Title: Evaluation of adverse clinical outcomes in patients with inflammatory bowel disease
receiving different sequences of first- and second-line biologic treatments: findings from
ROTARY
Version: 0 Date: 16 Dec 2023
Reviewer's report:
Many thanks for the kind opportunity to review this manuscript.
The authors of this important manuscript approached the subject of drug sequencing in IBD
from a different angle looking specifically at hospitalizations, surgeries, infections, dysplasia,
and CRC. For that purpose data was extracted from OPTUM clinical database, aiming to infer
which drug sequence carry lesser risk for adverse clinical outcomes.
I have a few comments, which I think would be useful in improving its quality.
Introduction
Line 60: It is safe to say infliximab therapy is associated with increased risk of infection than
Immunosupressors. I am not sure biologics in general are associated with increased risk of
infections compared to non-biologics (steroids, JakI).
Methods
• Line 123-126: It is unclear why the authors included only patients receiving anti-TNFs
as second line therapy. The authors notes that first line therapy with anti-TNFs is well
established, but so is first line therapy with vedolizumab and Ustekinumab (same references
10,11). Including real world data of adverse events following different sequencing of biologics
(vedolizuman, risankizumab or Ustekinumab as second line therapy) would increase the
generalizability of the findings and novelty of the manuscript.
• Line 140: IBD-related hospitalizations were identified based on the existence of a primary
diagnosis of UC or CD on at least one of the hospitalization events. I am not sure this is
enough to capture all IBD-related hospitalizations, such as VTEs, extracolonic-malignancies,
cardiovascular events, kidney stones, etc.
• Line 145: Why were viral infections like HBV reactivation or shingles not included in the
infection analysis for patients with CD?
Statistical Analysis
• Line 156: Please share which baseline demographics and clinical characteristics were included
in the logistic regression model.
Results
• Line 166 and table 1.: The baseline characteristics table does not contain statistical
calculations of the differences between patient groups receiving first-line therapy. Similarly,
these differences are not discussed fully in the results section. For instance, there is large
variation in patients’ age (patients on Ustekinumab are older), and disease behavior (penetrating
and perianal disease is less prevalent in patients on vedolizumab and Ustekinumab as first line
therapy).
• Line 175 and table 2.: The baseline characteristics table does not contain statistical calculations
of the differences between patient groups receiving first-line therapy.
• Please explain which variables were included in the logistic regression model.
• The more appropriate measure for incidence of adverse events is the incidence per patient years.
• What proportion of the time were the patients on each treatment? This would seem very
important, since time on therapy is an important factor in the risk for adverse events.
• How were dysplasia rates calculated? Did all patients have screening colonoscopy? Were
dysplasia rates calculated as proportion from the patients who underwent colonoscopy?
Limitations
• With the advent of small molecules, why did the authors choose to look only at biologic meds
sequencing?
• How do the authors correct for disease severity, disease duration, disease behavior, disease
extent (included only for UC patients), perianal disease, concurrent steroid use, concurrent
immunomodulators therapy, age of diagnosis, disease duration.
These factors are all associated with adverse clinical outcomes, and it should be noted that this
study does not take these into account.
• The most reasonable method of measuring AE rate would be incidence per patient years and
not absolute number or proportions.
• The sample size for patients treated with ustekinumab and vedolizumab were significantly
smaller than those treated with anti-TNF. Please mention this in the limitations.
Title: Evaluation of adverse clinical outcomes in patients with inflammatory bowel disease
receiving different sequences of first- and second-line biologic treatments: findings from
ROTARY
Version: 0 Date: 16 Dec 2023
Reviewer's report:
Many thanks for the kind opportunity to review this manuscript.
The authors of this important manuscript approached the subject of drug sequencing in IBD
from a different angle looking specifically at hospitalizations, surgeries, infections, dysplasia,
and CRC. For that purpose data was extracted from OPTUM clinical database, aiming to infer
which drug sequence carry lesser risk for adverse clinical outcomes.
I have a few comments, which I think would be useful in improving its quality.
Introduction
Line 60: It is safe to say infliximab therapy is associated with increased risk of infection than
Immunosupressors. I am not sure biologics in general are associated with increased risk of
infections compared to non-biologics (steroids, JakI).
Methods
• Line 123-126: It is unclear why the authors included only patients receiving anti-TNFs
as second line therapy. The authors notes that first line therapy with anti-TNFs is well
established, but so is first line therapy with vedolizumab and Ustekinumab (same references
10,11). Including real world data of adverse events following different sequencing of biologics
(vedolizuman, risankizumab or Ustekinumab as second line therapy) would increase the
generalizability of the findings and novelty of the manuscript.
• Line 140: IBD-related hospitalizations were identified based on the existence of a primary
diagnosis of UC or CD on at least one of the hospitalization events. I am not sure this is
enough to capture all IBD-related hospitalizations, such as VTEs, extracolonic-malignancies,
cardiovascular events, kidney stones, etc.
• Line 145: Why were viral infections like HBV reactivation or shingles not included in the
infection analysis for patients with CD?
