Interleukin-6 is associated with steroid resistance and reflects disease activity in severe pediatric ulcerative colitis

Eytan Wine; David R. Mack; Jeffrey Hyams; Anthony R. Otley; James Markowitz; Wallace V. Crandall; Neal Leleiko; Aleixo M. Muise; Anne M. Griffiths; Dan Turner

doi:10.1016/j.crohns.2012.12.012

Interleukin-6 is associated with steroid resistance and reflects disease activity in severe pediatric ulcerative colitis

Eytan Wine^*, David R. Mack, Jeffrey Hyams, Anthony R. Otley, James Markowitz, Wallace V. Crandall, Neal Leleiko, Aleixo M. Muise, Anne M. Griffiths, Dan Turner

^*Corresponding author for this work

Faculty of Medicine

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

47 Scopus citations

Abstract

Background and aim: Approximately one third of patients with acute severe ulcerative colitis (ASC) will fail intravenous corticosteroids (IVCS). Predicting response to IVCS to initiate early salvage therapy remains challenging. The aim of this study was to evaluate the role of serum inflammatory cytokines in ASC and determine their predictive utility with IVCS treatment failure. Methods: This preplanned ancillary study, part of the prospective multicenter OSCI study, evaluated pediatric ASC in North America. Serum samples were obtained from 79 children admitted for ASC on the third day of IVCS treatment. Twenty-three (29%) patients required second-line therapy. ELISA-based cytokine arrays were used [TNF-α, IFN-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, and IL-17], selected based on a systematic literature search. Results: In univariate analysis, only IL-6 was significantly different between responders and non-responders (P=0.003). The risk for IVCS failure increased by 40% per each pg/mL increase in IL-6 level. Factor analysis found IL-6 to be associated with IL-17, suggesting involvement of the T-helper (T_H)17 pathway. In a multivariate analysis, disease activity [judged by the Pediatric UC Activity Index (PUCAI)] assumed all the association with the treatment outcome while IL-6 was no longer significant (P=0.32; PUCAI score P<0.001). Conclusions: While IL-6 strongly predicted IVCS failure, it likely reflects disease activity and not direct interference with corticosteroid pathway. Nonetheless, IL-6 levels may have a role in predicting IVCS response in severe pediatric UC for treatment decision-making or potentially in medical intervention by virtue of anti-IL-6 antibodies in severe UC.

Original language	English
Pages (from-to)	916-922
Number of pages	7
Journal	Journal of Crohn's and Colitis
Volume	7
Issue number	11
DOIs	https://doi.org/10.1016/j.crohns.2012.12.012
State	Published - 2013

Bibliographical note

Funding Information:
This study was partially funded by Schering Plough Canada as an educational grant; the funder was not involved in the study design, in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. E.W. is an Alberta Innovates Health Solutions (AIHS) Clinical Investigator; infrastructure in his laboratory is supported through the AIHS-funded Alberta IBD Consortium. We thank all the patients, their families, and health providers that contributed to this study.

Keywords

Disease marker
Inflammatory bowel diseases
Methylprednisolone
Response to treatment

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10.1016/j.crohns.2012.12.012

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@article{dc1fcfc8562c42ce866afc50e52b1d3c,

title = "Interleukin-6 is associated with steroid resistance and reflects disease activity in severe pediatric ulcerative colitis",

abstract = "Background and aim: Approximately one third of patients with acute severe ulcerative colitis (ASC) will fail intravenous corticosteroids (IVCS). Predicting response to IVCS to initiate early salvage therapy remains challenging. The aim of this study was to evaluate the role of serum inflammatory cytokines in ASC and determine their predictive utility with IVCS treatment failure. Methods: This preplanned ancillary study, part of the prospective multicenter OSCI study, evaluated pediatric ASC in North America. Serum samples were obtained from 79 children admitted for ASC on the third day of IVCS treatment. Twenty-three (29%) patients required second-line therapy. ELISA-based cytokine arrays were used [TNF-α, IFN-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, and IL-17], selected based on a systematic literature search. Results: In univariate analysis, only IL-6 was significantly different between responders and non-responders (P=0.003). The risk for IVCS failure increased by 40% per each pg/mL increase in IL-6 level. Factor analysis found IL-6 to be associated with IL-17, suggesting involvement of the T-helper (TH)17 pathway. In a multivariate analysis, disease activity [judged by the Pediatric UC Activity Index (PUCAI)] assumed all the association with the treatment outcome while IL-6 was no longer significant (P=0.32; PUCAI score P<0.001). Conclusions: While IL-6 strongly predicted IVCS failure, it likely reflects disease activity and not direct interference with corticosteroid pathway. Nonetheless, IL-6 levels may have a role in predicting IVCS response in severe pediatric UC for treatment decision-making or potentially in medical intervention by virtue of anti-IL-6 antibodies in severe UC.",

keywords = "Disease marker, Inflammatory bowel diseases, Methylprednisolone, Response to treatment",

