197 Developmental Period Medicine, 2016;XX,3 IMiD, Wydawnictwo Aluna Monika Meglicka, Michał Szczepański, Maciej Dądalski, Jarosław Kierkuś CLINICAL EVALUATION OF CHILDREN WITH ULCERATIVE COLITIS TREATED BETWEEN 2013 2015 OWN EXPERIENCE OCENA KLINICZNA DZIECI Z WRZODZIEJĄCYM ZAPALENIEM JELITA GRUBEGO LECZONYCH W LATACH 2013 2015 DOŚWIADCZENIA WŁASNE Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children s Memorial Health Institute Abstract Aim: Evaluation of the changes in the endoscopic, laboratory and clinical status in children with ulcerative colitis (UC) with regard to the duration of the disease. Material and methods: 91 children with UC were involved in the study. Each of them had colonoscopy and their laboratory values were tested. We assessed the colonoscopy results by the Paris classification and by the Baron score. Moreover, demographic, clinical and anthropometric data were collected. We divided our patients into five subgroups depending on the duration of the disease. In order to assess the changes in the variables, we conducted the Mann-Whitney U test. Results: The most numerous group were patients whose disease had lasted between 1 and 2.5 years. At the time of assessment 39.6% did not have inflammation lesions in the mucosa and 60.4% were in sustained clinical remission. At the time of diagnosis 55% of the participants had pancolitis or extensive colitis and 66% had ulcers or ulcerations in the mucosa. We found a statistically significant decrease in the extension of the disease between the patient at diagnosis and the patient during the first year after diagnosis, with p=0.049, but there were no statistically significant differences in the activity of the inflammatory changes between those groups. No significant changes were found in laboratory values, apart from those pertaining to faecal calprotectin (FC). During our study 95% of the patients were exposed to mesalazin, 66% to corticosteroids, 57% to immunosuppressants and 10% to biologics. 20% of our patients were exposed to steroids more than once. Conclusions: The changes observed during colonoscopy in children with UC have a widespread localization and varied aggression. With the duration of the disease, inflammatory lesions tend to acquire more and more of the surface in the colon, but are not characterized by a progression of their activity. The issue requires further well-designed studies. Key words: ulcerative colitis, children, colonoscopy Streszczenie Cel pracy: Ocena zmian endoskopowych, laboratoryjnych i stanu klinicznego u dzieci z wrzodziejącym zapaleniem jelita grubego (UC) w trakcie leczenia z uwzględnieniem czasu trwania choroby. Materiały i metody: Do badania włączono 91 dzieci z UC. Każde z nich miało wykonaną kolonoskopię oraz badania laboratoryjne. Badania endoskopowe były oceniane w skali Paryskiej oraz skali Barona. Zebrano również dane demograficzne, kliniczne i antropometryczne. Naszych pacjentów podzielono na pięć podgrup w zależności od długości trwania choroby. W analizie użyto testu U Mann-Whitney. Wyniki: Najliczniejszą grupą byli pacjenci w okresie pomiędzy rokiem a 2,5 od postawienia rozpoznania. W momencie oceny 39,6% pacjentów nie miało zmian zapalnych w śluzówce jelita a 60,4% pozostawało w remisji klinicznej. W chwili rozpoznania 55% pacjentów miało zapalenie
198 Monika Meglicka et al. obejmujące całe lub większość jelita grubego, a 66% pacjentów w obrębie błony śluzowej miało owrzodzenia i nadżerki. Znaleźliśmy istotne statystycznie skrócenie zasięgu zmian zapalnych pomiędzy grupą pacjentów w momencie rozpoznania a pacjentami poniżej roku trwania choroby z p=0,049, ale nie znaleziono istotnej różnicy w aktywności zmian zapalnych między tymi grupami. Nie znaleziono istotnych zmian w wynikach badań laboratoryjnych skategoryzowanych według długości trwania choroby poza kalprotektyną w kale. W trakcie trwania badania 95% pacjentów było leczonych mesalazyną, 66% było narażonych na kortykosteroidy, 57% na immunosupresanty, a 10% na leki biologiczne. 