Outcomes following biosimilar TNF inhibitor use for inflammatory-mediated immune disorders in pregnancy.

Background: Biosimilar tumour necrosis factor inhibitors (TNFi) are increasingly used to treat inflammatory immune-mediated disorders as they cost less than the originator biologic drug. More women are therefore becoming pregnant on biosimilar TNFi. This is the first paper to explore the safety and efficacy of biosimilar therapies in pregnancy. Methods: A retrospective review of clinical data reviewed pregnancy outcomes and inflammatory disease activity in 18 pregnancies where the mother was using a biosimilar TNFi at conception. Results: Biosimilar therapy was not associated with congenital abnormalities, preterm birth or other adverse pregnancy outcomes. Stopping biosimilar TNFi in pregnancy was associated with childbirth at an earlier gestation, as well as a flare of inflammatory disease in pregnancy or post-partum. Conclusions: Women and clinicians should feel confident in using biosimilar TNFi in early pregnancy, and continuing them through pregnancy to prevent flares in late pregnancy or the early post-partum.

Echocardiographic findings in acromegaly: prevalence of concentric left ventricular remodeling in a large single-center cohort.

PURPOSE: Acromegaly is a rare disease and is associated with increased cardiovascular (CV) morbidity and mortality, especially in patients with uncontrolled disease. We aimed to analyze the prevalence and severity of cardiomyopathy and valvular heart disease in a large cohort of patients with a confirmed acromegaly diagnosis, at baseline and after treatment. METHODS: We retrospectively reviewed an institutional approved database; 190 patients with confirmed acromegaly and follow-up data available (years 2006-2018). Patients with at least one baseline echocardiogram, were included. Demographic, disease control and echocardiogram variables were collected for analysis. RESULTS: Of the 190 patients 110 (58%) had a baseline echocardiogram and 43 (39.1%) had at least one follow-up echocardiogram after surgical, medical or multimodal treatment. Baseline left ventricular hypertrophy (LVH) prevalence was 17.8% (64.7% concentric; 35.3% eccentric), diastolic and systolic dysfunction, and overt cardiomyopathy with heart failure were 15.8, 7.9, and 3.0%, respectively. Concentric remodeling of the left ventricle (LV) was noted in 31.4% of patients without LVH. Valve defects were found in 87.3% of patients (14.6% with significant valvular heart disease). CONCLUSION: Early diagnosis of acromegaly and disease control should be attempted to prevent LVH/LV dysfunction and development of valvular heart disease. Concentric LV remodeling develops prior to obvious LV hypertrophy in almost a third of patients with acromegaly, which is a novel finding. Similar to other epidemiological studies, we found a high prevalence of LVH/LV dysfunction. Although possible, reversal of systolic and diastolic dysfunction is sporadic after treatment of acromegaly.

Rare coding variant analysis in a large cohort of Ashkenazi Jewish families with inflammatory bowel disease.

Rare variants are thought to contribute to the genetics of inflammatory bowel disease (IBD), which is more common amongst the Ashkenazi Jewish (AJ) population. A family-based approach using exome sequencing of AJ individuals with IBD was employed with a view to identify novel rare genetic variants for this disease. Exome sequencing was performed on 960 Jewish individuals including 513 from 199 multiplex families with up to eight cases. Rare, damaging variants in loci prioritized by linkage analysis and those shared by multiple affected individuals within the same family were identified. Independent evidence of association of each variant with disease was assessed. A number of candidate variants were identified, including in genes involved in the immune system. The ability to achieve statistical significance in independent case/control replication data was limited by power and was only achieved for variants in the well-established Crohn's disease gene, NOD2. This work demonstrates the challenges of identifying disease-associated rare damaging variants from exome data, even amongst a favorable cohort of familial cases from a genetic isolate. Further research of the prioritized rare candidate variants is required to confirm their association with the disease.

