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Endoscopic and Clinical Variables That Predict Sustained Remission in Children With Ulcerative Colitis Treated With Infliximab
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;11:1460–1465
Endoscopic and Clinical Variables That Predict Sustained Remission in Children With Ulcerative Colitis Treated With Infliximab DAN TURNER,* ANNE M. GRIFFITHS,‡ GIGI VEERMAN,§ JEWEL JOHANNS,k LAKSHMI DAMARAJU,k MARION BLANK,k and JEFFREY HYAMS{ *Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel; ‡Division of Pediatric Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Canada; §UZ Brussels, Brussels, Belgium; kJanssen Research and Development, LLC, Spring House, Pennsylvania; and {Connecticut Children’s Medical Center, Hartford, Connecticut
BACKGROUND & AIMS: We aimed to identify early clinical, laboratory, and endoscopic factors associated with sustained remission in children with ulcerative colitis (UC) treated with infliximab.
METHODS:
We performed a post hoc analysis of data collected from 51 children (6–17 years old) with moderate-to-severe UC treated with infliximab for 1 year in the T72 clinical trial. The primary outcome was steroid-free remission at weeks 30 and 54 of treatment, which was based on patient and physician assessments. We compared the ability of the Pediatric UC Activity Index (PUCAI, a noninvasive clinical index), levels of C-reactive protein (CRP), and mucosal healing to predict which patients would be in steroid-free sustained remission after 1 year of treatment.
RESULTS:
Week 8 PUCAI scores best predicted which patients would be in steroid-free remission after 1 year of treatment; 9 of 17 patients who had PUCAI scores <10 points were in sustained remission (53%), compared with 4 of 20 who had PUCAI scores ‡10 (20%) (P [ .036). Mucosal healing at week 8 was associated with steroid-free remission at 1 year, but this did not reach significance; 7 of 16 patients with mucosal healing were in remission after 1 year (44%), compared with 6 of 21 without mucosal healing (29%) (P [ .34). The area under the receiver operating characteristic curve values for association with steroid-free sustained remission were 0.70 for the PUCAI (95% confidence interval [CI], 0.53–0.88), 0.56 for mucosal healing (95% CI, 0.36–0.76), and 0.44 for level of CRP (95% CI, 0.24–0.65). By using a multivariable logistic regression model, the week 8 PUCAI was the only factor associated with steroid-free remission at 1 year (P [ .038). PUCAI-defined remission had a high degree of concordance with complete mucosal healing at week 8 (33% of patients were in remission according to the PUCAI vs 31% with mucosal healing).
CONCLUSION:
On the basis of a post hoc analysis of data from the T72 clinical trial on the effect of infliximab in pediatric patients with UC, the PUCAI was no less predictive of sustained remission than mucosal healing at week 8, and both were superior to CRP level. Routine endoscopic evaluation in children with UC who are in complete clinical remission (ie, PUCAI <10 points) may not be necessary.
Keywords: Prognosis; IBD; AUROC; Predicting Response to Therapy.
See related article, Travis SPL et al, on page 987 in Gastroenterology.
T
here is increasing amount of literature on the importance of mucosal healing (MH) as an aim of treatment in ulcerative colitis (UC). In a sizeable cohort of 354 Norwegian adults with new-onset UC, those achieving MH 1 year after diagnosis were less likely than those without MH to undergo colectomy during 5 years of follow-up.1 Similarly, in the combined ACT cohorts of 484 infliximab-treated adult patients, those with lower week 8 endoscopic scores were less likely to progress to colectomy within 1 year of treatment.2 Others have presented similar findings indicating that complete MH (defined as Mayo endoscopic subscore of 0), or near MH
(subscores of at most 1), is associated with sustained clinical remission in adults with UC.3–6 The predictive utility of MH in pediatric-onset UC has not yet been explored. Moreover, the aforementioned adult studies did not systematically compare MH with the predictive utility of clinical
Abbreviations used in this paper: CI, confidence interval; CRP, Creactive protein; IQR, interquartile range; MH, mucosal healing; PaGA, patient global assessment; PGA, physician global assessment; PUCAI, Pediatric UC Activity Index; ROC, receiver operating characteristic; UC, ulcerative colitis. © 2013 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.04.049
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variables. In sharp contrast to Crohn’s disease, clinical assessment of symptoms in UC is an important predictor of shortterm and long-term outcome. Clinical judgment of disease activity predicted 3-month colectomy rates among 147 adults with acute UC treated with corticosteroids.7 The Pediatric Ulcerative Colitis Activity Index (PUCAI), which relies solely on clinical parameters, strongly predicted the need for second-line rescue therapy after corticosteroid treatment of acute severe colitis in hospitalized children8,9 and the need for treatment escalation in ambulatory children with UC10 better than did fecal inflammatory markers and C-reactive protein (CRP).11,12 Because of the paucity of data on early predictors of clinical outcomes in children with UC, we used the week 8 end of open 3-dose induction phase data from a multicenter trial of infliximab therapy to compare the utility of MH versus the PUCAI and CRP in predicting subsequent 1-year sustained remission in the randomized maintenance phase. Multicenter data accrued prospectively in this trial were also used to examine the relationship between PUCAI definitions of response and remission and those of Mayo score, thereby further facilitating comparisons between pediatric and adult clinical trial outcomes.
Methods In this investigator-driven post hoc analysis, we used the data set of the recent T72 clinical trial, which evaluated the 1-year effectiveness of infliximab in pediatric UC.13 Briefly, 60 children with moderate-severe UC (defined as having a Mayo score of 6–12 points with an endoscopy subscore 2) despite standard therapy were treated with a 3-dose induction treatment of 5 mg/kg infliximab at weeks 0, 2, and 6. As per the protocol, only those achieving response (defined by the Mayo score) at week 8 (n ¼ 45) were randomized to receive infliximab every 8 or 12 weeks through 1 year. Sigmoidoscopy was performed at baseline and week 8, whereas the PUCAI (range, 0–85 points) was calculated at every visit. The PUCAI was introduced after the launch of the trial as a late amendment, and thus PUCAI scores are not available on the first 9 included children. The PUCAI was completed by the physician after obtaining thorough medical history. In the primary analysis of the T72 data, the protocol allowed dose escalation or interval shortening of infliximab, but it was defined as drug failure. For the purpose of this analysis and similar to real-world clinical practice, we considered outcome at 1 year regardless of whether dose escalation was required, because individualization of the drug dose is encouraged and reflects personal pharmacokinetics properties. Per the original protocol, dose escalation and interval shortening were equally accessible to all patients.
