Marla Dubinsky

A Disease-Associated Microbial and Metabolomics State in Relatives of Pediatric Inflammatory Bowel Disease Patients

Background & Aims Microbes may increase susceptibility to inflammatory bowel disease (IBD) by producing bioactive metabolites that affect immune activity and epithelial function. We undertook a family based study to identify microbial and metabolic features of IBD that may represent a predisease risk state when found in healthy first-degree relatives. Methods Twenty-one families with pediatric IBD were recruited, comprising 26 Crohn’s disease patients in clinical remission, 10 ulcerative colitis patients in clinical remission, and 54 healthy siblings/parents. Fecal samples were collected for 16S ribosomal RNA gene sequencing, untargeted liquid chromatography–mass spectrometry metabolomics, and calprotectin measurement. Individuals were grouped into microbial and metabolomics states using Dirichlet multinomial models. Multivariate models were used to identify microbes and metabolites associated with these states. Results Individuals were classified into 2 microbial community types. One was associated with IBD but irrespective of disease status, had lower microbial diversity, and characteristic shifts in microbial composition including increased Enterobacteriaceae, consistent with dysbiosis. This microbial community type was associated similarly with IBD and reduced microbial diversity in an independent pediatric cohort. Individuals also clustered bioinformatically into 2 subsets with shared fecal metabolomics signatures. One metabotype was associated with IBD and was characterized by increased bile acids, taurine, and tryptophan. The IBD-associated microbial and metabolomics states were highly correlated, suggesting that they represented an integrated ecosystem. Healthy relatives with the IBD-associated microbial community type had an increased incidence of elevated fecal calprotectin. Conclusions Healthy first-degree relatives can have dysbiosis associated with an altered intestinal metabolome that may signify a predisease microbial susceptibility state or subclinical inflammation. Longitudinal prospective studies are required to determine whether these individuals have a clinically significant increased risk for developing IBD.

Diagnostic and Prognostic Microbial Biomarkers in Inflammatory Bowel Diseases

The microbiome plays multifaceted roles in the pathogenesis of inflammatory bowel diseases (IBD). Accordingly, the clinical challenge of patient heterogeneity in disease phenotype and response to treatment should in part be addressed by biomarkers that detect the host response to microbiota, and the levels of microbial taxa and products eliciting the host response in susceptible individuals. Molecular analysis has revealed much evidence for microbial taxonomic membership and microbial products in association with IBD, but their utility as clinical biomarkers is still in its infancy. A rich area of progress has been the development and validation of host serologic microbial biomarkers, which have achieved a distinctive position in the diagnosis and prognosis in IBD, and as a template for defining other categories of microbial biomarkers in disease state and phenotype.

Dissecting allele architecture of early onset IBD using high-density genotyping

Background The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent. Methods We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn’s disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn’s disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases. Conclusions The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

Preclinical disease and preventive strategies in IBD: perspectives, challenges and opportunities

IBDs, encompassing Crohns disease (CD) and UC, are chronic, relapsing and remitting, inflammatory diseases of the GI tract. IBD is emerging as a globally important disease with epidemiological studies showing that there is a significant increase in IBD’s incidence in most regions of the world.1 In high-incidence areas such as North America, disease already affects around 0.6% of the population.1 As low/middle-income countries continue to become more industrialised, an increasing incidence is also expected to occur in areas of the globe where IBD was previously considered rare.2 ,3 Furthermore, as trends in life expectancy increase globally, the emergence of chronic health conditions, including IBD, will represent a growing proportion of individual and society health impact. The recent acknowledgement that IBD is a progressive disease has changed the focus of therapeutic strategies. It is now widely accepted that treating effectively at earlier stages of disease, before bowel damage occurs, is likely to produce better outcomes, resulting in reduced rates of hospitalisation and surgery.4 Unfortunately, despite ongoing efforts to change therapeutic paradigms, combining early diagnosis with best available effective therapies, drug-free remission or absence of progression of bowel wall damage remains a challenge in many patients.5 ,6 Once the diagnosis of IBD is made, bowel damage has already occurred in a significant number of patients, and the immune dysregulation, dysbiosis and tissue injury associated with full-blown disease is set, and in many cases, irreversible.6 At present, all therapeutic interventions in IBD target well-established disease, and even the most potent agents are not able to prevent or reverse chronic damage often present at diagnosis. In order to truly change the natural history and long-term consequences of IBD, an effective intervention should ideally occur at an earlier phase, targeting the primary biological processes that drive disease …

Transition of Inflammatory Bowel Disease Care: Assessment of Transition Readiness Factors and Disease Outcomes in a Young Adult Population

