Accepted Manuscript Title: Managing paediatric acute severe ulcerative colitis according to the 2011 ECCO-ESPGHAN guidelines: efficacy of infliximab as a rescue therapy Author: Marina Aloi Giulia D’Arcangelo Martina Capponi Federica Nuti Francesca Vassallo Fortunata Civitelli Salvatore Oliva Giuseppe Pagliaro Salvatore Cucchiara PII: DOI: Reference:
S1590-8658(15)00179-6 http://dx.doi.org/doi:10.1016/j.dld.2015.01.156 YDLD 2821
To appear in:
Digestive and Liver Disease
Received date: Revised date: Accepted date:
20-12-2014 22-1-2015 28-1-2015
Please cite this article as: Aloi M, D’Arcangelo G, Capponi M, Nuti F, Vassallo F, Civitelli F, Oliva S, Pagliaro G, Cucchiara S, Managing paediatric acute severe ulcerative colitis according to the 2011 ECCO-ESPGHAN guidelines: efficacy of infliximab as a rescue therapy, Digestive and Liver Disease (2015), http://dx.doi.org/10.1016/j.dld.2015.01.156 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Managing paediatric acute severe ulcerative colitis according to the 2011 ECCOESPGHAN guidelines: efficacy of infliximab as a rescue therapy
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Marina Aloi, MD, PhD, Giulia D'Arcangelo, MD, Martina Capponi, MD, Federica Nuti, MD, Francesca Vassallo, MD, Fortunata Civitelli, MD, Salvatore Oliva, MD, Giuseppe
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Pagliaro, MD, and Salvatore Cucchiara, MD, PhD.
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Paediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University
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of Rome, Rome, Italy
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Corresponding author Salvatore Cucchiara, MD, PhD.
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Department of Pediatrics
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Paediatric Gastroenterology and Liver Unit Sapienza University of Rome,
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Viale Regina Elena 324 00161 Roma – Italy
tel +390649979324, fax +390649979325 [email protected]
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ABSTRACT Background: The effectiveness of medical therapy in paediatric acute severe colitis is
enrolled at Sapienza University of Rome between May 2010-12.
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scarcely described. We aimed to assess the efficacy of infliximab in children prospectively
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Methods: Clinical assessment and laboratory data were recorded at admission and at day 3 and 5. All patients received corticosteroids; infliximab was administered in refractory
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patients. Colectomy rate was assessed at 2-year follow-up.
Results: Thirty-one patients (mean age 10.6±4.9 years, 52% females) were included: 21
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responded to corticosteroids (68%), 10 were refractory and received infliximab (32%). Among the latter, 2 required urgent colectomy (20%); 80% responded, however 50% of
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these required elective colectomy during follow-up. Patients refractory to corticosteroids
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showed a significantly shorter interval from ulcerative colitis diagnosis to acute severe
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colitis compared to responders (7.4±9.6 vs. 23.1±21.6 months, respectively; p=0.01), and a higher rate of colectomy at follow-up (50% vs. 14%, respectively; p=0.007). More than 2
4.4).
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courses of corticosteroids before acute severe colitis were predictive of surgical need (OR
Conclusion: Despite its short-term efficacy, infliximab did not modify the long-term surgical rate of paediatric acute severe colitis in our cohort. Children with an early severe colitis commonly need a second-line therapy, whilst frequent courses of corticosteroids are predictive of a poor outcome.
Key words: PUCAI, colectomy, Paediatric ASC
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INTRODUCTION Paediatric ulcerative colitis (UC) is most often extensive and severe already at time of
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diagnosis. Some data report that up to 80% of children are affected by extensive colitis or pancolitis, whilst 25–30% will become corticosteroid-dependent by 1 year (1-5). The
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aggressive nature of paediatric UC is marked by the high frequency of acute severe
exacerbations of the disease, which occur in approximately 28% of children against 15%
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of adults (6). Paediatric acute severe colitis (ASC) is an emergent condition and an indication for hospitalization. Although in adults with UC several definitions have been
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used to identify an episode of ASC in clinical practice, in children a Paediatric Ulcerative Colitis Activity Index (PUCAI) of at least 65 points has been validated for the definition of
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this condition (7). Intravenous corticosteroids (CS) remain the mainstay of the treatment,
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since the trials of Truelove et al in 1955 and 1974 demonstrated their efficacy in avoiding
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colectomy in adults with ASC (8,9). Nevertheless, the rate of CS refractoriness is higher in children than in adults, therefore the choice of second line therapy is the greatest
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challenge in this setting (10). Cyclosporine and infliximab (IFX) have been proven to be effective in inducing a short-term remission in CS-refractory patients with ASC and colectomy is now reserved for patients who do not respond to these therapies (11). Several prospective trials conducted in adults have clearly demonstrated the short-term efficacy of both cyclosporine and IFX in avoiding colectomy in patients with ASC, with short-term remission rates of 70-80% for both drugs (11-13).While the long-term colectomy rate for patients who initially respond to cyclosporine reaches about 40%, very few data on long-term efficacy of IFX are available (14-16). A 19% colectomy rate at 1 year of IFX therapy has been reported in the only multicentre prospective study on paediatric ASC (7). Despite the few paediatric data available in this field, the 2011 ECCOESPGHAN guidelines for the management of ASC have provided very important 4 Page 3 of 22
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recommendations, especially regarding timing of introduction of rescue therapies (17). Primary objective of this study was to evaluate the effectiveness of IFX used as a secondline therapy in paediatric ASC treated according to the 2011 ECCO-ESPGHAN guidelines.
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As secondary outcomes we also sought to evaluate the short- and long-term colectomy rate in children with ASC and to identify clinical factors predictive of poor outcome at
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diagnosis.
