Unraveling the Place of Small Molecules in the Treatment of Fistulizing Crohn’s Disease—A Systematic Review and Network Meta-Analysis

With interest

With interest, we read the review by Dr. Singh et al. outlining the available medical options for perianal fistulizing Crohn's disease (CD). 1 We would like to clarify the comparative efficacy and ranking of available interventions, with an emphasis on small molecules, which was not analyzed in the review.
We conducted a Bayesian random-effects network metaanalysis (NMA) to account for trial heterogeneity, handling varying follow-ups in each trial as recommended. 2As of July 10, 2023, we identified 21 randomized controlled trials comprising 1452 patients.Compared to another NMA, 3 we included 4 studies of stem cells, [4][5][6][7] and 1 study each of upadacitinib, 8 ustekinumab, 9 and adalimumab versus ustekinumab. 10Based on CINeMA, confidence in findings was rated high between the active agents and placebo but low between active agents.
In conclusion, infliximab 5 mg/kg, ASCs, or upadacitinib 45 mg may be the best option for achieving fistula remission in patients with CD, despite no significant differentiation from other agents.
Dr. Singh et al. are commended for their important endeavor.Nevertheless, the absence of data on upadacitinib or comparative analyses undermines the ability to provide guidance for well-informed treatment choices.

Author Contributions
J.B.S. and M.A. conceived the study idea.M.A., J.B.S., and J.B. planned and designed the study.M.A. and D.N.R. conducted a systematic literature review.M.A. performed the statistical analyses and drafted the manuscript.All authors interpreted the results and contributed with a critical revision of the manuscript for important intellectual content.All authors had full access to all data in the study.J.B.S. had the final decision to submit for publication.All authors have approved the final draft of the manuscript.The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Figure 1 .
Figure 1.League plot for the comparison of advanced therapies in patients with fistulizing Crohn's disease for maintenance of fistula remission at Weeks 44-56.The values in each cell represent the relative treatment effect (hazard ratio and 95% credible intervals) of the column-defining treatment compared to the row-defining treatment.A double asterisk indicates statistical significance.ASCs, adipose-derived stem cells.