Outcomes and Definitions In this post hoc analysis, a stringent outcome of sustained corticosteroid-free remission was used, first by physician global assessment (PGA) and separately by patient global assessment (PaGA). Patients completed a 5-point scale (very good, fair, not very good, poor, and very poor in which remission was defined as at least fair), whereas the physicians completed a 4-point scale (remission, mild, moderate, and severe disease activity). Sustained steroid-free remission
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mandated patients to be in remission and without steroids at both weeks 30 and 54 visits. As an exploratory analysis, we also used a third outcome variable that was defined as both sustained corticosteroid-free remission (by PGA) and normal CRP at week 54. Endoscopic inflammation at week 8 was graded by using the Mayo subscore (scored as 0–3 points). For the prediction analysis we defined MH as complete MH (ie, a score of 0).
Statistical Analysis Data are presented as means ( standard deviation) or medians (interquartile range [IQR]), as appropriate. Point estimates (ie, odds ratios and area under the curve) are accompanied by 95% confidence intervals (CIs). Categorical data were compared by using c2 or Fisher exact test and continuous data by using the Student t test or Wilcoxon rank sum test, as appropriate. Per the original protocol, the last values were carried forward for missing observations, and baseline values were carried forward in patients who experienced treatment failure events including colectomy or ostomy, discontinuation of infliximab because of unsatisfactory therapeutic effect, and protocol-prohibited medication changes. To explore for the collective contribution of sigmoidoscopic score, PUCAI, and CRP in predicting sustained steroid-free 1-year remission, 2 multivariable logistic regression models were constructed by using physician and patient judgment of remission as the dependent variables. Agreement between the categories of disease activity (remission, mild, moderate, and severe) defined by the PUCAI and sigmoidoscopic score was computed by the kappa statistics with quadratic weighting. Correlations were sought by using Pearson or Spearman correlation coefficients as appropriate. Serial receiver operating characteristic (ROC) curves were used to compare the predictive utility of the different measures and to find the best cutoff of the PUCAI that corresponds to a Mayo score–defined remission (ie, total Mayo score of 2 points, with no subscore >1 point14,15) and response (ie, a decrease from baseline in the total Mayo score of 3 points and 30%, with a decrease in the subscore for rectal bleeding by 1 point or an absolute subscore of 0 or 114,15). All comparisons were made by using two-sided significance levels of .05. Statistical analyses were performed by using SPSS V15.0 (SPSS Inc, Chicago, IL).
Results Of the 60 enrolled children, the 9 earliest recruited patients in whom PUCAI scores were not measured were excluded. The demographic and baseline characteristics of the remaining 51 children are presented in Table 1. In the original study, 45 children who demonstrated a Mayo score “response” to the 3-dose induction protocol were randomized at week 8, of whom 37 had valid PUCAI and sigmoidoscopic evaluations at week 8. These were used for the prediction analyses.
Predicting One-year Sustained Remission Six of 16 (38%) who responded to infliximab at week 8 and had MH were in physician-defined (PGA) sustained remission at 1 year vs only 3 of 21 (14%) who did not have MH at week 8 assessment (P ¼ .14). Similar results were obtained for
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Table 1. Demographics and Baseline Characteristics of the 51 Included Children Total cohort (N ¼ 51) Males Age (y) Range Disease duration (y) (IQR) First attack Exacerbation Disease extent Left-sided Extensive PGA at week 0 Quiescent Mild Moderate Severe Concurrent medications Oral mesalamine Immunomodulators Corticosteroids
21 (41%) 13.5 3 6–17 1.3 (6.5–2.4) 4 (8%) 47 (92%) 11 (22%) 40 (78%) 0 3 38 10
(0%) (6%) (75%) (20%)
30 (59%) 24 (47%) 32 (63%)
NOTE. Medians (IQR) or mean ( standard deviation) are presented as appropriate for the data distribution.
the patient-defined (PaGA) sustained remission at 1 year (7 of 16 [44%] vs 6 of 21 [29%], respectively [P ¼ 0.34]) (Figure 1). Probably because of the small sample size, these trends did not reach statistical significance. Clinical remission by the PUCAI at week 8 (ie, <10 points) was a stronger predictor of sustained 1-year steroid-free remission, determined by both physicians and patients. Seven of 17 responders (41%) with week 8 PUCAI <10 were in physiciandefined sustained remission at 1 year vs 2 of 20 (10%) with PUCAI 10 (P ¼ .052); the corresponding figures for patientdefined sustained remission at 1 year were 9 of 17 (53%) vs 4 of 20 (20%) (P ¼ .036) (Figure 1). Further analyses demonstrated that the week 8 continuous PUCAI score (range, 0–85) was a significant predictor of sustained 1-year steroid-free remission (Figure 2). The median week 8 PUCAI score was 0 (IQR, 0–5 points) among those with 1-year physician-defined sustained remission vs 10 (IQR,
0–22.5 points) among those who did not achieve this outcome (P ¼ .05). Similarly, the median week 8 PUCAI score was 0 (IQR, 0–10 points) among those patients with 1-year patient-defined sustained remission vs 12.5 (2.5–22.5 points) among those patients who did not achieve this outcome (P ¼ .04). These results were reflected in a comparative ROC analysis (Figure 3). Clinical assessment by the PUCAI at week 8 seemed to be at least as good as MH in predicting 1-year sustained steroidfree remission (whether defined by patients or physicians), and both were better predictors than CRP (Figure 3). The results were similar when considering the same outcome combined with normal CRP at week 54 (area under the curve, 0.68; 95% CI, 0.5–0.87 for the PUCAI and 0.66; 95% CI, 0.46–0.85 for MH). In a multivariable logistic regression that included the PUCAI score, endoscopic subscore, and CRP at week 8 as the explanatory variables to predict patient-defined 1-year steroid-free sustained remission, the PUCAI was the only significant predictor (P ¼ .038 for the PUCAI) (odds ratio, 0.89; 95% CI, 0.8–0.993, P ¼ .68 for CRP and P ¼ .94 for endoscopic subscore). None of these variables assumed significance when using physician’s judgment of the same outcome, but the P values reflected the same rank order (P ¼ .191 for the PUCAI, P ¼ .76 for endoscopic subscore, and P ¼ .9 for CRP).
