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Perianal Crohn Disease in a Large Multicenter Pediatric Collaborative

Adler, Jeremy*,†; Dong, Shiming; Eder, Sally J.*,†; Dombkowski, Kevin J.for the ImproveCareNow Pediatric IBD Learning Health System

Journal of Pediatric Gastroenterology and Nutrition: May 2017 - Volume 64 - Issue 5 - p e117–e124
doi: 10.1097/MPG.0000000000001447
Original Articles: Gastroenterology: Inflammatory Bowel Disease

Background: Although perianal complications of Crohn disease (CD) are commonly encountered in clinical practice, the epidemiology of perianal CD among populations of children is poorly understood. We sought to characterize the prevalence of perianal disease in a large and diverse population of pediatric patients with CD.

Methods: We conducted retrospective analyses from a prospective observational cohort, the ImproveCareNow Network (May 2006–October 2014), a multicenter pediatric inflammatory bowel disease quality improvement collaborative. Clinicians prospectively documented physical examination and phenotype classification at outpatient visits. Perianal examination findings and concomitant phenotype change were used to corroborate time of new-onset perianal disease. Results were stratified by age, sex, and race and compared across groups with logistic regression. Cumulative incidence was estimated using Kaplan-Meier analyses and compared between groups with Cox proportional hazard regression models.

Results: The registry included 7076 patients with CD (41% girls). Missing/conflicting entries resulted in 397 (6%) patient exclusions. Among the remaining 6679 cases, 1399 (21%) developed perianal disease. Perianal disease was more common among boys (22%) than girls (20%; P = 0.013) and developed sooner after diagnosis among those with later rather than early onset disease (P < 0.001). Perianal disease was also more common among blacks (26%) compared with whites (20%; P = 0.017). Asians with later onset CD developed perianal disease earlier in their disease course (P = 0.01). There was no association between disease location or nutritional status at diagnosis and later development of perianal disease.

Conclusions: In this large multicenter collaborative, we found that perianal disease is more common among children with CD than previously recognized. Differences in the development of perianal disease were found across racial and other subgroups. Treatment strategies are needed to prevent perianal disease development.

Supplemental Digital Content is available in the text

*Division of Pediatric Gastroenterology

Child Health Evaluation and Research (CHEAR) Unit, University of Michigan, Ann Arbor, MI

ImproveCareNow, Inc., Burlington, VT.

Address correspondence and reprint requests to Jeremy Adler, MD, MSc, Division of Pediatric Gastroenterology, University of Michigan, 300 North Ingalls St, 6C15A, Ann Arbor, MI 48109-5456 (e-mail: jeradler@umich.edu).

Received 7 March, 2016

Accepted 19 October, 2016

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org).

www.trialregister.nl registration number: 3609.

This work was funded by the University of Michigan Pediatric Intramural Awards Program and the Charles Woodson Clinical Research Fund. No funding was received from other sources.

The authors have no conflicts of interest to declare.

What Is Known

  • Perianal complications of Crohn disease are frequently encountered in clinical practice.
  • Perianal complications of Crohn disease are difficult to treat and reoccur commonly.
  • Perianal Crohn disease leads to serious morbidity and negatively impacts quality of life.
  • What Is New
  • Perianal disease is more common among pediatric Crohn disease patients than previously described.
  • Racial differences appear to be present in the development of perianal disease.
  • Perianal disease is more common among those with Crohn disease diagnosis in adolescence than in those with very early onset Crohn disease.
  • The prevalence of perianal disease continues to increase with longer duration of Crohn disease.

Although perianal fistulas, fissures, skin tags, and other perianal lesions (collectively called “perianal disease”) are commonly encountered complications of Crohn disease (CD) (1), few population-based data exist to assess the frequency of these complications. Perianal fistula has been reported to be found in approximately 5% to 9% of adult patients with CD within 30 days after diagnosis and in 15% to 21% of adult patients after 5 to 10 years (1). The frequency with which pediatric patients with CD develop perianal disease is less clear. Available evidence suggests approximately 8% to 13% of patients with CD onset in childhood have perianal fistula present at the time of diagnosis (2–6). There is, however, little information about rates of subsequent perianal fistula development. Only 2 studies exist: One reported perianal disease development to occur in 5% of children with CD by 5 years after diagnosis in a multicenter registry study (2); a second study reported 27% developed perianal disease by 7 years after diagnosis in a regional population-based cohort (4).

