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AGA Abstracts
combination of clinical factors and antimicrobial antibodies is superior for determining
evolution to CD. In this cohort, the current validated genetic risk panel of 163 IBD susceptibility loci does not have an added value in making this distinction. This might be due to the
fact that there is a significant overlap between CD and UC-risk alleles and the fact that only
very few genes are specific for CD or UC.
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Lamina Propria T Helper Cell Subsets Distinguish Between Ulcerative Colitis
and Crohn's Disease
Ji Li, Aito Ueno, Miriam Fort Gasia, Christina Hirota, Mailin Deane, Ronald Chan,
Marietta Iacucci, Gilaad Kaplan, Remo Panaccione, Joanne Luider, Tie Wang, Michael R.
Tom, Jia M. Qian, Xianyong Gui, Subrata Ghosh
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BACKGROUND: Distinction between the two forms of inflammatory bowel disease (IBD),
ulcerative colitis (UC) and Crohn's disease (CD), can be challenging both clinically and
histopathologically. Aberrant mucosal adaptive immunity contributes to the pathogenesis of
IBD and suggests UC is a T helper type 2 (Th2)-like disease and CD is a Th1 disease.
However, there is considerable controversy as to whether the Th1 and Th2 paradigm truly
distinguishes UC from CD. The aim of this study was to clarify the discriminating potential
of CD4+T helper cell subsets in the lamina propria (LP) of IBD patients. METHODS:Fresh
colonoscopic biopsies were collected for isolation of LP mononuclear cells from macroscopically and microscopically inflamed intestinal mucosa of 72 IBD patients (CD 46, UC 26)
and from normal mucosa of 20 healthy controls. Multicolor flow cytometry was used to
detect specialized CD4+ T cell subsets characterized by key cytokines and master transcription
factors (IFNγ & T-bet for Th1, IL13 & Gata3 for Th2, IL17 & RORc for Th17, FoxP3 for
Treg). 20 CD and 20 UC patients, whose diagnoses were established based on current
diagnostic criteria, were categorized into the training cohort, while 18 patients with established IBD and 14 patients with newly diagnosed IBD were categorized into the test cohort.
Linear discriminant analysis was used to obtain the discriminant equation and receiveroperating characteristic (ROC) curves were constructed to assess the discriminating ability
by calculating the area under the ROC curve (AUC) in the training cohort. The equation
with the highest AUC was then applied in the test cohort to evaluate its discriminating
ability. RESULTS: In the training cohort we detected an increased prevalence of IFNγ+ or
T-bet+ cells and a decreased prevalence of IL13+ or Gata3+ cells among LP CD4+ T cells
from CD patients compared with UC patients (P<0.001, <0.001, 0.026, and <0.001, respectively). No significant difference in the prevalence of Th17 or Treg cells existed between
the two groups. IFNγ+ CD4+ T cells had the highest AUC (95% CI) of 0.828 (0.692-0.963)
individually. The discriminant equation composed of the four CD4+ T lymphocyte markers
(IFNg+ , T-bet+ , IL13+ and GATA3+) yielded the highest AUC of 0.945 (0.870-1.000) (Figure
1). In the test cohort, the sensitivity, specificity and accuracy for the diagnosis of CD (as
opposed to UC) based on the discriminant equation were 95.7%, 66.7% and 87.5%, respectively. In newly diagnosed IBD patients, the sensitivity, specificity and accuracy for the
diagnosis of CD based on the discriminant equation were 100.0%, 57.1% and 78.6%,
respectively. CONCLUSIONS:LP T helper cell subsets can distinguish UC from CD by their
Th2 versus Th1 polarization. The discriminating potential of polarizing T helper cell subsets
may be clinically useful in patients where such distinction is difficult.
Proximity Extension Assay Technology Identifies Novel Serum Biomarkers for
Predicting Inflammatory Bowel Disease: IBD Character Consortium
Rahul Kalla, Nicholas A. Kennedy, Fredrik N. Hjelm, Eddie Modig, Mikael Sundell, Johan
Söderholm, Bettina K. Andreassen, Daniel Bergemalm, Nicholas T. Ventham, Henrik
Hjortswang, Petr Ricanek, Morten H. Vatn, Jonas Halfvarson, Mats Gullberg, IBD
Character, Jack Satsangi
Background Technological advances in protein profiling using proximity extension assays
(PEA) have transformed our ability to compare concentrations of multiple proteins across
biological samples.[1] This technique utilises the specificity of antibody proximity and the
sensitivity of polymerase chain reaction (qPCR) to detect proteins of interest. As part of the
European Commission funded IBD Character initiative to discover biomarkers for clinical
use using multiomic technologies (www.ibdcharacter.eu), we performed high-throughput
prospective case-control serum profiling to identify protein biomarkers that can predict
Inflammatory Bowel Disease (IBD). Methods Utilising Proseek Multiplex panels (Olink
Bioscience, Uppsala, Sweden), serum profiling was performed in patients with a new diagnosis
of IBD. Our control group consisted of symptomatic individuals. Phenotypic data was
captured including age, sex, diagnosis and IBD medications. Statistical analysis was performed
using R. Data were normalised and then batch corrected using ComBAT. Linear models
were created for each protein including age and sex as covariates. After quality control, data
from 186 proteins was available for analysis. Results A total of 245 patient serum samples
(n=153 newly diagnosed IBD, n=92 symptomatic controls) from 4 IBD centres from Norway,
United Kingdom and Sweden were included in the study from December 2012 to June
2014. 70 had Crohn's disease (CD), 70 ulcerative colitis(UC) and 13 Inflammatory Bowel
Disease Unclassified (IBDU). The mean age of the entire cohort was 33 years (range 0-79
years) and 54% were female. Multivariable analysis identified a set of 48 protein markers
that were significantly associated with IBD. The 5 most significant protein markers were MMP12 (Holm-adjusted p=3.3×10-13), OSM (p=2.4×10-12), CXCL9 (p=1.7×10-9), MMP10 (p=
1.7×10-9) and EGFR (p=1.8×10-9). Of these five, all except EGFR were upregulated in IBD.