Association Between the Pediatric Ulcerative Colitis Activity Index, Sigmoidoscopic Evaluation, and the Mayo Score Of the 51 included children, 2 were missing a PUCAI score at week 0. All remaining 49 children were defined as having active disease by the PUCAI (ie, PUCAI 10) at week 0. Furthermore, 90% (44 of 49) had moderate-severe disease (ie, PUCAI 35–85), closely reflecting the sigmoidoscopic finding of moderate-severe disease in all children at that time. There was a good concordance between the different categories of disease activity judged by the PUCAI and sigmoidoscopy at week 8 (Figure 4A) (kappa ¼ 0.58; 95% CI, 0.26–0.89; P < .0001). Similarly, the PUCAI was highly correlated also with the Mayo score (r ¼ 0.88; P < .0001, n ¼ 51) (Figure 4B).
Figure 1. Percentage of children in sustained steroid-free 1-year clinical remission, stratified by those achieving remission at week 8 by the PUCAI and MH.
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Figure 2. Week 8 PUCAI score predicts 1-year steroid-free sustained remission.
The best cutoff of the PUCAI to define a Mayo score remission was <15 points (Figure 5A), with a sensitivity of 90%, specificity of 81%, and area under the ROC curve of 0.93 (95% CI, 0.86–1.0). The best cutoff of the PUCAI to define a Mayo score response was 20 points (Figure 5B), with a sensitivity of 97%, specificity of 90%, and area under the ROC curve of 0.97 (95% CI, 0.92–1.0).
Discussion Whether clinical assessment is a reliable means of judging MH in UC is more controversial than in Crohn’s disease, where the lack of correlation between symptoms and endoscopic appearance is indisputable. To increase feasibility of pediatric clinical trials, noninvasive methods to assess response and remission are preferable, if they are found to accurately reflect MH and predict clinically important outcomes. Our post hoc analysis suggests that the PUCAI appears to be sufficiently accurate to assess remission in pediatric UC. The noninvasive PUCAI was closely correlated with the sigmoidoscopic score and
Figure 3. ROC curve to reflect the ability of the PUCAI, sigmoidoscopy, and CRP at week 8 to predict sustained steroid-free remission defined by PGA (A) or PaGA (B). AUC, area under the curve.
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the full Mayo score that requires endoscopy. MH tended to predict 1-year sustained steroid-free remission, but the PUCAI appeared at least as predictive. Moreover, in a multivariable analysis, sigmoidoscopic assessment and CRP did not add predictive power to the clinical assessment by the PUCAI. This is in line with prior findings that adding an endoscopic component to the PUCAI did not significantly improve its performance.16 Likewise, it has been shown that the sigmoidoscopic item of both the Mayo score17 and St Mark’s Index18 could be removed without losing significant accuracy. In the former study, the endoscopic subscore contributed the lowest amount to the overall variance of the total Mayo score (7% vs 59% for stool frequency, 20% for rectal bleeding, and 14% for PGA). Our conclusions are supported by the adult study of Colombel et al2 in which MH had no predictive value among the subset of patients who were in clinical remission in the combined ACT cohorts of 466 adults with UC. Furthermore, clinical assessment of response to steroids has been shown to predict long-term clinically important outcomes in children with UC.8,9 There are several ways to explain the apparent advantage of the PUCAI over MH in predicting clinical disease course during the first subsequent year of therapy. First, endoscopic scoring by using the Mayo subscore is subjective with generally low interobserver reliability,19 whereas the PUCAI enjoys a high interobserver and test-retest reliability.10,16,20 Central reading of endoscopic appearance as part of clinical trials may improve this limitation. Second, MH lags behind clinical improvement, thereby perhaps underestimating response to short-term treatment (as observed here with a 8-week infliximab induction protocol), whereas the PUCAI is responsive to change10,16,20 even on a day-to-day basis in acute severe colitis.8,9,21 Indeed, although the sigmoidoscopic score–PUCAI concordance was excellent, more children were classified as being in the remission/mild categories by the PUCAI, and it is possible that these children also healed their mucosa shortly after the week 8 visit. Third, when performing limited sigmoidoscopy (as is customary in clinical trials), sigmoiditis and pancolitis yield similar endoscopic scoring, whereas the clinical implication of each might be very different. Disease extent in UC has been consistently associated with disease severity, and the PUCAI score is typically scored higher in children with extensive colitis as compared with those with more limited left-sided disease.16 This point is particularly
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Figure 4. Concordance between the PUCAI with sigmoidoscopic scoring (A) and with the Mayo scores (B) of 51 children 8 weeks after 3-dose induction with infliximab.
relevant in children, who present with extensive disease twice as often as in adults.22 It is possible that complete colonoscopic scoring may be more accurate than the PUCAI, but this is considered to be too invasive for routine monitoring in children, especially as part of clinical trials. Despite the results of this study, it should be emphasized that endoscopic evaluation of the colonic mucosa is of utmost importance in several scenarios in pediatric UC. First, when the clinical condition is in question, such as in mild ongoing symptoms that could be attributed clinically to reasons other than active disease (eg, irritable bowel syndrome, lactose intolerance, or side effect of medications). Second, when acute severe colitis is not responding to 3-day treatment with intravenous corticosteroids to exclude superinfection with cytomegalovirus and Clostridium difficile.21 Finally, it is reasonable to assess the colonic mucosa directly before major treatment changes such as when starting or stopping biologics and before referral for colectomy. It is has been encouraging to see that the PUCAI cutoff values that correspond to remission and response defined by the Mayo score had very high sensitivity, specificity, and area under the ROC curve. The cutoff in the PUCAI for a Mayo-defined
Figure 5. The cutoff values of the PUCAI that correspond best with remission (A) and response (B) defined by the Mayo score. AUROC, area under the ROC curve.