UK guideline on transition of adolescent and young persons with chronic digestive diseases from paediatric to adult care

The risks of poor transition include delayed and inappropriate transfer that can result in disengagement with healthcare. Structured transition care can improve control of chronic digestive diseases and long-term health-related outcomes. These are the first nationally developed guidelines on the transition of adolescent and young persons (AYP) with chronic digestive diseases from paediatric to adult care. They were commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology under the auspices of the Adolescent and Young Persons (A&YP) Section. Electronic searches for English-language articles were performed with keywords relating to digestive system diseases and transition to adult care in the Medline (via Ovid), PsycInfo (via Ovid), Web of Science and CINAHL databases for studies published from 1980 to September 2014. The quality of evidence and grading of recommendations was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The limited number of studies in gastroenterology and hepatology required the addition of relevant studies from other chronic diseases to be included.These guidelines deal specifically with the transition of AYP living with a diagnosis of chronic digestive disease and/or liver disease from paediatric to adult healthcare under the following headings;1. Patient populations involved in AYP transition. 2. Risks of failing transition or poor transition. 3. Models of AYP transition. 4. Patient and carer/parent perspective in AYP transition. 5. Surgical perspective.(AU)

Relapse after withdrawal from anti-TNF therapy for inflammatory bowel disease: an observational study, plus systematic review and meta-analysis.

BACKGROUND: Infliximab and adalimumab have established roles in inflammatory bowel disease (IBD) therapy. UK regulators mandate reassessment after 12 months' anti-TNF therapy for IBD, with consideration of treatment withdrawal. There is a need for more data to establish the relapse rates following treatment cessation. AIM: To establish outcomes following anti-TNF withdrawal for sustained remission using new data from a large UK cohort, and assimilation of all available literature for systematic review and meta-analysis. METHODS: A retrospective observational study was performed on 166 patients with IBD (146 with Crohn's disease (CD) and 20 with ulcerative colitis [UC) and IBD unclassified (IBDU)] withdrawn from anti-TNF for sustained remission. Meta-analysis was undertaken of all published studies incorporating 11 further cohorts totalling 746 patients (624 CD, 122 UC). RESULTS: Relapse rates in the UK cohort were 36% by 1 year and 56% by 2 years for CD, and 42% by 1 year and 47% by 2 years for UC/IBDU. Increased relapse risk in CD was associated with age at diagnosis [hazard ratio (HR) 2.78 for age <22 years], white cell count (HR 3.22 for >5.25 × 109 /L) and faecal calprotectin (HR 2.95 for >50 µg/g) at drug withdrawal. Neither continued immunomodulators nor endoscopic remission were predictors. In the meta-analysis, estimated 1-year relapse rates were 39% and 35% for CD and UC/IBDU respectively. Retreatment with anti-TNF was successful in 88% for CD and 76% UC/IBDU. CONCLUSIONS: Assimilation of all available data reveals remarkable homogeneity. Approximately one-third of patients with IBD flare within 12 months of withdrawal of anti-TNF therapy for sustained remission.

MRI enterography: what is the clinical impact of unsuspected extra-enteric findings?

To define the incidence and nature of incidental extra-enteric findings on magnetic resonance enterography (MRE) following the introduction of a new clinical service, to assess the volume of additional tests generated and to gauge the potential of MRE to reduce the need for subsequent abdominal imaging. The imaging and patient records of 500 consecutive patients undergoing MRE at a single institution were reviewed. Note was made of patient demographics, any extra-enteric findings reported on the MRE, whether additional tests were recommended by the reporting radiologists to clarify or follow up extra-enteric findings and whether the patients underwent additional abdominal or pelvic imaging in the 4 months after the MRE. 64% of the cohort was male. The mean age was 45 years (range 11-80 years). Overall 190 (38%) underwent MRE for assessment of known Crohn's disease and 310 (62%) for other indications, such as abdominal pain and anaemia. 26 non-bowel-related extra-enteric abnormalities were noted on the MRE report in just 15 patients (3%), and a total of 6 additional tests were recommended by the reporting radiologist. 13 patients (2.6%) underwent some form of abdominal imaging within 4 months of the MRE. None of these additional investigations revealed any abnormality missed on the MRE. Extra-enteric findings are unlikely to have a significant impact on healthcare resources after the introduction of an MRE service.

Republished research: Helminths: an unrecognised disease burden prevalent among migrants in the gastroenterology clinic.