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PATIENTS AND METHODS
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All children requiring hospitalization for an episode of ASC, defined as a PUCAI>65 (3), between May 2010 and May 2012 were consecutively included in the study. The study
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was conducted at the Gastroenterology and Liver Unit of Sapienza University of Rome (NCT02170714). The diagnosis of UC was established according to standard clinical,
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radiological, endoscopic and histological criteria (18). The study was approved by the
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ethical committee of the Hospital and written informed consent was obtained from all enrolled children and their parents. Clinical and demographic characteristics of all patients
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were recorded upon admission: age, sex, duration of disease, family history, extension of colitis according to Paris classification (19), previous steroid treatment and past and concomitant therapies. All patients with ASC were treated according to the ECCOESPGHAN 2011 guidelines (17). All therapies and nutritional data were recorded on standardized case report forms at baseline, at day 3 and 5 after starting first-line therapy, at introduction of second-line therapy and at discharge. Initial diagnostic evaluation included blood tests for electrolytes, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, complete blood count (CBC); cultures for enteric pathogens (Salmonella, Shigella, Campylobacter, and Escherichia coli), the collection of 3–5 stool samples for Clostridium difficile toxin; stool virology was performed only in the presence of fever or vomiting as well as with non-bloody diarrhoea. Normal diet was continued when 5 Page 4 of 22
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possible. Nutritional support via nasogastric tube was administered only in case of insufficient oral intake. In the presence of colonic dilatation (>40 mm or >56 mm in children aged>10 years) or when surgery was imminent, parenteral nutrition was started. All
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patients received intravenous methylprednisolone, 1.5 to 2 mg/kg/day to a maximum of 40 mg given in two divided daily doses. A sigmoidoscopy for the diagnosis of
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Cytomegalovirus (CMV) infection by tissue CMV-PCR was performed in children not-
responding to CS at day 3. PUCAI score was assessed daily to monitor the response to
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steroid treatment: a child with a PUCAI of >45 points on day 3 was prepared for second
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line therapy. According to ECCO-ESPGHAN guidelines, second-line medical therapy was initiate in case of a PUCAI >65 on day 5, and no patient underwent surgery after
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failure of first-line therapy (17). Corticosteroids were continued for an additional 2–5 days in children with a PUCAI of ≤ 60 and ≥ 35 points on day 5 and prepared to a second-
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line therapy in case of worsening. Infliximab was administered at the dose of 5 mg/kg iv at
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0, 2 and 6 weeks, after standard screenings. During follow up, at 6, 12, 18 and 24 months, patients were evaluated for indication to colectomy. The primary outcome was to assess
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the effectiveness of infliximab used as a second-line therapy in paediatric ASC treated according to the 2011 ECCO-ESPGHAN guidelines. Secondary end-points were to define the short- and long-term colectomy rate in children with ASC and to identify clinical predictive factors of poor outcome at the diagnosis. Statistical Analyses. All data were summarized and displayed as the mean±SD for continuous variables. Categorical data were expressed as frequencies and percentages. Comparison of groups was performed using Student's t test for unpaired data in two group comparison and one way analysis of variance (ANOVA) with Bonferroni's test for multiple group comparison. Chi square test with Fisher's correction was used to evaluate the differences for categorical variables wherever needed. A p value≤0.05 was considered significant. The Kaplan–Meier survival method was used to estimate the interval free from 6 Page 5 of 22
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colectomy during follow-up. Differences between curves were tested using the Log-Rank test. To determine predictors of colectomy, descriptive unifactorial analysis was performed on predefined potential variables recorded at admission. Unadjusted logistic regression
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was used to obtain the corresponding odds ratios (OR) and 95% confidence intervals (CI). Assessment of the relation between response to CS and clinical variables was performed
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using the Pearson partial correlation for continuous variables, and the Spearman
correlation procedure was used for categorical variables. The GraphPad statistical
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package was used to perform all statistical evaluations (GraphPad Software, Inc., San
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Diego, CA).
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RESULTS
From May 2010 to May 2012, 31/110 patients followed for UC in our centre (28%) were
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hospitalized for an episode of ASC. Mean age at diagnosis was 10.6±4.9 years; 22% had
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a family history of IBD. All patients had a full exploration of the gastrointestinal tract performed at diagnosis, including a complete ileocolonoscopy under general anaesthesia
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or deep sedation. Pancolitis (E4) and extensive colitis (E3) were present in 32% (n=10) and 26% (n=8) of patients, respectively; 19% (n=6) had a left-sided colitis (E2) and 22.5%, (n=7) proctitis (E1). Patients developed ASC a median of 19.6±20.5 months after diagnosis of UC and 11 patients (35%) presented with ASC at time of diagnosis. The demographic, clinical and biological characteristics of patients are shown in table 1. Figure 1 shows the clinical outcomes of the entire cohort of patients. Of the 31 patients hospitalized for ASC who received intravenous corticosteroids, 21 responded to the first line therapy(68%): 11 showed a decrease of PUCAI score to 35 after 3 days of intensive CS treatment (53%), while 10 were slow responders and improved after 3-5 days of additional corticosteroid treatment (47%). The remaining 10 patients (32%) received IFX for CS refractoriness after a median of 5.8±1.1 days. Nine non-responders (90%) 7 Page 6 of 22
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underwent sigmoidoscopy after 3.1±1.2 days from admission; in 2 non-responders tissue PCR was positive for CMV and patients were treated with antiviral therapy. In both patients, IFX was started after 2.9±0.9 days due to clinical worsening. Of the 10 patients
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treated with IFX, 2 underwent urgent colectomy (20%) after the first infusion due to clinical worsening; 8 responded to the therapy (80%) and were regularly discharged after a
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median of 14.25±6.8 days. At 2-year follow-up, 50% (n=5) of the IFX-treated patients and 14% (n=3) of CS-responders underwent elective colectomy for chronic clinical relapses
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(p=0.007). The overall colectomy rate at maximum follow up was 32% (Figure 2). The
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cumulative probability at 2-year follow-up of a course without surgery after the episode of ASC was 77%, 74%, 67% and 67% at 6, 12, 18 and 24 months respectively. The
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cumulative probability of a course free from colectomy was significantly higher in patients responding to CS, than in those requiring second-line therapy (Log-rank test p=0.0003;
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Figure 3). At univariate analysis between CS-responders and refractory patients, no
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statistically significant difference was found for demographic, clinical and laboratory data except for the shorter interval from the diagnosis of ulcerative
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colitis to the episode of ASC (p= 0.04) and the higher colectomy rate at maximum follow-up (p=0.007) observed in CS-refractory patients (table 2). As a secondary outcome of this study we sought to identify clinical predictors of poor outcome at the diagnosis: patients needing colectomy required significantly more frequent courses of CS prior to the episode of ASC compared to those responding to medical therapy (OR 4.4; 95% CI 0.7-25), while no differences were found for laboratory values, gender, disease location, disease extension, therapy, mean PUCAI, serological markers and family history (table 3). There were no cases of toxic megacolon or death in this cohort of patients.