response was a change of at least 20 points from baseline, identical to that previously determined for the PUCAI.10,16,20 However, the cutoff of the PUCAI for a Mayo-defined remission was <15 points, higher than generally accepted (ie, <10 points). This is understandable because the PUCAI-defined remission is a higher hurdle to obtain than the Mayo-defined remission; the latter allows some residual blood in the stool, whereas the former does not. The major strength of this study is the use of the robust prospective data set of the T72 trial with well-standardized clinical and endoscopic evaluations at predefined time points and long-term follow-up. A major limitation of this study is its small sample size, which likely explains some of the insignificant P values. Larger confirmatory studies are needed. It is encouraging that the predictive value of the PUCAI achieved significance even in this small cohort. Only a few patients had follow-up endoscopic evaluation at 1 year, and therefore we did not have an opportunity to look at the predictive value of the PUCAI or early MH with respect to MH at 1 year. However, PGA has been shown to correlate closely with colonoscopic findings in UC (r ¼ 0.79 in adults
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and r ¼ 0.77 in children; P < .001),20 and most studies found very high correlations between clinical indices and endoscopic findings at a range of 0.75–0.8.18,20 One study that showed lower correlation did not score both measures simultaneously and allowed up to 6-month interval between the clinical and endoscopic assessments.23 Moreover, we supplemented this clinical outcome by combining PGA with normal CRP to more closely reflect biological remission. It is reasonable to assume that our stringent outcome of sustained 1-year steroid-free remission reflects the lack of significant mucosal inflammation that would have likely manifested as a flare during a 1-year period. We used several outcomes and analyses, and the consistent findings support our conclusion. In conclusion, we have shown in children that sigmoidoscopic determination of MH at week 8 after infliximab was not better than the PUCAI in predicting the important outcome of sustained steroid-free clinical remission at 1 year. This finding should be regarded as preliminary because of the small sample size, but it does support the recent ECCO-ESPGHAN pediatric recommendation that routine endoscopic evaluation to ensure MH is not indicated in children who are in clinical remission by the PUCAI.24 The data presented in this article should also be considered in making recommendations for outcome measures in pediatric UC clinical trials. References 1. Froslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412–422. 2. Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology 2011; 141:1194–1201. 3. Gustavsson A, Järnerot G, Hertervig E, et al. Clinical trial: colectomy after rescue therapy in ulcerative colitis: 3-year follow-up of the Swedish-Danish controlled infliximab study. Aliment Pharmacol Ther 2010;32:984–989. 4. Ardizzone S, Cassinotti A, Duca P, et al. Mucosal healing predicts late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis. Clin Gastroenterol Hepatol 2011; 9:483–489. 5. Yamamoto T, Umegae S, Matsumoto K. Mucosal healing in patients with ulcerative colitis during a course of selective leukocytapheresis therapy: a prospective cohort study. Inflamm Bowel Dis 2010; 16:1905–1911. 6. Parente F, Molteni M, Marino B, et al. Are colonoscopy and bowel ultrasound useful for assessing response to short-term therapy predicting disease outcome of moderate-to-severe form of ulcerative colitis? A prospective study. Am J Gastroenterol 2010; 105:1150–1157. 7. Gustavsson A, Halfvarson J, Magnuson A, et al. Long-term colectomy rate after intensive intravenous corticosteroid therapy for ulcerative colitis prior to the immunosuppressive treatment era. Am J Gastroenterol 2007;102:2513–2519. 8. Turner D, Mack D, Leleiko N, et al. Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. Gastroenterology 2010;138:2282–2291. 9. Turner D, Walsh CM, Benchimol EI, et al. Severe paediatric ulcerative colitis: incidence, outcomes and optimal timing for second-line therapy. Gut 2008;57:331–338. 10. Turner D, Hyams J, Markowitz J, et al. Appraisal of the pediatric ulcerative colitis activity index (PUCAI). Inflamm Bowel Dis 2009; 15:1218–1223.
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11. Sylvester FA, Turner D, Draghi A 2nd, et al. Fecal osteoprotegerin may guide the introduction of second-line therapy in hospitalized children with ulcerative colitis. Inflamm Bowel Dis 2011;17:1726–1730. 12. Turner D, Leach ST, Mack D, et al. Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison of predicting outcomes and monitoring response. Gut 2010;59:1207–1212. 13. Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:391–399. 14. Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-tosevere ulcerative colitis. Gastroenterology 2012;142:257–265. 15. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353:2462–2476. 16. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology 2007;133:423–432. 17. Dhanda AD, Creed TJ, Greenwood R, et al. Can endoscopy be avoided in the assessment of ulcerative colitis in clinical trials? Inflamm Bowel Dis 2012;18:2056–2062. 18. Higgins PD, Schwartz M, Mapili J, et al. Is endoscopy necessary for the measurement of disease activity in ulcerative colitis? Am J Gastroenterol 2005;100:355–361. 19. Travis SP, Schnell D, Krzeski P, et al. Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Gut 2012; 61:535–542. 20. Turner D, Seow CH, Greenberg GR, et al. A systematic prospective comparison of noninvasive disease activity indices in ulcerative colitis. Clin Gastroenterol Hepatol 2009;7:1081–1088. 21. Turner D, Travis SP, Griffiths AM, et al. Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. Am J Gastroenterol 2011;106:574–588. 22. Van Limbergen J, Russell RK, Drummond HE, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 2008;135:1114–1122. 23. Regueiro M, Rodemann J, Kip KE, et al. Physician assessment of ulcerative colitis activity correlates poorly with endoscopic disease activity. Inflamm Bowel Dis 2011;17:1008–1014. 24. Turner D, Levine A, Escher JC, et al. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines. J Pediatr Gastroenterol Nutr 2012;55:340–361.
Reprint requests Address requests for reprints to: Dan Turner, MD, PhD, Pediatric Gastroenterology and Nutrition Unit, Shaare Zedek Medical Center, P.O.B 3235, Jerusalem 91031, Israel. e-mail: [email protected]; fax: þ972-2-6555756. Conflicts of interest Janssen Ortho-Biotech provided the data set to the principal investigator of this study (D.T.) but was not involved in the design and analysis of this study. These authors disclose the following: Jeffrey Hyams has received research support, served on an advisory board, and has received honoraria for speaking for Janssen Ortho-Biotech and has served on an advisory board for Abbott Pharmaceuticals. Dan Turner received consultation fee, research grant, royalties, or honorarium from MSD, Janssen, Shire, BMS, Hospital for Sick Children (PUCAI), and Abbott. Anne M. Griffiths has received research support from and has served on advisory boards for Janssen Ortho-Biotech and Abbott. Gigi Veerman has acted as consultant for MSD Belgium, Mead Johnson, and Abbott. Jewel Johanns, Lakshmi Damaraju, and Marion Blank are employees of Janssen Research and Development.