Perianal disease is clinically important and often leads to severe morbidity. Fistulas frequently invade the anal sphincter muscle complex and can involve other pelvic structures, such as the urethra, vagina, bladder, fallopian tubes, scrotum, labia, or other soft tissue, and boney structures (1,7–12). Perianal fistulas can lead to serious, sometimes debilitating complications, such as abscesses, osteomyelitis, and fecal incontinence (5,6,13–16). Perianal ulceration and other nonfistula perianal lesions also are associated with severe disease (17). The sequelae of perianal disease are highly distressing (17–20), and may include fecal incontinence, infertility, dyspareunia, chronically draining feculent wounds, intra-abdominal abscesses, and severe infections of the bladder, kidneys, uterus, or other internal structures (1,9). The invasive nature of perianal CD often requires treatments that are costly, frequently involving expensive biologic therapies, surgeries, and complex chronic management (21–23). Medical and surgical treatments are often only partially effective, and recurrence of perianal disease is common (24). Despite the profound effects on quality of life (19,25) and high health care costs (21), little is known about the epidemiology of perianal CD, particularly in children. Perianal disease is thought to be more common and more aggressive in patients with pediatric onset CD, (13,15,26,27), although population-based data are extremely limited (2,4,6).

Given the paucity of information, our objective was to characterize perianal disease in a large population of pediatric patients with CD. We hypothesized that the overall prevalence of perianal disease would be higher than previously reported and would vary among subgroups of pediatric patients.

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MATERIALS AND METHODS

Study Design

The study involved a limited dataset not linked to original patient data and was therefore granted an exemption from ongoing review by the Institutional Review Board of the University of Michigan (HUM00046270, 1/19/2011). We conducted a retrospective study of a national cohort of pediatric CD patients to assess the incidence of perianal disease over time. We evaluated longitudinal data from the ImproveCareNow (ICN) Network, a multicenter pediatric inflammatory bowel disease (IBD) quality improvement collaborative. At the time of this study, 65 sites were actively collecting data, including 64 in the United States and 1 in the United Kingdom. These included academic and nonacademic, and large and small practices (see Supplemental Digital Content, Table 1, http://links.lww.com/MPG/A825). This observational study was conducted in accordance with the Strengthening the Reporting of Observational studies in Epidemiology statement (28).

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Study Population

Patient data from the ICN registry were included if parents (or patients ≥18 years) provided consent to allow the data to be used for research. Our study population comprised pediatric patients <21 years with evidence of CD reported during the study period (May 2006–October 2014). The ICN registry includes patients with CD, ulcerative colitis, and indeterminate colitis. Clinicians prospectively record the diagnosis at each outpatient visit. For inclusion in the present study, patients were determined to have CD if they had consistently documented CD in the registry at every visit. For patients who first had ulcerative colitis or indeterminate colitis recorded in the registry and later changed diagnosis to CD, we required that patients have consistent documentation of CD after the time at which the diagnosis changed to CD. In all cases, consecutively recorded visits with CD diagnosis were required to be included as a CD case. One or 2-isolated visits with inconsistent diagnoses were permitted (as presumed documentation errors), but patients with >2 visits with inconsistent diagnoses were excluded from the study.

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Outcomes and Follow-up

Clinicians prospectively recorded data at each outpatient visit in which physical examination findings of perianal disease were scored as an element of the short pediatric CD activity index (sPCDAI) and recorded as an ordinal categorical variable (Supplemental Digital Content, Table 2, http://links.lww.com/MPG/A825) (29). In addition to physical examination findings, clinicians classified the anatomic distribution of each patients’ CD according to the Paris phenotype classification at each visit (30).

Perianal phenotype was denoted by the “perianal disease modifier,” which is defined according to the Paris Classification as perianal disease “only if fistula, anal canal ulcers, or abscess are present” (30). For the purposes of the present study, we took the conservative approach of requiring both perianal disease noted on examination and a concomitant change in Paris classification “perianal disease modifier” at the same outpatient visit to corroborate time of new-onset perianal disease.

We required consistency of perianal physical examination and perianal phenotype over time for each patient. If a single inconsistency in either physical examination finding or phenotype was present, the visit with the erroneous entry was excluded but the patient could otherwise be included. If multiple inconsistencies in either perianal physical examination or phenotype were, however, present, the patient, along with all their data, was excluded from the study. In accordance with the Paris classification of CD phenotype, once a patient developed perianal disease, from that point forward, that patient was always considered to have perianal phenotype thereafter (30). Any patient with a change in phenotype from perianal disease present to perianal disease absent would therefore be excluded from the study.

