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Background: Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy., Aim: The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed., Methods: The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab., Results: Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy., Conclusions: Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials., (© 2013 John Wiley & Sons Ltd.)

Background: Linkage data have now identified several inflammatory bowel disease (IBD) susceptibility loci but these data have not been consistently replicated in independent studies. One potential explanation for this is the possibility that patients enrolled in such studies may have been erroneously classified with respect to their diagnosis., Aims: To determine the rate and type of misclassification in a large population of individuals referred for participation in an IBD genetics study and to examine the effect of diagnostic misclassification on the power to detect linkage., Methods: The medical records of 1096 patients entered into an IBD genetics programme were reviewed using standardised diagnostic criteria. The original patient reported diagnoses were changed, if necessary, based on review, and the reasons for the change in diagnosis were recorded. To evaluate the effect of misclassification on linkage results, simulations were created with Gensim and analysed using Genehunter to evaluate a model for IBD inheritance., Results: Sixty eight of 1096 (6.2%) individuals had a change in diagnosis from that originally reported. The majority of changes were patients with either Crohn's disease or ulcerative colitis who were determined not to have IBD at all. The principal reasons for changes to the original diagnosis were discordance between the patients' subjective reports of diagnosis and actual clinical history, endoscopic, or pathological results; a change in disease pattern over time; and insufficient information available to confirm the original diagnosis. A 10% misclassification rate resulted in 28.4% and 40.2% loss of power to detect a true linkage when using a statistical model for a presumed IBD locus with lambda(s) values of 1.8 and 1.3, respectively., Conclusions: Diagnostic misclassification occurs in patients enrolled in IBD genetic studies and frequently involves assigning the diagnosis of IBD to non-affected individuals. Even low rates of diagnostic misclassification can lead to significant loss of power to detect a true linkage, particularly for loci with modest effects as are likely to be found in IBD.

Objective: The impact of chronic illness is influenced not just by physical symptoms but also by psychosocial factors. The aim of this study was to determine the concerns of inflammatory bowel disease (IBD) patients in a clinical sample, if concerns differ between patients from varied clinical and demographic variables, and if concerns influence well-being beyond the influence of physical symptoms., Methods: Subjects (n = 259) completed a validated measure of concerns specific to IBD and provided demographic and disease-related information., Results: The most intense concerns involved both physical (e.g., energy level) and psychosocial issues (e.g., achieving full potential). There were numerous differences in disease concerns based on ability to work but none based on disease duration. Factor analysis yielded three indices: body image and interpersonal concerns, general physical impact, and disease stigma. Age and education only affected certain concern indices in subgroups of patients. Greater concerns negatively influenced well-being beyond the influence of physical symptoms., Conclusion: Psychosocial factors, in addition to physical symptoms, play an important role on the impact of illness in patients with IBD.

Colorectal cancer (CRC) occurs with an increased incidence in individuals with chronic inflammatory bowel disease (IBD) of the colon. Recent data suggest that a family history of colorectal cancer is an independent risk factor for CRC in IBD, an observation that implies that genetic factors are relevant to the development of CRC in this context. Among the genetic defects associated with CRC, the APC I1307K mutation has been detected nearly exclusively in individuals of Ashkenazi Jewish (AJ) origin, occurring in 6%-7% of the AJ general population and in 10%-28% of AJ with a either a personal or family history of CRC or adenomatous polyps. These findings, together with the increased incidence of IBD in AJ, prompted the current analysis of the contribution of the APC I1307K variant of CRC in AJ IBD patients. APC I1307K carrier frequencies were determined in 306 AJ individuals affected with IBD and 308 of their unaffected relatives ascertained from a family collection obtained for the identification of IBD susceptibility genes. Prevalence of the I1307K variant was not significantly different among individuals with IBD, Crohn's disease, ulcerative colitis, and unaffected relatives (6.9%, 7.6%, 4.7%, and 6.2%, respectively), and the mutation was detected in only one of five IBD-affected individuals with a diagnosis of CRC. These results reveal that IBD patients of AJ origin carry the APC I1307K variant at the same rate as individuals within the general AJ population. Lack of an increased APC I1307K carrier rate suggests that this mutation does not account for the increased CRC susceptibility associated with IBD.