OBJECTIVE: To estimate the prevalence of, and implement a diagnostic strategy for, imported helminth infection in the gastroenterology clinic. DESIGN: A retrospective study of eosinophil count and probable tropical exposure (phase I) followed by a prospective study of parasitological investigation (phase II). SETTING: Gastroenterology service of an inner London hospital. PATIENTS: Adult patients newly attending general gastroenterology and inflammatory bowel disease clinics. INTERVENTIONS: In phase I, evidence of undiagnosed helminth infection was sought by analysing patient records for associations between eosinophil count and ethnicity. In phase II, a UK guideline for investigation of eosinophilia in migrants was implemented and diagnostic yield determined. MAIN OUTCOME MEASURES: In phase I, prevalence of eosinophilia was determined; in phase II, helminth prevalence and degree of eosinophilia before and after treatment were reported. Information on symptomatic response to treatment was recorded. Ethnicity was used as a proxy measure for tropical exposure. RESULTS: 426 new patients attended in a 12 month period. Eosinophilia was present in 27 (6.3%). 10/27 (37.0%) patients with eosinophilia were of African or Asian ethnicity whereas only 20% (85/426) of patients overall were from these ethnic groups (χ(2)=5.27, p=0.02). Following implementation of the protocol, 25/36 migrants with eosinophilia attended for parasitological investigations. Helminth infection was diagnosed in 10/25 (40%). Strongyloidiasis (six patients) and schistosomiasis (three patients) were the most common diagnoses. Median eosinophil count was 1.06×10(9)/l in those with helminths and 0.58×10(9)/l in those without (p=0.004). Eosinophil counts normalised in, and symptomatic improvement was reported by, most patients after treatment. CONCLUSIONS: Eosinophilia is associated with African or Asian ethnicity in an inner city gastroenterology service. This association is probably explained by imported helminths, which are prevalent in this setting, may be a cause of gastrointestinal symptoms and is easily diagnosed and treated by standard protocols.

Diagnostic and therapeutic impact of MR enterography in Crohn's disease.

AIM: To assess the impact of magnetic resonance enterography (MRE) on clinician diagnostic confidence and therapeutic strategy in patients under investigation for small bowel Crohn's disease. MATERIAL AND METHODS: Gastroenterologists completed a proforma before and following MRE in 51 patients (mean age 35 years, 26 female) under investigation for small bowel Crohn's disease, indicating percentage confidence for presence/absence of small bowel involvement. In suspected disease, diagnostic confidence (using a scoring system from 1=no to 6=yes) was scored for subcategories: extent >30 cm (DE), terminal ileum (lTI), jejunal (JD), colonic disease (CoD), strictures (ST), activity (AD), extraluminal complications (EL), and surgical need (NS). Therapeutic strategy was recorded. Patients were divided into three groups: 1=suspected disease, MRE normal (n=15); 2=suspected disease, MRE abnormal (n=30); 3=no suspected disease, MRE normal (n=6). Binomial exact and paired t-tests were use to compare confidence pre and post-MRE. RESULTS: Mean percentage confidence for the presence/absence of small bowel disease increased from 62 to 84% (p=0.003), 87 to 98% (p=0.0001), and 83 to 98% (p=0.005) after MRE for groups 1, 2, and 3, respectively. In suspected disease, confidence changed significantly for all of the subcategories (p<0.001) except EL in group 1. The percentage of patients with a confidence change ranged from 40% (CoD) to 87% (lTI; group 1) and from 7% (EL) to 93% (DE; group 2). Therapeutic strategy changed in 31/51 (61%, 95% CI 47-74%), 14 with a reduction in planned therapy and 17 with an increase. CONCLUSION: MRE had a positive diagnostic impact in patients under investigation for small bowel Crohn's disease and this influenced therapeutic strategy in 61% of the patients.

Use of small bowel imaging for the diagnosis and staging of Crohn's disease--a survey of current UK practice.

OBJECTIVES: This study used a postal survey to assess the current use of small bowel imaging investigations for Crohn's disease within National Health Service (NHS) radiological practice and to gauge gastroenterological referral patterns. METHODS: Similar questionnaires were posted to departments of radiology (n = 240) and gastroenterology (n = 254) identified, by the databases of the Royal College of Radiologists and British Society of Gastroenterologists. Questionnaires enquired about the use of small bowel imaging in the assessment of Crohn's disease. In particular, questionnaires described clinical scenarios including first diagnosis, disease staging and assessment of suspected extraluminal complications, obstruction and disease flare. The data were stratified according to patient age. RESULTS: 63 (27%) departments of radiology (20 in teaching hospitals and 43 in district general hospitals (DGHs)) and 73 (29%) departments of gastroenterology replied. These departments were in 119 institutions. Of the 63 departments of radiology, 55 (90%) routinely performed barium follow-though (BaFT), 50 (80%) CT, 29 (46%) small bowel ultrasound (SbUS) and 24 (38%) small bowel MRI. BaFT was the most commonly used investigation across all age groups and indications. SbUS was used mostly for patients younger than 40 years of age with low index of clinical suspicion for Crohn's disease (in 44% of radiology departments (28/63)). MRI was most frequently used in patients under 20 years of age for staging new disease (in 27% of radiology departments (17/63)) or in whom obstruction was suspected (in 29% of radiology departments (18/63)). CT was preferred for suspected extraluminal complications or obstruction (in 73% (46/63) and 46% (29/63) of radiology departments, respectively). Gastroenterological referrals largely concurred with the imaging modalities chosen by radiologists, although gastroenterologists were less likely to request SbUS and MRI. CONCLUSION: BaFT remains the mainstay investigation for luminal small bowel Crohn's disease, with CT dominating for suspected extraluminal complications. There has been only moderate dissemination of the use of MRI and SbUS.