Disease location was classified by the clinician based on macroscopic findings (endoscopic or imaging, but not histologic findings) according to the Paris phenotype classification guidelines (Supplemental Digital Content, Table 2, http://links.lww.com/MPG/A825) (30). Disease location was recorded in the registry, but the method by which this was determined (endoscopic or imaging) was not recorded. Patients were considered to have extensive small bowel disease if they had upper tract disease proximal to the ligament of Treitz and also had small bowel disease distal to the ligament of Treitz, regardless of whether or not they had colonic disease (Paris classification L4a and L4b). In addition, patients were considered to have colonic disease if they had either ileocolonic or colonic disease (Paris classification L2 or L3) (30).

The date (month and year) of initial onset of IBD was recorded by the treating clinician. The time to incident perianal disease was determined by the first occurrence of new-onset perianal disease following initial IBD diagnosis. For patients who had a change in diagnosis from ulcerative colitis or indeterminate colitis to CD, the date of the initial onset of IBD was considered the starting time for all time-to-event analyses regardless of when the change to CD diagnosis occurred. Age at IBD diagnosis was categorized according to the Paris classification scheme as early-onset (<10 years), childhood-onset (≥10–<17 years), or later-onset (≥17 years) for subgroup analyses (30). Race and ethnicity were recorded in the registry at the time of enrollment in ICN (Supplemental Digital Content, Table 3, http://links.lww.com/MPG/A825).

To investigate geographic distribution of perianal CD, we divided the US practices providing patient data by the 4 US Census Bureau regions (31). The possibility of a north-south gradient was evaluated by dichotomizing all practice sites as northern or southern, divided across the 37th parallel, as categorized by Betteridge et al (32). To investigate other early predictors of developing perianal disease, we analyzed the subset of patients who were enrolled in ICN within 60 days of diagnosis. In these patients we evaluated the physician global assessment (PGA) of disease activity, the sPCDAI recorded at the first visit after diagnosis, and normalized height, weight, and body mass index (BMI) using z scores (29). We also evaluated the anatomic distribution of disease, according to Paris classification, recorded at the first visit at or after diagnosis (30).

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Statistical Analysis

Results were stratified by age, sex, race, and geographic region; descriptive statistics were summarized. Bivariate and multivariate associations with perianal disease were assessed with logistic regression. Cumulative risk of perianal disease was estimated using the Kaplan-Meier survival analysis. Survival curves were compared using Cox proportional hazard regression models. Multivariate analyses were performed with Cox proportional hazard models. Both multivariate logistic regression and Cox regression models were calculated with robust-variance estimates clustered by practice site. Because information at time of diagnosis was only available for a subset of patients, multivariate analyses were additionally performed, including disease extent (by Paris classification) and sPCDAI at diagnosis. Descriptive and categorical statistical analyses were performed using SAS 9.3 for Windows (SAS Institute, Cary, NC). Survival and multivariate analyses were performed with Stata 13.1 (StataCorp, College Station, TX).

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RESULTS

Study Population

As of October 2014, the ICN registry included 10,969 unique pediatric patients with IBD and 71,046 individual outpatient visits (Supplemental Digital Content, Fig. 1, http://links.lww.com/MPG/A825). Of these patients, 7076 (65%) had CD documented at least once. Exclusions totaled 397 patients (5.6%) for missing or conflicting entries for diagnosis. Altogether, 6679 patients were included in the present study, 41% of whom were girls. Baseline demographic information of included patients is found in Table 1. The median age at IBD diagnosis was 12.4 years (interquartile range [IQR] 9.9–14.8). The median duration of patient enrollment in ICN at the time of the study was 1.3 years (IQR 0.5–2.6; range 0–7.5).

TABLE 1

TABLE 1

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Perianal Disease

In total, 1399 patients (21%) developed perianal disease at some point in the course of their disease. A diagnosis change was noted for 98 patients (7%), from either ulcerative colitis or indeterminate colitis to CD; of those, 9 (9%) had perianal disease recorded for the first time at the time of their diagnosis change. Overall findings of perianal disease development are summarized in Table 1.