Background:Limited data exist on what factors impact transition readiness and how readiness impacts short-term disease outcomes. Methods:Patients between the ages of 18 and 25 with an established inflammatory bowel disease diagnosis completed questionnaires at the time of an outpatient visit in the pediatric or adult setting, which included the Transition Readiness Assessment Questionnaire (TRAQ). After 6 months, electronic medical records were reviewed. Results:A total of 95 patients were enrolled, 46 in the adult care setting and 49 in the pediatric care setting. Patients in the adult setting had a significantly higher overall TRAQ score compared with the pediatric setting (median: 4.42 [IQR: 3.9–4.6] versus 4.06 [IQR: 3.4–4.4], P < 0.001). Logistic regression analysis demonstrated that age was independently associated with higher TRAQ scores (odds ratio: 1.49; 95 confidence interval%, 1.1–2.02). Nonadherent patients scored lower on the Managing Medications subscale (median: 4.25 [IQR: 3.3–4.8] versus 4.75 [IQR: 4.3–5.0], P < 0.01). Logistic regression showed that patients who scored <4.75 on the Medication Management subscale were 3.8 times more likely to be nonadherent than patients who scored ≥4.75 (95% confidence interval, 1.4–10.3). This remained significant after adjusting for gender and age. During the 6-month follow-up period, 9/95 patients (10%) had hospitalizations or ED visits related to inflammatory bowel disease. There were no associations between TRAQ scores and hospitalizations/ED visits. Conclusions:Age is the primary factor that drives transition readiness. Our findings suggest that administering the medication management portion of the TRAQ can be used to identify patients at risk for nonadherence. Follow-up studies are needed to determine how readiness impacts long-term disease outcomes.

Appropriateness of Testing for Anti–Tumor Necrosis Factor Agent and Antibody Concentrations, and Interpretation of Results

BACKGROUND & AIMS The availability of tests for blood concentrations of anti-tumor necrosis factor (TNF) agents and antibodies against these drugs could improve dose selection for patients with inflammatory bowel disease (IBD). However, there is little consensus on when to test and how to interpret test results. We used the RAND/UCLA Appropriateness Method to determine when these tests are appropriate and how to clinically interpret their results. METHODS We conducted a systematic literature search in November 2013 to identify observational or experimental studies of the measurement of anti-TNF drug and antibody concentrations in patients with IBD and interpretation of their results. We developed 35 scenarios that assessed the appropriateness of testing and 143 scenarios that addressed clinical strategies in response to test results, and presented the findings to an expert panel. The appropriateness of each scenario was rated before and after an in-person meeting with the panel. Panelists rated the appropriateness of various clinical management options including changing therapy within class, switching out of class, adjusting drug dose or interval, adding or adjusting concomitant immune modulators, and doing nothing for each of 6 permutations of high versus low drug concentrations and high, low, or undetectable antibody concentrations. Disagreement was assessed using a validated index. RESULTS Assessment of anti-TNF drug and antibody concentrations was rated appropriate at the end of induction therapy in primary nonresponders, in secondary nonresponders, at least once during the first year of maintenance therapy, and following a drug holiday. Routine assessment in responders at the end of induction was rated uncertain. In nearly all scenarios, escalation of drug dosing was rated appropriate when drug concentration was low in the absence of antibodies, and switching within class was rated appropriate when antibodies were present. Other recommendations depended on the specific clinical scenario for which the test was obtained. CONCLUSIONS Based on the RAND/UCLA Appropriateness Method of analysis, an expert panel recommends testing for drug and antibody concentrations in many clinical scenarios. The appropriate timing and best way to respond to anti-TNF drug and antibody testing for IBD depends on the specific clinical scenario. These recommendations can help guide clinicians to best optimize anti-TNF therapy.

Long-Term Efficacy and Safety of Adalimumab in Pediatric Patients with Crohn's Disease

