Title: Safety of infliximab and adalimumab in pediatric inflammatory bowel diseases: a
disproportionality analysis from the FAERS database
Version: 0 Date: 19 May 2025
Reviewer's report:
This study evaluates the safety profile of anti-TNF therapy in pediatric patients with
inflammatory bowel disease (IBD). The topic is highly relevant, as postmarketing
pharmacovigilance is particularly critical in children due to their unique physiological
and developmental considerations. However, substantial revisions are required before this
manuscript can be considered for publication.
________________________________________
Abstract
1. Please remove the word “inadequate” in the sentence: “However, their postmarketing
pharmacovigilance is inadequate and requires ongoing attention.”
# Suggested revision: “However, postmarketing pharmacovigilance requires ongoing attention.”
2. Psoriasiform skin eruptions related to anti-TNF therapy are well-documented and common
adverse effects, as acknowledged by the authors in the introduction. These reactions—as
well as depression—are listed among postmarketing adverse events in the labeling for both
adalimumab (ADA) and infliximab (IFX). However, they are not included in the approved
labeling. Therefore, this claim should be appropriately moderated.
________________________________________
Results
1. Pouchitis should not be categorized as an infection-related adverse event (AE), as it is
generally considered a manifestation of disease activity rather than an infectious process.
Please revise line 167 accordingly. # Suggested revision: “Other significant signals include
hematochezia, frequent bowel movements, pouchitis, and psoriasis.” Note that the first three are
more likely attributable to underlying disease activity, as discussed for ADA.
2. The term “fall” in line 169 is ambiguous and requires clarification—please specify the context
(e.g., accidental fall, syncope-related, orthostatic, etc.).
3. Anal abscess and perirectal abscess likely refer to the same clinical entity. Please consolidate
or clarify this duplication in Table 2.
4. Please correct terminology for clarity and accuracy:
o Enteritis infectious # Infectious enteritis
o Depression suicidal # Suicidal depression
o Rash pustular # Pustular rash
o Abscess intestinal # Intra-abdominal abscess
________________________________________
Discussion
1. The following sentence is inaccurate: “Typically, after adjusting the infusion rate and treating
with paracetamol, antihistamines or corticosteroids, the symptoms improve substantially or
resolve completely.” # Correction: Infusion rate adjustment applies only to intravenous therapies
(e.g., IFX), not to subcutaneously administered drugs like ADA. Please revise accordingly.
2. Reference 34 indicates a lower infection risk with IFX compared to ADA. This should be
discussed in the manuscript to contextualize infection risk profiles between the two agents.
3. Both anal abscess and intra-abdominal abscess are more likely consequences of underlying
Crohn’s disease, rather than drug-induced infections. Patients with Crohn’s are predisposed to
perianal disease and penetrating complications. Please adjust the interpretation accordingly.
4. Please rephrase the sentence: “The same may be true for the children's population” (line 342)
# Suggested revision: “This may also apply to pediatric populations.”
5. The pediatric IBD cohort study from Sweden [47] demonstrated a persistently elevated
risk of cancer—particularly gastrointestinal cancers—in patients with childhood-onset IBD,
independent of medication exposure. These findings suggest that chronic inflammation itself
may be the primary driver of malignancy risk. Future surveillance strategies should reflect this
understanding.
6. There is a paradoxical effect because anti-TNF therapy is also used successfully to treat
patients with psoriasis.
7. Recent evidence suggests that psoriasiform dermatitis in pediatric IBD patients may be driven
by peak IFX concentrations rather than trough levels [1]. This supports a pharmacokinetic
rationale for favoring subcutaneous formulations, which avoid high peak levels while
maintaining therapeutic exposure (area under the curve). Landemaine et al. [2] also showed that
cumulative IFX exposure, not trough concentration, correlates with increased infection risk.
o Ref 1: van Hoeve K, Thomas D, Hillary T, et al. J Pediatr Gastroenterol Nutr.
2024;78(1):95-104.
o Ref 2: Landemaine A, Petitcollin A, Brochard C, et al. Clin Gastroenterol Hepatol.
2021;19:288–95.e4.
8. Please include the following reference regarding sustained weight gain in IFX-treated
pediatric patients:
o Lepp J, Höög C, Forsell A, Fyrhake U, Lördal M, Almer S. Scand J Gastroenterol.
2020;55(12):1411–1418.
9. Nephrolithiasis is a known extraintestinal complication of IBD itself. However, anti-TNF
therapies have also been implicated in drug-induced nephropathies such as glomerulonephritis
and tubulointerstitial nephritis. This should be acknowledged using the following reference:
o van Hoeve K, Hoffman I. J Gastroenterol. 2022;57(9):619–629.
10. Abbreviations must be used consistently throughout the manuscript. Define each
abbreviation at its first use and use the abbreviated form thereafter.
________________________________________
Figure
1. Applying colored frames around the text significantly impairs readability. Please consider an
alternative visual presentation that preserves clarity while maintaining visual appeal.