Figure 1A illustrates the Kaplan-Meier analysis of the likelihood of developing perianal disease after the time of initial IBD diagnosis for all pediatric patients with CD, including those patients in whom their diagnosis changed to CD from ulcerative or indeterminate colitis. The estimated probability of developing perianal disease increased over time, from 4.0% (95% confidence interval [CI] 3.5%–4.5%) at 2 months after initial IBD diagnosis to 6.4% (95% CI 5.8%–7.0%) at 6 months, 9.1% (95% CI 8.4%–9.8%) at 1 year, 13.6% (95% CI 12.7%–14.5%) at 2 years, 17.6% (95% CI 16.5%–18.7%) at 3 years, 21.6% (95% CI 20.3%–22.9%) at 4 years, 26.1% (95% CI 24.7%–27.6%) at 5 years, and 30.1% (95% CI 28.4%–31.8%) at 6 years after diagnosis (Table 2).

FIGURE 1

FIGURE 1

TABLE 2

TABLE 2

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Sex

Overall, 865 boys (21.9%) and 534 girls (19.6%) developed perianal disease. The odds of males developing perianal disease was greater than females in bivariate analysis (odds ratio [OR] 1.49; P = 0.017); this difference persisted in multivariate analysis (OR 1.19; P = 0.013; Table 3). In Cox proportional analysis, boys also developed perianal disease earlier in the course of their disease than girls (hazard ratio [HR] 1.16; P = 0.007).

TABLE 3

TABLE 3

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Age at Diagnosis

The overall proportion of patients who developed perianal disease according to age at initial diagnosis with IBD was 21.4% for those diagnosed at <10 years of age, 20.8% for the ≥10 to <17-year-old group, and 20.6% for the ≥17-year-old group. The odds of developing perianal disease was not associated with age at diagnosis in either bivariate (P = 0.84) or multivariate (P = 0.81) analyses. However, Cox proportional hazard analysis showed that those who were older at the time of IBD diagnosis developed perianal disease earlier in the course of their disease than those with younger age at IBD diagnosis (HR 1.13; P < 0.001; Supplemental Digital Content, Fig. 2, http://links.lww.com/MPG/A825).

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Race and Ethnicity

We found that perianal disease developed among 24.1% of Asian, 25.8% of black, and 20.3% of white patients. Black patients were the only group with increased odds of perianal disease compared with whites in both bivariate (OR 1.37; P = 0.001) and multivariate analyses (OR 2.47; P = 0.017). In multivariate logistic regression, there was an interaction effect between race and age at diagnosis for Asians, such that increased age at diagnosis was associated with a greater risk of developing perianal disease (OR 1.14; P = 0.01; Supplemental Digital Content, Fig. 3, http://links.lww.com/MPG/A825).

Despite small numbers (n = 108), the same interaction between race and age at IBD diagnosis was also found in the Cox proportional hazard analysis that showed Asians with older age at IBD diagnosis not only developed perianal disease more commonly, but perianal disease also developed earlier in the course of their disease (HR 1.14; P = 0.012; Supplemental Digital Content, Fig. 4, http://links.lww.com/MPG/A825). There was no such interaction with age at diagnosis for other racial groups in either logistic or Cox proportional hazard regression models.

When all non-white patients were compared with white patients, the non-white patients had a greater hazard of developing perianal disease earlier in the course of their disease than white patients on Cox proportional hazard analysis (HR 1.38; P < 0.001; Fig. 1B).

Although Hispanics developed perianal disease more commonly (24.3%) than non-Hispanics (21.3%), this was not significant (P = 0.31). Furthermore, half of all patients had missing data for ethnicity, calling the reliability of this assessment into question. Therefore, ethnicity was not included in the multivariate models.

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Geographic Region

Regionally, perianal disease was seen more commonly in the Northeast (25.3%, OR 1.35; P < 0.001) and Western US (23.8%, OR 1.25; P = 0.046) and less commonly in the Midwest US (17.2%, OR 0.83; P = 0.017) compared with the Southern US. There was no difference for London, UK (24.5%; P = 0.42). On multivariate analysis, London was, however, found to have increased odds of perianal disease (OR 1.37; P < 0.001). In the United States, only the Northeast region remained increased (OR 1.44; P = 0.050); the Midwest and Western US did not remain significantly different from the Southern US (P = 0.14 and P = 0.20, respectively). In Cox proportional hazard analysis, London was the only region that had significantly earlier time to identification of perianal disease (HR 2.32; P < 0.001). There were no other regional differences. When the practice locations were divided into northern versus southern regions, there was no clear north-south gradient in the proportion of patients who developed perianal disease (north 21.5%, south 20.1%; P = 0.17). There was also no north-south difference found in Cox proportional hazard analysis (P = 0.26).

