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©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
Impaired granulocyte-macrophage colony-stimulating factor bioactivity accelerates surgical recurrence in ileal Crohn’s disease
Grace Gathungu, Yuanhao Zhang, Xinyu Tian, Erin Bonkowski, Leahana Rowehl, Julia Krumsiek, Billy Nix, Claudia Chalk, Bruce Trapnell, Wei Zhu, Rodney Newberry, Lee Denson, Ellen Li
Grace Gathungu, Julia Krumsiek, Department of Pediatrics, Division of Pediatric Gastroenterology, Stony Brook University, Stony Brook, NY 11794, United States
Yuanhao Zhang, Xinyu Tian, Leahana Rowehl, Ellen Li, Department of Medicine, Division of Gastroenterology, Stony Brook University, Stony Brook, NY 11794, United States
Erin Bonkowski, Claudia Chalk, Bruce Trapnell, Lee Denson, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3026, United States
Billy Nix, Rodney Newberry, Department of Medicine, Washington University St. Louis, St. Louis, MO 63110, United States
Wei Zhu, Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, United states
Author contributions: Gathungu G, Li E and Denson L designed and performed the research, contributed to the analysis and wrote the paper; Zhang Y, Tian X, Zhu W, Trapnell B and Newberry R designed the research, contributed to the analysis and supervised the report; Krumsiek J, Rowehl L, Bonkowski E, Chalk C and Nix B performed the research and data extraction and contributed to the analysis.
Supported by (in part) the National Institutes of Health, No. R01 DK098231, R01 DK078683 and No. P30DK052574.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board at Washington University Hospital.
Informed consent statement: Adult patients are recruited in a consecutive fashion by the Washington University Digestive Diseases Research Tissue Procurement Facility and provide verbal and written consent for chart abstraction, blood, stool, tissue biopsies and/or surgical waste collection with analysis for research purposes and for their information to be stored in the hospital database. The IRB at Washington University approved this consent procedure.
Conflict-of-interest statement: The authors have declared that no potential conflicts (financial, professional, or personal) exist that are relevant to the manuscript.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Grace Gathungu, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Gastroenterology, Stony Brook University Medical Center, HSC T11-080, Stony Brook, NY 11794, United States.
grace.gathungu@stonybrookmedicine.edu
Telephone: +1-631-4448115 Fax: +1-631-4446045
Received: November 14, 2017
Peer-review started: November 16, 2017
First decision: November 30, 2017
Revised: December 5, 2017
Accepted: December 12, 2017
Article in press: December 12, 2017
Published online: February 7, 2018
Processing time: 77 Days and 5 Hours
AIM
To examine the relationship between elevated granulocyte-macrophage colony-stimulating factor (GM-CSF) auto-antibodies (Ab) level and time to surgical recurrence after initial surgery for Crohn’s disease (CD).
METHODS
We reviewed 412 charts from a clinical database at tertiary academic hospital. Patients included in the study had ileal or ileocolonic CD and surgical resection of small bowel or ileocecal region for management of disease. Serum samples were analyzed for serological assays including GM-CSF cytokine, GM-CSF Ab, ASCA IgG and IgA, and genetic markers including SNPs rs2066843, rs2066844, rs2066845, rs2076756 and rs2066847 in NOD2, rs2241880 in ATG16L1, and rs13361189 in IRGM. Cox proportional-hazards models were used to assess the predictors of surgical recurrence.
RESULTS
Ninety six percent of patients underwent initial ileocecal resection (ICR) or ileal resection (IR) and subsequently 40% of patients required a second ICR/IR for CD. GM-CSF Ab level was elevated at a median of 3.81 mcg/mL. Factors predicting faster time to a second surgery included elevated GM-CSF Ab [hazard ratio (HR) 3.52, 95%CI: 1.45-8.53, P = 0.005] and elevated GM-CSF cytokine (HR = 2.48, 95%CI: 1.31-4.70, P = 0.005). Factors predicting longer duration between first and second surgery included use of Immunomodulators (HR = 0.49, 95%CI: 0.31-0.77, P = 0.002), the interaction effect of low GM-CSF Ab levels and smoking (HR = 0.60, 95%CI: 0.45-0.81, P = 0.001) and the interaction effect of low GM-CSF cytokine levels and ATG16L1 (HR = 0.65, 95%CI: 0.49-0.88, P = 0.006).
CONCLUSION
GM-CSF bioavailability plays a critical role in maintaining intestinal homeostasis. Decreased bioavailability coupled with the genetic risk markers and/or smoking results in aggressive CD behavior.
Core tip: This retrospective study assesses the risk of surgery for management of ileal Crohn’s disease (CD) among patients with elevated granulocyte-macrophage colony-stimulating factor (GM-CSF) auto-antibodies (Ab). In this cohort, 396 subjects underwent initial ileocecal resection or ileal resection for management of disease. Subsequently 165 patients (41.7%) required a second ICR or IR. Factors predicting faster time to a second surgery were elevated GM-CSF Ab and elevated GM-CSF cytokine. Patients with low GM-CSF cytokine levels and the protective allele for ATG16L1 had longer intervals between a first and second surgery. To improve long term outcomes for patients with Ileal CD we need to optimize therapeutic options for patients with low GM-CSF bioavailability and genetic risk markers for ATG16L1.
