Title: Comparison of surgery rates in biologic-naïve patients with Crohn’s disease treated with
vedolizumab or ustekinumab: findings from SOJOURN
Version: 2 Date: 07 Dec 2022
Reviewer's report:
This manuscript reports on results from the observational SOJOURN study which uses a claims
database to assess comparative effectiveness of UST and VDZ in prevention of surgery in
Crohn’s disease. The authors attempt to include only bio-naïve patients (see major comment
1 below) to compare the primary effectiveness of these non-TNF antagonist, newer biologics.
They conclude that at 1 year, VDZ was associated with lower rates of surgery 7.7% vs 11.6%.
While a relatively large study, this is derived from a claims database without granular disease
activity data or ability to adjudicate patient details, and therefore is subject to numerous
methodological limitations. Please find my detailed critique below.
Major Items:
1. The authors followed patients for 6 months prior to start of VDZ or UST and then call these
patients “bio-naïve” if no medication was used during the pre-study period. While many patients
on a previous biologic would transition to a new biologic in less than 6 months after stopping the
prior agent, how can you guarantee these patients truly never were treated with a prior biologic?
2. Do you have data on patients with prior surgery before cohort entry?
3. Do you have baseline disease activity at onset of UST/VDZ induction? This would likely
impact effectiveness outcomes. Similarly, disease duration, baseline biomarkers would be
important variables to consider in establishing comparative effectiveness
4.  Did you perform a sensitivity analysis according to type of surgery performed? For example,
I would be most interested in the effectiveness of each agent to prevent bowel resection moreso
than fistula or abscess exploration.
5. Did you control for patient age or other variables in the comparative effectiveness evaluation?
The vedolizumab cohort (as expected) was older, also echoed by the higher proportion of patients
with Medicare. Disease severity has been inversely associated with advanced age. Therefore,
uncontrolled confounders (and reason for real-world patient selection) might help to explain why
VDZ was not associated with higher surgery rates, as data from the registration trials suggest a
marginal overall efficacy for VDZ in CD. Similarly, there was a higher proportion of ileocolonic
disease in the UST cohort, compatible with higher surgery risk and furthermore more perianal
disease, so therefore higher rates of perianal surgery for fistula and abscess. One suggestion
would be to use propensity score matching to control for this variation and limit confounding
variables.
6. Can you comment on the difference in surgery rates by one year but the convergence of the
curves by 2 years?
7. Can you account for real-world dose increases for either medication? In observational studies,
patients will be managed according to local practice not permitted in the registration trials but
allowing re-induction and more frequent (q4 or q6 week dosing) in this setting.
8. The minor point about directly observed VDZ infusion therapy vs. unobserved home injection
of UST is potentially substantial. Real-world insurance delays for the very expensive UST and
other shipment delays or non-adherence are major problems in clinical practice and cannot be
controlled for in this study beyond claims for the medication being shipped. For example, our
center often has several unused doses for some patients which were delivered (and therefore
have a paid claim) but not administered.
Minor points:
1. This was funded by Takeda and found favorable (and unexpected) results for VDZ as
compared to UST. I am concerned the above confounders and flaws in the study design could
be the result of bias.
Title: Comparison of surgery rates in biologic-naïve patients with Crohn’s disease treated with
vedolizumab or ustekinumab: findings from SOJOURN
Version: 2 Date: 07 Dec 2022
Reviewer's report:
This manuscript reports on results from the observational SOJOURN study which uses a claims
database to assess comparative effectiveness of UST and VDZ in prevention of surgery in
Crohn’s disease. The authors attempt to include only bio-naïve patients (see major comment
1 below) to compare the primary effectiveness of these non-TNF antagonist, newer biologics.
They conclude that at 1 year, VDZ was associated with lower rates of surgery 7.7% vs 11.6%.
While a relatively large study, this is derived from a claims database without granular disease
activity data or ability to adjudicate patient details, and therefore is subject to numerous
methodological limitations. Please find my detailed critique below.
Major Items:
1. The authors followed patients for 6 months prior to start of VDZ or UST and then call these
patients “bio-naïve” if no medication was used during the pre-study period. While many patients
on a previous biologic would transition to a new biologic in less than 6 months after stopping the
prior agent, how can you guarantee these patients truly never were treated with a prior biologic?
2. Do you have data on patients with prior surgery before cohort entry?
3. Do you have baseline disease activity at onset of UST/VDZ induction? This would likely
impact effectiveness outcomes. Similarly, disease duration, baseline biomarkers would be
important variables to consider in establishing comparative effectiveness
4.  Did you perform a sensitivity analysis according to type of surgery performed? For example,
I would be most interested in the effectiveness of each agent to prevent bowel resection moreso
than fistula or abscess exploration.
