Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Role of Sex in the Treatment and Clinical Outcomes of Pediatric Patients With Inflammatory Bowel Disease
Lee, Grace J.*; Kappelman, Michael D.†; Boyle, Brendan‡; Colletti, Richard B.§; King, Eileen||; Pratt, Jesse M.||; Crandall, Wallace V.‡
*Pediatric Gastroenterology Fellowship Program, Nationwide Children's Hospital, Columbus, OH
†Division of Gastroenterology and Hepatology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC
‡Division of Gastroenterology, Nationwide Children's Hospital, Columbus, OH
§Department of Pediatrics, University of Vermont, Burlington, VT
||Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Address correspondence and reprint requests to Grace J. Lee, MD, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205 (e-mail: email@example.com).
Received 23 December, 2011
Accepted 14 June, 2012
Participating ImproveCareNow centers and their physician leaders are Advocate Lutheran General Children's Hospital, James Berman; Arkansas Children's Hospital, George Fuchs; Arnold Palmer Children's Hospital, Devendra Mehta/Jeffrey Bornstein; Children's Healthcare of Atlanta/Emory Children's Center, Bess T. Schoen; Children's Hospital Boston, Leslie Higuchi; Children's Hospital of Colorado, Deborah Neigut/Edward Hoffenberg; Children's Hospital of the King's Daughters, Marc Tsou; Children's Hospital of Philadelphia, Andrew Grossman/Robert Baldassano; Children's Mercy Hospital, William San Pablo; Cincinnati Children's Hospital Medical Center, Shehzad Saeed/Ted Denson; Great Ormond Street Hospital, Mamoun Elawad; Inova Pediatric Digestive Disease Center, Ian Leibowitz/Lynn Duffy; Levine Children's Hospital, Victor Piñeiro; Maine Medical Center, Rebecca Carey; Massachusetts General Children's Hospital, George Russell/Esther Israel; Mayo Clinic, Jeanne Tung; Nationwide Children's Hospital, Wallace Crandall/Brendan Boyle; Nemours Children's Clinic, Fernando del Rosario/David Milov; Northwest Pediatric Gastroenterology, LLC, Jacqueline Fridge; Oakland Children's Hospital, Sabina Ali; Oklahoma University Medical Center, John Grunow; Pediatric Gastroenterology and Nutrition Associates, Howard Baron; Texas Children's Hospital, Seema Mehta/George Ferry; University of Michigan-Ann Arbor, Jeremy Adler; University of Minnesota, Boris Sudel; University of North Carolina at Chapel Hill, Michael Kappelman/Sandra Kim; UT Southwestern Medical Center, Ashish Patel; Vermont Children's Hospital, Richard Colletti.
The authors report no conflicts of interest.
Objective: To examine sex differences in medical therapy and clinical outcomes in pediatric patients with inflammatory bowel disease (IBD).
Methods: We performed a cross-sectional analysis of children with Crohn disease (CD) and ulcerative colitis (UC) using data from the ImproveCareNow Network collected between May 2007 and May 2010. Clinical remission, disease severity, body mass index (BMI) z scores, normal height velocity, and medication use were analyzed by sex and age.
Results: One thousand four hundred nine patients were included (993 had CD and 416 had UC). No significant sex differences were found in disease severity, BMI, height velocity, or use of medications. Further analysis of combination therapy with infliximab + 6-mercaptopurine/azathioprine and infliximab + methotrexate also did not reveal any differences. No sex differences were found after mediation use was stratified by age (those younger than 13 years and those 13 years old or older).
Conclusions: In this sample of CD and UC pediatric patients, no significant sex differences were found in disease severity, BMI, height velocity, or medication use. Our data do not support the use of sex as a major factor in patient risk stratification for children with IBD. In addition, despite concerns for sex-specific complications of some medications, our analysis did not suggest any sex differences in medication use.
Inflammatory bowel disease (IBD) includes Crohn disease (CD) and ulcerative colitis (UC) and is an idiopathic, chronic disorder of the gastrointestinal tract that affects between 71 and 212 of every 100,000 children in North America (1–3). The approach to the treatment of IBD has been evolving with increasing interest in “top-down” therapy, in which antitumor necrosis factor therapy with or without a concurrent immunomodulator would be used at the time of diagnosis (4–6).
The idea of top-down therapy may be particularly appealing in patients who are likely to experience a severe course of disease, including those at greater risk of developing complications. Therefore, there is renewed interest in being able to determine the risk of a severe, complicated disease course at the time of diagnosis, so that early, aggressive therapy can be considered. Sex is one possible predictor of clinical outcomes and may be considered as a variable in risk stratification.