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DISCUSSION The current study focuses on the long-term outcome of Paediatric ASC treated according
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to the recent joint statement from ECCO, ESPGHAN, and the Porto IBD group of ESPGHAN. Until 2011 the management of children with ASC was based on adult
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recommendations, but, although the pathogenesis and most disease-related factors are
comparable to adult-onset disease, several variables make management of children with
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ASC peculiar. Paediatric UC is often extensive already at time of diagnosis and exhibits
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frequent acute exacerbations during its course (1-5); moreover treatment of children with ASC encompasses issues such as the long-term safety profile of medical treatment and
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the outcome of surgery, as well as factors related to the chronic inflammation itself (i.e. growth and pubertal development, bone density accrual and emotional development). All
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these considerations influenced the development of standardized paediatric guidelines,
escalation.
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aimed at allowing the effective monitoring of paediatric ASC and guide timely treatment
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In our study, we prospectively recruited children who experienced an episode of ASC, and treated them strictly according to the above-mentioned guidelines. Similarly to previous paediatric data (6,20,21), 28% (n=31) of the 110 patients with UC followed at our centre during the study period were hospitalized for an episode of ASC: Turner et al, in a population cohort study of 196 children with UC reported a rate of hospitalization for ASC of 28% (6). All patients received intensive CS treatment at admission, in agreement with the ECCO-ESPGHAN guidelines. In our series the response rate and refractoriness to CS (68 and 32%, respectively) was similar to that reported in previous adult (8,22) and paediatric studies (20,23). When evaluating clinical predictive factors of CS refractoriness, a shorter interval from the diagnosis of UC to the episode of ASC was significantly more common in children not-responding to first line therapy, thus suggesting 9 Page 8 of 22
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that the severity of the disease early after diagnosis is strictly related to the development of a more severe disease course. IFX was used as a rescue therapy in all patients who failed to respond to intravenous CS. Although the ECCO-ESPGHAN guidelines
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recommend the use of either IFX or calcineurin inhibitors as second line therapy, intravenous cyclosporine has been rarely used for ASC in our centre, and between 2010–
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2012 none of the patients received cyclosporine. Of the 10 non-responder children, 8
were successfully treated with IFX (80%) and avoided urgent colectomy, whilst 2 needed
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urgent surgery due to no response. However, at 2-year follow-up, 5 patients required
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elective surgery (50%) for chronic relapsing course (40% within 3 months from the episode of ASC).
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There are only scarce data on the efficacy of IFX as a rescue therapy in paediatric ASC (7). Adult studies suggest a high short-term efficacy in avoiding urgent colectomy (70-
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80%), whilst long-term prognosis is poorly described (24-26). Sjoberg et al. in a recent
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study evaluating 211 adults with ASC treated with IFX as a rescue therapy reported 71%, 64%, 59% and 53% avoided colectomy at 3, 12, 36 and 60 months, respectively (27).
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However, it is worth noting that a flexible IFX induction regimen was used and approximately 50% of patients received a single infusion, while in our study all patients received a standard three-dose induction regimen. Recently, a large study from the Italian Group for the study of Inflammatory Bowel Disease (IG-IBD) of 113 adult patients with steroid-refractory severe UC treated with a standard induction IFX regimen reported colectomy rates of 18.6% and 25.6% at 3 and 12 months respectively(28). Consistent with those data, we found a 12-month colectomy rate of 22%. Additional smaller studies have described colectomy rates ranging from 28% to 80% (24-26, 29-34). However, comparison of these populations is flawed by several factors, such as the definitions of CS refractoriness, different second-line therapies and small number of patients. In our series, 2 non-responder patients had positive tissue PCR for 10 Page 9 of 22
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CMV, and were treated accordingly. In both cases, antiviral treatment failed to demonstrate a favourable impact on clinical and biological outcomes, suggesting CMV to be an innocent bystander of clinical relapses, as reported in previous studies (35-38) .
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At 2-year follow-up the overall colectomy rate was 32%, similar to previous paediatric data (6,7,20). This seems to suggest that, even with the timely use of second-line IFX according
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to current guidelines, the natural history of acute exacerbations might not be modified by the current treatment strategies. However, these results need to be confirmed with larger,
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randomized controlled trials.
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Strikingly, the long term colectomy rate was higher in IFX-treated patients, than in those responding to intravenous CS; moreover, patients who underwent second-line therapy had
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a shorter course free from colectomy compared to those responding to CS. This difference was statistically significant but a type 1 error cannot be excluded due to the small number
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of IFX-treated patients in our study. Interestingly, frequent courses of CS therapy before
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the episode of ASC were associated with a poor outcome. We can speculate that CSrefractory patients, who didn’t achieve remission with IFX, have a more severe disease
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compared to CS-responsive patients: this can explain the shorter colectomy-free course in CS-not responders.
Our study has several strengths, as all patients were prospectively recruited and managed according to the ECCO-ESPGHAN guidelines and were followed for a relatively long period, providing valuable, real-life data on outcomes of ASC. Limitations could be the relatively small population of patients, for which we may have overlooked clinical variables related to a poor outcome. In conclusion, although its short-term effectiveness as a rescue therapy to avoid urgent colectomy in CS-refractory children, IFX, used at the dose and scheme recommended by the current guidelines, does not modify the long-term colectomy rate in ASC. A short interval from the diagnosis of UC to the episode of ASC seems to be related to CS therapy 11 Page 10 of 22
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failure, whilst frequent courses of CS before the episode of ASC are predictive of a poor outcome. Larger, multicentre, prospective studies are needed to confirm those data and to define the
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optimal therapeutic strategy of paediatric ASC, including the effect of IFX therapy
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optimization.
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12.Laharie D, Bourreille A, Branche J, et al. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet. 2012;380:1909-15. 13.Bitton A, Buie D, Enns R, et al. Treatment of hospitalized adult patients with severe ulcerative colitis: Toronto consensus statements. Am J Gastroenterol 2012;107:179-94.
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17.Turner D, Travis SP, Griffiths AM, et al. Consensus for managing acute severe
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22.Aratari A, Papi C, Clemente V, et al. Colectomy rate in acute severe ulcerative colitis in the infliximab era. Dig Liver Dis 2008;40:821-6. 23.Turner D, Kolho KL, Mack DR, et al. Glucocorticoid bioactivity does not predict
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28.Monterubbianesi R, Aratari A, Armuzzi A, et al. Infliximab three-dose induction regimen in severe corticosteroid-refractory ulcerative colitis: Early and late outcome and predictors of colectomy. J Crohns Colitis 2014;8:852-8.
