Statistically significant clinical factors identified in bivariate analysis (weight loss at diagnosis, medical therapy) and factors thought to be clinically relevant (age, sex, white race, laboratory values present at time of diagnosis, family history of IBD) were included in the multivariate analysis (Table 2). Children presenting with weight loss (hazard ratio [HR] 2.55, P < 0.001) or serum albumin < 3.5 g/dL (HR 6.05, P < 0.001) at the time of diagnosis, and children with a first-degree relative with UC (HR 1.8, P < 0.001) required earlier surgical intervention than children without these characteristics. Furthermore, children treated with cyclosporine (HR 6.1, P < 0.001) or tacrolimus (HR 3.66, P < 0.001) also required earlier surgical management of their UC compared with children not treated with calcineurin inhibitors. Of note, albumin <3.5 g/dL at time of diagnosis and having a first-degree relative with UC were not predictive of 2-year risk of colectomy, whereas they were predictive of overall risk of colectomy. History of azathioprine (HR 0.06, 99% confidence interval [CI] 0.01–0.27) or 6-MP (HR 0.21, 99% CI 0.05–0.88) use was associated with a decreased 2-year risk of colectomy, whereas these factors did not affect overall risk of colectomy. Each factor predictive of overall colectomy was associated with an increased rate of 2-year and overall colectomy (Table 3); however, for albumin <3.5 g/dL and having a first-degree relative with UC, the risk of colectomy 2 years after diagnosis was notably attenuated (Fig. 2).
This is the first study to use a large, multicenter disease-specific database to identify clinical predictors of colectomy in children with UC. Our analysis identified hypoalbuminemia and significant weight loss at time of diagnosis as predictive of earlier colectomy, indicating that nutritional status and/or extent of protein losing enteropathy play an integral role in the clinical severity of UC in children. This finding underscores the importance of thoroughly assessing nutritional status at the time of diagnosis of UC. We also found that having a first-degree relative with UC and previous use of cyclosporine and tacrolimus predicted an earlier need for surgery. Overall, our results indicate that children with more severe disease burden at time of diagnosis likely do not have sufficient physical reserve (ie, low albumin, immunosuppression, muscle wasting), develop recalcitrant symptomatology and ultimately require colectomy for optimal disease control.
Poor nutritional status has previously been identified in the literature as predictive of clinical course in patients with UC. Low albumin levels after first induction therapy were reported by Shiga et al (4) to predict UC relapse and need for colectomy; however, the study of Shiga et al did not find low albumin at time of diagnosis to be predictive of surgery. In our initial analysis, we examined albumin as a continuous variable and found that it was not independently predictive of colectomy. When albumin was analyzed, however, as a dichotomous variable with a cutoff of <3.5 g/dL, albumin levels became significantly predictive in our model. This implies that once a nutritional threshold is passed, children with UC are likely not able to recover as robustly as their more healthy counterparts. Furthermore, >20% of our subjects had an albumin <3.5 g/dL, indicating that our cohort was likely to detect a difference between groups.
The greatest risk factor for developing UC in childhood is having a first-degree relative with UC, even though lesser than the genetic contribution observed in Crohn disease (9,10). Our results agree with reports that there is a hereditary component to UC, although the UC phenotype is likely more driven by environmental factors. The present findings imply that children with a first-degree relative with UC are likely to have more severe clinical manifestations of UC, thereby requiring colectomy at an earlier date. Although multiple genetic contributors of UC have been established (11), the pathogenesis of UC is likely multifactorial and those with a familial predisposition may express a more severe phenotype than those without a genetic contribution.
Children with a more severe disease burden typically require more potent immunosuppressive regimens and require colectomy at a higher rate. Tacrolimus and cyclosporine are used most commonly in steroid-refractory UC, so it was not surprising that use of these calcineurin inhibitors was greatly predictive of early colectomy in the cohort. Our results imply that calcineurin inhibitors are likely a proxy for disease severity. This is in agreement with prior studies reporting colectomy rates in up to 60% of children with steroid refractory UC treated with tacrolimus (5). Furthermore, our results also coincide with studies showing that the use of azathioprine, 6-MP, and infliximab does not predict colectomy (12). Of note, 1 limitation of our study is that the use of infliximab for refractory UC has increased in the last 10 years and the present study took place before this clinical trend was more established. Our findings, however, disagree with the report of Tremaine et al of increased colectomy in patients receiving aminosalicylate, prednisone, and azathioprine/6-MP therapy (13). The final regression analysis in the latter study did not examine the use of more potent immunosuppressants such as cyclosporine and tacrolimus as the number of participants using these drugs was small. Owing to the exclusion of calcineurin inhibitors, it may be that maximal medical therapy was thereby defined as patients who received aminosalicylate, prednisone, azathioprine, or 6-MP. Patients receiving these drugs therefore had a more severe disease burden compared with the rest of their cohort and therefore were in higher proportion in the colectomy arm. Additionally, Tremaine et al. conducted a single-institution study in a predominantly adult population, and therefore the external validity of the conclusions of the study may be limited in the pediatric setting.