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Patient Factors at Inflammatory Bowel Disease Diagnosis

Among the 1664 patients enrolled within 60 days of IBD diagnosis (25% of the cohort), Table 1 shows the frequency with which perianal disease was associated with anatomic distribution of disease recorded at the first visit. Overall, we found no association between any anatomic disease distribution and subsequent development of perianal disease. Although colonic distribution of disease approached significance in bivariate analysis (P = 0.089), neither colonic (P = 0.20) nor other anatomic distributions were associated with later perianal disease development in the multivariate model.

Regarding growth and nutrition at the first visit at or after IBD diagnosis, there was no association between the first weight (P = 0.18), height (P = 0.89), height velocity (P = 0.94), or BMI z score (P = 0.26) and subsequent development of perianal disease. There were too few patients with sufficient data to determine height velocity z score at the first visit after diagnosis (n = 197), so height velocity was excluded from the multivariate model. Weight, height, and BMI z scores remained nonsignificant in the multivariate model (P = 0.95, P = 0.77, P = 0.71, respectively). Neither the first sPCDAI (P = 0.77) nor the first PGA (P = 0.21) were associated with later development of perianal disease. PGA was excluded from the multivariate model due to collinearity, and sPCDAI remained nonsignificant in multivariate analysis (P = 0.43).

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DISCUSSION

This is the largest study of pediatric perianal CD using multicenter, prospectively collected data that is clinician classified. Our findings indicate that by 6 years after initial IBD diagnosis perianal disease is more common among children and adolescents with CD (30%) than previously described in adult (15%–21%) or pediatric studies (1,2). Our results, although are similar to other findings that reported a rate of 27% among children at 7 years in a smaller regional cohort (n = 472) (4). We also identified important subgroups of pediatric patients with substantially greater rates of perianal disease.

We found that perianal disease most commonly develops among pediatric patients with onset of IBD at older age, in adolescents and young adults, compared with those with early-onset IBD; this is in contrast to some earlier reports (33,34). This finding is, however, consistent with more recent reports showing decreased severity and complexity of care and healthcare utilization among those with very early-onset CD (35–37). The reason for a lower incidence of perianal disease among those with early-onset IBD is unclear. There is growing recognition that children with very early onset IBD (VEO-IBD) may have underlying immune deficiencies or other diseases that phenotypically appear as IBD but have different underlying pathophysiology (38,39). Specific immune deficiencies, such as IL-10 and leukocyte adhesion disorders, can lead to aggressive fistulizing disease, which often presents in infancy (38,39). The epidemiology of VEO-IBD has, however, been incompletely characterized, and it remains unclear what proportion of patients with VEO-IBD have immune deficiencies. It is also unclear who among the patients with VEO-IBD in the ICN registry have immune deficiencies. It is possible that among young children enrolled in ICN, few have perianal disease because those with neonatal immune deficiencies, once diagnosed, are excluded from the registry (36). It is also possible that children with aggressive immune deficiencies represent a minority of children with VEO-IBD. Although we cannot determine the reason from the present study, our findings are consistent with other population-based studies that demonstrated few individuals with VEO-IBD have complex or fistulizing disease. Although immune deficiencies are important to identify among those with aggressive disease, the low frequency of perianal disease among patients with VEO-IBD in the ICN population raises the question of how common aggressive immune deficiency syndromes are among the broader population of children with VEO-IBD (35–37).

Regarding racial differences, we found that perianal disease was more common among black patients compared with their white counterparts. This difference was not seen within the first few months after initial IBD diagnosis but became more apparent after 12 to 18 months. When other lesser-represented racial groups were included, the earlier detection of perianal disease among non-white relative to white patients is detectable by 6 months after initial IBD diagnosis. The reason for these differences is unclear and requires further investigation; we cannot determine from the present study whether this represents a difference in disease biology, medical therapy, frequency of perianal examination (ie, differential detection), or access to care. We found that the groups with the highest incidence of perianal disease were Asian patients, who experienced initial onset of IBD in their adolescent and early adult years, and black patients, regardless of age at IBD diagnosis. These findings have potentially important implications for medical management. If patients can be identified who are at greater risk of developing perianal complications of CD, then it may be possible to develop strategies to prevent these devastating complications.