29.Actis GC, Bruno M, Pinna-Pintor M, et al. Infliximab for treatment of steroidrefractory ulcerative colitis. Dig Liver Dis 2002; 34: 631–4. 30.Bressler B, Law JK, Al Nahdi Sheraisher N, et al. The use of infliximab for treatment of hospitalized patients with acute severe ulcerative colitis. Can J Gastroenterol 2008; 22: 937–40.
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31.Lees CW, Heys D, Ho GT, et al. A retrospective analysis of the efficacy and safety of infliximab as rescue therapy in acute severe ulcerative colitis. Aliment Pharmacol Ther 2007; 26: 411–9.
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34.Yamamoto-Furusho JK, Uzcanga LF. Infliximab as a rescue therapy for hospitalized patients with severe ulcerative colitis refractory to systemic corticosteroids. Dig Surg
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2008; 25: 383–6.
35.Delvincourt M, Lopez A, Pillet S, et al. The impact of cytomegalovirus reactivation
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36.Matsuoka K, Iwao Y, Mori T, et al. Cytomegalovirus is frequently reactivated and
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disappears without antiviral agents in ulcerative colitis patients. Am J Gastroenterol 2007; 102:331–7.
37.Leveque N, Brixi-Benmansour H, Reig T, et al. Low frequency of cytomegalovirus infection during exacerbations of inflammatory bowel diseases. J Med Virol 2010; 82: 1694–700.
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FIGURE LEGEND
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Figure 1. Clinical outcomes of 31 children admitted for an episode of acute severe colitis.
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UC: ulcerative colitis; ASC: acute severe colitis; iv: intravenous; PUCAI: Paediatric ulcerative colitis activity index; CS: corticosteroids; IFX: infliximab.
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Figure 2. Cumulative probability of a disease course without colectomy following the episode of acute severe colitis (urgent and elective colectomy are considered).
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Figure 3. Cumulative probability of a disease course free from colectomy in children with
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acute severe colitis who responded to intravenous steroids (Responders) and in steroid-
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refractory patients (Non-Responders).
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Table 1. Clinical characteristics of 31 patients admitted for an episode of acute severe colitis. 10.6±4.88
Female gender
16 (52%)
Mean BMI ± SD
17±2.8
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Mean age ± SD (years)
Location of disease at diagnosis, n(%)
7 (22.5%)
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E1
6 (19%)
E2
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E3 E4
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Mean Hb g/dl ±SD Mean Albumin g/L ± SD
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Mean CRP mg/L ± SD Mean ESR mm/h ± SD
Family history, n(%)
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p-ANCA, n(%)
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Extraintestinal manifestation, n(%)
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Mean PUCAI ± SD
8 (26%) 10 (32%) 10.9±1.4 35.7±13 14.2±21.5 36.63±23.43 71±10 8 (26%) 5 (16%) 4 (13%)
Mean time from diagnosis to ASC ± SD (months)
19.58±20.5
ASC at the diagnosis of UC (%)
11 (35%)
Therapy prior to the episode of ASC (%) Mesalamine
20 (64.5%)
Steroids
18 (58%)
AZA
9 (29%)
BMI, Body Mass Index; Hb, Hemoglobin; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PUCAI, pediatric ulcerative colitis activity index; p-ANCA, Perinuclear Anti-Neutrophil Cytoplasmic Antibodies; ASC, acute severe colitis, AZA: azathioprine.
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Table 2. Univariate analysis of clinical and laboratory variables in Responders and Nonresponders to corticosteroids Responders,
Non-Responders, OR (95% CI)
p
n=10
Female gender (%)
12 (57%)
5 (50%)
Mean age ± SD (years)
11.61±5.056
10±5.59
6 (28.5%)
1(10%)
6 (28.5%)
0
4 (19%)
4 (40%)
0.3 (0.07-2.0) 0.38
5 (24%)
5 (50%)
0.3 (0.06-1.5) 0.22
E2 E3 E4
18.2±39.5
Mean ESR mm/h ± SD
41.73±29.65
Mean PUCAI ± SD
72±15
pANCA, n(%)
1 (5%)
Family history, n(%)
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3.6 (0.3-34) 0.31
8.8 (0.4-173) 0.14
30.3±14.32
1.9 (0.3-2.7) 0.73
71±20
0.9 (0.4-6.1) 0.92
3 (30%)
0.1 (0.01-1.3) 0.08
3 (14%)
5(50%)
0.1 (0.02-0.9) 0.07
23.121.6
7.49.6
7.3 (1.2-42.8) 0.01
7 (33%)
4 (40%)
2.6 (0.4-15) 0.90
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ASC at the diagnosis of UC
0.4 (0.2-5.6) 0.42
1.2 (0.5-4.3) 0.51
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ASC ± SD (months)
0.76
9.38±13.6
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Mean CRP mg/L ± SD
Mean time from diagnosis to
1.3 (0.2-6)
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E1
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Location of the disease,n (%)
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n=21
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PUCAI, pediatric ulcerative colitis activity index; p-ANCA, Perinuclear Anti-Neutrophil Cytoplasmic Antibodies; ASC, acute severe colitis; UC, ulcerative colitis.
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Table 3. Clinical variables at the diagnosis in patients requiring surgery compared to those responding to medical therapy. Colectomy, n=10 No Colectomy, n=21 OR (95% CI) 5 (50%)
9 (43%)
Mean age ± SD
8.7 ± 5.7
11.3 ± 4.3
E1
2 (20%)
5 (24%)
E2
1 (10%)
5 (24%)
0.3 (0.3-3.5)
E3
3 (30%)
5 (24%)
1.3 (0.2-7.3)
E4
4 (40%)
CRP (>10 mg/L)
6 (60%)
ESR (>25 mm/h)
5 (50%
Albumin (65
7 (70%)
ASC at the diagnosis Disease extension, n(%)
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1.1 (0.2-5.2)
11 (52%)
0.9 (0.2-4.1)
9 (43%)
1.3 (0.2-6.0)
13 (62%)
1.4 (0.2-7.2)
4 (40%)
6 (28.5%
1.6 (0.3-8.0)
2 (20%)
8(38%)
0.4 (0.4-2.6)
6 (28.5%)
1.0 (0.2-5.5)
8 (80%)
11 (38%)
4.4 (0.7-25)
7 (70%)
15 (71%)
0.9 (0.1-4.8)
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1.6 (0.3-8.0)
3 (30%)
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AZA
1.0 (0.1-6.5)
6 (29%)
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Therapy before ASC, n(%)
0.2 (0.12-5.9)
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Location of the disease (%)
1.2 (0.2-6.0)
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Male gender (%)
Courses of CS from the diagnosis (>2) (%)
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Mesalamine
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PUCAI, pediatric ulcerative colitis activity index; ASC, acute severe colitis; AZA, azathioprine; CS, corticosteroids.