Helminths: an unrecognised disease burden prevalent among migrants in the gastroenterology clinic.

OBJECTIVE: To estimate the prevalence of, and implement a diagnostic strategy for, imported helminth infection in the gastroenterology clinic. DESIGN: A retrospective study of eosinophil count and probable tropical exposure (phase I) followed by a prospective study of parasitological investigation (phase II). SETTING: Gastroenterology service of an inner London hospital. PATIENTS: Adult patients newly attending general gastroenterology and inflammatory bowel disease clinics. INTERVENTIONS: In phase I, evidence of undiagnosed helminth infection was sought by analysing patient records for associations between eosinophil count and ethnicity. In phase II, a UK guideline for investigation of eosinophilia in migrants was implemented and diagnostic yield determined. MAIN OUTCOME MEASURES: In phase I, prevalence of eosinophilia was determined; in phase II, helminth prevalence and degree of eosinophilia before and after treatment were reported. Information on symptomatic response to treatment was recorded. Ethnicity was used as a proxy measure for tropical exposure. RESULTS: 426 new patients attended in a 12 month period. Eosinophilia was present in 27 (6.3%). 10/27 (37.0%) patients with eosinophilia were of African or Asian ethnicity whereas only 20% (85/426) of patients overall were from these ethnic groups (χ2=5.27, p=0.02). Following implementation of the protocol, 25/36 migrants with eosinophilia attended for parasitological investigations. Helminth infection was diagnosed in 10/25 (40%). Strongyloidiasis (six patients) and schistosomiasis (three patients) were the most common diagnoses. Median eosinophil count was 1.06×109/l in those with helminths and 0.58×109/l in those without (p=0.004). Eosinophil counts normalised in, and symptomatic improvement was reported by, most patients after treatment. CONCLUSIONS: Eosinophilia is associated with African or Asian ethnicity in an inner city gastroenterology service. This association is probably explained by imported helminths, which are prevalent in this setting, may be a cause of gastrointestinal symptoms and is easily diagnosed and treated by standard protocols.

Efficacy of methotrexate in Crohn's disease and ulcerative colitis patients unresponsive or intolerant to azathioprine /mercaptopurine.

BACKGROUND: Despite the wide use of azathioprine/mercaptopurine (AZA/MP) therapy in the management of both Crohn's disease (CD) and ulcerative colitis (UC), approximately 20% of patients cannot tolerate the drugs and 30% do not respond. AIM: To examine the efficacy and safety profile of methotrexate (MTX) in patients with CD or UC who are either intolerant or non-responsive to AZA/MP. METHODS: A total of 131 patients with IBD treated with MTX were identified. Retrospective data were obtained by case note review. Clinical response (defined as steroid withdrawal, normalization of previously raised CRP or physician's clinical assessment of improvement) was assessed at 6 months. RESULTS: Clinical response in Crohn's disease occurred in 18 of 29 patients (62%) refractory to AZA/MP and 42 of 70 patients (60%) intolerant to AZA/MP, with no difference between the groups (P = 1.0). In UC, clinical response was seen in 7 of 9 (78%) patients refractory to AZA/MP and 15 of 23 (65%) intolerant to thiopurines. MTX was well tolerated in a majority of individuals. CONCLUSIONS: Methotrexate appears effective in both CD and UC patients who fail to respond to or are intolerant to AZA/MP therapy.

A rare case of vomiting: fourth ventricular B-cell lymphoma.