Endoscopic and Clinical Variables That Predict Sustained Remission in Children With Ulcerative Colitis Treated With Infliximab DAN TURNER,* ANNE M. GRIFFITHS,‡ GIGI VEERMAN,§ JEWEL JOHANNS,k LAKSHMI DAMARAJU,k MARION BLANK,k and JEFFREY HYAMS{ *Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel; ‡Division of Pediatric Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Canada; §UZ Brussels, Brussels, Belgium; kJanssen Research and Development, LLC, Spring House, Pennsylvania; and {Connecticut Children’s Medical Center, Hartford, Connecticut
BACKGROUND & AIMS: We aimed to identify early clinical, laboratory, and endoscopic factors associated with sustained remission in children with ulcerative colitis (UC) treated with infliximab.
METHODS:
We performed a post hoc analysis of data collected from 51 children (6–17 years old) with moderate-to-severe UC treated with infliximab for 1 year in the T72 clinical trial. The primary outcome was steroid-free remission at weeks 30 and 54 of treatment, which was based on patient and physician assessments. We compared the ability of the Pediatric UC Activity Index (PUCAI, a noninvasive clinical index), levels of C-reactive protein (CRP), and mucosal healing to predict which patients would be in steroid-free sustained remission after 1 year of treatment.
RESULTS:
Week 8 PUCAI scores best predicted which patients would be in steroid-free remission after 1 year of treatment; 9 of 17 patients who had PUCAI scores <10 points were in sustained remission (53%), compared with 4 of 20 who had PUCAI scores ‡10 (20%) (P [ .036). Mucosal healing at week 8 was associated with steroid-free remission at 1 year, but this did not reach significance; 7 of 16 patients with mucosal healing were in remission after 1 year (44%), compared with 6 of 21 without mucosal healing (29%) (P [ .34). The area under the receiver operating characteristic curve values for association with steroid-free sustained remission were 0.70 for the PUCAI (95% confidence interval [CI], 0.53–0.88), 0.56 for mucosal healing (95% CI, 0.36–0.76), and 0.44 for level of CRP (95% CI, 0.24–0.65). By using a multivariable logistic regression model, the week 8 PUCAI was the only factor associated with steroid-free remission at 1 year (P [ .038). PUCAI-defined remission had a high degree of concordance with complete mucosal healing at week 8 (33% of patients were in remission according to the PUCAI vs 31% with mucosal healing).
CONCLUSION:
On the basis of a post hoc analysis of data from the T72 clinical trial on the effect of infliximab in pediatric patients with UC, the PUCAI was no less predictive of sustained remission than mucosal healing at week 8, and both were superior to CRP level. Routine endoscopic evaluation in children with UC who are in complete clinical remission (ie, PUCAI <10 points) may not be necessary.
Keywords: Prognosis; IBD; AUROC; Predicting Response to Therapy.
See related article, Travis SPL et al, on page 987 in Gastroenterology.
T
here is increasing amount of literature on the importance of mucosal healing (MH) as an aim of treatment in ulcerative colitis (UC). In a sizeable cohort of 354 Norwegian adults with new-onset UC, those achieving MH 1 year after diagnosis were less likely than those without MH to undergo colectomy during 5 years of follow-up.1 Similarly, in the combined ACT cohorts of 484 infliximab-treated adult patients, those with lower week 8 endoscopic scores were less likely to progress to colectomy within 1 year of treatment.2 Others have presented similar findings indicating that complete MH (defined as Mayo endoscopic subscore of 0), or near MH
(subscores of at most 1), is associated with sustained clinical remission in adults with UC.3–6 The predictive utility of MH in pediatric-onset UC has not yet been explored. Moreover, the aforementioned adult studies did not systematically compare MH with the predictive utility of clinical
Abbreviations used in this paper: CI, confidence interval; CRP, Creactive protein; IQR, interquartile range; MH, mucosal healing; PaGA, patient global assessment; PGA, physician global assessment; PUCAI, Pediatric UC Activity Index; ROC, receiver operating characteristic; UC, ulcerative colitis. © 2013 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.04.049
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variables. In sharp contrast to Crohn’s disease, clinical assessment of symptoms in UC is an important predictor of shortterm and long-term outcome. Clinical judgment of disease activity predicted 3-month colectomy rates among 147 adults with acute UC treated with corticosteroids.7 The Pediatric Ulcerative Colitis Activity Index (PUCAI), which relies solely on clinical parameters, strongly predicted the need for second-line rescue therapy after corticosteroid treatment of acute severe colitis in hospitalized children8,9 and the need for treatment escalation in ambulatory children with UC10 better than did fecal inflammatory markers and C-reactive protein (CRP).11,12 Because of the paucity of data on early predictors of clinical outcomes in children with UC, we used the week 8 end of open 3-dose induction phase data from a multicenter trial of infliximab therapy to compare the utility of MH versus the PUCAI and CRP in predicting subsequent 1-year sustained remission in the randomized maintenance phase. Multicenter data accrued prospectively in this trial were also used to examine the relationship between PUCAI definitions of response and remission and those of Mayo score, thereby further facilitating comparisons between pediatric and adult clinical trial outcomes.
Methods In this investigator-driven post hoc analysis, we used the data set of the recent T72 clinical trial, which evaluated the 1-year effectiveness of infliximab in pediatric UC.13 Briefly, 60 children with moderate-severe UC (defined as having a Mayo score of 6–12 points with an endoscopy subscore 2) despite standard therapy were treated with a 3-dose induction treatment of 5 mg/kg infliximab at weeks 0, 2, and 6. As per the protocol, only those achieving response (defined by the Mayo score) at week 8 (n ¼ 45) were randomized to receive infliximab every 8 or 12 weeks through 1 year. Sigmoidoscopy was performed at baseline and week 8, whereas the PUCAI (range, 0–85 points) was calculated at every visit. The PUCAI was introduced after the launch of the trial as a late amendment, and thus PUCAI scores are not available on the first 9 included children. The PUCAI was completed by the physician after obtaining thorough medical history. In the primary analysis of the T72 data, the protocol allowed dose escalation or interval shortening of infliximab, but it was defined as drug failure. For the purpose of this analysis and similar to real-world clinical practice, we considered outcome at 1 year regardless of whether dose escalation was required, because individualization of the drug dose is encouraged and reflects personal pharmacokinetics properties. Per the original protocol, dose escalation and interval shortening were equally accessible to all patients.