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Figure 1
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Figure 2
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Figure 3
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S1590-8658(15)00179-6 http://dx.doi.org/doi:10.1016/j.dld.2015.01.156 YDLD 2821
To appear in:
Digestive and Liver Disease
Received date: Revised date: Accepted date:
20-12-2014 22-1-2015 28-1-2015
Please cite this article as: Aloi M, D’Arcangelo G, Capponi M, Nuti F, Vassallo F, Civitelli F, Oliva S, Pagliaro G, Cucchiara S, Managing paediatric acute severe ulcerative colitis according to the 2011 ECCO-ESPGHAN guidelines: efficacy of infliximab as a rescue therapy, Digestive and Liver Disease (2015), http://dx.doi.org/10.1016/j.dld.2015.01.156 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Managing paediatric acute severe ulcerative colitis according to the 2011 ECCOESPGHAN guidelines: efficacy of infliximab as a rescue therapy
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Marina Aloi, MD, PhD, Giulia D'Arcangelo, MD, Martina Capponi, MD, Federica Nuti, MD, Francesca Vassallo, MD, Fortunata Civitelli, MD, Salvatore Oliva, MD, Giuseppe
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Pagliaro, MD, and Salvatore Cucchiara, MD, PhD.
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Paediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University
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of Rome, Rome, Italy
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Corresponding author Salvatore Cucchiara, MD, PhD.
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Department of Pediatrics
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Paediatric Gastroenterology and Liver Unit Sapienza University of Rome,
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Viale Regina Elena 324 00161 Roma – Italy
tel +390649979324, fax +390649979325 [email protected]
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ABSTRACT Background: The effectiveness of medical therapy in paediatric acute severe colitis is
enrolled at Sapienza University of Rome between May 2010-12.
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scarcely described. We aimed to assess the efficacy of infliximab in children prospectively
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Methods: Clinical assessment and laboratory data were recorded at admission and at day 3 and 5. All patients received corticosteroids; infliximab was administered in refractory
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patients. Colectomy rate was assessed at 2-year follow-up.
Results: Thirty-one patients (mean age 10.6±4.9 years, 52% females) were included: 21
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responded to corticosteroids (68%), 10 were refractory and received infliximab (32%). Among the latter, 2 required urgent colectomy (20%); 80% responded, however 50% of
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these required elective colectomy during follow-up. Patients refractory to corticosteroids
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showed a significantly shorter interval from ulcerative colitis diagnosis to acute severe
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colitis compared to responders (7.4±9.6 vs. 23.1±21.6 months, respectively; p=0.01), and a higher rate of colectomy at follow-up (50% vs. 14%, respectively; p=0.007). More than 2
4.4).
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courses of corticosteroids before acute severe colitis were predictive of surgical need (OR
Conclusion: Despite its short-term efficacy, infliximab did not modify the long-term surgical rate of paediatric acute severe colitis in our cohort. Children with an early severe colitis commonly need a second-line therapy, whilst frequent courses of corticosteroids are predictive of a poor outcome.
Key words: PUCAI, colectomy, Paediatric ASC
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INTRODUCTION Paediatric ulcerative colitis (UC) is most often extensive and severe already at time of
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diagnosis. Some data report that up to 80% of children are affected by extensive colitis or pancolitis, whilst 25–30% will become corticosteroid-dependent by 1 year (1-5). The
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aggressive nature of paediatric UC is marked by the high frequency of acute severe
exacerbations of the disease, which occur in approximately 28% of children against 15%
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of adults (6). Paediatric acute severe colitis (ASC) is an emergent condition and an indication for hospitalization. Although in adults with UC several definitions have been
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used to identify an episode of ASC in clinical practice, in children a Paediatric Ulcerative Colitis Activity Index (PUCAI) of at least 65 points has been validated for the definition of
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this condition (7). Intravenous corticosteroids (CS) remain the mainstay of the treatment,
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since the trials of Truelove et al in 1955 and 1974 demonstrated their efficacy in avoiding
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colectomy in adults with ASC (8,9). Nevertheless, the rate of CS refractoriness is higher in children than in adults, therefore the choice of second line therapy is the greatest
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challenge in this setting (10). Cyclosporine and infliximab (IFX) have been proven to be effective in inducing a short-term remission in CS-refractory patients with ASC and colectomy is now reserved for patients who do not respond to these therapies (11). Several prospective trials conducted in adults have clearly demonstrated the short-term efficacy of both cyclosporine and IFX in avoiding colectomy in patients with ASC, with short-term remission rates of 70-80% for both drugs (11-13).While the long-term colectomy rate for patients who initially respond to cyclosporine reaches about 40%, very few data on long-term efficacy of IFX are available (14-16). A 19% colectomy rate at 1 year of IFX therapy has been reported in the only multicentre prospective study on paediatric ASC (7). Despite the few paediatric data available in this field, the 2011 ECCOESPGHAN guidelines for the management of ASC have provided very important 4 Page 3 of 22
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recommendations, especially regarding timing of introduction of rescue therapies (17). Primary objective of this study was to evaluate the effectiveness of IFX used as a secondline therapy in paediatric ASC treated according to the 2011 ECCO-ESPGHAN guidelines.
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As secondary outcomes we also sought to evaluate the short- and long-term colectomy rate in children with ASC and to identify clinical factors predictive of poor outcome at
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diagnosis.
