Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease

Dutch Initiative on Crohn’s and Colitis (ICC); J. E. Kreijne; R. L. Goetgebuer; N. S. Erler; N. K. De Boer; A. G. Siebers; G. Dijkstra; F. A. van Kemenade; F. Hoentjen; B. Oldenburg; A. E. van der Meulen; C. I.J. Ponsioen; M. J. Pierik; C. J. van der Woude; A. C. de Vries

doi:10.1111/apt.17555

Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease

Dutch Initiative on Crohn’s and Colitis (ICC), J. E. Kreijne^*, R. L. Goetgebuer, N. S. Erler, N. K. De Boer, A. G. Siebers, G. Dijkstra, F. A. van Kemenade, F. Hoentjen, B. Oldenburg, A. E. van der Meulen, C. I.J. Ponsioen, M. J. Pierik, C. J. van der Woude, A. C. de Vries^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background: Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+). Aim: To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+. Methods: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models. Results: The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08–1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77–4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33–2.27) were also risk factors for CIN2+ detection. Conclusion: Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted.

Original language	English
Pages (from-to)	207-217
Number of pages	11
Journal	Alimentary Pharmacology and Therapeutics
Volume	58
Issue number	2
Early online date	23 May 2023
DOIs	https://doi.org/10.1111/apt.17555
Publication status	Published - Jul 2023

Bibliographical note

Funding Information:
We would like to thank all the IBD patients who participate in the Parelsnoer Institute. We wish to acknowledge Judith Manniën and Erik Flikkenschild from the Parelsnoer Institute, IBD research coordinator Florien Toxopeus from the Parelsnoer Institute and Annette Gijsbers from PALGA for their contributions in data collection and data management and for providing the infrastructure to perform this study. Support for interfacing was provided by NWO grant BBMRI2.0 (FK).

Funding Information:
We would like to thank all the IBD patients who participate in the Parelsnoer Institute. We wish to acknowledge Judith Manniën and Erik Flikkenschild from the Parelsnoer Institute, IBD research coordinator Florien Toxopeus from the Parelsnoer Institute and Annette Gijsbers from PALGA for their contributions in data collection and data management and for providing the infrastructure to perform this study. Support for interfacing was provided by NWO grant BBMRI2.0 (FK).

Publisher Copyright:
© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

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Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel diseaseFinal published version, 924 KBLicence: CC BY-NC-ND

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Dutch Initiative on Crohn’s and Colitis (ICC), Kreijne, J. E., Goetgebuer, R. L., Erler, N. S., De Boer, N. K., Siebers, A. G., Dijkstra, G., van Kemenade, F. A., Hoentjen, F., Oldenburg, B., van der Meulen, A. E., Ponsioen, C. I. J., Pierik, M. J., van der Woude, C. J., & de Vries, A. C. (2023). Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease. Alimentary Pharmacology and Therapeutics, 58(2), 207-217. https://doi.org/10.1111/apt.17555

@article{fd6456dbb29549ed82bf0411f1241cfb,

title = "Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease",

abstract = "Background: Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+). Aim: To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+. Methods: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models. Results: The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08–1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77–4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33–2.27) were also risk factors for CIN2+ detection. Conclusion: Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted.",

author = "{Dutch Initiative on Crohn{\textquoteright}s and Colitis (ICC)} and Kreijne, {J. E.} and Goetgebuer, {R. L.} and Erler, {N. S.} and De Boer, {N. K.} and Siebers, {A. G.} and G. Dijkstra and {van Kemenade}, {F. A.} and F. Hoentjen and B. Oldenburg and {van der Meulen}, {A. E.} and Ponsioen, {C. I.J.} and Pierik, {M. J.} and {van der Woude}, {C. J.} and {de Vries}, {A. C.}",