Background & Aims: Linkage data derived from genome-wide scans of inflammatory bowel disease (IBD) sibling-pair families have identified 4 loci on chromosomes 3, 7, 12, and 16 as potential sites for IBD susceptibility genes. The aim of this study was to investigate whether linkage analysis of another independently collected set of sibling pairs with IBD would provide further evidence of linkage between these previously reported loci and IBD., Methods: Using the MAPMAKER/SIBS program, the segregation of 21 microsatellite marker loci spanning the 4 putative IBD gene loci was analyzed in a study population comprising 161 families with 114 Crohn's disease, 36 ulcerative colitis, and 50 mixed IBD sibling pairs from the Greater Toronto area., Results: The results of multipoint linkage analysis showed no evidence for linkage between IBD and each of the 21 marker loci studied; the logarithm of odds scores in all instances were less than 0.8. These linkage data were found, by exclusion mapping analysis, to exclude values of lambdas ranging from 1.5 to 3.0, depending on the locus evaluated., Conclusions: The loci previously suggested as representing IBD susceptibility loci are not linked to IBD in the Toronto population examined in this analysis.

Background: People with inflammatory bowel disease (IBD) cope with a number of disease-specific concerns, which may result in referrals for supportive counselling., Objective: To determine differences between the health-related concerns of people with IBD who seek counselling or are referred for psychiatric assessment and those who have no recent contact with counselling or psychiatry., Methods: Forty-five consecutive patients with IBD referred for psychiatric consultation and 31 IBD out-patients who had recent counselling were compared with 190 IBD out-patients at the same hospital with no recent history of counselling. Disease-related concerns, demographic data and perceived symptom severity were assessed with self-report instruments., Results: Counselling patients had greater overall intensity of concern. Counselling patients differed from noncounselling patients on several measures related to illness severity and were more likely to be female. Correcting statistically for illness severity and sex, the counselled patients had significantly higher levels of concern about being a burden, pain and suffering, feeling out of control, financial difficulties, feeling alone, sexual performance, feeling dirty or smelly and being treated as different., Conclusions: Beyond the intensity of their physical suffering, patients who seek counselling report a pattern of concern in which interpersonal and emotional concerns are prominent compared with those of out-patients who do not seek counselling. Clinicians should be aware of interpersonal concerns, which may increase the need for empathic support. Psychosocial interventions in IBD may be indicated without respect to psychiatric comorbidity.

Unlabelled: Health-related quality of life (HRQOL) is a quantitative measurement of subjective perception of health state, including emotional and social aspects. It can be reliably measured with several valid instruments. Previous reviews of the literature suggested inadequate attention to HRQOL in studies of interventions in inflammatory bowel disease., Purpose: This study was undertaken to assess the current status of the quality of measurement of HRQOL in studies of inflammatory bowel disease and to review the clinical conclusions warranted by the literature., Method: Medicine was searched for articles relating to ulcerative colitis, Crohn's disease, or inflammatory bowel disease and quality of life since 1981. The articles found were reviewed for citations of further articles. The adequacy of HRQOL measure was assessed and graded, and the study design was categorized to assess the strength of the literature on the whole., Results: A trend was found toward higher quality of HRQOL measurement in the period 1988 to 1994 compared with 1981 to 1987. Most of the improvement was because of increased use of standardized and multidomain but unvalidated and unpublished questionnaires for measurement., Conclusions: Confidence in the following clinical conclusions in studies of surgical interventions in inflammatory bowel disease is limited by study design: that pelvic pouch is not inferior to ileostomy, that specific domains of HRQOL are differentially affected by different surgical procedures, and (with less confidence) that surgery is helpful in Crohn's disease. Medical studies have demonstrated that high quality HRQOL measures can be integrated into randomized, prospective trials. Clinically equivalent treatments have shown differential effects or HRQOL: 9 mg daily of budesonide is superior to 15 mg, and hydrocortisone foam enemas are superior to prednisolone. Home parenteral nutrition has received modest support, limited again by study design. It is recommended that standard tests of HRQOL be used to increase comparability of studies and to increase the quality of this literature in general. In particular the Inflammatory Bowel Disease Questionnaire, Rating Form of Inflammatory Bowel Disease Concerns, and Direct Questioning of Objectives are recommended.