20% naszych pacjentów przeszło kurację steroidami więcej niż raz. Wnioski: Zmiany stwierdzane w jelicie grubym u dzieci z UC charakteryzują się dużym zasięgiem i agresywnością. Wraz z długością trwania choroby zmiany zapalne mają tendencję do obejmowania coraz rozleglejszych powierzchni jelita grubego, jednak nie charakteryzują się progresją ich aktywności. Zagadnienie wymaga dalszych dobrze zaplanowanych badań. Słowa kluczowe: wrzodziejące zapalenie jelita grubego, dzieci, kolonoskopia DEV PERIOD MED. 2016;XX,3:197 204 INTRODUCTION Ulcerative colitis (UC) is the most common inflammatory bowel disease (IBD) in children [1] The incidence of UC in the paediatric population worldwide is increasing [2]. To improve the diagnostic process and patient management, as well as to understand the disease better we must closely look into its natural history. The disorder is common enough in children for most paediatricians and other paediatric clinicians to encounter children with UC in their general practice. 10 20% of the patients with IBD present the first signs of the disease before the age of 18 years [3]. Therefore, knowledge of the laboratory and clinical characteristics of UC patients is helpful in rapid diagnosis, as well as in monitoring the disease. There are several methods for monitoring UC activity. Some are non-invasive, for example the paediatric ulcerative colitis activity index (PUCAI) and laboratory assessment, others are more complicated, such as endoscopic evaluation. Nowadays new non-invasive biomarkers have been developed. The most popular, cheap and quick one is faecal calprotectin (FC). Szczepański et al. showed that FC is closely related to the state of mucosa in paediatric patients with IBD [4]. Due to the chronic character of the disease, both the patients and their parents have many questions about possible therapies, monitoring procedures and outcomes. This study gives a simple look into the natural history of UC and provides answers to these questions. AIM Evaluation of the changes in the endoscopic, laboratory and clinical status in children with ulcerative colitis (UC) in the course of the duration of the disease. MATERIAL AND METHODS Pa ents The study involved 91 children with UC (45 females, 46 males, median age 14.79) enrolled in our Institute between 2013 and 2015 as in- and out-patients. We divided our patients into five subgroups depending on the duration of the disease: Patient characteristics are presented in Table I. Table I. Characteris cs of study par cipants (n=91). Tabela I. Charakterystyki pacjentów biorących udział w badaniu (n=91). Dura on Czas trwania choroby pa ents at diagnosis pacjenci w momencie diagnozy pa ents <1 year pacjenci <1 roku 1 year<pa ents<2.5 years 1 rok<pacjenci<2,5 roku 2.5years<pa ents<5 years 2,5 roku<pacjenci<5 lat 5 years<pa ents 5 lat<pacjenci Number Liczba Females Dziewczynki Males Chłopcy Age Wiek 9 (9.9%) 3 (33.3%) 6 (66.7%) 15.35 20 (21.9%) 10 (50%) 10 (50%) 13.41 27 (29.7%) 12 (44.4%) 15 (55.6%) 14.78 20 (21.9%) 13 (65%) 7 (35%) 15.69 15 (16.5%) 7 (46.7%) 8 (53.3%) 15.79
Clinical evaluation of children with ulcerative colitis treated between 2013-2015 199 Methods Each of the patients had colonoscopy and laboratory tests performed, such as the erythrocyte sedimentation rate (ESR), haematocrit (HT), platelets (PLT), C-reactive protein (CRP), and FC within a week before measurement. To assess the extension of the inflammation in gut mucosa we used the Paris classification and as the definition of full mucosal healing we used 0 [5]. Moreover, we used the Baron score to assess the activity of inflammation lesions during endoscopy [6]. The level of FC was assessed with the Bühlmann Quantum Blue Calprotectin test. Quantum Blue Calprotectin is an immunologic test of double-binding which uses two types of mouse monoclonal antibodies (mab) which are highly specific to human calprotectin. The test is a disposable cartridge which allows FC assessment within only about 45 minutes. After assessment, the outcome is registered with a reader [7]. All the patients had their body mass index (BMI) defined as being in clinical remission [8]. We collected demographic and anthropometric data from all the patients, such as: age at diagnosis, age at time of assessment, gender, previous and actual therapies for UC, weight and height. Sta s cs All the statistics was performed by Statistica 12 (StatSoft, Tulusa, OK, United States) and Real Statistics Resource Pack (release 4.4.3, copyright (2013-2015) Charles Zaiontz, www.real-statistics.com) software. Quantitative variables were tested for normality by the Shapiro-Wilk test. Those with normal distribution were