Outcomes and Definitions In this post hoc analysis, a stringent outcome of sustained corticosteroid-free remission was used, first by physician global assessment (PGA) and separately by patient global assessment (PaGA). Patients completed a 5-point scale (very good, fair, not very good, poor, and very poor in which remission was defined as at least fair), whereas the physicians completed a 4-point scale (remission, mild, moderate, and severe disease activity). Sustained steroid-free remission
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mandated patients to be in remission and without steroids at both weeks 30 and 54 visits. As an exploratory analysis, we also used a third outcome variable that was defined as both sustained corticosteroid-free remission (by PGA) and normal CRP at week 54. Endoscopic inflammation at week 8 was graded by using the Mayo subscore (scored as 0–3 points). For the prediction analysis we defined MH as complete MH (ie, a score of 0).
Statistical Analysis Data are presented as means ( standard deviation) or medians (interquartile range [IQR]), as appropriate. Point estimates (ie, odds ratios and area under the curve) are accompanied by 95% confidence intervals (CIs). Categorical data were compared by using c2 or Fisher exact test and continuous data by using the Student t test or Wilcoxon rank sum test, as appropriate. Per the original protocol, the last values were carried forward for missing observations, and baseline values were carried forward in patients who experienced treatment failure events including colectomy or ostomy, discontinuation of infliximab because of unsatisfactory therapeutic effect, and protocol-prohibited medication changes. To explore for the collective contribution of sigmoidoscopic score, PUCAI, and CRP in predicting sustained steroid-free 1-year remission, 2 multivariable logistic regression models were constructed by using physician and patient judgment of remission as the dependent variables. Agreement between the categories of disease activity (remission, mild, moderate, and severe) defined by the PUCAI and sigmoidoscopic score was computed by the kappa statistics with quadratic weighting. Correlations were sought by using Pearson or Spearman correlation coefficients as appropriate. Serial receiver operating characteristic (ROC) curves were used to compare the predictive utility of the different measures and to find the best cutoff of the PUCAI that corresponds to a Mayo score–defined remission (ie, total Mayo score of 2 points, with no subscore >1 point14,15) and response (ie, a decrease from baseline in the total Mayo score of 3 points and 30%, with a decrease in the subscore for rectal bleeding by 1 point or an absolute subscore of 0 or 114,15). All comparisons were made by using two-sided significance levels of .05. Statistical analyses were performed by using SPSS V15.0 (SPSS Inc, Chicago, IL).
Results Of the 60 enrolled children, the 9 earliest recruited patients in whom PUCAI scores were not measured were excluded. The demographic and baseline characteristics of the remaining 51 children are presented in Table 1. In the original study, 45 children who demonstrated a Mayo score “response” to the 3-dose induction protocol were randomized at week 8, of whom 37 had valid PUCAI and sigmoidoscopic evaluations at week 8. These were used for the prediction analyses.
Predicting One-year Sustained Remission Six of 16 (38%) who responded to infliximab at week 8 and had MH were in physician-defined (PGA) sustained remission at 1 year vs only 3 of 21 (14%) who did not have MH at week 8 assessment (P ¼ .14). Similar results were obtained for
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Table 1. Demographics and Baseline Characteristics of the 51 Included Children Total cohort (N ¼ 51) Males Age (y) Range Disease duration (y) (IQR) First attack Exacerbation Disease extent Left-sided Extensive PGA at week 0 Quiescent Mild Moderate Severe Concurrent medications Oral mesalamine Immunomodulators Corticosteroids
21 (41%) 13.5 3 6–17 1.3 (6.5–2.4) 4 (8%) 47 (92%) 11 (22%) 40 (78%) 0 3 38 10
(0%) (6%) (75%) (20%)
30 (59%) 24 (47%) 32 (63%)
NOTE. Medians (IQR) or mean ( standard deviation) are presented as appropriate for the data distribution.
the patient-defined (PaGA) sustained remission at 1 year (7 of 16 [44%] vs 6 of 21 [29%], respectively [P ¼ 0.34]) (Figure 1). Probably because of the small sample size, these trends did not reach statistical significance. Clinical remission by the PUCAI at week 8 (ie, <10 points) was a stronger predictor of sustained 1-year steroid-free remission, determined by both physicians and patients. Seven of 17 responders (41%) with week 8 PUCAI <10 were in physiciandefined sustained remission at 1 year vs 2 of 20 (10%) with PUCAI 10 (P ¼ .052); the corresponding figures for patientdefined sustained remission at 1 year were 9 of 17 (53%) vs 4 of 20 (20%) (P ¼ .036) (Figure 1). Further analyses demonstrated that the week 8 continuous PUCAI score (range, 0–85) was a significant predictor of sustained 1-year steroid-free remission (Figure 2). The median week 8 PUCAI score was 0 (IQR, 0–5 points) among those with 1-year physician-defined sustained remission vs 10 (IQR,
0–22.5 points) among those who did not achieve this outcome (P ¼ .05). Similarly, the median week 8 PUCAI score was 0 (IQR, 0–10 points) among those patients with 1-year patient-defined sustained remission vs 12.5 (2.5–22.5 points) among those patients who did not achieve this outcome (P ¼ .04). These results were reflected in a comparative ROC analysis (Figure 3). Clinical assessment by the PUCAI at week 8 seemed to be at least as good as MH in predicting 1-year sustained steroidfree remission (whether defined by patients or physicians), and both were better predictors than CRP (Figure 3). The results were similar when considering the same outcome combined with normal CRP at week 54 (area under the curve, 0.68; 95% CI, 0.5–0.87 for the PUCAI and 0.66; 95% CI, 0.46–0.85 for MH). In a multivariable logistic regression that included the PUCAI score, endoscopic subscore, and CRP at week 8 as the explanatory variables to predict patient-defined 1-year steroid-free sustained remission, the PUCAI was the only significant predictor (P ¼ .038 for the PUCAI) (odds ratio, 0.89; 95% CI, 0.8–0.993, P ¼ .68 for CRP and P ¼ .94 for endoscopic subscore). None of these variables assumed significance when using physician’s judgment of the same outcome, but the P values reflected the same rank order (P ¼ .191 for the PUCAI, P ¼ .76 for endoscopic subscore, and P ¼ .9 for CRP).