The top 2 markers, MMP-12 and OSM were able to discriminate IBD from controls with
an area under the receiver operator characteristics curve of 0.81 and 0.75 respectively. Using
linear discriminant analysis, a combined biomarker consisting of MMP-12 and OSM was
able to discriminate IBD from controls with a sensitivity and specificity of 80% and 72%
respectively. Conclusions We have identified serum biomarkers that can predict IBD. These
data demonstrate a potential for a PEA multiplex technology in IBD diagnostics and its
ability to identify novel proteins that may be relevant in disease pathogenesis. References
1) Assarsson E et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity,
specificity, and excellent scalability. PLoS One.9(4): e95192
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Utility of Emergency Room Use of Abdominal Pelvic Computed Tomography
in the Clinical Management of Crohn's Disease
Jenna Koliani-Pace, Byron Vaughn, Shoshana J. Herzig, Joshua C. Obuch, Adam S.
Cheifetz
Background: Computer tomography (CT) scans are used extensively by emergency departments (ED) to evaluate patients who present with gastrointestinal complaints. As the imaging
modality has become more widely available, patients with Crohn's disease (CD) have been
undergoing more CT scans, which is both costly and exposes patients to higher levels of
ionizing radiation. The primary aim of this study was to determine how often CT scans had
positive findings and to describe factors predictive of both positive and negative findings.
Methods: We performed a retrospective chart review of all patients with CD who underwent
a CT scan in the ED between January 2008 and December 2011 at Beth Israel Deaconess
Medical Center. We identified 118 patients with CD patients who underwent 194 CT scans.
We reviewed each CT to determine how many had positive findings, defined as an abscess,
fistula, stricture, perforation, SBO, or LBO in addition to other non-CD related findings that
would change management. To identify independent predictors of a positive CT scan, we
utilized a multivariable generalized estimating equation (GEE) model with logit link and
exchangeable working correlation structure. Therefore, we were able to take into account
within-subject correlated data resulting from several patients having multiple admissions
during the study time period. Results: 92/194 (47%) of the CT scans performed in the ED
on patients with CD had clinically significant CD findings. Predictors of positive CT scans
were patients with small bowel disease (OR 4.6, p<0.024), Ileocolonic disease (OR 3.0,
p<0.047), stricturing disease (3.5, p<0.044), and WBC >12 (OR 2.1, p<0.026). Conversely,
predictors of a negative CT scan were patients with isolated peri-anal or colonic disease
(OR 4.6, p<0.024), inflammatory disease (OR 3.5, p<0.044), WBC <12 (OR 2.1, p<0.026)
and a negative CT scan performed in the preceding month (OR 4.5, p<0.005). Conclusion:
We were able to determine several useful predictors of clinically significant CT findings in
patients with CD perfomed in the ED. The factors can help determine if a patient with CD
is likely to have significant findings and require imaging in the ED.
AGA Abstracts
Figure 1. Receiver operating characteristic (ROC) curves showing the ability of the individual
and combined cell populations to discriminate between Crohn's disease and ulcerative colitis
in the training cohort. AUC: Area under the ROC curve.
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Association Between Eleven Thiopurine Metabolites and Mucosal Healing in
Patients With Crohn's Disease
Sieglinde Reinisch, Ute Hofmann, Cornelia Lichtenberger, Stefan Winter, Alexander Eser,
Alexander Teml, Clemens Dejaco, Gottfried Novacek, Harald Vogelsang, Elke Schaeffeler,
Matthias Schwab, Walter Reinisch
Introduction: Thiopurine-related drug response in treatment of patients with Crohn's disease
(CD) is still incompletely understood. Thus, therapeutic monitoring of thioguanine nucleotides (TGN) and methylthioinosine derivatives (MMPR) has been suggested to improve
thiopurine therapy, however with limited success. The comprehensive assessment of thiopurine metabolite pattern instead of determination of total TGN and MMPR levels has been
suggested to be beneficial for prediction of thiopurine response. Aim: To evaluate the
association between eleven thiopurine metabolites and mucosal healing in patients with CD
Methods: Patients with CD on maintenance treatment with azathioprine (AZA) and a stable
dose for at least 4 weeks were eligible. We established a novel highly sensitive liquid
chromatography-tandem mass spectrometry method for simultaneous quantitation of eleven
thiopurine metabolites including mono-, di-, and triphosphates of thioguanosine (TGMP,
TGDP, TGTP), methylthioinosine (meTIMP, meTIDP, meTITP), methylthioguanosine
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