presented as means and standard deviations and others with medians and quartiles. Binary variables were shown as numbers and percentages. The Mann-Whitney U test was used to compare quantitative variables. The threshold of statistical significance was set at p RESULTS Endoscopic characteris cs A statistically and clinically significant decrease in the area of the inflamed bowel was observed between patients at diagnosis and patients with under 1 year of the disease duration, with p=0.049. However, the severity of inflammatory lesions between those two groups did not change in the statistical significance range. Nevertheless, when we compared patients at diagnosis and patients with a duration of the disease of over 5 years, the statistically and clinically significant decrease of the Baron score was found to be p=0.0009. Looking closer at figure 1 we can see how the extension of the disease differed between groups. At the time of diagnosis 44% of the patients had pancolitis and 11% had extensive colitis in comparison to patients after 5 years of the disease s duration, more than 50% of whom were in remission and 34 % had pancolitis or extensive colitis. During the assessment 39.6% of our patients did not have inflammation lesions in mucosa. Figure 2 shows pie charts of the study s participants with the Baron score categorized by the duration of the disease. In the Baron score we observed similar trends as in the Paris classification. At diagnosis more than 60% of the patients presented with ulcers and ulcerations in their mucosa. In comparison to patients with more than 5 years of the disease s duration, only 20% had ulcerations and 53% were in endoscopic remission. Laboratory characteris cs We found a statistically and clinically significant decrease of FC levels between patients at diagnosis and patients below 1 year of the disease s duration, with p=0.04. Furthermore, we found a statistically significant increase of CRP levels between patients from 2.5 years to 5 years of disease duration and patients with over 5 years of disease duration, with p=0.03, but this was not clinically significant. Table II presents the laboratory characteristics of patients. Figure 3 shows histograms of FC levels categorized by the duration of the disease. As we can see in Figure 3, the median FC level dramatically decreased between the group of patients at diagnosis and in other groups. Not only the median but also the interquartile range is much higher in the group of patients at diagnosis than in other groups. The duration of UC does not have an impact on the rest of the laboratory values. Patients presented slightly elevated or even normal values of CRP and ESR, while HT and PLT were predominantly in normal ranges. Clinical characteris cs Interestingly, we found a statistically and clinically significant increase in the BMI of patients with under 1 year of disease duration in comparison to those between 1 and 2.5 years of disease duration. Other points in time did not show statistically significant changes. The histograms of BMI are shown in figure 4. 60.4% of our patients sustained clinical remmission during assesment, based on PUCAI. As it was expected, the PUCAI achieved a statistically and clinicaly significant decrease between newly-dignosed patients and patients under 1 year of disease duration, with p=0.005. As shown in figure 5, other time points also achieved statistically and clinically lower levels of PUCAI than at the time of diagnosis. At the time of diagnosis 22.2% of the children were in clinical remission based on PUCAI in comparison to other groups, where over 50% or even 70% of the patients were in sustained clinical remission, similarly to the group between 1 to 2.5 years of disease duration. Table III shows the participants clinical characteristics. Demographic and therapeu c characteris cs The median age at diagnosis in our group of patients was 11.62 (9.16-14.25) years. The gender groups were almost equinumerous, with 49% of females and 51% of males. Our most numerous group from the point of view of disease duration were patients between 1 and 2.5 years of disease duration, including about 30% of our patients. At the diagnosis stage we identified only 9 patients, which accounted for 10% of our study population. Table I shows the demographic data of the study participants.
