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Why don't we just measure infliximab drug levels in IBD?
Infliximab (IFX) is potentially immunogenic, causing anti-infliximab antibodies that may interfere with the clinical efficacy and safety of the drug. There is an industry in measuring these antibodies, but the technicalities are legion, association with response poor and if they affect pharmacokinetics, it is by influencing drug levels. In contrast, IFX levels are associated with clinical response. So why make it complex? In this paper, we evaluate studies reporting the incidence of IFX antibodies in IBD, their impact on efficacy, safety and pharmacokinetics of IFX.
Management of Crohn's today - The European perspective
A number of therapeutic trials are based in central and eastern Europe where guidelines have yet to be published. The aim of this article is to promote a European prospective on the management of inflammatory bowel diseases. Summarized are the European Crohn's and Colitis Organization (ECCO) Guidelines which address the differences in practice in the U.S. and Europe.
Gastrointestinal function
Climbers lose weight above 5,000 m, which impairs physical performance and reduces safety margins. Although widely assumed to be due to energy imbalance, with expenditure exceeding nutritional intake, weight loss has been observed in mountaineers at rest at high altitude. Basal metabolic rate is increased and some evidence points to carbohydrate malabsorption. This chapter examines how the normal physiological processes of carbohydrate, fat, and protein absorption change at altitudes above 5,000 m, in a standard format briefly describing normal physiology, experimental models, and then field studies at altitude. Other aspects of gut function, from gastric acid secretion to mucosal morphology, mesenteric blood flow, motility, liver function, and the effect of hypoxia inducible factor on gut function are then described before gastrointestinal diseases in short-term visitors and residents at high altitude are addressed.
Incorporating patient experience into drug development for ulcerative colitis: development of the Urgency Numeric Rating Scale, a patient-reported outcome measure to assess bowel urgency in adults.
BACKGROUND: Bowel urgency, the sudden or immediate need to have a bowel movement, is a common, bothersome and disruptive symptom of ulcerative colitis (UC). UC treatment goals include control of urgency; however, it is not consistently assessed in UC clinical trials. The Urgency Numeric Rating Scale (NRS) is a new patient-reported measure to assess severity of bowel urgency in adults with UC developed in accordance with Food and Drug Administration guidelines. METHODS: Qualitative interviews were used to develop Urgency NRS. The scale asks patients to report the immediacy status of their UC symptom over the past 24 h on an 11-point horizontal numeric rating scale [0 (No urgency) to 10 (Worst possible urgency)]. Higher scores indicate worse urgency severity. A 2-week diary study assessed floor and ceiling effects, test-retest reliability (intraclass correlation coefficient (ICC) (2,1) between Week 1 and 2), and construct validity (Spearman correlation using Week 1 scores). Weekly scores were calculated as mean score over each 7-day period. RESULTS: Qualitative interviews with 16 UC patients (mean age 37.9 ± 11.6 years; 50% female; 56% White) confirmed relevance, content, and comprehensiveness. The 2-week diary study included 41 UC patients (mean age 44.2 ± 14.6 years; 51% female; 56% White). No ceiling or floor effects were identified. Test-retest reliability was high (ICC = 0.877). Average Urgency NRS and patient global rating of severity scores were highly correlated, with a moderate correlation between average Urgency NRS and stool frequency, demonstrating construct validity. CONCLUSIONS: Bowel urgency is a distinct symptom of UC. The Urgency NRS is a well-defined, content-valid, and reliable measurement of bowel urgency in adults with UC.
Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition.
BACKGROUND: It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups. METHODS: The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists). RESULTS: We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries. CONCLUSIONS: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.
Toxic dilatation of the colon
Toxic megacolon is a potentially fatal condition that represents the end of a spectrum of severe colitis. Typically, a complication of ulcerative colitis, it is increasingly a consequence of infective colitis. Diagnosis of toxic megacolon requires radiographic evidence of a dilated colon and tachycardia or fever in a patient with severe colitis of any cause. Unprepared flexible sigmoidoscopy should be performed on admission to confirm colitis and exclude complications such as cytomegalovirus infection. CT scanning is more sensitive than plain films for detecting perforation. Joint management between surgeons and physicians is fundamental. Medical therapy includes steroids, antibiotics, fluid and electrolyte management. Up to half respond to medical treatment. Colectomy is indicated if dilatation persists beyond the first 24 hours of admission. Delayed decision-making increases the likelihood of perforation with a concomitant rise in morbidity and mortality. © 2006 Elsevier Ltd. All rights reserved.