author = "Eytan Wine and Mack, {David R.} and Jeffrey Hyams and Otley, {Anthony R.} and James Markowitz and Crandall, {Wallace V.} and Neal Leleiko and Muise, {Aleixo M.} and Griffiths, {Anne M.} and Dan Turner",

note = "Funding Information: This study was partially funded by Schering Plough Canada as an educational grant; the funder was not involved in the study design, in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. E.W. is an Alberta Innovates Health Solutions (AIHS) Clinical Investigator; infrastructure in his laboratory is supported through the AIHS-funded Alberta IBD Consortium. We thank all the patients, their families, and health providers that contributed to this study. ",

year = "2013",

doi = "10.1016/j.crohns.2012.12.012",

language = "אנגלית",

volume = "7",

pages = "916--922",

journal = "Journal of Crohn's and Colitis",

issn = "1873-9946",

publisher = "Oxford University Press",

number = "11",

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T1 - Interleukin-6 is associated with steroid resistance and reflects disease activity in severe pediatric ulcerative colitis

AU - Wine, Eytan

AU - Mack, David R.

AU - Hyams, Jeffrey

AU - Otley, Anthony R.

AU - Markowitz, James

AU - Crandall, Wallace V.

AU - Leleiko, Neal

AU - Muise, Aleixo M.

AU - Griffiths, Anne M.

AU - Turner, Dan

N1 - Funding Information: This study was partially funded by Schering Plough Canada as an educational grant; the funder was not involved in the study design, in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. E.W. is an Alberta Innovates Health Solutions (AIHS) Clinical Investigator; infrastructure in his laboratory is supported through the AIHS-funded Alberta IBD Consortium. We thank all the patients, their families, and health providers that contributed to this study.

PY - 2013

Y1 - 2013

N2 - Background and aim: Approximately one third of patients with acute severe ulcerative colitis (ASC) will fail intravenous corticosteroids (IVCS). Predicting response to IVCS to initiate early salvage therapy remains challenging. The aim of this study was to evaluate the role of serum inflammatory cytokines in ASC and determine their predictive utility with IVCS treatment failure. Methods: This preplanned ancillary study, part of the prospective multicenter OSCI study, evaluated pediatric ASC in North America. Serum samples were obtained from 79 children admitted for ASC on the third day of IVCS treatment. Twenty-three (29%) patients required second-line therapy. ELISA-based cytokine arrays were used [TNF-α, IFN-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, and IL-17], selected based on a systematic literature search. Results: In univariate analysis, only IL-6 was significantly different between responders and non-responders (P=0.003). The risk for IVCS failure increased by 40% per each pg/mL increase in IL-6 level. Factor analysis found IL-6 to be associated with IL-17, suggesting involvement of the T-helper (TH)17 pathway. In a multivariate analysis, disease activity [judged by the Pediatric UC Activity Index (PUCAI)] assumed all the association with the treatment outcome while IL-6 was no longer significant (P=0.32; PUCAI score P<0.001). Conclusions: While IL-6 strongly predicted IVCS failure, it likely reflects disease activity and not direct interference with corticosteroid pathway. Nonetheless, IL-6 levels may have a role in predicting IVCS response in severe pediatric UC for treatment decision-making or potentially in medical intervention by virtue of anti-IL-6 antibodies in severe UC.

AB - Background and aim: Approximately one third of patients with acute severe ulcerative colitis (ASC) will fail intravenous corticosteroids (IVCS). Predicting response to IVCS to initiate early salvage therapy remains challenging. The aim of this study was to evaluate the role of serum inflammatory cytokines in ASC and determine their predictive utility with IVCS treatment failure. Methods: This preplanned ancillary study, part of the prospective multicenter OSCI study, evaluated pediatric ASC in North America. Serum samples were obtained from 79 children admitted for ASC on the third day of IVCS treatment. Twenty-three (29%) patients required second-line therapy. ELISA-based cytokine arrays were used [TNF-α, IFN-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, and IL-17], selected based on a systematic literature search. Results: In univariate analysis, only IL-6 was significantly different between responders and non-responders (P=0.003). The risk for IVCS failure increased by 40% per each pg/mL increase in IL-6 level. Factor analysis found IL-6 to be associated with IL-17, suggesting involvement of the T-helper (TH)17 pathway. In a multivariate analysis, disease activity [judged by the Pediatric UC Activity Index (PUCAI)] assumed all the association with the treatment outcome while IL-6 was no longer significant (P=0.32; PUCAI score P<0.001). Conclusions: While IL-6 strongly predicted IVCS failure, it likely reflects disease activity and not direct interference with corticosteroid pathway. Nonetheless, IL-6 levels may have a role in predicting IVCS response in severe pediatric UC for treatment decision-making or potentially in medical intervention by virtue of anti-IL-6 antibodies in severe UC.

KW - Disease marker

KW - Inflammatory bowel diseases

KW - Methylprednisolone

KW - Response to treatment

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IS - 11

ER -

Interleukin-6 is associated with steroid resistance and reflects disease activity in severe pediatric ulcerative colitis

Abstract

Bibliographical note

Keywords

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