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• W2561489700 abstract "See “Prostaglandin E-major Urinary Metabolite as a Biomarker for Pediatric Ulcerative Colitis Activity” by Hagiwara et al on page 955. Clinicians increasingly acknowledge that the deeper the remission in inflammatory bowel diseases, the better are the short- and long-term outcomes. This has led to moving away from clinical remission as the therapeutic goal, toward deep remission with no mucosal inflammation. Indeed, numerous studies show that achieving deep remission after treatment is associated with lower colectomy risk, better symptom control and long-term clinical remission (1). Nonetheless, “deep remission” is a concept rather than a practical tool, since there are several possible options to measure this concept, and an “absolute measure” is unlikely to be found. Macroscopic evaluation of the bowel mucosa is of the most important measures of “deep remission” but even within endoscopic evaluation there is a controversy whether Mayo endoscopic subscore of 0, is superior to near-complete mucosal healing (MH) (endoscopic subscore 1) in ulcerative colitis (UC) (2). Moreover, some advocate focusing on histologic remission, which has also shown utility in predicting clinical relapse (3,4). Fecal calprotectin reflects the histological activity of colitis rather than macroscopic appearance and thus complete normalization of calprotectin, another predictive goal, is not often achieved. Similarly, “transmural healing” detected by imaging studies, even in the absence of mucosal inflammation, has been associated with improved clinical outcomes. Finally, preliminary data suggest that normalization of the microbiome pattern, mucosal cytokine array, and gene expression profile may also be associated with deep remission and improved outcomes. All aforementioned measures pertain to different aspects of the “deep remission” concept, and it is plausible to assume that disease-related outcomes improve in a linear relation with the number of measures indicative of remission. How all these measures, and others, come into play for a final practical goal is, however, yet to be determined, and can only be determined after factoring the number-needed-to-treat, cost and safety of the drugs required for achieving that goal. UC, unlike in Crohn disease, is more straightforward in that complete clinical remission is highly associated with MH. Several studies from children and adults showed that approximately 75% to 80% of UC patients in complete remission (1–2 formed stools without blood or other associated symptoms) have an endoscopic Mayo score of 0 to 1 at most (5,6), and that elevated fecal calprotectin can easily detect the others (6,7). Endoscopic evaluation is an invasive procedure and thus should be reserved mainly for those with unexplained symptoms or elevated calprotectin, as well as before major treatment changes and cancer surveillance (8). In this regard, Hagiwara et al (9) present in this issue their elegant study on prostaglandin E-major urinary metabolite (PGE-MUM) as a potential biomarker for active inflammation in UC. PGE-MUM was significantly higher in 24 children with endoscopically active disease than in 5 with Mayo score of 0. They demonstrated a positive correlation between PGE-MUM and PUCAI, endoscopic Mayo score and histologic score. PGE-MUM had an impressive 100% negative (NPV) and 92% positive predictive values to distinguish Mayo 0 from Mayo 1 to 3. With regard to distinguishing histologic remission from histologic activity, the NPV fell to 67%, but was still superior to serum inflammatory markers. Nonetheless, there were only a handful of patients fulfilling the inactive categories. Although the study is novel and intriguing as a proof-of-concept, more data on a larger sample size are required before incorporating the test in clinical practice. First, the utility of any new noninvasive diagnostic measure in UC must show its added benefit only in those who are in clinical remission, because diagnostic tests are usually unnecessary in children with bloody diarrhea. Second, the added benefit of PGE-MUM over clinical assessment should be shown for long-term clinical outcomes, while calculating the number-needed-to-test for detecting 1 extra poor outcome. Its utility in this regard must be at least equal to current clinical indices (eg, PUCAI, partial Mayo score) which have been shown to predict long-term outcomes in UC, not less than endoscopic evaluation, both in children (5,6,10), and in adults (11). Beyond the utility of PGE-MUM as a marker of mucosal inflammation in clinical practice, the findings presented by Hagiwara et al may have a more far-reaching application. The association of elevated PGE-MUM with active inflammation may contribute to our understanding of the molecular basis of UC in general, and PGE's role in modulating inflammation in particular. PGE2 is known to modulate various steps of the inflammatory process in both pro-inflammatory and anti-inflammatory directions (12). The ability to detect its metabolite can contribute to the ongoing endeavor of exploring new treatment targets in UC. Although efforts to identify proxy markers to better reflect extent and severity of UC are praiseworthy, the long-term clinical utility and cost of these markers must be critically assessed against current readily available clinical tools. In order to be considered for clinical practice, new proxy markers must show a demonstrable advantage as a marker of mucosal or histologic inflammation, over freely available measures of clinical remission for predicting outcome and superiority to the increasingly available fecal calprotectin. Nonetheless, the creative report by Hagiwara et al is encouraging and we await further studies to understand the role of PGE-MUM in evaluating UC." @default.
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• W2561489700 title "Seeing Without Looking: Predicting Mucosal Healing Without Endoscopic Evaluation in Pediatric Ulcerative Colitis" @default.
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