Jason Shapiro

Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

BACKGROUND Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohns disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. METHODS We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohns disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. FINDINGS Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohns disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the models specificity improved to 71%. INTERPRETATION Our findings support the usefulness of risk stratification of paediatric patients with Crohns disease at diagnosis, and selection of anti-TNFα therapy. FUNDING Crohns and Colitis Foundation of America, Cincinnati Childrens Hospital Research Foundation Digestive Health Center.

Rates and Predictors of Oral Medication Adherence in Pediatric Patients with IBD

Background:Symptoms of inflammatory bowel disease (IBD) include bloody diarrhea, fatigue, abdominal pain, and weight loss. Long-term management of remission for most patients requires adherence to taking 1 or more oral medications daily, in the absence of symptoms. We investigated whether disease characteristics and behavioral characteristics predict adherence to prescribed medical regimens. Methods:Patients aged 8 to 17.5 years, newly diagnosed with IBD, and a matched cohort previously diagnosed were studied over a 6-month period. Adherence was assessed using medication electronic monitoring devices (Medication Event Monitoring Systems); participants and parents completed questionnaires regarding emotional and behavioral functioning, and biological parameters were monitored. Results:Adherence was monitored for 45 newly and 34 previously diagnosed patients. In total, 16,478 patient-days (including 12,066 discrete days) were electronically monitored. Overall, 70.6% of 5-aminosalicylic acid and 65.4% of 6-mercaptopurine doses were taken. Only 25% and 15% of older adolescents took at least 80% of their 5-aminosalicylic acid and 6-mercaptopurine, respectively, compared with about 83% and 64% of 8-year-olds to 11-year-olds. Only age and behavioral issues were statistically linked to rates of adherence. Conclusions:Adherence to commonly prescribed oral medications for IBD is challenging for patients. Screening for emotional and behavioral problems, especially among older adolescents, would be important in identifying patients at risk of poor adherence, who might benefit from interventions. Biological solutions, although critical, when applied without attention to behavioral issues, are not likely to provide the level of therapeutic benefit that can be provided in a combined biobehavioral approach.

Depressive symptoms in youth with inflammatory bowel disease compared with a community sample.

Background:Previous investigations have produced mixed findings on whether youth with inflammatory bowel disease (IBD) experience elevated rates of depressive symptoms. Our first aim was to compare self-report of depressive symptoms by youth with IBD with a community sample. The second aim was to examine the relationship between symptoms of depression and measures of disease activity. Methods:Item-level responses on the Childrens Depression Inventory among a sample of 78 youth diagnosed with IBD were compared with responses from a community sample using 1-sample t-tests. Particular attention was given to items assessing somatic symptoms of depression given the potential overlap with IBD disease symptoms. The relationship between depressive symptoms and IBD disease activity was evaluated using Spearmans rank correlation coefficients and linear regression. Results:Youth with IBD reported lower levels of depressive symptoms compared with the community sample on the Childrens Depression Inventory Total Score, and similar or lower levels of difficulty on items assessing somatic symptoms. Most of the sample had inactive or mild disease activity at the time of participation, with 14% experiencing moderate/severe disease activity. Higher ratings of disease activity were related to greater depressive symptoms. Responses on somatic items from the Childrens Depression Inventory were not differentially related to disease activity. Conclusions:As a group, pediatric patients with IBD did not experience the clinical levels of depressive symptoms or elevations in depressive symptoms when compared with a community sample. Somatic symptoms of depression do not differentiate youth with IBD experiencing elevations in disease activity from youth experiencing nonsomatic symptoms of depression.

6-Thioguanine levels in pediatric IBD patients: adherence is more important than dose.

Background:Thiopurine immunosuppressants such as 6-mercaptopurine (6-MP) are widely used to maintain remission in children with both Crohns disease and ulcerative colitis. Therapeutic efficacy is associated with higher red blood cell levels of the thiopurine metabolite 6-thioguanine (6-TGN). Studies in both children and adults have inexplicably failed to demonstrate a significant correlation between prescribed dose and level of 6-TGN. We aimed to quantify the relationship between 6-TGN levels and adherence. Methods:We used electronic monitoring devices to assess adherence in children and adolescents with inflammatory bowel diseases who were prescribed 6-MP. Results:During 3230 days of monitoring in 19 subjects, adherence to 6-MP was 74.2%. Due to the generally low adherence to the prescribed dose of 6-MP, the 6-TGN level was not correlated with the prescribed dose. The 6-TGN level was significantly correlated with the adherence-adjusted dose (R2 = 0.395). It was also significantly correlated to adherence alone (R2 = 0.478). Adherence to 5-aminosalicylic acid and 6-MP were significantly positively correlated (rs (9) = 0.82, P = 0.00), and a significant relationship was found between 5-aminosalicylic acid adherence and 6-TGN levels independent of 6-MP adherence. Furthermore, low adherence to 6-MP was associated with increased likelihood of escalation of medical therapy. Conclusions:Red blood cell 6-TGN levels are strongly correlated with the dose, when the dose is actually taken. Lack of efficacy of thiopurines may often be the result of poor adherence. Novel ways of assessing and improving adherence are necessary. Future trials should assess adherence in study participants. Intake of 5-aminosalicylic acid positively influences 6-TGN levels.

