Jessica J. Lee

Established genetic risk factors do not distinguish early and later onset Crohn's disease

Background: Early‐onset disease is frequently examined in genetic studies because it is presumed to contain a more severe subset of patients under a higher influence of genetic effects. In light of the dramatic success of Crohns disease (CD) gene discovery efforts, we aimed to characterize the contribution of established common risk variants to pediatric CD. Methods: Using 35 confirmed CD risk alleles, we genotyped 384 parent–child trios (mean age of onset 11.7 years) along with 321 healthy controls. We performed association tests on the independent pediatric cohort and compared results to those previously published.1 We also computed a weighted CD genetic risk score for each affected person. Six variants not previously validated in children (at 5q33, 1q24, 7p12, 12q12, 8q24, and 1q32) were significantly associated with pediatric CD (P < 0.03). Results: We detected no significant association between risk score and age at onset through age 30. This analysis illustrates that the genetic effect of established CD risk variants is similar in early and later onset CD. Conclusions: These results motivate joint analyses of genome‐wide association data in early and late onset cohorts and suggest that, rather than established risk variants, independent variants or environmental exposures should be sought as modulators of age of onset.

Agreement between patient- and physician-completed Pediatric Ulcerative Colitis Activity Index scores.

Objectives:Currently validated ulcerative colitis (UC) activity measures are physician based, but incorporate patient reports of symptoms. We aimed to assess whether patient-completed Pediatric UC Activity Index (PUCAI) scores are comparable to those of physician scores. Patients and Methods:We performed a single-center prospective study to assess agreement between patient- and physician-completed PUCAI scores. Seventy patients with UC (ages 4–29) representative of all of the disease activity categories (inactive, mild, moderate, and severe) in the currently published physician-completed scoring system were recruited. Agreement was analyzed for PUCAI scores both as continuous and categorical measures. To ascertain validity, we compared both patient- and physician-completed PUCAI scores with the physician global assessment and serum inflammatory markers. Results:Patient- and physician-completed PUCAI summary scores were identical 49% of the time, were different but within the minimal clinically important difference (MCID) of 20 points 48% of the time, and were at or beyond the MCID only 3% of the time. In general, patients reported higher mean disease severity on their questionnaires than did their physicians, with a mean difference in PUCAI scores of 3 ± 8 (95% confidence interval 2%–5%). A categorical comparison of the 2 sets of questionnaires using the disease activity groups demonstrated perfect agreement for 60 (86%) pairs (kappa coefficient 0.78; 95% confidence interval 0.65%–0.90%). Both patient- and physician-completed PUCAI scores also correlated well with the physician global assessment and serum inflammatory markers. Conclusions:Our data indicate strong agreement between PUCAI scores obtained directly from patients and those completed by physicians. Hence, a patient-based PUCAI could complement existing instruments in both clinical and research settings.

Association of linear growth impairment in pediatric Crohn's disease and a known height locus: a pilot study

The etiology of growth impairment in Crohns disease (CD) has been inadequately explained by nutritional, hormonal, and/or disease‐related factors, suggesting that genetics may be an additional contributor. The aim of this cross‐sectional study was to investigate genetic variants associated with linear growth in pediatric‐onset CD. We genotyped 951 subjects (317 CD patient–parent trios) for 64 polymorphisms within 14 CD‐susceptibility and 23 stature‐associated loci. Patient height‐for‐age Z‐score < −1.64 was used to dichotomize probands into growth‐impaired and nongrowth‐impaired groups. The transmission disequilibrium test (TDT) was used to study association to growth impairment. There was a significant association between growth impairment in CD (height‐for‐age Z‐score < −1.64) and a stature‐related polymorphism in the dymeclin gene DYM (rs8099594) (OR = 3.2, CI [1.57–6.51], p = 0.0007). In addition, there was nominal over‐transmission of two CD‐susceptibility alleles, 10q21.1 intergenic region (rs10761659) and ATG16L1 (rs10210302), in growth‐impaired CD children (OR = 2.36, CI [1.26–4.41] p = 0.0056 and OR = 2.45, CI [1.22–4.95] p = 0.0094, respectively). Our data indicate that genetic influences due to stature‐associated and possibly CD risk alleles may predispose CD patients to alterations in linear growth. This is the first report of a link between a stature‐associated locus and growth impairment in CD.