Statistical Analysis
• Line 156: Please share which baseline demographics and clinical characteristics were included
in the logistic regression model.
Results
• Line 166 and table 1.: The baseline characteristics table does not contain statistical
calculations of the differences between patient groups receiving first-line therapy. Similarly,
these differences are not discussed fully in the results section. For instance, there is large
variation in patients’ age (patients on Ustekinumab are older), and disease behavior (penetrating
and perianal disease is less prevalent in patients on vedolizumab and Ustekinumab as first line
therapy).
• Line 175 and table 2.: The baseline characteristics table does not contain statistical calculations
of the differences between patient groups receiving first-line therapy.
• Please explain which variables were included in the logistic regression model.
• The more appropriate measure for incidence of adverse events is the incidence per patient years.
• What proportion of the time were the patients on each treatment? This would seem very
important, since time on therapy is an important factor in the risk for adverse events.
• How were dysplasia rates calculated? Did all patients have screening colonoscopy? Were
dysplasia rates calculated as proportion from the patients who underwent colonoscopy?
Limitations
• With the advent of small molecules, why did the authors choose to look only at biologic meds
sequencing?
• How do the authors correct for disease severity, disease duration, disease behavior, disease
extent (included only for UC patients), perianal disease, concurrent steroid use, concurrent
immunomodulators therapy, age of diagnosis, disease duration.
These factors are all associated with adverse clinical outcomes, and it should be noted that this
study does not take these into account.
• The most reasonable method of measuring AE rate would be incidence per patient years and
not absolute number or proportions.
• The sample size for patients treated with ustekinumab and vedolizumab were significantly
smaller than those treated with anti-TNF. Please mention this in the limitations.
Please review this paper.
user
Title: Evaluation of adverse clinical outcomes in patients with inflammatory bowel disease
receiving different sequences of first- and second-line biologic treatments: findings from
ROTARY
Version: 0 Date: 16 Dec 2023
Reviewer's report:
Many thanks for the kind opportunity to review this manuscript.
The authors of this important manuscript approached the subject of drug sequencing in IBD
from a different angle looking specifically at hospitalizations, surgeries, infections, dysplasia,
and CRC. For that purpose data was extracted from OPTUM clinical database, aiming to infer
which drug sequence carry lesser risk for adverse clinical outcomes.
I have a few comments, which I think would be useful in improving its quality.
Introduction
Line 60: It is safe to say infliximab therapy is associated with increased risk of infection than
Immunosupressors. I am not sure biologics in general are associated with increased risk of
infections compared to non-biologics (steroids, JakI).
Methods
• Line 123-126: It is unclear why the authors included only patients receiving anti-TNFs
as second line therapy. The authors notes that first line therapy with anti-TNFs is well
established, but so is first line therapy with vedolizumab and Ustekinumab (same references
10,11). Including real world data of adverse events following different sequencing of biologics
(vedolizuman, risankizumab or Ustekinumab as second line therapy) would increase the
generalizability of the findings and novelty of the manuscript.
• Line 140: IBD-related hospitalizations were identified based on the existence of a primary
diagnosis of UC or CD on at least one of the hospitalization events. I am not sure this is
enough to capture all IBD-related hospitalizations, such as VTEs, extracolonic-malignancies,
cardiovascular events, kidney stones, etc.
• Line 145: Why were viral infections like HBV reactivation or shingles not included in the
infection analysis for patients with CD?
Statistical Analysis
• Line 156: Please share which baseline demographics and clinical characteristics were included
in the logistic regression model.
Results
• Line 166 and table 1.: The baseline characteristics table does not contain statistical
calculations of the differences between patient groups receiving first-line therapy. Similarly,
these differences are not discussed fully in the results section. For instance, there is large
variation in patients’ age (patients on Ustekinumab are older), and disease behavior (penetrating
and perianal disease is less prevalent in patients on vedolizumab and Ustekinumab as first line
therapy).
• Line 175 and table 2.: The baseline characteristics table does not contain statistical calculations
of the differences between patient groups receiving first-line therapy.
• Please explain which variables were included in the logistic regression model.
• The more appropriate measure for incidence of adverse events is the incidence per patient years.
• What proportion of the time were the patients on each treatment? This would seem very
important, since time on therapy is an important factor in the risk for adverse events.
• How were dysplasia rates calculated? Did all patients have screening colonoscopy? Were
dysplasia rates calculated as proportion from the patients who underwent colonoscopy?
Limitations
• With the advent of small molecules, why did the authors choose to look only at biologic meds
sequencing?
• How do the authors correct for disease severity, disease duration, disease behavior, disease
extent (included only for UC patients), perianal disease, concurrent steroid use, concurrent
immunomodulators therapy, age of diagnosis, disease duration.
These factors are all associated with adverse clinical outcomes, and it should be noted that this
study does not take these into account.
• The most reasonable method of measuring AE rate would be incidence per patient years and
not absolute number or proportions.
• The sample size for patients treated with ustekinumab and vedolizumab were significantly
smaller than those treated with anti-TNF. Please mention this in the limitations.
assistant