Malnutrition is a frequent occurrence in patients with acute inflammatory bowel disease. Total nutritional support provided either parentally (TPN) or enterally (TEN) has been advocated not only as an adjunct for improving nutrition but also as primary therapy. For patients with acute Crohn's disease, short-term rates of remission after TEN are equivalent to TPN. Coupled with certain advantages when compared with TPN, including simpler administration, fewer side effects, and preservation of the intestinal mucosal barrier, TEN may therefore be the preferred route for nutrient delivery. Controlled trials indicate equivalent or superior efficacy when enteral polymeric diets are compared with elemental diets for inducing remission in acute Crohn's disease. Moreover, when provided as an elemental diet, TEN is as effective as corticosteroids for achieving remission in acute Crohn's disease, but corticosteroids appear to be more effective than polymeric diets. Although the provision of nutritional support rather than bowel rest is the major factor contributing to symptomatic improvement, the optimal nutrient composition and the precise mechanisms whereby nutritional support achieves clinical remission remain to be clarified. In contrast to Crohn's disease, nutritional support is not effective for achieving remission in patients with ulcerative colitis. Thus, enteral nutritional support is an effective therapy for the short-term management of acute Crohn's disease. Whether long-term remission is equivalent to treatment with drugs or surgery requires prospective evaluation. Future avenues of investigation also include defining the optimal nutrient composition and the underlying mechanisms that achieve maximal nutritional repletion, promote mucosal cell renewal, and potentially directly retard production of inflammatory mediators.

Background Patients with Crohn's disease ( CD) may experience disease relapse on maintenance infliximab. Anti-drug antibodies likely contribute to loss of response, and serum infliximab levels likely correlate with efficacy. Aim To prospectively evaluate the relationship between trough serum infliximab concentration and disease activity. Methods Adult patients ( N = 327) with a diagnosis of CD who had received at least five consecutive infliximab infusions and who planned to receive at least two additional infusions were enrolled. The Crohn's Disease Activity Index ( CDAI), serum infliximab, C-reactive protein ( CRP) and antibodies-to-infliximab ( ATI) were assessed at baseline, week 4 and week 8. Receiver operating characteristic ( ROC) analysis examined the relationship between infliximab concentrations and disease activity. Results The mean CDAI score, which decreased 1.05 points between infusions, did not correlate with the mean change in trough infliximab concentration (+0.39 μg/mL; r = 0.099, P = 0.083), but was associated with the mean change in CRP concentration ( r = 0.19, P < 0.001). Trough infliximab concentrations below 2.8-4.6 μg/mL best predicted a ≥ 70 point increase in the CDAI between infusions, and those below 2.7-2.8 μg/mL best predicted CRP >5 mg/mL at the second infusion. ATI at either visit decreased the proportion of patients with therapeutic infliximab trough levels compared with patients who were ATI negative (17.5% vs. 77.3% at visit 1 and 13.8% vs. 75.6% at visit 3; P < 0.001 for both comparisons). Conclusions This prospective study confirms the relationship between trough infliximab concentrations, inflammation and antibodies-to-infliximab. Infliximab trough concentrations below 3 μg/mL may increase the likelihood of symptoms and inflammation (ClinicalTrials.gov identifier: NCT00676988). [ABSTRACT FROM AUTHOR]