Association Between the Pediatric Ulcerative Colitis Activity Index, Sigmoidoscopic Evaluation, and the Mayo Score Of the 51 included children, 2 were missing a PUCAI score at week 0. All remaining 49 children were defined as having active disease by the PUCAI (ie, PUCAI 10) at week 0. Furthermore, 90% (44 of 49) had moderate-severe disease (ie, PUCAI 35–85), closely reflecting the sigmoidoscopic finding of moderate-severe disease in all children at that time. There was a good concordance between the different categories of disease activity judged by the PUCAI and sigmoidoscopy at week 8 (Figure 4A) (kappa ¼ 0.58; 95% CI, 0.26–0.89; P < .0001). Similarly, the PUCAI was highly correlated also with the Mayo score (r ¼ 0.88; P < .0001, n ¼ 51) (Figure 4B).
Figure 1. Percentage of children in sustained steroid-free 1-year clinical remission, stratified by those achieving remission at week 8 by the PUCAI and MH.
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Figure 2. Week 8 PUCAI score predicts 1-year steroid-free sustained remission.
The best cutoff of the PUCAI to define a Mayo score remission was <15 points (Figure 5A), with a sensitivity of 90%, specificity of 81%, and area under the ROC curve of 0.93 (95% CI, 0.86–1.0). The best cutoff of the PUCAI to define a Mayo score response was 20 points (Figure 5B), with a sensitivity of 97%, specificity of 90%, and area under the ROC curve of 0.97 (95% CI, 0.92–1.0).
Discussion Whether clinical assessment is a reliable means of judging MH in UC is more controversial than in Crohn’s disease, where the lack of correlation between symptoms and endoscopic appearance is indisputable. To increase feasibility of pediatric clinical trials, noninvasive methods to assess response and remission are preferable, if they are found to accurately reflect MH and predict clinically important outcomes. Our post hoc analysis suggests that the PUCAI appears to be sufficiently accurate to assess remission in pediatric UC. The noninvasive PUCAI was closely correlated with the sigmoidoscopic score and
Figure 3. ROC curve to reflect the ability of the PUCAI, sigmoidoscopy, and CRP at week 8 to predict sustained steroid-free remission defined by PGA (A) or PaGA (B). AUC, area under the curve.
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the full Mayo score that requires endoscopy. MH tended to predict 1-year sustained steroid-free remission, but the PUCAI appeared at least as predictive. Moreover, in a multivariable analysis, sigmoidoscopic assessment and CRP did not add predictive power to the clinical assessment by the PUCAI. This is in line with prior findings that adding an endoscopic component to the PUCAI did not significantly improve its performance.16 Likewise, it has been shown that the sigmoidoscopic item of both the Mayo score17 and St Mark’s Index18 could be removed without losing significant accuracy. In the former study, the endoscopic subscore contributed the lowest amount to the overall variance of the total Mayo score (7% vs 59% for stool frequency, 20% for rectal bleeding, and 14% for PGA). Our conclusions are supported by the adult study of Colombel et al2 in which MH had no predictive value among the subset of patients who were in clinical remission in the combined ACT cohorts of 466 adults with UC. Furthermore, clinical assessment of response to steroids has been shown to predict long-term clinically important outcomes in children with UC.8,9 There are several ways to explain the apparent advantage of the PUCAI over MH in predicting clinical disease course during the first subsequent year of therapy. First, endoscopic scoring by using the Mayo subscore is subjective with generally low interobserver reliability,19 whereas the PUCAI enjoys a high interobserver and test-retest reliability.10,16,20 Central reading of endoscopic appearance as part of clinical trials may improve this limitation. Second, MH lags behind clinical improvement, thereby perhaps underestimating response to short-term treatment (as observed here with a 8-week infliximab induction protocol), whereas the PUCAI is responsive to change10,16,20 even on a day-to-day basis in acute severe colitis.8,9,21 Indeed, although the sigmoidoscopic score–PUCAI concordance was excellent, more children were classified as being in the remission/mild categories by the PUCAI, and it is possible that these children also healed their mucosa shortly after the week 8 visit. Third, when performing limited sigmoidoscopy (as is customary in clinical trials), sigmoiditis and pancolitis yield similar endoscopic scoring, whereas the clinical implication of each might be very different. Disease extent in UC has been consistently associated with disease severity, and the PUCAI score is typically scored higher in children with extensive colitis as compared with those with more limited left-sided disease.16 This point is particularly
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Figure 4. Concordance between the PUCAI with sigmoidoscopic scoring (A) and with the Mayo scores (B) of 51 children 8 weeks after 3-dose induction with infliximab.
relevant in children, who present with extensive disease twice as often as in adults.22 It is possible that complete colonoscopic scoring may be more accurate than the PUCAI, but this is considered to be too invasive for routine monitoring in children, especially as part of clinical trials. Despite the results of this study, it should be emphasized that endoscopic evaluation of the colonic mucosa is of utmost importance in several scenarios in pediatric UC. First, when the clinical condition is in question, such as in mild ongoing symptoms that could be attributed clinically to reasons other than active disease (eg, irritable bowel syndrome, lactose intolerance, or side effect of medications). Second, when acute severe colitis is not responding to 3-day treatment with intravenous corticosteroids to exclude superinfection with cytomegalovirus and Clostridium difficile.21 Finally, it is reasonable to assess the colonic mucosa directly before major treatment changes such as when starting or stopping biologics and before referral for colectomy. It is has been encouraging to see that the PUCAI cutoff values that correspond to remission and response defined by the Mayo score had very high sensitivity, specificity, and area under the ROC curve. The cutoff in the PUCAI for a Mayo-defined
Figure 5. The cutoff values of the PUCAI that correspond best with remission (A) and response (B) defined by the Mayo score. AUROC, area under the ROC curve.