Title: Safety of infliximab and adalimumab in pediatric inflammatory bowel diseases: a
disproportionality analysis from the FAERS database
Version: 0 Date: 19 May 2025
Reviewer's report:
This study evaluates the safety profile of anti-TNF therapy in pediatric patients with
inflammatory bowel disease (IBD). The topic is highly relevant, as postmarketing
pharmacovigilance is particularly critical in children due to their unique physiological
and developmental considerations. However, substantial revisions are required before this
manuscript can be considered for publication.
________________________________________
Abstract
1. Please remove the word “inadequate” in the sentence: “However, their postmarketing
pharmacovigilance is inadequate and requires ongoing attention.”
# Suggested revision: “However, postmarketing pharmacovigilance requires ongoing attention.”
2. Psoriasiform skin eruptions related to anti-TNF therapy are well-documented and common
adverse effects, as acknowledged by the authors in the introduction. These reactions—as
well as depression—are listed among postmarketing adverse events in the labeling for both
adalimumab (ADA) and infliximab (IFX). However, they are not included in the approved
labeling. Therefore, this claim should be appropriately moderated.
________________________________________
Results
1. Pouchitis should not be categorized as an infection-related adverse event (AE), as it is
generally considered a manifestation of disease activity rather than an infectious process.
Please revise line 167 accordingly. # Suggested revision: “Other significant signals include
hematochezia, frequent bowel movements, pouchitis, and psoriasis.” Note that the first three are
more likely attributable to underlying disease activity, as discussed for ADA.
2. The term “fall” in line 169 is ambiguous and requires clarification—please specify the context
(e.g., accidental fall, syncope-related, orthostatic, etc.).
3. Anal abscess and perirectal abscess likely refer to the same clinical entity. Please consolidate
or clarify this duplication in Table 2.
4. Please correct terminology for clarity and accuracy:
o Enteritis infectious # Infectious enteritis
o Depression suicidal # Suicidal depression
o Rash pustular # Pustular rash
o Abscess intestinal # Intra-abdominal abscess
________________________________________
Discussion
1. The following sentence is inaccurate: “Typically, after adjusting the infusion rate and treating
with paracetamol, antihistamines or corticosteroids, the symptoms improve substantially or
resolve completely.” # Correction: Infusion rate adjustment applies only to intravenous therapies
(e.g., IFX), not to subcutaneously administered drugs like ADA. Please revise accordingly.
2. Reference 34 indicates a lower infection risk with IFX compared to ADA. This should be
discussed in the manuscript to contextualize infection risk profiles between the two agents.
3. Both anal abscess and intra-abdominal abscess are more likely consequences of underlying
Crohn’s disease, rather than drug-induced infections. Patients with Crohn’s are predisposed to
perianal disease and penetrating complications. Please adjust the interpretation accordingly.
4. Please rephrase the sentence: “The same may be true for the children's population” (line 342)
# Suggested revision: “This may also apply to pediatric populations.”
5. The pediatric IBD cohort study from Sweden [47] demonstrated a persistently elevated
risk of cancer—particularly gastrointestinal cancers—in patients with childhood-onset IBD,
independent of medication exposure. These findings suggest that chronic inflammation itself
may be the primary driver of malignancy risk. Future surveillance strategies should reflect this
understanding.
6. There is a paradoxical effect because anti-TNF therapy is also used successfully to treat
patients with psoriasis.
7. Recent evidence suggests that psoriasiform dermatitis in pediatric IBD patients may be driven
by peak IFX concentrations rather than trough levels [1]. This supports a pharmacokinetic
rationale for favoring subcutaneous formulations, which avoid high peak levels while
maintaining therapeutic exposure (area under the curve). Landemaine et al. [2] also showed that
cumulative IFX exposure, not trough concentration, correlates with increased infection risk.
o Ref 1: van Hoeve K, Thomas D, Hillary T, et al. J Pediatr Gastroenterol Nutr.
2024;78(1):95-104.
o Ref 2: Landemaine A, Petitcollin A, Brochard C, et al. Clin Gastroenterol Hepatol.
2021;19:288–95.e4.
8. Please include the following reference regarding sustained weight gain in IFX-treated
pediatric patients:
o Lepp J, Höög C, Forsell A, Fyrhake U, Lördal M, Almer S. Scand J Gastroenterol.
2020;55(12):1411–1418.
9. Nephrolithiasis is a known extraintestinal complication of IBD itself. However, anti-TNF
therapies have also been implicated in drug-induced nephropathies such as glomerulonephritis
and tubulointerstitial nephritis. This should be acknowledged using the following reference:
o van Hoeve K, Hoffman I. J Gastroenterol. 2022;57(9):619–629.
10. Abbreviations must be used consistently throughout the manuscript. Define each
abbreviation at its first use and use the abbreviated form thereafter.
________________________________________
Figure
1. Applying colored frames around the text significantly impairs readability. Please consider an
alternative visual presentation that preserves clarity while maintaining visual appeal.
