Urinary PGE-MUM (PROSTAGLANDIN E-MAJOR URINARY METABOLITE) as Inflammatory Marker in Chronic Inflammatory Bowel Disease
Condition: Inflammatory Bowel Diseases
MeSH terms: Intestinal Diseases; Inflammatory Bowel Diseases
Study type: Observational

Summary: 
      The inflammatory bowel diseases (IBD) are lifelong, relapsing-remitting diseases. 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. The use of
      endoscopy as means of predicting relapse is not suitable for regular use. The potential role
      of Fecal calprotectin (FC) in IBD in predicating the risk of relapse has been well
      investigated with key studies. Its fecal concentration is proportional to neutrophilic influx
      into the intestinal tract, which is a feature of active IBD. FC correlates well with the
      severity of endoscopic lesions. After excretion, FC remains stable in the feces for 1 week at
      room temperature. However, its considerable daily variation suggests interfering factors
      discrete from inflammatory disease. There is increasing research into novel markers with high
      correlation to the presence of mucosal healing constitute a cost-effective substitute to
      repeated endoscopies. Recent studies have reported that the prostaglandin E-major urinary
      metabolite (PGE-MUM) level was significantly higher in the active phase of patients with
      ulcerative disease (UC) than those in the remission phase. 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. PGE2
      plays an important role in the progression of inflammation. A precise measure of serum PGE2
      is difficult due to the short half-life of PGE2 in the blood. Conversely, the urinary
      metabolite of prostaglandin E-major (PGE-MUM, 7-hydroxy-5,11-diketotetranor-prosta-1,16-dioic
      acid) is stable and may reflects the histological severity of inflammation. The aim of this
      concept study is to evaluate the PGE-MUM concentration in urine of patients with IBD in
      parallel with the standard investigation of Calprotectin in stool and to assess if urinary
      PGE-MUM should be able to serve as a simple and robust substitutive biomarker for the
      non-invasive evaluation of the inflammation of the mucous membrane tissues. The measurement
      of PGE-MUM in urine could give patients with IBD more comfort than the measurement of
      calprotectin in stool.
    

Detailed description: 
      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.

      There is currently no study comparing urinary PGE-MUM and FC, which is the most validated and
      consensus biomarker of inflammation of the intestinal mucosa in Western countries. The
      proposed study aims to evaluate the correlation and bias between these two methods. The
      target population will be adult patients followed for chronic inflammatory bowel disease
      (IBD) diagnosed with certainty as Crohn's disease (CD) or ulcerative colitis (UC). The
      subjects will be recruited by specialized doctors in gastroenterology, IBD and nutrition
      assistance, on a voluntary basis after information and consent. These are patients benefiting
      from the usual IBD management circuit, either in outpatient for regular follow-up or
      hospitalized in case of recurrence for care aiming to limit the symptoms and duration of the
      acute inflammatory, and for whom a prescription for the measurement of fecal calprotectin and
      blood markers are required in routine care.

      This proof-of-concept study might be used to direct future clinical validation.
    

Intervention name(s): Urine and stoll samples
Intervention type(s): Biological
Intervention description(s): Urine collection will be proposed to patient during consultations or medical examinations corresponding to routine care of patients with IBD at the time of prescribing a FC test. The urine sample, as for stool samples, will be collected in an ordinary universal container at any time of the day (no dietary restriction is required). Urine and stool samples should be taken during the same period (for example, the same day, or within a maximum of one week if no change in treatment)
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Adults with inflammatory bowel disease (IBD or UC) consulting, for the follow-up of their
        chronic disease, the gastroenterology department of Beaujon Hospital.
      
Biospecimen description: 
      urine and stool samples
    
Keywords: Inflammatory bowel diseases; urinary marker