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PATIENTS AND METHODS
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All children requiring hospitalization for an episode of ASC, defined as a PUCAI>65 (3), between May 2010 and May 2012 were consecutively included in the study. The study
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was conducted at the Gastroenterology and Liver Unit of Sapienza University of Rome (NCT02170714). The diagnosis of UC was established according to standard clinical,
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radiological, endoscopic and histological criteria (18). The study was approved by the
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ethical committee of the Hospital and written informed consent was obtained from all enrolled children and their parents. Clinical and demographic characteristics of all patients
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were recorded upon admission: age, sex, duration of disease, family history, extension of colitis according to Paris classification (19), previous steroid treatment and past and concomitant therapies. All patients with ASC were treated according to the ECCOESPGHAN 2011 guidelines (17). All therapies and nutritional data were recorded on standardized case report forms at baseline, at day 3 and 5 after starting first-line therapy, at introduction of second-line therapy and at discharge. Initial diagnostic evaluation included blood tests for electrolytes, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, complete blood count (CBC); cultures for enteric pathogens (Salmonella, Shigella, Campylobacter, and Escherichia coli), the collection of 3–5 stool samples for Clostridium difficile toxin; stool virology was performed only in the presence of fever or vomiting as well as with non-bloody diarrhoea. Normal diet was continued when 5 Page 4 of 22
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possible. Nutritional support via nasogastric tube was administered only in case of insufficient oral intake. In the presence of colonic dilatation (>40 mm or >56 mm in children aged>10 years) or when surgery was imminent, parenteral nutrition was started. All
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patients received intravenous methylprednisolone, 1.5 to 2 mg/kg/day to a maximum of 40 mg given in two divided daily doses. A sigmoidoscopy for the diagnosis of
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Cytomegalovirus (CMV) infection by tissue CMV-PCR was performed in children not-
responding to CS at day 3. PUCAI score was assessed daily to monitor the response to
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steroid treatment: a child with a PUCAI of >45 points on day 3 was prepared for second
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line therapy. According to ECCO-ESPGHAN guidelines, second-line medical therapy was initiate in case of a PUCAI >65 on day 5, and no patient underwent surgery after
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failure of first-line therapy (17). Corticosteroids were continued for an additional 2–5 days in children with a PUCAI of ≤ 60 and ≥ 35 points on day 5 and prepared to a second-
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line therapy in case of worsening. Infliximab was administered at the dose of 5 mg/kg iv at
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0, 2 and 6 weeks, after standard screenings. During follow up, at 6, 12, 18 and 24 months, patients were evaluated for indication to colectomy. The primary outcome was to assess
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the effectiveness of infliximab used as a second-line therapy in paediatric ASC treated according to the 2011 ECCO-ESPGHAN guidelines. Secondary end-points were to define the short- and long-term colectomy rate in children with ASC and to identify clinical predictive factors of poor outcome at the diagnosis. Statistical Analyses. All data were summarized and displayed as the mean±SD for continuous variables. Categorical data were expressed as frequencies and percentages. Comparison of groups was performed using Student's t test for unpaired data in two group comparison and one way analysis of variance (ANOVA) with Bonferroni's test for multiple group comparison. Chi square test with Fisher's correction was used to evaluate the differences for categorical variables wherever needed. A p value≤0.05 was considered significant. The Kaplan–Meier survival method was used to estimate the interval free from 6 Page 5 of 22
7
colectomy during follow-up. Differences between curves were tested using the Log-Rank test. To determine predictors of colectomy, descriptive unifactorial analysis was performed on predefined potential variables recorded at admission. Unadjusted logistic regression
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was used to obtain the corresponding odds ratios (OR) and 95% confidence intervals (CI). Assessment of the relation between response to CS and clinical variables was performed
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using the Pearson partial correlation for continuous variables, and the Spearman
correlation procedure was used for categorical variables. The GraphPad statistical
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package was used to perform all statistical evaluations (GraphPad Software, Inc., San
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Diego, CA).
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RESULTS
From May 2010 to May 2012, 31/110 patients followed for UC in our centre (28%) were
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hospitalized for an episode of ASC. Mean age at diagnosis was 10.6±4.9 years; 22% had
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a family history of IBD. All patients had a full exploration of the gastrointestinal tract performed at diagnosis, including a complete ileocolonoscopy under general anaesthesia
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or deep sedation. Pancolitis (E4) and extensive colitis (E3) were present in 32% (n=10) and 26% (n=8) of patients, respectively; 19% (n=6) had a left-sided colitis (E2) and 22.5%, (n=7) proctitis (E1). Patients developed ASC a median of 19.6±20.5 months after diagnosis of UC and 11 patients (35%) presented with ASC at time of diagnosis. The demographic, clinical and biological characteristics of patients are shown in table 1. Figure 1 shows the clinical outcomes of the entire cohort of patients. Of the 31 patients hospitalized for ASC who received intravenous corticosteroids, 21 responded to the first line therapy(68%): 11 showed a decrease of PUCAI score to 35 after 3 days of intensive CS treatment (53%), while 10 were slow responders and improved after 3-5 days of additional corticosteroid treatment (47%). The remaining 10 patients (32%) received IFX for CS refractoriness after a median of 5.8±1.1 days. Nine non-responders (90%) 7 Page 6 of 22
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underwent sigmoidoscopy after 3.1±1.2 days from admission; in 2 non-responders tissue PCR was positive for CMV and patients were treated with antiviral therapy. In both patients, IFX was started after 2.9±0.9 days due to clinical worsening. Of the 10 patients
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treated with IFX, 2 underwent urgent colectomy (20%) after the first infusion due to clinical worsening; 8 responded to the therapy (80%) and were regularly discharged after a
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median of 14.25±6.8 days. At 2-year follow-up, 50% (n=5) of the IFX-treated patients and 14% (n=3) of CS-responders underwent elective colectomy for chronic clinical relapses
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(p=0.007). The overall colectomy rate at maximum follow up was 32% (Figure 2). The
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cumulative probability at 2-year follow-up of a course without surgery after the episode of ASC was 77%, 74%, 67% and 67% at 6, 12, 18 and 24 months respectively. The
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cumulative probability of a course free from colectomy was significantly higher in patients responding to CS, than in those requiring second-line therapy (Log-rank test p=0.0003;
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Figure 3). At univariate analysis between CS-responders and refractory patients, no
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statistically significant difference was found for demographic, clinical and laboratory data except for the shorter interval from the diagnosis of ulcerative
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colitis to the episode of ASC (p= 0.04) and the higher colectomy rate at maximum follow-up (p=0.007) observed in CS-refractory patients (table 2). As a secondary outcome of this study we sought to identify clinical predictors of poor outcome at the diagnosis: patients needing colectomy required significantly more frequent courses of CS prior to the episode of ASC compared to those responding to medical therapy (OR 4.4; 95% CI 0.7-25), while no differences were found for laboratory values, gender, disease location, disease extension, therapy, mean PUCAI, serological markers and family history (table 3). There were no cases of toxic megacolon or death in this cohort of patients.