We document the case of a 69-year-old man presenting with 6 weeks of intractable vomiting. Magnetic Resonance Imaging showed a homogenously enhancing mass in the caudal fourth ventricle. Surgical exploration and biopsy was performed and pathological examination demonstrated a high-grade B-cell lymphoma. The lesion was a primary tumour in an immuno-competent patient. Despite the increasing incidence of primary central nervous system lymphomas this is believed to be only the third ever case to have occurred at this rare site. We suggest that primary B-cell lymphoma should be considered with homogenous lesions of the fourth ventricle.

Management of chronic severe pain: cerebral neuromodulatory and neuroablative approaches.

Two approaches are utilized when targeting the brain to treat pain. The first, a non-destructive approach, uses either electrical stimulation of brain targets thought to modulate the process of pain perception, or pharmacological agents are introduced into ventricular spaces to target pain modulating receptors. Electrical stimulation targets include; the thalamic nuclei, the periventricular and periaqueductal grey (PVG and PAG) matter or the motor cortex. Currently, the pharmacological agent of choice for intracerebroventricular injection is morphine. In general, electrical stimulation is used for nonmalignant type pain, and pharmacological modulation for malignant type pain. The second, a destructive approach, is usually employed with the goal of interrupting the signals that lead to pain perception at various levels. Neuroablation is usually performed on cellular complexes such as "nuclei, or gyri" or on tracts with the aim of disrupting the sensory and limbic pathways involved in the emotional processes associated with pain. Specific cerebral neuroablation targets include; the thalamic medial group of nuclei, the cingulated gyrus, and the trigeminal nucleus and tract. There are fewer reports in the literature detailing the brain, when compared to the spine, as a target to treat pain, and further research is required.

Management of chronic severe pain: spinal neuromodulatory and neuroablative approaches.

The spinal cord is the target of many neurosurgical procedures used to treat pain. Compactness and well-defined tract separation in addition to well understood dermatomal cord organization make the spinal cord an ideal target for pain procedures. Moreover, the presence of opioid and other receptors involved in pain modulation at the level of the dorsal horn increases the suitability of the spinal cord. Neuromodulative approaches of the spinal cord are either electrical or pharmacological. Electrical spinal cord modulation is used on a large scale for various pain syndromes including; failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS), neuropathic pain, angina, and ischemic limb pain. Intraspinal delivery of medications e.g. opioids is used to treat nociceptive and neuropathic pains due to malignant and cancer pain etiologies. Neuroablation of the spinal cord pain pathway is mainly used to treat cancer pain. Targets involved include; the spinothalamic tract, the midline dorsal column visceral pain pathway and the trigeminal tract in the upper spinal cord. Spinal neuroablation can also involve cellular elements such as with trigeminal nucleotomy and the dorsal root entry zone (DREZ) operation. The DREZ operation is indicated for phantom type pain and root avulsion injuries. Due to its reversible nature spinal neuromodulation prevails, and spinal neuroablation is performed in a few select cases.

Modified skin window technique for the extended characterisation of acute inflammation in humans.

OBJECTIVE: To modify the skin window technique for extended analysis of acute inflammatory responses in humans, and demonstrate its applicability for investigating disease. SUBJECTS: 15 healthy subjects and 5 Crohn's patients. TREATMENT: Skin windows, created by dermal abrasion, were overlaid for various durations with filter papers saturated in saline, 100 ng/ml muramyl dipeptide (MDP) or 10 microg/ml interleukin-8 (IL-8). METHODS: Exuded leukocytes were analyzed by microscopy, immunoblot, DNA-bound transcription factor arrays and RT-PCR. Inflammatory mediators were quantified by ELISA. RESULTS: Infiltrating leukocytes were predominantly neutrophils. Numerous secreted mediators were detectable. MDP and IL-8 enhanced responses. Many signalling proteins were phosphorylated with differential patterns in Crohn's patients, notably PKC alpha/beta hyperphosphorylation (11.3 +/- 3.1 vs 1.2 +/- 0.9 units, P < 0.02). Activities of 44 transcription factors were detectable, and sufficient RNA isolated for expression analysis of over 400 genes. CONCLUSIONS: The modifications enable broad characterisation of inflammatory responses and administration of exogenous immunomodulators.

Endothelin content, expression, and receptor type in normal and diseased human gallbladder.