Little is known about sex differences in patients with IBD, especially in the pediatric population. Regarding the clinical course of patients, studies of adults have suggested that female patients with CD have a higher mortality risk (7,8), higher prevalence of extraintestinal manifestations (9–11), greater recurrence of disease after resection (8), and increased harmful effects of smoking (12). Studies in pediatric patients have suggested that female patients with CD have more severe disease based on a higher prevalence of extraintestinal manifestations and hypoalbuminemia at diagnosis (13) and an increased risk of surgery (14). Varying sex differences in weight at diagnosis and nutrition status and growth failure have also been found (13,15–18).
We conducted a cross-sectional analysis to further explore whether sex differences in clinical outcomes exist in pediatric patients with CD and UC and therefore may be a significant factor in patient risk stratification.
ImproveCareNow is a multicenter network of health care providers formed in January 2007 to improve the quality of care of children and adolescents with IBD. The ImproveCareNow patient registry contains disease and treatment data collected prospectively and longitudinally during outpatient clinical encounters. Both existing and newly diagnosed patients were enrolled in the network. Patients were managed according to the usual practice of the primary gastroenterologist, although quality improvement methodology was used to reduce any unintended variation. Examples of quality improvement measures included standardized dosing of medication, documentation of particular variables such as disease activity and growth and nutrition status, pre-visit planning, and population management as previously described (19).
We performed a cross-sectional analysis of children with CD and UC enrolled in the ImproveCareNow Network patient registry from May 2007 to May 2010. Patients were included if they had 1 visit that was at least 90 days after diagnosis and had >1 visit recorded in the registry.
We examined sex differences for each of the following clinical outcomes and treatment modalities: clinical remission, disease severity, body mass index (BMI), normal height velocity, and use of corticosteroids, immunomodulators, and biologic agents. Clinical remission was primarily assessed by physician global assessment (PGA). The validated short Pediatric Crohn's Disease Activity Index (sPCDAI) (20) (remission defined as a score <15) and the Pediatric Ulcerative Colitis Activity Index (PUCAI) (21) (remission defined as a score <10) were also used to assess remission in patients with CD and UC, respectively, when there were sufficient data to generate the full score. Disease severity was defined as the proportion of patients in remission, with mild disease, and moderate to severe diseases based on the PGA, sPCDAI, and PUCAI. BMI was assessed using z scores based on the Centers for Disease Control and Prevention (CDC) sex-specific growth charts. Normal height velocity was defined as a z score >−1, also based on CDC normative data, and results are expressed in percentage of patients with normal height velocity. Medication use with prednisone, 6-mercaptopurine (6-MP), or azathioprine (Aza), methotrexate, and infliximab was determined for the entire study population and also stratified by age (patients younger than 13 years and patients 13 years old or older). In addition, combination therapy with infliximab + 6-MP/Aza and infliximab + methotrexate was determined and also stratified by age. Results are expressed in the percentage of patients using the medication at the time of the visit. Age, disease duration, and time of enrollment in the registry were also evaluated. Data from the visit closest to, but not following, May 31, 2010 were used to perform these analyses.
All calculations were performed using SAS 9.2 (SAS Institute, Cary, NC). t tests were used to compare BMI z scores. The χ2 test was used to compare percentages for height velocity, clinical remission status, disease severity, and usage of medications. The Fisher exact test was performed to compare medication use. The Wilcoxon rank sum test was used to compare age, disease duration, and time of enrollment. To control for multiple testing P ≤ 0.01 were considered to be statistically significant.
For patients with CD, with 537 male and 415 female PGA responses and 366 male and 267 female PCDAI responses, this study has at least 80% power to detect an 11% difference in remission rates based on PGA and a 14% difference based on PCDAI between men and women using a χ2 test at α 0.01. Similarly, for patients with UC, with 187 male and 209 female PGA responses and 136 male and 171 female PUCAI responses, this study has at least 80% power to detect an 18% difference in remission rates based on PGA and a 19% difference based on PUCAI at α 0.01.
Data for 1409 patients from 13 sites were available from the registry with 652 (46%) female patients. There were 993 (70%) with CD and 416 (30%) with UC. There were more men than women in the registry with CD (56.9% vs 43.1%) and more women than men with UC (53.8% vs 46.2%) (Table 1).
The median age, length of disease duration, and length of enrollment in the registry for patients with CD and those with UC are presented in Table 1. There were no significant differences in median age between men and women for both patients with CD and those with UC. Women with CD had a slightly longer disease duration of 3.6 years (interquartile range [IQR] 1.9–5.9) versus 2.9 years (IQR 1.4–5.3) for men (P = 0.01). Women with UC had a slightly longer time of enrollment in the registry: 15.7 months (IQR 8.6–26.6) versus 12.8 months (IQR 6.2–21.1) for men (P = 0.01).
The distribution of patients enrolled across centers is displayed in Table 2. The time from diagnosis to enrollment decreased over the course of the collaborative from 2007 to 2010 because initially there were primarily previously diagnosed patients available for enrollment and later primarily newly diagnosed patients available for enrollment. There were no other definable biases in the enrollment of patients in general or at specific centers (19).