Please review this paper.
user
Title: Safety of infliximab and adalimumab in pediatric inflammatory bowel diseases: a
disproportionality analysis from the FAERS database
Version: 0 Date: 19 May 2025
Reviewer's report:
This study evaluates the safety profile of anti-TNF therapy in pediatric patients with
inflammatory bowel disease (IBD). The topic is highly relevant, as postmarketing
pharmacovigilance is particularly critical in children due to their unique physiological
and developmental considerations. However, substantial revisions are required before this
manuscript can be considered for publication.
________________________________________
Abstract
1. Please remove the word “inadequate” in the sentence: “However, their postmarketing
pharmacovigilance is inadequate and requires ongoing attention.”
# Suggested revision: “However, postmarketing pharmacovigilance requires ongoing attention.”
2. Psoriasiform skin eruptions related to anti-TNF therapy are well-documented and common
adverse effects, as acknowledged by the authors in the introduction. These reactions—as
well as depression—are listed among postmarketing adverse events in the labeling for both
adalimumab (ADA) and infliximab (IFX). However, they are not included in the approved
labeling. Therefore, this claim should be appropriately moderated.
________________________________________
Results
1. Pouchitis should not be categorized as an infection-related adverse event (AE), as it is
generally considered a manifestation of disease activity rather than an infectious process.
Please revise line 167 accordingly. # Suggested revision: “Other significant signals include
hematochezia, frequent bowel movements, pouchitis, and psoriasis.” Note that the first three are
more likely attributable to underlying disease activity, as discussed for ADA.
2. The term “fall” in line 169 is ambiguous and requires clarification—please specify the context
(e.g., accidental fall, syncope-related, orthostatic, etc.).
3. Anal abscess and perirectal abscess likely refer to the same clinical entity. Please consolidate
or clarify this duplication in Table 2.
4. Please correct terminology for clarity and accuracy:
o Enteritis infectious # Infectious enteritis
o Depression suicidal # Suicidal depression
o Rash pustular # Pustular rash
o Abscess intestinal # Intra-abdominal abscess
________________________________________
Discussion
1. The following sentence is inaccurate: “Typically, after adjusting the infusion rate and treating
with paracetamol, antihistamines or corticosteroids, the symptoms improve substantially or
resolve completely.” # Correction: Infusion rate adjustment applies only to intravenous therapies
(e.g., IFX), not to subcutaneously administered drugs like ADA. Please revise accordingly.
2. Reference 34 indicates a lower infection risk with IFX compared to ADA. This should be
discussed in the manuscript to contextualize infection risk profiles between the two agents.
3. Both anal abscess and intra-abdominal abscess are more likely consequences of underlying
Crohn’s disease, rather than drug-induced infections. Patients with Crohn’s are predisposed to
perianal disease and penetrating complications. Please adjust the interpretation accordingly.
4. Please rephrase the sentence: “The same may be true for the children's population” (line 342)
# Suggested revision: “This may also apply to pediatric populations.”
5. The pediatric IBD cohort study from Sweden [47] demonstrated a persistently elevated
risk of cancer—particularly gastrointestinal cancers—in patients with childhood-onset IBD,
independent of medication exposure. These findings suggest that chronic inflammation itself
may be the primary driver of malignancy risk. Future surveillance strategies should reflect this
understanding.
6. There is a paradoxical effect because anti-TNF therapy is also used successfully to treat
patients with psoriasis.
7. Recent evidence suggests that psoriasiform dermatitis in pediatric IBD patients may be driven
by peak IFX concentrations rather than trough levels [1]. This supports a pharmacokinetic
rationale for favoring subcutaneous formulations, which avoid high peak levels while
maintaining therapeutic exposure (area under the curve). Landemaine et al. [2] also showed that
cumulative IFX exposure, not trough concentration, correlates with increased infection risk.
o Ref 1: van Hoeve K, Thomas D, Hillary T, et al. J Pediatr Gastroenterol Nutr.
2024;78(1):95-104.
o Ref 2: Landemaine A, Petitcollin A, Brochard C, et al. Clin Gastroenterol Hepatol.
2021;19:288–95.e4.
8. Please include the following reference regarding sustained weight gain in IFX-treated
pediatric patients:
o Lepp J, Höög C, Forsell A, Fyrhake U, Lördal M, Almer S. Scand J Gastroenterol.
2020;55(12):1411–1418.
9. Nephrolithiasis is a known extraintestinal complication of IBD itself. However, anti-TNF
therapies have also been implicated in drug-induced nephropathies such as glomerulonephritis
and tubulointerstitial nephritis. This should be acknowledged using the following reference:
o van Hoeve K, Hoffman I. J Gastroenterol. 2022;57(9):619–629.
10. Abbreviations must be used consistently throughout the manuscript. Define each
abbreviation at its first use and use the abbreviated form thereafter.
________________________________________
Figure
1. Applying colored frames around the text significantly impairs readability. Please consider an
alternative visual presentation that preserves clarity while maintaining visual appeal.
assistant