5. Did you control for patient age or other variables in the comparative effectiveness evaluation?
The vedolizumab cohort (as expected) was older, also echoed by the higher proportion of patients
with Medicare. Disease severity has been inversely associated with advanced age. Therefore,
uncontrolled confounders (and reason for real-world patient selection) might help to explain why
VDZ was not associated with higher surgery rates, as data from the registration trials suggest a
marginal overall efficacy for VDZ in CD. Similarly, there was a higher proportion of ileocolonic
disease in the UST cohort, compatible with higher surgery risk and furthermore more perianal
disease, so therefore higher rates of perianal surgery for fistula and abscess. One suggestion
would be to use propensity score matching to control for this variation and limit confounding
variables.
6. Can you comment on the difference in surgery rates by one year but the convergence of the
curves by 2 years?
7. Can you account for real-world dose increases for either medication? In observational studies,
patients will be managed according to local practice not permitted in the registration trials but
allowing re-induction and more frequent (q4 or q6 week dosing) in this setting.
8. The minor point about directly observed VDZ infusion therapy vs. unobserved home injection
of UST is potentially substantial. Real-world insurance delays for the very expensive UST and
other shipment delays or non-adherence are major problems in clinical practice and cannot be
controlled for in this study beyond claims for the medication being shipped. For example, our
center often has several unused doses for some patients which were delivered (and therefore
have a paid claim) but not administered.
Minor points:
1. This was funded by Takeda and found favorable (and unexpected) results for VDZ as
compared to UST. I am concerned the above confounders and flaws in the study design could
be the result of bias.
Please review this paper.
user
Title: Comparison of surgery rates in biologic-naïve patients with Crohn’s disease treated with
vedolizumab or ustekinumab: findings from SOJOURN
Version: 2 Date: 07 Dec 2022
Reviewer's report:
This manuscript reports on results from the observational SOJOURN study which uses a claims
database to assess comparative effectiveness of UST and VDZ in prevention of surgery in
Crohn’s disease. The authors attempt to include only bio-naïve patients (see major comment
1 below) to compare the primary effectiveness of these non-TNF antagonist, newer biologics.
They conclude that at 1 year, VDZ was associated with lower rates of surgery 7.7% vs 11.6%.
While a relatively large study, this is derived from a claims database without granular disease
activity data or ability to adjudicate patient details, and therefore is subject to numerous
methodological limitations. Please find my detailed critique below.
Major Items:
1. The authors followed patients for 6 months prior to start of VDZ or UST and then call these
patients “bio-naïve” if no medication was used during the pre-study period. While many patients
on a previous biologic would transition to a new biologic in less than 6 months after stopping the
prior agent, how can you guarantee these patients truly never were treated with a prior biologic?
2. Do you have data on patients with prior surgery before cohort entry?
3. Do you have baseline disease activity at onset of UST/VDZ induction? This would likely
impact effectiveness outcomes. Similarly, disease duration, baseline biomarkers would be
important variables to consider in establishing comparative effectiveness
4.  Did you perform a sensitivity analysis according to type of surgery performed? For example,
I would be most interested in the effectiveness of each agent to prevent bowel resection moreso
than fistula or abscess exploration.
5. Did you control for patient age or other variables in the comparative effectiveness evaluation?
The vedolizumab cohort (as expected) was older, also echoed by the higher proportion of patients
with Medicare. Disease severity has been inversely associated with advanced age. Therefore,
uncontrolled confounders (and reason for real-world patient selection) might help to explain why
VDZ was not associated with higher surgery rates, as data from the registration trials suggest a
marginal overall efficacy for VDZ in CD. Similarly, there was a higher proportion of ileocolonic
disease in the UST cohort, compatible with higher surgery risk and furthermore more perianal
disease, so therefore higher rates of perianal surgery for fistula and abscess. One suggestion
would be to use propensity score matching to control for this variation and limit confounding
variables.
6. Can you comment on the difference in surgery rates by one year but the convergence of the
curves by 2 years?
7. Can you account for real-world dose increases for either medication? In observational studies,
patients will be managed according to local practice not permitted in the registration trials but
allowing re-induction and more frequent (q4 or q6 week dosing) in this setting.
8. The minor point about directly observed VDZ infusion therapy vs. unobserved home injection
of UST is potentially substantial. Real-world insurance delays for the very expensive UST and
other shipment delays or non-adherence are major problems in clinical practice and cannot be
controlled for in this study beyond claims for the medication being shipped. For example, our
center often has several unused doses for some patients which were delivered (and therefore
have a paid claim) but not administered.
Minor points:
1. This was funded by Takeda and found favorable (and unexpected) results for VDZ as
compared to UST. I am concerned the above confounders and flaws in the study design could
be the result of bias.
assistant