. We explored the impact of sociodemographic factors, comorbidity and healthcare pathways on the risk of CDI. FINDINGS: CDI rates per admission and per bed-days increased from 1997/98 to 2006/07, then decreased significantly by >50% from 2008/9 and 2009/10. This pattern was similar for patients regardless of probable source of infection but the proportion of probable community-acquired CDI cases rose steadily from 7% in 1997/98 to 13% in 2009/10. CDI rates were higher among older patients (odds ratio: >65 years, 10.9), those with more comorbid conditions (odds ratio for Charlson index: >5, 5.6), and among patients admitted as an emergency compared with elective admissions, but no relationship was found with deprivation score. CONCLUSION: Our findings support not only the falling trend in CDI found in the national mandatory surveillance scheme from the Health Protection Agency, but a growing proportion of CDI presenting on admission with no evidence of prior hospital exposure in the previous 90 days. We suggest that these may be community-acquired CDI cases.

Meta-analysis: diagnostic medical radiation exposure in inflammatory bowel disease.

BACKGROUND: Diagnostic imaging plays a pivotal role in the diagnosis and management of inflammatory bowel disease (IBD); however, increasing use has led to concerns about the malignant potential of ionising radiation. Several studies have demonstrated that diagnostic imaging can result in exposure to potentially harmful levels of ionising radiation in IBD patients. AIM: To determine the pooled prevalence of increased exposure and pooled odds ratio of risk factors associated with exposure to potentially harmful levels of diagnostic medical radiation. METHODS: We searched Medline, EMBASE, CINHAL and reference lists of identified articles, without language restrictions in October 2011. RESULTS: Six studies with 1704 participants provided data on the proportion of patients receiving potentially harmful levels of radiation defined as ≥50 milli-sieverts (mSv)-equivalent to 5 CT abdomen scans. The pooled prevalence was 8.8% (95% CI 4.4-16.8) for IBD patients and 11.1% (95% CI 5.7-20.5%) and 2% (95% CI 0.8-4.9%) for Crohn's disease and ulcerative colitis patients respectively. Five studies involving 2627 participants provided data for risk factors. IBD-related surgery and corticosteroid use were significant with pooled adjusted odds ratio of 5.4 (95% CI 2.6-11.2) and 2.4 (95% CI 1.7-3.4) respectively. CONCLUSIONS: About 1 in 10 patients may be exposed to potentially harmful levels of diagnostic medical radiation. Corticosteroid use and IBD related surgery increased this risk. Strategies to reduce radiation exposure while assessing disease activity need to be considered.

Diagnostic accuracy of small intestine ultrasonography using an oral contrast agent in Crohn's disease: comparative study from the UK.

AIM: To evaluate the usefulness of small intestine contrast-enhanced ultrasonography (SICUS) using an oral contrast agent in routine clinical practice by assessing the level of agreement with the established techniques, small bowel follow-through (SBFT) and computed tomography (CT), and diagnostic accuracy compared with the final diagnosis in the detection of small bowel Crohn's disease (CD) and luminal complications in a regional centre. MATERIALS AND METHODS: All symptomatic known or suspected cases of CD who underwent SICUS were retrospectively reviewed. The level of agreement between SICUS and SBFT, CT, histological findings, and C-reactive protein (CRP) level was assessed using kappa (κ) coefficient. Sensitivity was demonstrated using the final diagnosis as the reference standard defined by the outcome of clinical assessment, follow-up, and results of investigations other than SICUS. RESULTS: One hundred and forty-three patients underwent SICUS of these 79 (55%) were female. Eighty-six (60%) were known to have CD and 57 (40%) had symptoms suggestive of intestinal disease with no previous diagnosis. Forty-six (55%) of the known CD patients had had at least one previous surgical resection. The sensitivity of SICUS in detecting active small bowel CD in known CD and undiagnosed cases was 93%. The kappa coefficient was 0.88 and 0.91 with SBFT and CT, respectively. SICUS detected nine patients who had one or more small bowel strictures and six patients with a fistula all detected by SBFT or CT. CONCLUSION: SICUS is not only comparable to SBFT and CT but avoids radiation exposure and should be more widely adopted in the UK as a primary diagnostic procedure and to monitor disease complications in patients with CD.

Increased health burden associated with Clostridium difficile diarrhoea in patients with inflammatory bowel disease.