PGA data for 95.9% (952/993) and sPCDAI data for 63.7% (633/993) of CD patients were available. In patients with UC, 95.2% (396/416) and 73.8% (307/416) had PGA and PUCAI data available. For patients with CD, there were no significant sex differences in remission rates based on PGA or the sPCDAI. There were also no significant differences between sexes for patients with UC based on PGA or the PUCAI (Table 3).
Separate analysis of disease severity to classify patients by those in remission, with mild disease, and with moderate to severe disease did not result in any significant sex differences based on PGA or the sPCDAI for patients with CD or by PGA or the PUCAI for patients with UC (Table 4).
Nutrition and Growth Status
BMI z scores and the percentage of patients with normal height velocity did not differ by sex for patients with CD or those with UC (Table 5).
For patients with CD and those with UC, there were no sex differences in the use of prednisone, 6-MP/Aza, methotrexate, or infliximab in the study population as a whole (Table 6) or when stratified by age (data not shown). Combination therapy with infliximab + 6-MP/Aza and infliximab + methotrexate also did not differ by sex in the study population as a whole or when stratified by age (data not shown).
After correcting for multiple testing, our study did not find any significant sex difference in remission rates based on PGA and the sPCDAI for patients with CD and the PUCAI for patients with UC. Further analysis stratifying patients by disease severity into remission, mild, and moderate to severe also did not reveal any significant difference.
In addressing medication use, we did not find any sex differences in patients with CD or those with UC. Given the concern about methotrexate therapy and risk of pregnancy in adolescent girls, we analyzed medication use by age but did not find any sex differences. With the possible association between hepatosplenic T-cell lymphoma and the use of immunomodulators and biologics in patients with CD (22), combination therapy was examined and again we did not find any sex differences in the sample population as a whole or when stratified by age.
Previous research on sex differences in outcomes of pediatric IBD patients is limited. In 2 retrospective cross-sectional studies examining 989 pediatric patients with CD, Gupta et al (13,14) suggested that girls have a more severe disease course based on findings of higher prevalence of extraintestinal manifestations, including mouth sores and erythema nodosum, hypoalbuminemia at diagnosis, and increased risk for surgical resection. Previous studies on sex differences in nutrition and growth are contradictory for those with CD at diagnosis (13,15,18) and over time (16,17,23). We did not demonstrate any significant sex differences in nutrition or growth status based on BMI z scores and height velocity. Of note, our data also did not show any major growth abnormalities in our population of patients with CD and those with UC.
The varying results found in the few studies on sex differences in patients with IBD highlight the difficulty in examining this topic. There is no consensus on what outcome measures are most appropriate for evaluation, and multiple measures have been reported (24). Remission is an important outcome; however, there are multiple approaches to assessing remission status with scales such as PGA and patient disease severity indices, laboratory review, and endoscopic evaluation. Hospitalization, surgery rates, and laboratory markers can also provide information regarding disease severity. In the pediatric population, growth and nutrition is of particular interest, especially with longitudinal assessments. Agreement on appropriate outcome measures for assessment will allow for more uniform analysis and determination of variables that should be accounted for in patient risk stratification.
There are several potential limitations of our study. First, the cross-sectional nature of the analysis does not allow us to assess disease course or growth and nutrition status over time. Although traditionally cross-sectional studies are considered to provide only weak evidence of causality due to the possibility of temporal bias, we believe this was a valid study design to answer our specific research question because sex, generally speaking, is an immutable trait. Additionally, by assessing clinical outcomes at or near the same point in time for all subjects, we have avoided the possibility of contamination of our results by secular trends. We recognize that PGA is a subjective measure of disease activity, but chose to use PGA as the primary outcome measure because it is a commonly used measure both clinically and in observational pediatric IBD research, was unlikely to be affected by any systematic bias in scoring across multiple sites, and is the standard against which other disease activity measures have been compared and validated. Of note, there was no difference in our results whether using PGA or sPCDAI/PUCAI as the outcome variable. Tanner stage, an independent factor in body composition, was not uniformly assessed, and therefore not adjusted for in our analysis of growth and nutrition status. Nor did we adjust for medication use in analyzing BMI and height, because longitudinal use of medications was not assessed. However, given that there were no sex differences in corticosteroid, methotrexate, 6-MP/Aza, or infliximab use, individually or as combination therapy, at the time of assessment, it seems unlikely that medication differences were an important factor. Finally, we had a limited number of outcome variables conducive to analysis and were unable to examine differences in other key outcome measures such as rates of surgery and hospitalization.
No significant sex differences in disease severity, BMI, height velocity, or medication use were found in this sample of pediatric patients with CD and those with UC. Consequently, our data do not support the use of sex alone as a major factor in patient risk stratification for children with IBD. In addition, despite concerns for sex-specific complications of some medications, our analysis did not suggest any sex differences in medication use.
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