200 Monika Meglicka et al... Fig. 1. Pie charts with the Paris classifica on of inflammatory lesions categorized by the dura on of the disease. Ryc. 1. Wykresy kołowe opisujące rozkład klasyfikacji paryskiej z uwzględnieniem długości trwania choroby. The following numbers determine the extension with the percentage distribu on of pa ents in different periods of the disease: 0 no inflammatory lesions; 1 proc s; 2 le side coli s (distal to splenic flexure); 3 extensive coli s (distal to hepa c flexure); 4 pancoli s (proximal to hepa c flexure). Cyframi oznaczono zasięg zmian zapalnych z procentowym rozłożeniem pacjentów w poszczególnych okresach trwania choroby: 0 bez zmian zapalnych; 1 zmiany zapalne ograniczone do odbytnicy; 2 zmiany zapalne sięgające do zagięcia śledzionowego; 3 zmiany zapalne sięgające do zagięcia wątrobowego; 4 zmiany zapalne obejmujące całe jelito grube. Table II. Laboratory characteris cs of study par cipants. Tabela II. Charakterystyki wyników badań laboratoryjnych uczestników badania. Dura on Czas trwania choroby FC (µg/g) CRP (mg/l) ESR (mm/h) HT (%) PLT (10 3 /mm) pa ents at diagnosis pacjenci w momencie diagnozy 1800 (554-1800) 0.17 (0.1-0.74) 14 (9-26) 32.5 (29.9-37.2) 270 (238-366) pa ents<1 year pacjenci <1 roku 257.5 (66-547.5) 0.1 (0.03-0.57) 12 (5-23) 37.5 (35.3-39.3) 306 (243-408) 1 year<pa ents<2.5 years 1 rok<pacjenci<2,5 roku 113 (52-336) 0.09 (0.03-0.47) 12 (6-20) 38.8 (37.3-40.9) 291 (233-341) 2.5 years<pa ents<5 years 2,5 roku<pacjenci<5 lat 135.5 (48-352) 0.03 (0.03-0.12) 8 (3-13) 38.8 (37-41.3) 283 (246-363) 5 years<pa ents 5 lat<pacjenci 176 (40-743) 0.17 (0.04-0.42) 11 (2-30) 37.8 (34.4-44.6) 310 (232-359)
Clinical evaluation of children with ulcerative colitis treated between 2013-2015 201.. Fig. 2. Pie charts of the Baron score categorized by the dura on of the disease. Ryc. 2. Wykresy kołowe opisujące rozkład punktacji w skali Barona z uwzględnieniem długości trwania choroby. The following numbers determine the aggressiveness of inflammatory lesions in the Baron score with the percentage distribu on of pa ents in different periods of the disease: 0 no inflammatory lesions; 1 erythema, decreased vascular pa ern; 2 marked erythema, loss of vascular pa ern, mucosal friability; 3 spontaneous bleeding; ulcers. Cyframi oznaczono agresywność zmian zapalnych określoną według skali Barona, z procentowym rozłożeniem pacjentów w poszczególnych okresach trwania choroby: 0 bez zmian zapalnych; 1 zaczerwienienie, zniesienie rysunku naczyniowego; 2 zaczerwienienie, zniesienie rysunku naczyniowego, krwawliwość kontaktowa; 3 spontanicznie krwawienie, owrzodzenia. Fig. 3. Histograms with faecal calprotec n in children with ulcera ve coli s categorized by the dura on of the disease. Ryc. 3. Histogramy przedstawiające rozkład kalprotektyny w kale u pacjentów w poszczególnych okresach choroby. Fig. 4. Histograms with body mass index categorized by the dura on of the disease. Ryc. 4. Histogramy przedstawiające indeksy masy ciała skategoryzowane w stosunku do czasu trwania choroby.