Transatlantic divide: First-line therapy for acute colitis
American Gastroenterologists are astonished by the low threshold that European colleagues have for using corticosteroids to treat acute ulcerative colitis. Likewise, European Gastroenterologists regard the massive doses of aminosalicylates used by US colleagues with interest, because they have yet to be convinced about the efficacy of this approach. As patient concern about steroid-induced side-effects increased, it seemed that Europeans were moving to a mid-Atlantic position, but case discussions at recent meetings have highlighted persistent differences in the initial treatment of a common condition. This is in spite of guidelines published on both sides of the Atlantic within the past 18 months (1,2), whose recommendations are not that dissimilar. They are, after all, based on the same evidence. The essence of the argument between the continents comes down to differences in emphasis placed on the speed and the degree of response.
Food and nutritional intake at high altitude
Individuals who ascend to altitude too rapidly invariably develop acute mountain sickness (AMS) although a high carbohydrate diet may lessen these symptoms. Specific questions addressed in this study were: changes in diet prior to sojourning at altitude; changes in food consumption/nutritional intake, food acceptability, flavour and taste intensities. Nineteen subjects assembled for three days at sea level for baseline measurements consuming a diet of dehydrated rations. This regimen was repeated 18 days later in the Bolivian Andes at approximately 5,600m once subjects were acclimatised. Results confirm a common phenomenon; a reduced dietary intake and body weight loss at high altitude. Other results, flavour and taste intensities and overall food acceptability indicate the suitability of these foods in both environments. © 1998, MCB UP Limited
Endoscopy in Inflammatory Bowel Disease: Western Perspective—Europe
Endoscopy for IBD in Europe has in the last decade been driven by an agenda focussed on endoscopic quality and quality assurance. This has affected endoscopy in IBD practice in two specific areas; the use of chromoendoscopy for dysplasia detection, and endoscopic scoring systems of disease severity. Chromoendoscopy studies for dysplasia detection have been positive; however, it was not recommended until 2010 when the British Society of Gastroenterology (BSG) led change with a new guideline, subsequently supported by the European Crohn’s and Colitis Organisation (ECCO) and European Society for Gastrointestinal Endoscopy (ESGE), which has become the standard of care in IBD in Europe. North America still lags behind Europe in this regard. Validated scoring systems for colitis are key to ensure we speak an international “common language” between countries, but also to precisely convert research finding into clinical practice. Two validated scoring systems have become available recently, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and the Ulcerative Colitis Colonoscopic Index of Severity (UCCIS). Regulatory agencies including the Food and Drug Administration (FDA) and European Medicines Agency (EMA) are taking an active interest in scoring systems and outcome measures in clinical trials. Quality and quality assurance are now embedded in IBD endoscopy in Europe by the use of chromoendoscopy and validated scoring systems. We need to evaluate whether this improves outcomes for patients.
Assessment of disease activity in ulcerative colitis
Management of ulcerative colitis (UC) is guided by the anatomical distribution of disease, severity of symptoms, response to medical therapy and ability of the patient to tolerate treatment. In its most severe form, acute ulcerative colitis can carry major morbidity and can be fatal. Disease severity indices help guide clinical decisions regarding appropriate initial treatment and are particularly helpful for patients who fail to show adequate response to first-line therapy but are also essential for evaluating therapeutic response and defining outcomes in clinical trials (D’Haens et al., Gastroenterology 132:763–786, 2007). Indeed, severity indices were all developed for use in clinical trials, although almost none have been formally validated and none have had responsiveness defined in clinical practice.
Toxic dilatation of the colon
Toxic megacolon (TM) is defined as total or non-segmental obstructive dilatation of the colon to an external diameter of 6.0 cm or greater, associated with systemic toxicity. It is a potentially fatal condition that represents the end of a spectrum of severe colitis. Typically a complication of ulcerative colitis, it is increasingly seen as a consequence of infective colitis. This reflects the increasing prevalence and severity of pseudomembranous colitis. TM associated with Clostridium difficile infection proves fatal in as many as two out of every three patients. © 2010 Elsevier Ltd. All rights reserved.