note = "Funding Information: We would like to thank all the IBD patients who participate in the Parelsnoer Institute. We wish to acknowledge Judith Manni{\"e}n and Erik Flikkenschild from the Parelsnoer Institute, IBD research coordinator Florien Toxopeus from the Parelsnoer Institute and Annette Gijsbers from PALGA for their contributions in data collection and data management and for providing the infrastructure to perform this study. Support for interfacing was provided by NWO grant BBMRI2.0 (FK). Funding Information: We would like to thank all the IBD patients who participate in the Parelsnoer Institute. We wish to acknowledge Judith Manni{\"e}n and Erik Flikkenschild from the Parelsnoer Institute, IBD research coordinator Florien Toxopeus from the Parelsnoer Institute and Annette Gijsbers from PALGA for their contributions in data collection and data management and for providing the infrastructure to perform this study. Support for interfacing was provided by NWO grant BBMRI2.0 (FK). Publisher Copyright: {\textcopyright} 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.",

year = "2023",

month = jul,

doi = "10.1111/apt.17555",

language = "English",

volume = "58",

pages = "207--217",

journal = "Alimentary Pharmacology and Therapeutics",

issn = "0269-2813",

publisher = "John Wiley & Sons Inc.",

number = "2",

}

Dutch Initiative on Crohn’s and Colitis (ICC), Kreijne, JE, Goetgebuer, RL, Erler, NS, De Boer, NK, Siebers, AG, Dijkstra, G, van Kemenade, FA, Hoentjen, F, Oldenburg, B, van der Meulen, AE, Ponsioen, CIJ, Pierik, MJ, van der Woude, CJ & de Vries, AC 2023, 'Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease', Alimentary Pharmacology and Therapeutics, vol. 58, no. 2, pp. 207-217. https://doi.org/10.1111/apt.17555

Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease. / Dutch Initiative on Crohn’s and Colitis (ICC); Kreijne, J. E.; Goetgebuer, R. L. et al.
In: Alimentary Pharmacology and Therapeutics, Vol. 58, No. 2, 07.2023, p. 207-217.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease

AU - Dutch Initiative on Crohn’s and Colitis (ICC)

AU - Kreijne, J. E.

AU - Goetgebuer, R. L.

AU - Erler, N. S.

AU - De Boer, N. K.

AU - Siebers, A. G.

AU - Dijkstra, G.

AU - van Kemenade, F. A.

AU - Hoentjen, F.

AU - Oldenburg, B.

AU - van der Meulen, A. E.

AU - Ponsioen, C. I.J.

AU - Pierik, M. J.

AU - van der Woude, C. J.

AU - de Vries, A. C.

N1 - Funding Information: We would like to thank all the IBD patients who participate in the Parelsnoer Institute. We wish to acknowledge Judith Manniën and Erik Flikkenschild from the Parelsnoer Institute, IBD research coordinator Florien Toxopeus from the Parelsnoer Institute and Annette Gijsbers from PALGA for their contributions in data collection and data management and for providing the infrastructure to perform this study. Support for interfacing was provided by NWO grant BBMRI2.0 (FK). Funding Information: We would like to thank all the IBD patients who participate in the Parelsnoer Institute. We wish to acknowledge Judith Manniën and Erik Flikkenschild from the Parelsnoer Institute, IBD research coordinator Florien Toxopeus from the Parelsnoer Institute and Annette Gijsbers from PALGA for their contributions in data collection and data management and for providing the infrastructure to perform this study. Support for interfacing was provided by NWO grant BBMRI2.0 (FK). Publisher Copyright: © 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

PY - 2023/7

Y1 - 2023/7

N2 - Background: Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+). Aim: To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+. Methods: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models. Results: The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08–1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77–4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33–2.27) were also risk factors for CIN2+ detection. Conclusion: Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted.

AB - Background: Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+). Aim: To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+. Methods: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models. Results: The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08–1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77–4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33–2.27) were also risk factors for CIN2+ detection. Conclusion: Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted.

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U2 - 10.1111/apt.17555

DO - 10.1111/apt.17555

M3 - Article

C2 - 37221820

AN - SCOPUS:85160050290

SN - 0269-2813

VL - 58

SP - 207

EP - 217

JO - Alimentary Pharmacology and Therapeutics

JF - Alimentary Pharmacology and Therapeutics

IS - 2

ER -

Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease

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