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DISCUSSION The current study focuses on the long-term outcome of Paediatric ASC treated according
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to the recent joint statement from ECCO, ESPGHAN, and the Porto IBD group of ESPGHAN. Until 2011 the management of children with ASC was based on adult
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recommendations, but, although the pathogenesis and most disease-related factors are
comparable to adult-onset disease, several variables make management of children with
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ASC peculiar. Paediatric UC is often extensive already at time of diagnosis and exhibits
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frequent acute exacerbations during its course (1-5); moreover treatment of children with ASC encompasses issues such as the long-term safety profile of medical treatment and
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the outcome of surgery, as well as factors related to the chronic inflammation itself (i.e. growth and pubertal development, bone density accrual and emotional development). All
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these considerations influenced the development of standardized paediatric guidelines,
escalation.
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aimed at allowing the effective monitoring of paediatric ASC and guide timely treatment
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In our study, we prospectively recruited children who experienced an episode of ASC, and treated them strictly according to the above-mentioned guidelines. Similarly to previous paediatric data (6,20,21), 28% (n=31) of the 110 patients with UC followed at our centre during the study period were hospitalized for an episode of ASC: Turner et al, in a population cohort study of 196 children with UC reported a rate of hospitalization for ASC of 28% (6). All patients received intensive CS treatment at admission, in agreement with the ECCO-ESPGHAN guidelines. In our series the response rate and refractoriness to CS (68 and 32%, respectively) was similar to that reported in previous adult (8,22) and paediatric studies (20,23). When evaluating clinical predictive factors of CS refractoriness, a shorter interval from the diagnosis of UC to the episode of ASC was significantly more common in children not-responding to first line therapy, thus suggesting 9 Page 8 of 22
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that the severity of the disease early after diagnosis is strictly related to the development of a more severe disease course. IFX was used as a rescue therapy in all patients who failed to respond to intravenous CS. Although the ECCO-ESPGHAN guidelines
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recommend the use of either IFX or calcineurin inhibitors as second line therapy, intravenous cyclosporine has been rarely used for ASC in our centre, and between 2010–
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2012 none of the patients received cyclosporine. Of the 10 non-responder children, 8
were successfully treated with IFX (80%) and avoided urgent colectomy, whilst 2 needed
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urgent surgery due to no response. However, at 2-year follow-up, 5 patients required
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elective surgery (50%) for chronic relapsing course (40% within 3 months from the episode of ASC).
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There are only scarce data on the efficacy of IFX as a rescue therapy in paediatric ASC (7). Adult studies suggest a high short-term efficacy in avoiding urgent colectomy (70-
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80%), whilst long-term prognosis is poorly described (24-26). Sjoberg et al. in a recent
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study evaluating 211 adults with ASC treated with IFX as a rescue therapy reported 71%, 64%, 59% and 53% avoided colectomy at 3, 12, 36 and 60 months, respectively (27).
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However, it is worth noting that a flexible IFX induction regimen was used and approximately 50% of patients received a single infusion, while in our study all patients received a standard three-dose induction regimen. Recently, a large study from the Italian Group for the study of Inflammatory Bowel Disease (IG-IBD) of 113 adult patients with steroid-refractory severe UC treated with a standard induction IFX regimen reported colectomy rates of 18.6% and 25.6% at 3 and 12 months respectively(28). Consistent with those data, we found a 12-month colectomy rate of 22%. Additional smaller studies have described colectomy rates ranging from 28% to 80% (24-26, 29-34). However, comparison of these populations is flawed by several factors, such as the definitions of CS refractoriness, different second-line therapies and small number of patients. In our series, 2 non-responder patients had positive tissue PCR for 10 Page 9 of 22
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CMV, and were treated accordingly. In both cases, antiviral treatment failed to demonstrate a favourable impact on clinical and biological outcomes, suggesting CMV to be an innocent bystander of clinical relapses, as reported in previous studies (35-38) .
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At 2-year follow-up the overall colectomy rate was 32%, similar to previous paediatric data (6,7,20). This seems to suggest that, even with the timely use of second-line IFX according
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to current guidelines, the natural history of acute exacerbations might not be modified by the current treatment strategies. However, these results need to be confirmed with larger,
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randomized controlled trials.
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Strikingly, the long term colectomy rate was higher in IFX-treated patients, than in those responding to intravenous CS; moreover, patients who underwent second-line therapy had
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a shorter course free from colectomy compared to those responding to CS. This difference was statistically significant but a type 1 error cannot be excluded due to the small number
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of IFX-treated patients in our study. Interestingly, frequent courses of CS therapy before
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the episode of ASC were associated with a poor outcome. We can speculate that CSrefractory patients, who didn’t achieve remission with IFX, have a more severe disease
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compared to CS-responsive patients: this can explain the shorter colectomy-free course in CS-not responders.
Our study has several strengths, as all patients were prospectively recruited and managed according to the ECCO-ESPGHAN guidelines and were followed for a relatively long period, providing valuable, real-life data on outcomes of ASC. Limitations could be the relatively small population of patients, for which we may have overlooked clinical variables related to a poor outcome. In conclusion, although its short-term effectiveness as a rescue therapy to avoid urgent colectomy in CS-refractory children, IFX, used at the dose and scheme recommended by the current guidelines, does not modify the long-term colectomy rate in ASC. A short interval from the diagnosis of UC to the episode of ASC seems to be related to CS therapy 11 Page 10 of 22
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failure, whilst frequent courses of CS before the episode of ASC are predictive of a poor outcome. Larger, multicentre, prospective studies are needed to confirm those data and to define the
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optimal therapeutic strategy of paediatric ASC, including the effect of IFX therapy
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optimization.
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34.Yamamoto-Furusho JK, Uzcanga LF. Infliximab as a rescue therapy for hospitalized patients with severe ulcerative colitis refractory to systemic corticosteroids. Dig Surg
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2008; 25: 383–6.
