Inflammatory Bowel Disease
Table 1: Classification by Three-gene Crohn’s Disease/ Ulcerative Colitis Differential Blood Biomarker
Biomarker Classification
Crohn’s disease Ulcerative colitis
Clinical Diagnosis
Crohn’s Disease Ulcerative Colitis 89 8
12 83
Fisher’s exact odds ratio (two-sided) = 73.7; p<2x10-16.
Table 2: Diagnostic Performance of Three-gene Crohn’s Disease/Ulcerative Colitis Differential Blood Biomarker
Accuracy* Sensitivity Specificity
Positive predictive value* Negative predictive value* AUC-ROC
*Based on study prevalences. AUC-ROC = area under the curve-receiver operating characteristic.
bacterial flagellin (anti-CBir)14 diagnosis of UC or CD.
can also contribute to a differential Fecal Calprotectin and Lactoferrin
Calprotectin is a protein secreted by neutrophils and macrophages. It is measured in stool specimens as a marker of abnormal white cell shedding into the lumen. As such it is used in the diagnosis of IBD and may be useful as a screening tool,15 false-negative rate.16
albeit with a significant Similarly, the secreted protein lactoferrin has
been used as an aid in the diagnosis of CD, with similar performance.17,18
not been demonstrated. C-reactive Protein
CRP is an acute-phase protein that is used clinically as a general indicator of inflammation. CRP levels elevate rapidly in response to infection, inflammation, and other acute phase stimuli. Levels decrease rapidly when the acute phase stimulus is removed. These changes make CRP measurement a valuable aid to the detection and follow-up of inflammatory events.
Clinical studies (reviewed in Vermeire et al.19 and Desai et al.20 ) have
demonstrated that CRP levels are a useful aid for IBD diagnosis and are correlated with disease activity in IBD patients, although CD patients have a stronger CRP response and therefore higher level than UC patients. Furthermore, CRP is a useful biomarker for predicting relapse, risk for surgery in subgroups of both UC and CD,21
and in assessing
response to anti-tumor necrosis factor-alpha (TNF-α) therapy. As the sensitivity of CRP is much higher in CD patients (70–100%) than in UC patients (50–60%);22 UC and CD is limited.
however, CRP’s utility for differential diagnosis of Erythrocyte Sedimentation Rate
ESR is an indirect measurement of plasma acute-phase protein concentration and a non-specific indicator of inflammation. It is based
66 Their utility as differentiators between CD and UC has
Crohn’s Disease 90% 92% 87% 88% 91%
0.94
Ulcerative Colitis 90% 87% 92% 91% 88%
on the observation that inflammation results in an increased proportion of blood fibrinogen, causing clumping and stacking of red blood cells (rouleaux), which then sediment more rapidly in an anticoagulated blood specimen.23
In comparison to CRP, the ESR increases and decreases more slowly in response to acute phase stimuli and therefore provides a less reliable ‘realtime’ snapshot of inflammation. Despite this, ESR is a good biomarker for monitoring disease activity in IBD patients when the disease is restricted to certain locations. It is also a
useful predictor of relapse when combined algorithmically with α2 globulin and α1 glycoprotein, or when combined with CRP,20
there are few data to suggest it has utility as a differential diagnostic for UC and CD.
Next-generation Gene Expression Test Genes are not simply turned on or off, but rather are expressed in a finely orchestrated manner by each gene having its own customized ‘volume knob’ that regulates the amount of messenger RNA (mRNA) made. These expression levels can be altered by disease states in specific ways and can reliably be measured in the clinical laboratory. This report describes one of a new type of laboratory tests available to gastroenterologists that use expression levels of specific genes as an aid in diagnosis.
The use of gene expression biomarkers as a non-invasive diagnostic tool for the diagnosis of IBD is supported in the literature. Two separate papers have reported expression profiles obtained from peripheral mononuclear cells for the molecular classification of IBD patients. The first paper24
although
reported a small study of seven CD and five UC patients with controls using a limited 2,400-gene custom array; two separate large sets of genes were shown to be differentially expressed in CD and UC. The second paper25
is from a larger study (59 CD and 26 UC patients, with controls) using a genome-wide gene expression microarray. It reported a large set of genes with differential expression between CD and UC, including a 14-transcript classifier.
There is additional evidence for gene expression profiles that can discriminate between UC and CD in colonic biopsies.26
Several
small independent cohorts were utilized in a stepwise manner to discover and confirm expression biomarkers that distinguish UC and CD colon tissue.
Biomarkers Differentiating between Crohn’s Disease and Ulcerative Colitis
Exagen Diagnostics performed a study to identify gene expression biomarkers useful for the differentiation of CD from UC based on gene expression levels in circulating lymphocytes. First, computational analysis of genome-wide lymphocyte gene expression data allowed the discovery of gene expression patterns, based on small combinations of specific genes, which were significantly different between these two subtypes of IBD. Using a direct global combinatorial approach, rather than a single-gene-at-a-time approach, the interactions across multiple physiologic systems were captured without prior knowledge or specification of those interactions. The primary aim of the study was to discover a marker combination consisting of a small set of specific genes that differentiates between CD and UC. The second aim was to evaluate the combination in a separate clinical cohort.
US GASTROENTEROLOGY & HEPATOLOGY REVIEW
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