Body image dissatisfaction in patients with inflammatory bowel disease.

Background:Despite the fact that the inflammatory bowel diseases (IBD) and their treatments may affect physical appearance, the effect of IBD on body image is poorly understood. The aims of this study were to determine whether body image dissatisfaction (BID) changes over time in patients with IBD and to examine the demographic and disease-related variables associated with decreased body image. Methods:Adults aged 18 and above in the Ocean State Crohns and Colitis Area Registry with at least 2 years of follow-up were eligible for this study. All patients were enrolled within 6 months of IBD diagnosis and followed prospectively. BID was assessed using a modified version of the Adapted Satisfaction With Appearance questionnaire. Total Adapted Satisfaction With Appearance scores and 2 subscores were calculated. To assess for changes over time, general linear models for correlated data were used for continuous outcomes, and generalized estimating equations were used for discrete outcomes. Results:Two hundred seventy-four patients were studied. BID was found to be stable over time among men and women with IBD despite overall improvements in disease activity. No differences were found in BID according to IBD subtype. Female gender, greater disease activity, higher symptom burden, longer duration of steroid use, dermatologic and musculoskeletal manifestations of IBD, and ileocolonic disease location among patients with Crohns disease were associated with greater BID. Greater BID was associated with lower health-related quality of life. Conclusions:BID remains stable in an incident cohort of IBD despite improved disease activity and is associated with lower health-related quality of life.

Serum Proteome Profiles in Stricturing Crohn's Disease: A Pilot Study.

Background:Crohns disease (CD) is a form of inflammatory bowel disease with different described behaviors, including stricture. At present, there are no laboratory studies that can differentiate stricturing CD from other phenotypes of inflammatory bowel disease. We performed a pilot study to examine differences in the proteome among patients with stricturing CD, nonstricturing CD, and ulcerative colitis. Methods:Serum samples were selected from the Ocean State Crohns and Colitis Area Registry, an established cohort of patients with inflammatory bowel disease. Patients with CD with surgically resected stricture were matched with similar patients with CD without known stricture and with ulcerative colitis. Serum samples from each patient were digested and analyzed using liquid chromatography–mass spectrometry to characterize the proteome. Statistical analyses were performed to identify peptides and proteins that can differentiate CD with stricture. Results:Samples from 9 patients in each group (27 total patients) were analyzed. Baseline demographic characteristics were similar among the 3 groups. We quantified 7668 peptides and 897 proteins for analysis. Receiver operating characteristic analysis identified a subset of peptides with an area under the curve greater than 0.9, indicating greater separation potential. Partial least squares discriminant analysis was able to distinguish among the three groups with up to 70% accuracy by peptides and up to 80% accuracy by proteins. We identified the significantly different proteins and peptides and determined their function based on previously published literature. Conclusions:The serum of patients with stricturing CD, nonstricturing CD, and ulcerative colitis is distinguishable through proteomic analysis. Some of the proteins that differentiate the stricturing phenotype have been implicated in complement activation, fibrinolytic pathways, and lymphocyte adhesion.

Incidence of Crohn's Disease and Ulcerative Colitis in Rhode Island: Report from the Ocean State Crohn's and Colitis Area Registry.

Background:Studies describing the incidence of Crohns disease (CD) and ulcerative colitis (UC) are uncommon in the United States. We sought to determine the incidence of CD and UC in the state of Rhode Island. Methods:The Ocean State Crohns and Colitis Area Registry is a state-based inception cohort of patients newly diagnosed with inflammatory bowel disease (IBD) in Rhode Island. To confirm a diagnosis of CD, UC, or IBD unclassified (IBDU), the National Institute of Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium criteria were applied in a review of medical records from gastroenterology practices located in the state of Rhode Island and adjacent to the Rhode Island border in Massachusetts and Connecticut. Using population-based data, we determined the statewide incidence of IBD in Rhode Island from 2008 to 2010. Results:A total of 971 Rhode Island residents were diagnosed with IBD, including 444 with CD, 486 with UC, and 41 with IBD unclassified from 2008 to 2010. The overall age- and sex-adjusted IBD incidence was 30.2 (95% confidence interval, 28.3–32.1) per 100,000 persons in this time frame with 13.9, 15.1, and 1.3 per 100,000 diagnosed with CD, UC, and IBD unclassified, respectively. Of the total incident cases in Rhode Island, 30% (n = 291) were enrolled in Ocean State Crohns and Colitis Area Registry for follow-up. Conclusions:The incidence of IBD in Rhode Island is higher than that previously reported by other population-based cohorts in the United States. Prospective follow-up of individuals enrolled in the community-based Ocean State Crohns and Colitis Area Registry cohort is ongoing.