The aims of this study were to characterize the endothelin (ET) system in human gallbladder by determining (1) the tissue content of ET-1 and ET-2 by ELISA; (2) the expression of mRNA of the ET precursors preproendothelin-1, -2, and -3; and (3) mRNA expression for the ETA and ETB receptors. Median content of ET-1/2 was significantly reduced in severely inflamed gallbladders compared to gallbladders with mild inflammation. There was an inverse correlation between content of ET-1/2 and inflammation score. mRNA for preproendothelin-2 was highly expressed in all samples, whereas mRNA for preproendothelin-1 was present in negligible quantities and mRNA for preproendothelin-3 was undetectable. mRNA for ETA receptors was expressed in all samples analyzed, whereas mRNA for ETB receptors was expressed at a much lower level. This study demonstrates the presence of ET-1/2 in human gallbladder. ET-1/2 content is decreased with increasing degrees of histological inflammation. ET-2 is likely to be the physiologically significant endothelin isopeptide expressed and ETA receptors appear to predominate in the human gallbladder.

Ridogrel, a dual thromboxane synthase inhibitor and receptor antagonist: anti-inflammatory profile in inflammatory bowel disease.

BACKGROUND: Thromboxanes, prostaglandins, reactive oxygen metabolites and pro-inflammatory cytokines are produced in excess in inflammatory bowel disease. Preliminary reports suggest that ridogrel, a thromboxane synthesis inhibitor and receptor blocker, may have therapeutic benefits in ulcerative colitis. AIMS: To investigate the anti-inflammatory profile of ridogrel. METHODS: The effects of ridogrel on the production of eicosanoids, reactive oxygen metabolites and cytokines by cultured inflamed colorectal mucosal biopsies were made using ELISA and chemiluminescence, reactive oxygen metabolite generation in a cell-free system, and platelet activation using flow cytometry. The effects of oral ridogrel on mucosal release of eicosanoids in two patients with active ulcerative colitis were assessed using rectal dialysis. RESULTS: Ridogrel significantly reduced the release of thromboxane B2, but not prostaglandin E2 or tumour necrosis factor-alpha, from biopsies (P < 0.01 for 10 microM ridogrel). Ridogrel showed no direct antioxidant activity but significantly reduced reactive oxygen metabolite production from cultured biopsies (P < 0.01 for 10 microM ridogrel). Platelet activation in vitro was inhibited by ridogrel (P /= 10 microM ridogrel). Mean rectal mucosal thromboxane B2 release was reduced to 86% of pre-treatment levels in two patients treated with oral ridogrel. CONCLUSIONS: Its inhibition of mucosal production of thromboxane B2, reactive oxygen metabolites, and of platelet activation, suggests that ridogrel could have a therapeutic role in inflammatory bowel disease.

Selective COX-2 inhibitors and human inflammatory bowel disease.

BACKGROUND: Much recent effort has been made to produce selective inhibitors of cyclo-oxygenase-2 (COX-2) in the belief that these will lack the gastrointestinal damaging effects of traditional non-steroidal anti-inflammatory drugs (NSAIDs). Inflammatory bowel disease is associated with increased local production of prostanoids. These prostanoids, particularly PGE2 and PGI2, may well be protective as inflammatory bowel disease is aggravated by NSAID use. AIM: To examine the effects of a traditional NSAID and a highly selective COX-2 inhibitor on the production of these prostanoids in human inflammatory bowel disease. METHODS: Colonic mucosal biopsies were obtained from patients undergoing routine colonoscopy and biopsy for diagnostic or surveillance purposes. Biopsies were incubated in culture medium containing 10% foetal calf serum and antibiotics, plus test drugs or vehicle for 24 h, after which time the medium was removed and the content of PGE2, PGI2 (measured as 6 keto-PGF1alpha) and thromboxane (Tx) A2 (measured as TxB2) determined. RESULTS: Biopsies obtained from diseased colonic mucosa produced significantly more PGE2, PGI2 and thromboxane A2 than did controls (for example, PGE2: ulcerative colitis, 4.17+/-1.06; Crohn's disease, 3.97+/-1.66; control, 0.12 +/-0.13 ng/mL, n = 8-12). These increases were inhibited to a similar extent by either a highly selective COX-2 inhibitor (L-745,337) or a traditional non-selective NSAID (indomethacin). CONCLUSIONS: Until selective COX-2 inhibitors have been assessed adequately in human inflammatory bowel disease, these compounds should not be assumed to be safe for the gastrointestinal tract in inflammatory bowel disease.