Alternate endpoints and clinical outcome assessments in pediatric ulcerative colitis registration trials.

Objectives: Presently, there is no consensus on endpoint measures to assess clinical outcomes for pediatric ulcerative colitis (UC). This study reviewed the endpoints used in the registration trials of approved drugs for pediatric UC. Methods: The primary efficacy endpoints of all registration trials completed from 1950 to 2008 that led to Food and Drug Administration approval for indications in pediatric and adult UC were reviewed. Results: Colazal and Remicade have been approved for pediatric UC indication, and clinical response was used as a primary endpoint in these registration trials. The clinical response in the adult Colazal trials was defined as a reduction of rectal bleeding and improvement in at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physicians global assessment) assessed by the Sutherland UC Activity Index. The pediatric Colazal trial defined clinical response using the Modified Sutherland UC Activity Index, which excluded abdominal pain and functional assessment. Both adult and pediatric Remicade trials used clinical response defined by the Mayo score as the primary endpoint. The Pediatric Ulcerative Colitis Activity Index was used to measure various secondary endpoints in the pediatric Remicade trial. Conclusions: Pediatric-specific endpoints were used, but outcome measures and definition of clinical response were not consistent in pediatric UC trials. Consensus on the definition of successful treatment outcome (clinical response and/or remission) and collaboration in the development of well-defined and reliable measures of signs and symptoms for use in conjunction with endoscopic parameters of mucosal healing will facilitate pediatric drug development.

Well-defined and reliable clinical outcome assessments for pediatric Crohn disease: a critical need for drug development.

Objectives: The aim of the present study was to identify areas for further development of clinical outcome assessment (COA) in pediatric Crohn disease (CD). Methods: The study analyzed the measurement properties of all existing COA tools for pediatric CD in literature and published registration trials of approved drugs for pediatric CD based on criteria described in Food and Drug Administration guidance for patient-reported outcome (PRO) development. Results: The Pediatric Crohns Disease Activity Index (PCDAI) and its derivatives (abbreviated, short, modified, and weighted PCDAIs) were reviewed. The Crohns Disease Activity Index (CDAI) and Harvey-Bradshaw index (HBI), designed for adult patients, have been adapted for use in a few pediatric CD studies. The use of PCDAI as an endpoint in Remicade and Humira trials led to the Food and Drug Administration–approved indication in pediatric CD. Common issues in measurement properties of COA tools included the absence of direct patient or caregivers’ input to generate the items measuring signs and symptoms; absence of evidence demonstrating correlation with clinically relevant inflammation observed with endoscopic measures; lack of standardization in measurement, age-appropriate interviewer script, and response rating criteria for the physician interviewer. Conclusions: Available evidence indicates that CDAI, HBI, and 5 versions of the PCDAI lack adequate measurement properties for use as a primary endpoint for phase 3 trials intended to support approval of products intended to treat pediatric CD. In order to facilitate pediatric drug development, a well-defined, reliable, sensitive, and globally recognized PRO that measures signs and symptoms in children with CD and that can be used in conjunction with endoscopy-based endpoints and/or biomarkers is sorely needed.

Late adolescent linear growth pattern in pediatric-onset inflammatory bowel disease.

ABSTRACT The late adolescent linear growth pattern of pediatric patients with inflammatory bowel disease (IBD) has rarely been studied. We retrospectively reviewed the height measurements of 475 patients with IBD at 16, 18, and 20 years old for girls, and 18 and 20 years old for boys. We also compared Bayley-Pinneau bone age–predicted and –measured adult heights. Female patients had mean height-for-age z scores of −0.25 ± 1.0 at 16 years and −0.23 ± 1.0 at 18 years (P = 0.189); boys had z scores of −0.30 ± 1.1 at 18 years and −0.26 ± 1.0 at 20 years, respectively (P = 0.105). Bayley-Pinneau height predictions were 1.5 and 2.4 cm greater than measured height for 18-year-old girls (P = 0.060) and 20-year-old boys (P = 0.017), respectively. Our data indicate that most patients with IBD attain adult height within normal timing for the population. Hence, early identification of growth impairment is critical to appropriate management in IBD.

