Observational Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 14, 2018; 24(18): 2036-2046
Published online May 14, 2018. doi: 10.3748/wjg.v24.i18.2036
Thiopurines are negatively associated with anthropometric parameters in pediatric Crohn’s disease
Neera Gupta, Robert H Lustig, Cewin Chao, Eric Vittinghoff, Howard Andrews, Cheng-Shiun Leu
Neera Gupta, Division of Gastroenterology and Nutrition, Department of Pediatrics, Weill Cornell Medicine, New York, NY 10021, United States
Robert H Lustig, Division of Endocrinology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, United States
Cewin Chao, Department of Nutrition and Food Services, University of California, San Francisco, San Francisco, CA 94143, United States
Eric Vittinghoff, Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, United States
Howard Andrews, Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY 10032, United States
Cheng-Shiun Leu, Department of Biostatistics, Columbia University Medical Center, New York, NY 10032, United States
Author contributions: Gupta N initial concept, secured funding; Gupta N, Lustig RH, Vittinghoff E and Leu CS study design; Gupta N data collection; Lustig RH bone age interpretation; Chao C anthropometric measurements; Gupta N and Leu CS data management; Gupta N, Vittinghoff E and Leu CS statistical analyses; Gupta N, Lustig RH, Chao C, Vittinghoff E, Andrews H and Leu CS data interpretation; Gupta N initial manuscript preparation; Gupta N, Lustig RH, Chao C, Vittinghoff E, Andrews H and Leu CS manuscript editing and revising; Gupta N finalized submission.
Supported by National Institutes of Health, No. DK077734 (NG); Children’s Digestive Health and Nutrition Foundation (now known as North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Foundation)/Crohn’s and Colitis Foundation of America (now known as Crohn’s and Colitis Foundation) Award for New Investigators, No. CDHNF-06-002 (NG); Crohn’s and Colitis Foundation of America (now known as Crohn’s and Colitis Foundation) Career Development Award, No. Award ID 1743 (NG); University of California San Francisco Department of Pediatrics Pediatric Clinical Research Center Clinical Research Pilot Funding Award (NG), and National Institutes of Health/National Center for Research Resources University of California San Francisco-Clinical and Translational Science Institute, No. UL1 RR024131.
Institutional review board statement: We obtained Institutional Review Board Approval for the study protocol.
Conflict-of-interest statement: Robert H Lustig wrote two trade books on metabolic health, but not related to the issues of this paper. The other authors have no conflicts of interest relevant to this article to disclose.
STROBE statement: The guidelines of the STROBE Statement have been adopted.
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: Neera Gupta, MD, MAS, Associate Professor, Division of Gastroenterology and Nutrition, Department of Pediatrics, Weill Cornell Medicine, 505 East 70th Street, Helmsley Tower, 3rd Floor, New York, NY 10021, United States. neg9020@med.cornell.edu
Telephone: +1-646-9623869 Fax: +1-646-9620246
Received: February 3, 2018
Peer-review started: February 3, 2018
First decision: February 20, 2018
Revised: April 12, 2018
Accepted: April 26, 2018
Article in press: April 26, 2018
Published online: May 14, 2018
Processing time: 97 Days and 11.5 Hours
ARTICLE HIGHLIGHTS
Research background

Similar to impaired statural growth (height velocity), a dynamic marker of disease status, body composition deficits may reflect poorly controlled disease despite the absence of overt clinical intestinal symptoms. Delayed bone age (BA) is common in pediatric Crohn’s disease (CD). Determination of BA allows clinically meaningful interpretation of growth in the context of skeletal maturity in pediatric CD. The impact of accounting for BA in the interpretation of body composition is unclear. Accurate interpretation of body composition is important since it reflects nutritional and disease status. Not only is nutritional status an important determinant of pubertal development and growth velocity, it is a prognostic factor for disease course. The association between medications and serum inflammatory and hormonal biomarkers with anthropometric measurements is not well delineated in pediatric CD, particularly after adjusting for maturational status (BA).

Research motivation

Nutritional status is an important factor to consider when making therapeutic decisions given its association with poor outcomes. Yet, the impact of treatments on anthropometric measurements is poorly defined and has not received sufficient attention.

Research objectives

Our aims were to determine the distribution of anthropometric parameters based on CA (CA z-scores) and BA (BA z-scores) and characterize the associations between medications and serum biomarkers with anthropometric parameter z-scores in pediatric CD.

Research methods

CD patients [< chronological age (CA) 21 years] were prospectively enrolled in a cross-sectional study. Descriptive statistics were generated for participants’ demographic characteristics and key variables of interest. Paired t-tests were used to compare anthropometric parameter z-scores calculated based on CA (CA z-scores) and BA (BA z-scores) for interpretation of anthropometric parameters. Linear regression was utilized to examine associations between medications and serum biomarkers with anthropometric parameter z-scores calculated based on CA (n = 82) and BA (n = 49). We reported regression coefficients as well as their corresponding p-values and 95% confidence intervals.

Research results

Mean CA at the time of the study visit was 15.3 ± 3.5 (standard deviation; range = 4.8-20.7) years. Mean triceps skinfold, subscapular skinfold and mid-arm circumference (MAC) BA z-scores were higher than corresponding CA z-scores. Medications were positively associated with subscapular skinfold (adalimumab and methotrexate) and BMI (adalimumab) CA z-scores. Azathioprine/6-mercaptopurine were negatively associated with MAC, subscapular skinfold, weight and BMI CA z-scores . ESR, CRP, and WBC count were negatively associated, while albumin and IGF-1 BA z-scores were positively associated with specific AP z-scores. Mean height CA z-scores were higher in females, not males, treated with infliximab. Hemoglobin was positively associated, while platelets, ESR and CRP were negatively associated with height CA z-scores in males, not females.

Research conclusions

Our findings reinforce the importance of accounting for BA when interpreting anthropometric parameters in pediatric CD. The main findings of our study raise intriguing questions. Thiopurines were negatively associated with specific anthropometric parameters. Do thiopurines have a negative effect on nutritional status/disease status? Alternatively, is the efficacy of thiopurines suboptimal? Infliximab was positively associated with standardized height in females only. Is there a sex difference in response to infliximab from the standpoint of statural growth? Specific serum biomarkers were associated with standardized height in males only, supporting the hypothesis that inflammation has a more detrimental effect on statural growth in males. Our results suggest a mechanistic relationship between medications, inflammation and anthropometric status/disease status, as well as a difference by sex. The studies presented herein contribute to a better understanding of the relationship between medications and serum inflammatory and hormonal biomarkers with anthropometric parameters in pediatric CD. Prospective longitudinal study is required as a next step to further investigate these intriguing findings and would allow further risk stratification which will improve patient counseling, guide expectations, and facilitate an individualized treatment approach.

Research perspectives

These findings serve as a foundation on which to build future studies with the goal of identifying patients at highest risk for poor outcomes, enhancing treatment algorithms, and ultimately developing individual treatment approaches based on risk stratification. The present study may provide a basis for mechanistic studies in many pediatric chronic inflammatory conditions.