Background
Ulcerative colitis (UC) is an idiopathic chronic inflammatory disorder characterized by diarrhea, bloody stool, abdominal pain, fever, anemia, and weight loss [
1], and its clinical course is characteristic of repeating remission and relapse [
2]. Although assessing the disease activity and response to treatment is important to achieving better disease control, current studies have recommended that achieving mucosal healing is the treatment goal of UC since it is associated with sustained clinical remission, decreased hospitalization rates, and the avoidance of colectomy [
3]. Endoscopic evaluations are important because patients with UC can be asymptomatic despite the presence of mucosal inflammation. However, colonoscopy is expensive and invasive, making frequent examinations difficult. Therefore, non-invasive biomarkers of mucosal status with accuracy comparable to that of endoscopy are needed.
Serum C-reactive protein (CRP) is the most common biomarker used to assess inflammation in patients with IBD. However, some reports have stated that CRP levels may remain within the physiological range or only show mild abnormalities even in patients with endoscopically active UC [
4]. Fecal calprotectin (FC) and the fecal immunochemical occult blood test (FIT) are minimally invasive techniques that reflect the endoscopic severity of UC [
5‐
8]. However, fecal samples can be more difficult to obtain than blood or urine samples because patients are reluctant to bring fecal samples to the hospital and it is difficult to collect fecal sample from diarrhea stool. However, these problems can be circumvented by examinations using urine samples. Arai et al. reported that prostaglandin E-major urinary metabolite (PGE-MUM) was a reliable biomarker of the colonoscopic and histological appearance of UC, suggesting that it was more sensitive than those previously utilized to evaluate UC-related mucosal inflammation [
9]. Here we investigated the usefulness of PGE-MUM versus FIT as a biomarker for evaluating the endoscopic activity of patients with UC.
Discussion
The release of prostaglandin E 2 (PGE 2), a major chemical mediator involved in promoting and suppressing inflammation, is reportedly increased in the mucosa of UC patients versus healthy subjects [
15]. Since PGE2 is produced at the site of inflammation and metabolized and decomposed upon its release into the blood, taking direct measurements is difficult. However, PGE-MUM, a urinary metabolite of PGE 2, is known to stabilize and reflect systemic PGE 2 production. In fact, although Arai et al. reported that PGE-MUM reflects mucosal inflammation severity in UC, it remains unclear whether PGE-MUM accurately reflects endoscopic severity either immediately after onset or in long-term patients [
9]. Our study revealed that PGE-MUM was significantly correlated with endoscopic severity, even in patients with a disease duration ≥5 years. The usefulness of biomarkers such as fecal calprotectin and FIT for IBD was recently reported. Although fecal examinations are non-invasive, feces have the possibility of directly reflecting inflammatory changes of the colonic mucosa and may pick up latent inflammation earlier, leading to the identification of several problems. First, due to heterogeneity, results may vary depending on the site of sample collection.
The value of FC is reportedly wide, even in the same stool sample collected on the same day [
16]. Moreover, patients may find it cumbersome to bring stool samples from home to the hospital. On the other hand, urine specimens can be collected at the hospital and have the advantage of being more convenient and non-invasive. These are great benefits for pediatric patients with UC who experience difficulty undergoing frequent invasive endoscopic examinations. Hagiwara et al. reported that PGE-MUM is useful for pediatric patients with UC to evaluate their disease activity [
17].
Here we compared the usefulness of PGE-MUM to that of FIT using urine samples. FIT, which is reportedly useful as a biomarker for patients with UC, is less expensive than other fecal biomarkers such as FC, can be performed at many facilities, and boasts immediately available results. Although FC requires 5–10 g of fecal material, FIT can be examined using only smaller samples [
18,
19]. FC reflects the volume of inflammatory cells in the intestinal tract, while FIT reflects blood originating from the damaged mucosa. PGE-MUM is similar to FC from the point of view of such an inflammation-derived mechanism. Although current reports show that FIT and FC can efficiently predict mucosal healing of UC, FIT was more sensitive than FC for predicting only eMayo 0 [
20]. For the above reasons, we selected FIT rather than FC for comparison with PGE-MUM. Ideal biomarkers are able to detect the recurrence of intestinal mucosal inflammation in an asymptomatic state. In our study, PGE-MUM and FIT were correlated with endoscopic severity and differed significantly between patients with and those without endoscopic activity. Considering its simplicity and minimal invasiveness, PGE-MUM seems clinically useful. From our results, neither PGE-MUM nor FIT was correlated with CRP or ESR, blood biomarkers reflecting mucosal inflammation. However, it is interesting to note that serum Alb, a biomarker representing nutritional status, has a significant negative correlation with both PGE-MUM and FIT. Few reports show correlations between serum Alb and PGE-MUM or serum Alb and FIT, and the mechanism by which serum Alb or nutritional status affects the values of PGE-MUM and FIT is unknown. However, when the serum Alb value deviates significantly from normal or is abnormally low, caution may be required when evaluating PGE-MUM and FIT as biomarkers of UC activity.
The PGE-MUM values at baseline (eMayo 0 score), which are shown in Fig.
2a, were relatively higher than those published in a previous report. In a study by Arai et al., the mean PGE-MUM value was 15.9 μg/g·Cr in the eMayo 0 group, whereas in this study, it was 24.3 μg/g·Cr [
9]. Laxative administration has been reported to increase the PGE-MUM value [
21]. As almost all the enrolled patients were administered laxatives 1 day before the examination, the mean PGE-MUM value in this study may have been higher than that in a previous study.
PGE-MUM and FIT showed a significant positive correlation with eMayo in the group of patients with a disease duration of < 5 years. Although PGE-MUM and eMayo were significantly correlated in patients with a disease duration of ≥5 years, FIT was not correlated with eMayo in that group. In the group of patients with a disease duration of < 5 years, FIT was significantly higher in the eMayo 2, 3 subgroup than in the eMayo 0, 1, but there was no significant difference between FIT and eMayo in the group with a disease duration of ≥5 years. On the other hand, regarding PGE-MUM, no significant differences were seen between the eMayo 0, 1 and eMayo 2, 3 subgroups in patients with a disease duration of < 5 years, but PGE-MUM tended to be higher in eMayo 2, 3 than in eMayo 0, 1 in patients with a disease duration ≥5 years (P = 0.054). Patients with a long disease duration often experience repeated relapse and remission, and there are many sites of scarring and rough-surfaced mucosa in their intestinal tract. In these patients, the degree of bleeding is small although endoscopic abnormalities are recognized. Since FIT reflects the amount of bleeding itself, it may be difficult to reflect endoscopic abnormalities associated with inflammation in long-term diseased patients. On the other hand, since PGE-MUM reflects intestinal tract inflammation, it is likely able to reflect endoscopic abnormalities associated with inflammation in UC patients with long disease duration. Our results show that PGE-MUM may be a more useful biomarker for predicting endoscopic severity when disease duration is prolonged; however, the accumulation of cases is necessary to confirm these results.
There are some limitations to this study. First, it was performed in a single center and included a small number of patients. Also, in this study, it was not proven whether PGE-MUM can predict UC recurrence. To clarify that point, there is a need for periodic measurements of PGE-MUM to be performed in the same patient and prospective follow-up be performed of patients with relapse. In recent years, treatments aimed at histological healing more advanced than mucosal healing have also been required, and reports of the comparison between histological healing and biomarkers have been found [
22‐
25]. Further studies are needed to determine if PGE-MUM could be a biomarker to predict histologic healing.
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