Bridging the Gap Between Host Immune Response and Intestinal Dysbiosis in Inflammatory Bowel Disease: Does Immunoglobulin A Mark the Spot?

Inflammatory bowel disease (IBD) is a chronic, debilitating condition characterized by relapsing and remitting episodes of gastrointestinal inflammation. As the incidence and prevalence have increased, so has our understanding of the pathophysiology of this complex, immunologically mediated disease. With advances in bacterial and human gene sequencing technologies, a significant amount of work has focused on how alterations in the intestinal microbiome affect disease onset and progression. A recent study in Cell suggests that it may be possible to identify specific bacteria responsible for promoting a proinflammatory state by assessing the degree to which they are coated by the immunoglobulin (Ig) A. A combination of antibody-based bacterial cell sorting, flow cytometry, and 16s ribosomal RNA gene sequencing was used to identify IgA-coated bacteria from stool of specific pathogen-free mice. This technique was used to demonstrate that IgA-coated bacteria were indeed detectable and increased in a mouse model of colitis. Stool from patients with IBD was then used to generate 2 groups of IgA+ and IgA- bacterial consortia. When transplanted into specific pathogen-free mice, no initial clinical differences were noted. However, when mice with dextran sodium sulfate-induced colitis were transplanted with the IgA+ bacterial strains, they exhibited severe exacerbation of intestinal inflammation, whereas the IgA- group developed minimal symptoms. These findings suggest that bacteria highly coated with IgA are potentially responsible for driving gut inflammation in patients with IBD. These results may represent a critical advance in our understanding of the complex interactions between the host immune system and commensal microorganisms as it relates to the development and disease course of IBD. Future work will focus on how these findings can be translated into the development of individualized, microbiota-specific therapies.

Durability of Infliximab Is Associated With Disease Extent in Children With Inflammatory Bowel Disease.

Objectives: The aim of the study was to evaluate infliximab (IFX) dosing and treatment durability relative to luminal disease burden in patients with inflammatory bowel disease. Methods: Records from 98 pediatric patients treated with IFX between 2012 and 2014 were reviewed. Disease extent was classified as “limited,” “moderate,” or “extensive” based on cumulative assessment of mucosal involvement. Patients started taking standard 5 mg/kg dosing were compared with those initiated taking 10 mg/kg with regard to treatment durability. Results: Overall, 26.4%, 58.3%, and 70% with limited, moderate, or extensive disease, respectively, started taking a standard IFX dose of 5 mg/kg required therapy escalation. Patients with moderate and extensive disease, started taking the 5 mg/kg per dose, showed statistically significant shorter times to escalation than those with limited disease. The percentage of patients remaining on their initial 5 mg/kg per dose at 12 months was 80.1%, 56.9%, and 40.0% for limited, moderate, and extensive disease, respectively. Among patients started taking 10 mg/kg, 100% remained on this dose. All the patients with limited disease who required dose escalation continued on the higher dose at the time of analysis; however, among those with the most extensive disease, 43% failed escalation because of nonresponse or infusion reaction. Conclusions: Patients with extensive disease started taking 5 mg/kg of IFX were more likely to require dose escalation compared to those with limited or moderate disease. All of the patients with moderate and extensive disease started taking 10 mg/kg of IFX remained on this dose. These results suggest that patients with more extensive disease may benefit from higher initial IFX dosing as it relates to durability of the treatment.

Testing for Clostridium difficile in Patients Newly Diagnosed with Inflammatory Bowel Disease in a Community Setting

Background:The incidence of Clostridium difficile infection (CDI) in inflammatory bowel disease (IBD) is increasing, and CDI has a negative impact on IBD outcomes with both increased morbidity and mortality. Data are lacking regarding the rate of appropriate testing for CDI at the time of diagnosis. Methods:We sought to determine the rate of CDI testing and CDI positivity at diagnosis of IBD using data collected through the Ocean State Crohns and Colitis Area Registry (OSCCAR), a prospective cohort of patients with newly diagnosed IBD. CDI testing and CDI positivity were determined by reviewing the medical records of patients enrolled into the registry and diagnosed with IBD between January 2008 and July 2011. Results:Of 320 enrolled patients, 227 (70.9%) reported diarrhea, and CDI testing was performed for 113 (49.8%) of the 227 patients. CDI testing was not recorded as being performed for the remaining 114 patients who reported having diarrhea. An additional 24 patients were tested for CDI but did not report having diarrhea. Seven (5.1%) of the 137 patients tested for CDI were positive. Conclusions:Testing for CDI is significantly lower than expected at diagnosis of IBD. Although the prevalence of CDI among tested patients is approximately 5%, a low testing rate suggests a significant quality issue in the diagnosis of IBD, with the potential for delayed diagnosis of CDI.