Potential role of IGF-1 z score to predict permanent linear growth impairment in children with IBD.

ABSTRACT In this pilot study, we analyzed serum insulin-like growth factor 1 (IGF-1)- and IGF-binding protein-3-for-age z scores from 54 inflammatory bowel disease children with no, temporary, or permanent growth impairment. Although our findings did not reach statistical significance, patients with permanent linear growth impairment had lower IGF-1-for-age z scores (−1.76 [−2.25 to −0.43]) compared with those with no or temporary growth impairment (−0.84 [−1.49 to −0.3]) and −1.16 [−1.59 to −1.51], respectively). IGF-binding protein-3 levels were similar across the 3 groups. In the absence of significant inflammation and malnutrition, lower IGF-1-for-age z scores may help distinguish patients likely to have permanent growth impairment from those whose growth impairment is likely to be temporary.

Su1083 Can Crohn's Disease Activity Index Differentiate Clinical Remission Induced by Placebo Versus Biologics Treatment? – Analyses of Six Clinical Trials for Crohn's Disease

Crohns Disease Activity Index (CDAI), a composite score based on eight subcomponents, has been used to assess the efficacy of drugs for Crohns Disease (CD). However, the existence of a high placebo rate has been a challenge in clinical trials that have used CDAI as the primary endpoint. To better understand the placebo effect, we evaluated the change from baseline in CDAI and its subcomponents in patients who achieved remission in response to placebo or active treatment. Patient-level data were reviewed from six phase 2 and phase 3 clinical trials that were submitted to FDA in support of three biological products for treatment of CD. Clinical remission was defined as CDAI < 150 in all six trials, and the induction of remission was assessed at a pre-defined time-point. We evaluated the overall change from baseline in CDAI and its subcomponents in achieving remission and identified major contributing subcomponents. We compared changes in CDAI and major contributing subcomponents in patients who achieved remission by placebo or active treatments. Mean baseline CDAI across trials ranged from 294 to 313 in placebo groups and 295 to 312 in active treatment groups. The rate of remission ranged from 8.2% to 30.3% among the placebo groups and 22.2% to 39.6% among the active treatment groups across six trials. For remitters, the average decrease from baseline in CDAI score was 167 in the placebo groups and 186 in active treatment groups across six trials. Greater than 80% of the decrease in the overall CDAI score was attributed to a decrease in three subcomponent scores: general well-being [WB] (40%), abdominal pain [AP] (25%), and stool frequency [SF] (22%). The relative contribution of each subcomponent to achieve remission was similar between placebo

Role of intestinal gene expression profiles in the diagnosis of Inflammatory Bowel Disease: P-174.

by short loops. The mutation lies in the splice acceptor site of intron 3 of the seven exon gene, and affects a thymine base five nucleotides from the next exon. cDNA sequencing revealed that the mutation results in skipping of exon 4. Splicing of exon 3 to exon 5 creates a frameshift and a premature stop codon. The Klein-Zschocher mouse showed severe weight loss after administration of 1% DSS in the drinking water. Periodic acid-Schiff stain staining of small intestines and colons of Klein-Zschocher mice revealed reduced numbers of Paneth and goblet cells in naı̈ve mutant mice. Furthermore, electron microscopy of the small intestine and colon of naive Klein-Zschocher mice showed abnormal vesicles in Paneth and goblet cells of the mutant mice. Defective Paneth cells of KleinZschocher mutant mice show enhanced autophagy as demonstrated by LC3 Western blotting. In addition, the intestinal permeability was increased 85% in KleinZschocher mice demonstrating epithelial barrier dysfunction in these mice. Disturbed epithelial integrity together with abnormal Paneth and goblet cells explain the increased susceptibility in the DSS colitis model. Taken together, using random mutagenesis and the DSS mouse model we found new genes and new functions of known genes that might play a role in IBD. A coherent picture of the essential events required for homeostasis has begun to emerge.