response was a change of at least 20 points from baseline, identical to that previously determined for the PUCAI.10,16,20 However, the cutoff of the PUCAI for a Mayo-defined remission was <15 points, higher than generally accepted (ie, <10 points). This is understandable because the PUCAI-defined remission is a higher hurdle to obtain than the Mayo-defined remission; the latter allows some residual blood in the stool, whereas the former does not. The major strength of this study is the use of the robust prospective data set of the T72 trial with well-standardized clinical and endoscopic evaluations at predefined time points and long-term follow-up. A major limitation of this study is its small sample size, which likely explains some of the insignificant P values. Larger confirmatory studies are needed. It is encouraging that the predictive value of the PUCAI achieved significance even in this small cohort. Only a few patients had follow-up endoscopic evaluation at 1 year, and therefore we did not have an opportunity to look at the predictive value of the PUCAI or early MH with respect to MH at 1 year. However, PGA has been shown to correlate closely with colonoscopic findings in UC (r ¼ 0.79 in adults
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and r ¼ 0.77 in children; P < .001),20 and most studies found very high correlations between clinical indices and endoscopic findings at a range of 0.75–0.8.18,20 One study that showed lower correlation did not score both measures simultaneously and allowed up to 6-month interval between the clinical and endoscopic assessments.23 Moreover, we supplemented this clinical outcome by combining PGA with normal CRP to more closely reflect biological remission. It is reasonable to assume that our stringent outcome of sustained 1-year steroid-free remission reflects the lack of significant mucosal inflammation that would have likely manifested as a flare during a 1-year period. We used several outcomes and analyses, and the consistent findings support our conclusion. In conclusion, we have shown in children that sigmoidoscopic determination of MH at week 8 after infliximab was not better than the PUCAI in predicting the important outcome of sustained steroid-free clinical remission at 1 year. This finding should be regarded as preliminary because of the small sample size, but it does support the recent ECCO-ESPGHAN pediatric recommendation that routine endoscopic evaluation to ensure MH is not indicated in children who are in clinical remission by the PUCAI.24 The data presented in this article should also be considered in making recommendations for outcome measures in pediatric UC clinical trials. References 1. Froslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412–422. 2. Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology 2011; 141:1194–1201. 3. Gustavsson A, Järnerot G, Hertervig E, et al. Clinical trial: colectomy after rescue therapy in ulcerative colitis: 3-year follow-up of the Swedish-Danish controlled infliximab study. Aliment Pharmacol Ther 2010;32:984–989. 4. Ardizzone S, Cassinotti A, Duca P, et al. Mucosal healing predicts late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis. Clin Gastroenterol Hepatol 2011; 9:483–489. 5. Yamamoto T, Umegae S, Matsumoto K. Mucosal healing in patients with ulcerative colitis during a course of selective leukocytapheresis therapy: a prospective cohort study. Inflamm Bowel Dis 2010; 16:1905–1911. 6. Parente F, Molteni M, Marino B, et al. Are colonoscopy and bowel ultrasound useful for assessing response to short-term therapy predicting disease outcome of moderate-to-severe form of ulcerative colitis? A prospective study. Am J Gastroenterol 2010; 105:1150–1157. 7. Gustavsson A, Halfvarson J, Magnuson A, et al. Long-term colectomy rate after intensive intravenous corticosteroid therapy for ulcerative colitis prior to the immunosuppressive treatment era. Am J Gastroenterol 2007;102:2513–2519. 8. Turner D, Mack D, Leleiko N, et al. Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. Gastroenterology 2010;138:2282–2291. 9. Turner D, Walsh CM, Benchimol EI, et al. Severe paediatric ulcerative colitis: incidence, outcomes and optimal timing for second-line therapy. Gut 2008;57:331–338. 10. Turner D, Hyams J, Markowitz J, et al. Appraisal of the pediatric ulcerative colitis activity index (PUCAI). Inflamm Bowel Dis 2009; 15:1218–1223.
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11. Sylvester FA, Turner D, Draghi A 2nd, et al. Fecal osteoprotegerin may guide the introduction of second-line therapy in hospitalized children with ulcerative colitis. Inflamm Bowel Dis 2011;17:1726–1730. 12. Turner D, Leach ST, Mack D, et al. Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison of predicting outcomes and monitoring response. Gut 2010;59:1207–1212. 13. Hyams J, Damaraju L, Blank M, et al. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:391–399. 14. Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-tosevere ulcerative colitis. Gastroenterology 2012;142:257–265. 15. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353:2462–2476. 16. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology 2007;133:423–432. 17. Dhanda AD, Creed TJ, Greenwood R, et al. Can endoscopy be avoided in the assessment of ulcerative colitis in clinical trials? Inflamm Bowel Dis 2012;18:2056–2062. 18. Higgins PD, Schwartz M, Mapili J, et al. Is endoscopy necessary for the measurement of disease activity in ulcerative colitis? Am J Gastroenterol 2005;100:355–361. 19. Travis SP, Schnell D, Krzeski P, et al. Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Gut 2012; 61:535–542. 20. Turner D, Seow CH, Greenberg GR, et al. A systematic prospective comparison of noninvasive disease activity indices in ulcerative colitis. Clin Gastroenterol Hepatol 2009;7:1081–1088. 21. Turner D, Travis SP, Griffiths AM, et al. Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. Am J Gastroenterol 2011;106:574–588. 22. Van Limbergen J, Russell RK, Drummond HE, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 2008;135:1114–1122. 23. Regueiro M, Rodemann J, Kip KE, et al. Physician assessment of ulcerative colitis activity correlates poorly with endoscopic disease activity. Inflamm Bowel Dis 2011;17:1008–1014. 24. Turner D, Levine A, Escher JC, et al. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines. J Pediatr Gastroenterol Nutr 2012;55:340–361.
Reprint requests Address requests for reprints to: Dan Turner, MD, PhD, Pediatric Gastroenterology and Nutrition Unit, Shaare Zedek Medical Center, P.O.B 3235, Jerusalem 91031, Israel. e-mail: [email protected]; fax: þ972-2-6555756. Conflicts of interest Janssen Ortho-Biotech provided the data set to the principal investigator of this study (D.T.) but was not involved in the design and analysis of this study. These authors disclose the following: Jeffrey Hyams has received research support, served on an advisory board, and has received honoraria for speaking for Janssen Ortho-Biotech and has served on an advisory board for Abbott Pharmaceuticals. Dan Turner received consultation fee, research grant, royalties, or honorarium from MSD, Janssen, Shire, BMS, Hospital for Sick Children (PUCAI), and Abbott. Anne M. Griffiths has received research support from and has served on advisory boards for Janssen Ortho-Biotech and Abbott. Gigi Veerman has acted as consultant for MSD Belgium, Mead Johnson, and Abbott. Jewel Johanns, Lakshmi Damaraju, and Marion Blank are employees of Janssen Research and Development.