Proof-of-concept Study to Assess Urinary PGE-MUM Concentration (PROSTAGLANDIN E-MAJOR URINARY METABOLITE) as a Potential Marker of Inflammation in Inflammatory Bowel Disease (IBD) - Comparison With Fecal Calprotectin Level (FC)

Inflammatory bowel diseases (IBD) include Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammations of the digestive tract with periods of remission of variable duration. As the timing of relapse is unpredictable, and current monitoring is symptoms-based, there remains a window between the initial upregulation of the inflammatory response and the onset of clinical symptoms at which point the inflammatory episode is well established. Endoscopy displays direct evidence of mucosal injury but as means of predicting relapse is not suitable for regular use. Biological examinations are looking for signs of inflammation such as the presence of inflammatory anemia or thrombocytosis, frequently found, or increased C-reactive protein (CRP), a nonspecific marker poorly correlated with endoscopic inflammation; or looking for signs of malabsorption such as hypoalbuminemia or vitamin deficiencies. These serum markers are limited in fulfilling the role as a prognostic marker of relapse.

The best non-invasive biomarker compared to endoscopic examination for the monitoring of IBD is the fecal calprotectin (CF). Calprotectin is a 36 kiloDalton, calcium- and zinc-binding protein that comprises up to 60% of cytosolic proteins in neutrophils, being released during apoptosis or necrosis. Its fecal concentration is therefore proportional to neutrophilic influx into the intestinal tract, which is a feature of active IBD. FC is therefore an accurate surrogate marker of active endoscopic disease in IBD patients, its sensitivity is between 70% - 100%, with a specificity of 44% - 100%, depending on the threshold value used. FC measurement is now widely available and is being incorporated into routine clinical practice. The advantages of fecal biomarkers are that samples (feces) are easy to obtain, can be collected at home, can be serially obtained, and can be relatively easy to analyze with the sample posted to the laboratory for analysis.

Point-of-care urinary markers can represent interesting candidates as tools for monitoring inflammatory activity in IBD and for assessing the risk of imminent disease flares. According to the latter concept, clinical remission should be paired with biological and endoscopic evidence of mucosal inflammatory inactivity in IBD patients. Expressed in ratio to creatinine, the more complicated collection of 24 hours urine is useless.

Recent studies have reported that prostaglandin E2 (PGE2) is produced in the mucosa of the intestine of areas affected by IBD and the PGE2 plays important role in the progression of inflammation. In the active UC phase, the stimulation of inflammatory cytokines, such as tumor necrosis factor-α, leads to the upregulation of cyclooxygenase-2 (COX-2) leading to PGE2 secretion in mucosal tissue. In blood, PGE2 is immediately metabolized by 15-hydroxy prostaglandin dehydrogenase (15-PGDH), which is present in the lung and colon, into 15-keto-PGE2. Next, in the liver and kidney, 15-keto-PGE2 is converted into 13,14-dihydro-15-keto PGE2 by the action of Δ13-reductase, followed by β-oxidation and ω-oxidation; this is finally converted to PGE-MUM (7α-hydroxy-5,11-diketotetranor-prosta-1,16-dioic acid) and excreted along with urine. A precise measure in the blood of PGE2 was considered difficult due to the short half-life of PGE2 in the blood. Conversely, the urinary metabolite of prostaglandin E-major (PGE-MUM, 7-acid 5-hydroxy, 11-diketotetranor-prosta-1, 16-dioecious) is stable.

A correlation was reported (Arai, 2014) between PGE-MUM and inflammatory activity in IBD using the 3 severity score indexes - clinical, colonoscopic, and histological - Simple clinical colitis activity index (SCCAI), Mayo endoscopic scoring and Matts grading respectively (. When the cutoff value was set to 17 mg/g creatinine to distinguish Matts 1 from Matts 2-5, the sensitivity (equals to specificity), positive predictive value, negative predictive value, and accuracy of PGE-MUM were 0.82, 0.67, 0.93, and 0.83, respectively, compared with 0.69, 0.49, 0.93, and 0.69 for CRP respectively. The odds ratio was of 35 for the differentiation between cases in remission and active cases.