Factors predictive of 2-year risk of colectomy did not entirely coincide with those predictive of overall risk of colectomy. Albumin <3.5 g/dL at time of diagnosis and having a first-degree relative with UC were not predictive of 2-year risk of colectomy, whereas they were predictive of overall risk of colectomy. This implies that these factors may have less effect on short-term risk of colectomy for children with UC but maintain significance when predicting overall risk of colectomy. Furthermore, history of use of azathioprine or 6-MP was associated with a decreased 2-year risk of colectomy, whereas these factors did not affect overall risk of colectomy. This latter finding likely implies that the use of azathioprine and 6-MP may delay early disease progression significantly for children with UC but that overall, their long-term clinical benefit may be uncertain. Finally, weight loss at diagnosis and previous use of cyclosporine and tacrolimus remained significant predictors of both 2-year and overall colectomy risk. This finding underscores the prognostic significance of a child's nutritional status at the time of diagnosis and also affirms the use of calcineurin inhibitors in the present study cohort as the probable limit of medical therapy for UC before proceeding with colectomy.
Contrary to the most recent single-center report by Moore et al (14), low hemoglobin and leukocytosis at the time of diagnosis did not predict colectomy in our analysis. This may be because of the abnormally high colectomy rate reported in Moore cohort (16.7% at 1 year and 35.6% at 3 years). The overall cumulative rate of colectomy in children with UC is typically lower, with rates reported from 5% to 8% at 1 year after diagnosis, and up to 20% at 5 years (1,15). The overall colectomy rate in our study was 14% with a median time to surgery of 3.8 years, which is closer to reported average colectomy rates for children with UC. Owing to the profound effect UC has on overall development and growth in children, we agree with the authors in concluding that creation of a risk stratification tool would facilitate counseling at time of diagnosis; however, the risk score calculated in their study may only be most applicable within their institution.
Unfortunately, patients with UC and their families often do not have an accurate understanding of what their medical treatment may entail (16). Knowledge of the clinical factors identified in the present study will likely facilitate more accurate risk stratification at the time of diagnosis and throughout medical treatment. This will ultimately encourage earlier preoperative counseling and surgical referral. Children undergoing restorative proctocolectomy for UC have a high quality of life after surgery (17–19), and consideration of earlier surgical intervention for children with UC has been reported (20).
One limitation of the present study is that our analysis did not incorporate more global measurements of disease severity such as the Pediatric Ulcerative Colitis Activity Index (PUCAI). First validated in 2007 (21), the PUCAI has been demonstrated to aid in determining timely introduction of second-line therapy in severe acute UC (22). Furthermore, the Food and Drug Administration endorsed the PUCAI as a substitute to endoscopic evaluation for the primary outcome measure in a pediatric clinical trial evaluating a 5-ASA regimen. The PediIBDC dataset used for the present study predates the PUCAI, and included only dichotomized information on stooling patterns as opposed to the numerical gradations found in the PUCAI. Noninvasive, global clinical assessments such as the PUCAI are likely to have high predictive capabilities when determining need for colectomy in children with UC. Looking ahead toward future uses of the PediIBDC, now with 18 centers throughout the United States, Austria, and Hungary submitting data, a richer source of data may lead to further findings.
Unfortunately, like much of the literature examining clinical predictors of colectomy in children with UC, the present study is also limited by the relatively low number of children undergoing colectomy in the cohort. This limits the external validity of our predictors and those identified by previous groups, which may explain why there is notable variation between studies. Our results highlight the fact that even within centers of excellence in pediatric IBD care, there are relatively low numbers of colectomies performed overall. This makes identifying reliable surgical predictors a challenge for anyone examining health care utilization for children with UC and highlights the increased need for large, transnational, multiinstitutional collaborations.
In conclusion, children with a more severe disease burden are more likely to undergo surgical management of their UC. Specifically, children presenting with clinical and laboratory evidence of malnutrition, those with a first-degree family member with UC, and those treated with calcineurin inhibitors have an increased likelihood of undergoing surgery. Early identification and recognition of these factors should be used to facilitate preoperative counseling and patient-based planning for medical and surgical care of children with UC.
The authors thank the Pediatric Inflammatory Bowel Disease Foundation for sponsoring the Consortium and this work.
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Keywords:Copyright 2012 by ESPGHAN and NASPGHAN
colectomy; proctocolectomy; ulcerative colitis