BACKGROUND: Clostridium difficile (C. difficile) infection in hospitals in developed countries continues to be a major public health hazard despite increased control measures including review of antibiotic policies and hygiene measures. Patients with colitis are thought to be particularly vulnerable to C. difficile associated diarrhoea (CDAD). Identifying the clinical burden among hospitalised patients admitted with inflammatory bowel disease is an essential first step towards identifying and treating severe C. difficile infection in such individuals. AIM: To determine excess morbidity and in-hospital mortality associated with hospital acquired CDAD in patients with inflammatory bowel disease (IBD-CDAD-HAI) admitted to NHS hospitals in England compared with those admitted for inflammatory bowel disease alone. METHODS: Time trends study of all admissions to NHS hospitals between 2002/03 and 2007/08. We developed case definitions for IBD-CDAD-HAI patients. The primary outcomes were in-hospital mortality and length of stay. The secondary outcome was gastrointestinal surgery. RESULTS: Patients in the IBD-CDAD-HAI group were more likely to die in hospital (adjusted OR 6.32), had 27.9 days longer in-patient stays and higher gastrointestinal surgery rates (adjusted OR 1.87) than patients admitted for inflammatory bowel disease alone. CONCLUSION: Patients with inflammatory bowel disease admitted to NHS hospitals in England with co-existent C. difficile infection are at risk of greater in-hospital mortality and morbidity than patients admitted for inflammatory bowel disease alone.

Determining the proximal extent of ulcerative colitis: white cell scan correlates well with histological assessment.

BACKGROUND: Assessing the extent of ulcerative colitis determines therapeutic strategies and provides prognostic information. Colonoscopy with mucosal biopsy is considered unsafe in patients with severe disease. AIM: To assess the correlation between proximal extent of ulcerative colitis as determined by Technitium-99-m hexamethylpropylene amine oxime labelled leucocyte scan (white cell scan) with that determined by histological assessment. METHODS: One hundred and thirty-five patients, with histologically-confirmed ulcerative colitis, who had a white cell scan and histological assessment of colonic inflammation within 6 months of each other, during the years 1991-2004, were included. Overall agreement, quadratic-weighted kappa (kappa) and polychoric correlations (rho) were calculated to estimate the inter-rater reliability. RESULTS: The correlation between white cell scan and histological extent was excellent (kappa = 0.7 rho = 0.8). Macroscopic appearance on colonoscopy did not correlate as well with histological extent (kappa = 0.62 and rho = 0.67). White cell scans correlated significantly better in patients with extensive disease (P = 0.02). Colonoscopy predicted disease extent more accurately in patients with limited colitis (P = 0.002). CONCLUSIONS: Proximal extent of ulcerative colitis determined by white cell scans correlates well with histological assessment especially in patients with more extensive disease. White cell scans offer a reasonable alternative to colonoscopy with mucosal biopsies in determining the proximal extent of colitis.

A potential role for interleukin-18 in inhibition of the development of Cryptosporidium parvum.

Accumulating evidence suggests that intestinal epithelial cells (IECs) constitutively express the immunoregulatory cytokine interleukin (IL)-18. IECs also serve as the host cell for the intracellular parasitic protozoan Cryptosporidium parvum. In the present study, C. parvum infection of a human enterocyte cell-line HCT-8 resulted in increased expression of IL-18 mRNA as measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). IL-18 protein was detected in control uninfected cells and following infection there was increased expression as measured by enzyme-linked immunosorbent assay (ELISA). Gene expression revealed the presence of the IL-18 receptor subunits not only in cell-lines but also in freshly isolated IECs, suggesting that IL-18-mediated signalling events may contribute to epithelial host defence during infection. Recombinant IL-18 inhibited intracellular development of the parasite in HCT-8 and HT-29 cells. Increased expression of bactericidal antibiotic peptides LL-37 and alpha-defensin 2 by IL-18 in HCT-8 and HT-29 cells may represent one mode of action by which this pluripotent cytokine aids in limiting the development of intracellular pathogens such as C. parvum in the gastrointestinal tract.

Systematic review of postoperative complications in patients with inflammatory bowel disease treated with immunomodulators.

BACKGROUND: This systematic review examined the use of immunomodulators and the risk of postoperative complications after abdominal surgery in patients with inflammatory bowel disease. METHODS: Electronic databases (PubMed, Embase, Ingenta, Zetoc and Ovid) were searched and the reference lists in all articles identified were hand-searched for further relevant papers. Studies were included if they evaluated postoperative complications and defined exposure to individual immunomodulators. RESULTS: All 11 studies that met the inclusion criteria were observational studies; two were reported only in abstract form. Five studies reported risks associated with azathioprine, five reported risks associated with cyclosporin and three reported risks associated with infliximab. None showed an increased risk of either total or infectious complications associated with immunomodulator use. However, subgroup analysis in one study, published as an abstract, suggested increased rates of anastomotic complications and reoperation associated with azathioprine. CONCLUSION: Available evidence does not suggest an increased rate of postoperative complications associated with immunomodulator use.