Advances in the Treatment of Ulcerative Colitis—From Conventional Therapies to Targeted Biologics and Small Molecules

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript by Wilk et al. attempts to provide a comprehensive overview of the therapeutic landscape for ulcerative colitis (UC), spanning from established conventional agents to emerging small molecules and biologics. The authors have done a commendable job collating a significant amount of information regarding the mechanism of action (MoA) and clinical positioning of these drugs. However, I believe the manuscript needs major revisions before it can be considered for publication, as detailed in my comments below.

Specific comments

1. Abstract

The authors mention the "step-up strategy." While this is the traditional teaching, modern IBD management often advocates for an "accelerated step-up" or "top-down" approach in high-risk patients to prevent bowel damage. The abstract should reflect this paradigm shift rather than adhering strictly to the older step-up dogma.

Lines 16-17: "bleeding, intestinal perforation, or the need for colectomy." Toxic megacolon is a critical complication of severe acute UC that should be mentioned here.

2. Introduction

Line 33: The term "lead-pipe" colon is a radiological descriptor (barium enema), not a pathological condition itself. The sentence implies it is a condition. It should be rephrased to indicate that the loss of haustra results in the appearance of a lead pipe on imaging.

Lines 54-55: "tobacco cessation... Conversely, protective factors comprise... active smoking." While epidemiologically true, listing active smoking as a "protective factor" without immediate clinical context or ethical qualification is jarring. It should be clarified that while nicotine may have anti-inflammatory effects in UC, smoking carries prohibitive systemic health risks.

Line 70: The comparison of Fecal Calprotectin (FC) to CRP is valid, but the text should explicitly state that CRP is normal in up to 25% of patients with active UC, which is why FC is superior.

3. Conventional treatment options

Line 86, section title: "Conventional treatment options." In standard gastroenterology literature, "conventional" refers to 5-ASA, corticosteroids, and immunomodulators (thiopurines/methotrexate).

Lines 139, glucocorticoids: This section is overly academic regarding the genomic vs. non-genomic mechanisms of steroids. While interesting, it takes up nearly a page of text for drugs that we are trying to phase out of maintenance therapy. I recommend condensing this to focus on why steroids fail (steroid resistance mechanisms), which is more relevant to the transition to biologics.

Lines 246, adrenomodulin: Adrenomodulin is not a conventional treatment. It is not in standard guidelines (ECCO, ACG, AGA) as a routine therapy. It is an experimental agent. Placing it in Section 2 implies it is a standard of care alongside Mesalazine.

Line 270: "Thiopurines... can be used exceptionally in mild to moderate UC." This contradicts current guidelines. Thiopurines are maintenance agents, typically for steroid-dependent moderate-to-severe disease, not mild disease.

4. Biological treatment

Line 354: "The subcutaneous formulation of infliximab has been available since December 2022." This date is specific to a certain region (likely Poland) or the FDA/EMA approval date needs to be specified. Infliximab SC was approved in Europe earlier and the US later. Please clarify the jurisdiction or use the global first approval.

Line 380: "Salman et al." Please ensure the citation format matches the journal style. Usually, a number is preferred in the text.

Lines 415-430, vedolizumab vs. natalizumab: This comparison is largely historical and irrelevant for a dedicated UC review. Natalizumab is indicated for Crohn’s Disease and MS, not Ulcerative Colitis. Dedicating a subsection to comparing a UC drug to a non-UC drug is confusing.

Line 432, etrolizumab: The authors should note that Roche halted the development of Etrolizumab for UC in 2020/2021 due to mixed Phase III results. Discussing it as a current viable option without mentioning the trial halts/failures is misleading.

Line 520, guselkumab and mirikizumab: This section is too brief. Mirikizumab is the first IL-23p19 inhibitor approved for UC (FDA/EMA 2023). It deserves a detailed discussion of the LUCENT-1 and LUCENT-2 trial data. Lumping it with Guselkumab (which is still in trials for UC or recently completed) dilutes the importance of Mirikizumab's approval.

5. Other drugs

Line 548, apremilast: Similar to Adrenomodulin, the inclusion of Apremilast as a major header is puzzling. The text (Lines 557-562) admits that statistical significance was not achieved in UC. If the drug failed or showed no benefit, it should not be presented as a "treatment option." It belongs in a discussion about pathway exploration, not active treatment.

Line 770: "atrioventricular block, which has been observed in studies." It is important to clarify that with Ozanimod, the dose titration scheme effectively mitigates this, unlike the first-generation S1P modulators (Fingolimod).

Line 906, obefazimod: The authors should update the status of Obefazimod. While promising in Phase 2, the Phase 3 trials are the current benchmark. Ensure the data cited is the most recent available.

6. Figures

The manuscript has very few figures, which are insufficient to attract readers.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The review provides a broad overview of novel therapeutic approaches available for ulcerative colitis and other related inflammatory bowel diseases. Nevertheless, I would like to offer the following recommendations to improve the quality of the presented data.

1. Given the length extension of the manuscript, the authors could consider to include tables compiling the cited studies on different biological therapies. Moreover, figures illustrating targets and mechanisms of action of each therapy would enhance study comprehension.
2. Table 1 lacks references for cited information; therefore, appropriate references should be added.
3. Several abbreviations are reintroduced in their full form after being previously defined, leading to repetition of the information.
4. The term “E-cadherin” is repeatedly misspelled as “E-cahdrin” and should be corrected in the manuscript.
5. In some sections of the manuscript, the focus of the text is lost, as the authors describe pathologies not directly related to inflammatory bowel disease. Authors might summarize additional information to avoid confusion.

 

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Can be accepted.