35.Delvincourt M, Lopez A, Pillet S, et al. The impact of cytomegalovirus reactivation
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Ther 2014;39:712-20.
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and its treatment on the course of inflammatory bowel disease. Aliment Pharmacol
36.Matsuoka K, Iwao Y, Mori T, et al. Cytomegalovirus is frequently reactivated and
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disappears without antiviral agents in ulcerative colitis patients. Am J Gastroenterol 2007; 102:331–7.
37.Leveque N, Brixi-Benmansour H, Reig T, et al. Low frequency of cytomegalovirus infection during exacerbations of inflammatory bowel diseases. J Med Virol 2010; 82: 1694–700.
38.de Saussure P, Lavergne-Slove A, Mazeron MC, et al. A prospective assessment of cytomegalovirus infection in active inflammatory bowel disease. Aliment Pharmacol Ther 2004; 20: 1323–7.
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FIGURE LEGEND
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Figure 1. Clinical outcomes of 31 children admitted for an episode of acute severe colitis.
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UC: ulcerative colitis; ASC: acute severe colitis; iv: intravenous; PUCAI: Paediatric ulcerative colitis activity index; CS: corticosteroids; IFX: infliximab.
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Figure 2. Cumulative probability of a disease course without colectomy following the episode of acute severe colitis (urgent and elective colectomy are considered).
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Figure 3. Cumulative probability of a disease course free from colectomy in children with
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acute severe colitis who responded to intravenous steroids (Responders) and in steroid-
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refractory patients (Non-Responders).
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Table 1. Clinical characteristics of 31 patients admitted for an episode of acute severe colitis. 10.6±4.88
Female gender
16 (52%)
Mean BMI ± SD
17±2.8
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Mean age ± SD (years)
Location of disease at diagnosis, n(%)
7 (22.5%)
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E1
6 (19%)
E2
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E3 E4
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Mean Hb g/dl ±SD Mean Albumin g/L ± SD
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Mean CRP mg/L ± SD Mean ESR mm/h ± SD
Family history, n(%)
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p-ANCA, n(%)
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Extraintestinal manifestation, n(%)
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Mean PUCAI ± SD
8 (26%) 10 (32%) 10.9±1.4 35.7±13 14.2±21.5 36.63±23.43 71±10 8 (26%) 5 (16%) 4 (13%)
Mean time from diagnosis to ASC ± SD (months)
19.58±20.5
ASC at the diagnosis of UC (%)
11 (35%)
Therapy prior to the episode of ASC (%) Mesalamine
20 (64.5%)
Steroids
18 (58%)
AZA
9 (29%)
BMI, Body Mass Index; Hb, Hemoglobin; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PUCAI, pediatric ulcerative colitis activity index; p-ANCA, Perinuclear Anti-Neutrophil Cytoplasmic Antibodies; ASC, acute severe colitis, AZA: azathioprine.
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Table 2. Univariate analysis of clinical and laboratory variables in Responders and Nonresponders to corticosteroids Responders,
Non-Responders, OR (95% CI)
p
n=10
Female gender (%)
12 (57%)
5 (50%)
Mean age ± SD (years)
11.61±5.056
10±5.59
6 (28.5%)
1(10%)
6 (28.5%)
0
4 (19%)
4 (40%)
0.3 (0.07-2.0) 0.38
5 (24%)
5 (50%)
0.3 (0.06-1.5) 0.22
E2 E3 E4
18.2±39.5
Mean ESR mm/h ± SD
41.73±29.65
Mean PUCAI ± SD
72±15
pANCA, n(%)
1 (5%)
Family history, n(%)
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3.6 (0.3-34) 0.31
8.8 (0.4-173) 0.14
30.3±14.32
1.9 (0.3-2.7) 0.73
71±20
0.9 (0.4-6.1) 0.92
3 (30%)
0.1 (0.01-1.3) 0.08
3 (14%)
5(50%)
0.1 (0.02-0.9) 0.07
23.121.6
7.49.6
7.3 (1.2-42.8) 0.01
7 (33%)
4 (40%)
2.6 (0.4-15) 0.90
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ASC at the diagnosis of UC
0.4 (0.2-5.6) 0.42
1.2 (0.5-4.3) 0.51
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ASC ± SD (months)
0.76
9.38±13.6
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Mean CRP mg/L ± SD
Mean time from diagnosis to
1.3 (0.2-6)
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E1
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Location of the disease,n (%)
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n=21
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PUCAI, pediatric ulcerative colitis activity index; p-ANCA, Perinuclear Anti-Neutrophil Cytoplasmic Antibodies; ASC, acute severe colitis; UC, ulcerative colitis.
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Table 3. Clinical variables at the diagnosis in patients requiring surgery compared to those responding to medical therapy. Colectomy, n=10 No Colectomy, n=21 OR (95% CI) 5 (50%)
9 (43%)
Mean age ± SD
8.7 ± 5.7
11.3 ± 4.3
E1
2 (20%)
5 (24%)
E2
1 (10%)
5 (24%)
0.3 (0.3-3.5)
E3
3 (30%)
5 (24%)
1.3 (0.2-7.3)
E4
4 (40%)
CRP (>10 mg/L)
6 (60%)
ESR (>25 mm/h)
5 (50%
Albumin (65
7 (70%)
ASC at the diagnosis Disease extension, n(%)
us 12 (58%)
1.1 (0.2-5.2)
11 (52%)
0.9 (0.2-4.1)
9 (43%)
1.3 (0.2-6.0)
13 (62%)
1.4 (0.2-7.2)
4 (40%)
6 (28.5%
1.6 (0.3-8.0)
2 (20%)
8(38%)
0.4 (0.4-2.6)
6 (28.5%)
1.0 (0.2-5.5)
8 (80%)
11 (38%)
4.4 (0.7-25)
7 (70%)
15 (71%)
0.9 (0.1-4.8)
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1.6 (0.3-8.0)
3 (30%)
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AZA
1.0 (0.1-6.5)
6 (29%)
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Therapy before ASC, n(%)
0.2 (0.12-5.9)
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Location of the disease (%)
1.2 (0.2-6.0)
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Male gender (%)
Courses of CS from the diagnosis (>2) (%)
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Mesalamine
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PUCAI, pediatric ulcerative colitis activity index; ASC, acute severe colitis; AZA, azathioprine; CS, corticosteroids.
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Figure 2
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Figure 3
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