Background: IMAgINE 1 assessed 52-week efficacy and safety of adalimumab in children with moderate to severe Crohns disease. Long-term efficacy and safety of adalimumab for patients who entered the IMAgINE 2 extension are reported. Methods: Patients who completed IMAgINE 1 could enroll in IMAgINE 2. Endpoints assessed from weeks 0 to 240 of IMAgINE 2 were Pediatric Crohns Disease Activity Index remission (Pediatric Crohns Disease Activity Index ⩽ 10) and response (Pediatric Crohns Disease Activity Index decrease ≥15 from IMAgINE 1 baseline) using observed analysis and hybrid nonresponder imputation (hNRI). For hNRI, discontinued patients were imputed as failures unless they transitioned to commercial adalimumab (with study site closure) or adult care, where last observation was carried forward. Corticosteroid-free remission in patients receiving corticosteroids at IMAgINE 1 baseline, discontinuation of immunomodulators (IMMs) in patients receiving IMMs at IMAgINE 2 baseline, and linear growth improvement were reported as observed. Adverse events were assessed for patients receiving ≥1 adalimumab dose in IMAgINE 1 and 2 through January 2015. Results: Of 100 patients enrolled in IMAgINE 2, 41% and 48% achieved remission and response (hNRI) at IMAgINE 2 week 240. Remission rates were maintained by 45% (30/67, hNRI) of patients who entered IMAgINE 2 in remission. At IMAgINE 2 week 240, 63% (12/19) of patients receiving corticosteroids at IMAgINE 1 baseline achieved corticosteroid-free remission and 30% (6/20) of patients receiving IMMs at IMAgINE 2 baseline discontinued IMMs. Adalimumab treatment led to growth velocity normalization. No new safety signals were identified. Conclusions: Efficacy and safety profiles of prolonged adalimumab treatment in children with Crohns disease were consistent with IMAgINE 1 and adult Crohns disease adalimumab trials.

Real World Experience With Natalizumab at a Tertiary Care Pediatric IBD Center.

Objectives: Natalizumab is a humanized monoclonal antibody inhibiting lymphocyte migration and prescribed in patients with Crohn disease (CD) failing anti-tumor necrosis factor (TNF) therapies. Because of the risk of progressive multifocal leukoencephalopathy in patients with John Cunningham virus (JCV) positive, natalizumab is not widely used in clinical practice. Published experience of the use of natalizumab in pediatric patients is lacking. We aimed to describe the experience of natalizumab in patients with CD, including those who are JCV positive, at a tertiary care pediatric inflammatory bowel disease center. Methods: A retrospective chart review was performed in patients with CD <21 years receiving natalizumab therapy before March 2014. Patient and disease information, prior treatments and response to natalizumab, including Harvey Bradshaw Index (HBI), were recorded. Descriptive statistics were computed. Results: Nine patients received natalizumab with a median age at diagnosis of 10 (range 7–16) years and median disease duration 72 (range 13–156) months. All of the patients had failed at least 1 anti-TNF agent. At baseline, the median HBI was 8 (IQR 6.5–11). By week 10, the median HBI was 4.5 (IQR 2–6), with 4 of 8 (50%) patients with CD being in remission. Forty-four percent (4/9) of patients were JCV antibody positive at baseline and had anti-JCV antibody index >0.9 (median 3.36). There were no serious adverse events, including progressive multifocal leukoencephalopathy. All of the patients were transitioned to vedolizumab. Conclusions: In our experience, natalizumab is a safe and efficacious medication in pediatric in patients with inflammatory bowel disease. Given the favorable results with natalizumab, pediatric studies with the more gut targeted anti-integrin agent vedolizumab are warranted.

The Influence of Hormonal Fluctuation on Inflammatory Bowel Disease Symptom Severity—A Cross-Sectional Cohort Study

Background Many women with inflammatory bowel disease (IBD) report changes in symptoms in association with hormonal changes during menses, pregnancy, and hormonal contraceptive use, suggesting a hormonal influence on disease activity. We aimed to identify and characterize IBD symptom fluctuations in women during times of hormonal variation. Methods From June 2012 through September 2012, women enrolled in Crohns and Colitis Foundation of America Partners , an online Internet cohort of patients with IBD, were invited to participate in this study. Using a 5-point Likert scale, participants were asked to rate symptom changes during their menstrual cycle, pregnancy, the postpartum period, and after menopause. Clinical and demographic differences were assessed using univariate and multivariable methods. Results A total of 1,203 female patients with Crohns disease (CD) and ulcerative colitis (UC) participated (64% CD, 34% UC). Over half of the women with IBD reported worsening symptoms during menses. Symptom changes were similar between women with CD vs UC, except in pregnancy, where symptom worsening during pregnancy was more commonly seen in UC than CD (P = 0.02). Overall, women reporting symptom worsening were younger at the time of IBD diagnosis (P < 0.01), had lower quality of life (SIBDQ) scores (P < 0.01), and had a higher BMI (25 vs 24) than women without symptom worsening. Conclusions Women with IBD report changes in symptom severity during times of hormone fluctuation. Further clarification of the role of hormones in IBD is warranted in order to understand these relationships and to identify potential management strategies for women with IBD and hormonally sensitive gastrointestinal symptoms.

Gut microbiota density influences host physiology and is shaped by host and microbial factors

To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn’s disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.