Review for 10.1186/s12876-025-03733-1 (2025)

Title: Effect of montelukast on remission maintenance in patients with ulcerative colitis: A
Randomized, double-blind controlled clinical trial
Version: 2 Date: 24 Jan 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-While excluding patients on biologics (e.g., anti-TNF-# inhibitors) ensures homogeneity in
the study population, it limits the generalizability of the results to patients receiving biologic
therapies, which are increasingly used in UC management. Including a subgroup of biologic-
treated patients could provide insight into how Montelukast might work in combination with or
as an adjunct to biologics.
-The study focuses on UC patients with pancolitis who have achieved remission with
corticosteroids and Mesalamine. The exclusion of patients with other disease manifestations
(e.g., proctitis or left-sided colitis) may limit the applicability of results to all UC subtypes. A
broader cohort would enhance the external validity of the findings.
The study provides an 8-week follow-up after Montelukast and placebo treatments end.
-While this duration is useful for assessing short-term relapse prevention, it does not capture
longer-term outcomes. UC patients may experience relapses beyond the 8-week mark. A longer
follow-up period (e.g., 6 months or 1 year) would better inform clinicians about the sustainability
of the benefits of Montelukast in maintaining remission and preventing long-term relapse.
-While the sample size was calculated to account for dropouts, the handling of missing data
is not discussed. The review would benefit from an explicit mention of how missing data will
be handled (e.g., intention-to-treat analysis) to mitigate any potential bias due to participant
attrition.
-The background discusses the role of leukotrienes in UC and inflammation but does not delve
deeply into the specific mechanisms through which Montelukast might exert its effects on the
colonic inflammation seen in UC. A better understanding of this would strengthen the rationale
for using Montelukast in UC treatment. Additionally, biomarker measurements (e.g., changes in
cytokine levels) could offer more mechanistic insight into Montelukast’s effect on the immune
system.
-The authors mention the lack of histopathological remission as a limitation but fail to fully
address how this could impact the study’s conclusions. While fecal calprotectin is a good
surrogate marker, the absence of histopathological evidence (i.e., endoscopic or biopsy data
showing mucosal healing) is a significant limitation. The authors should further discuss
the potential implications of relying solely on non-invasive markers and acknowledge that
histopathological remission is the gold standard for assessing mucosal healing in UC.
-While the statistical corrections for baseline differences are valid, the authors should provide a
more in-depth discussion of how these initial differences might influence the study outcomes.
Were these adjustments sufficient, or could the differences have confounded the results,
particularly in terms of relapse-free period and biomarker levels?
-The authors discuss anti-inflammatory mechanisms such as the reduction of pro-inflammatory
cytokines and the inhibition of COX-2, but the connection between these mechanisms and the
observed clinical outcomes is not fully explored. While it’s plausible that Montelukast’s anti-
leukotriene effects contributed to the observed clinical benefits, further biomarker analyses or
mechanistic data would have strengthened the argument.