We found that there are regional differences in the prevalence of perianal disease. Despite higher rates of perianal disease in the Northeast US and UK, there, however, does not appear to be a clear north-south gradient in the proportion of patients who developed perianal disease. There have been conflicting reports of increased incidence of IBD and increased severity of disease in northern versus southern locations (40–43). Although there appear to be regional differences, our findings do not support a north-south gradient for perianal disease.

Contrary to our expectations, we did not find that patients with nutritional or growth deficiencies or those with extensive small bowel disease or colonic disease around the time of IBD diagnosis were at increased risk of later developing perianal disease. We expected to find an association with colonic disease, because this has previously been reported to be associated with perianal fistula development, although little pediatric data exist (17,44). The lack of prognostic value of these disease features is informative as we attempt to develop means of predicting perianal fistulizing disease behavior. The European Crohn's and Colitis Organization consensus guidelines for pediatric CD consider severe mucosal disease, poor mucosal healing, extensive disease, marked growth retardation, and penetrating/perianal disease at diagnosis to be predictors of poor outcome (45). Other evidence suggests that poor nutrition, smoke exposure, and genotype have prognostic value as well (45–48). Information on smoke exposure, mucosal disease, and genotype are not available in the ICN database and could not be considered in our study.

The present study has important limitations. Because of the way diagnosis date is recorded in the ICN database (month and year), it is not possible to differentiate between phenotype at diagnosis from phenotype after 1 month. Consequently, we limited our analyses to 60 days after diagnosis. Despite this limitation, we found clearly discernible differences between subgroups of patients apparent 60 days after diagnosis.

The perianal examination classification strategy used does not distinguish patients with indolent fistulas from complex fistulizing disease or abscesses. Therefore, we were unable to investigate differences in severity of perianal disease. In addition, we required findings on both physical examination and documentation of perianal disease by Paris classification in order for a patient to be characterized as having perianal disease. It is likely that patients have been missed by this method if they had a perianal abscess or fistula identified on imaging or during colonoscopy. The registry only includes outpatient data; data pertaining to imaging and endoscopy are unavailable. Patients also may have been missed if they had a rectovaginal fistula, or other fistula in which no external fistula opening was observed. Missing these patients would lead to underclassification of perianal disease. This would imply that the true prevalence of perianal fistulas is likely to be higher than that found in the present study. The sPCDAI-based physical examination classification used also does not distinguish between inflamed perianal skin tags and indolent fistulas. Therefore, there may also be patients with skin tags but no fistula who were misclassified as having perianal fistulas in the present study, leading to over-representation of perianal fistulas. The extent to which these over- and underclassifications occur in the data are unknown. We recommend future modifications of the perianal examination classification system that would allow distinction between perianal fistula and other perianal lesions. This would improve the ability to conduct future research and facilitate quality improvement efforts focused on improving outcomes of perianal disease in pediatric CD (23,30).

The present study has important implications, because perianal disease causes great morbidity in patients and the treatment of fistulizing disease results in high cost for payers. Although medical therapy for perianal fistulas has improved since the advent of antitumor necrosis factor-α medications, they remain difficult complications to treat, with high rates of incomplete healing and recurrence (6,49,50). The therapies that are most effective for treating perianal disease are costly and place a great burden on families and payers (21,22,51). Consequently, early CD therapy should focus on prevention of perianal complications. Information is, however, scarce regarding strategies for preventing the development of perianal disease (52,53). The high prevalence of perianal disease in this large pediatric population should serve to stress the importance for developing such preventive strategies.

In conclusion, this large multicenter study suggests that perianal CD is common among adolescents and children with CD. The proportion of children who develop these difficult complications is higher than previously recognized and continues to increase in prevalence with increasing duration of disease. These findings underscore the critical need to develop effective strategies for prevention of perianal fistulizing disease among children with CD. Such strategies may be based on risk profiles modeled from the patient factors identified in the present study. These studies will help ensure early identification of children at high risk of complications such as perianal fistulas and allow for timely initiation of aggressive therapies that support deep remission to prevent fistulizing complications.

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Acknowledgments

The authors wish to thank Acham Gebremariam for his statistical expertise and Caroline Shevrin for her assistance with proofreading. The authors especially wish to thank the patients of the ImproveCareNow Network and their families, without whose support and commitment this study would not have been possible. The authors wish to acknowledge the ICN Network and all the participating centers https://improvecarenow.org/about/where-we-serve/centers.

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Keywords:

Crohn disease; epidemiology; fistula; incidence; pediatric; perianal disease

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