202 Monika Meglicka et al. Fig. 5. Histograms with the paediatric ulcera ve coli s ac vity index categorized by the dura on of the disease. Ryc. 5. Histogramy przedstawiające pediatryczną skale aktywności wrzodziejącego zapalenia jelita grubego skategoryzowane w stosunku do długości trwania choroby. of our findings are likely to be important and pertinent both to basic research and to clinical practice, and may be useful in patient counselling. We have demonstrated that the phenotype of childhood-onset UC is characterized by extensive anatomic involvement (extensive colitis and pancolitis) and aggressive lesions (ulcers and ulcerations). These observations are in line with other paediatric studies [9-12]. However, we did not observe as high a rate (>80%) of extensive colitis and pancolitis at diagnosis as in Kugathasan s or Van Limbergen s study [13, 14]. This difference could be due to our small group of patients at the time of diagnosis. In order to investigate this problem further, more prospective populationbased cohort studies are needed. Our findings on the remission rate after 5 years from the diagnosis were the same as reported by Malaty et al. [11]. The majority of population-based cohort studies have shown progression of the disease s extension in children. This is closely related to our finding that more patients had pancolitis Table III. Clinical characteris cs of the study par cipants. Tabela III. Charakterystyki kliniczne uczestników badania. Dura on Czas trwania choroby pa ents at diagnosis pacjenci w momencie diagnozy pa ents<1 year pacjenci <1 roku 1 year<pa ents<2.5 years 1 rok<pacjenci<2.5 roku 2.5 years<pa ents<5 years 2.5 roku<pacjenci<5 lat 5 years<pa ents 5 lat<pacjenci BMI PUCAI 19.27 (16.23-20.83) 45 (15-60) 18.16 (16.04-19.63) 0 (0-20) 21.15 (17.82-22.31) 0 (0-10) 20.34 (16.23-23.03) 0 (0-12.5) 19.65 (16.89-21.68) 0 (0-25) Table III shows the clinical characteris cs of the par cipants. The parameters are presented as medians, interquar le ranges are presented in brackets; BMI body mass index; PUCAI- paediatric ulcera ve coli s ac vity index. W Tabeli III są pokazane charakterystki kliniczne uczestników. Parametry są przedstawione jako mediany, w nawiasach umieszczono zakres rezstępu międzykwartylowego; BMI indeks masy ciała; PUCAI- pediatryczna skala aktywności wrzodziejącego zapalenia jelita grubego. Over 2 years of observation 95% of our patients were exposed to 5-aminosalicylates. More than two-thirds received corticosteroid therapy in the past, and about 20% of all the patients were exposed to steroids more than once. More than a half of the children were treated with immunosuppressants like azathioprine or cyclosporine during assessment and 57% had previously been exposed to them. Only 10% of the study population were exposed to anti-tnf therapy during our 2 years of observation. DISSCUSION The present study represents a simple view of the natural history of ulcerative colitis in children. A number after 5 years from diagnosis than those at diagnosis (57% vs 44%). Although we did not conduct a populationbased cohort study, our observations about endoscopic evaluation in the course of disease duration are similar to those reported by other authors [9-15]. Interestingly, none of the previously cited articles assesses the Baron score depending on disease duration. We observed that patients below 1 year of disease duration have more aggressive lesions than those 5 years from diagnosis, but those results need to be proven by other studies. Moreover, we found that the level of FC in our participants was higher at the time of diagnosis than at other time points. It was shown by D Haens et al.
Clinical evaluation of children with ulcerative colitis treated between 2013-2015 203 that the FC level is correlated with endoscopic disease activity, therefore our observation can be explained by endoscopic findings [4, 16]. Furthermore, having analysed our data we can say that the FC level depends not only on the disease activity defined by the Baron score, but also on the extension of the disease. These results are the baseline for further analysis. Similarly to Malaty et al. we demonstrated that BMI was lowest in patients with under one year of the disease s duration and had a tendency to increase at other time points. 11 The majority of our participants received 5-aminosalicylates, in accordance to recent guidelines from the European Crohn s and Colitis Organisation and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition that recommend 5-aminosalicylates as first line therapy in the induction of response and remission, as well as in maintenance [17]. Similarly to Fumery et al., we found that overall about two thirds of our patients were exposed to corticosteroids and about 20% need to receive the induction therapy more than once [15]. In comparison to Malaty s study we observed that more than a half of our study population was exposed to immunosuppressants, furthermore the same trend was observed by Fumery et al [11, 17]. Overall only 10% of the patients received biologic therapy, although 5 years after diagnosis 57% still had pancolitis. This observation is in accordance with the findings of Fumery at al [17]. This low percentage of biologics composition in the treatment of paediatric UC patients depends on national and financial arrangements. The downside of our study was the lack of a follow-up period, so the observations were made on independent groups, which may involve other risk factors at the beginning of the disease. Moreover, we also did not examine our population regarding colectomy or the rate of other surgical interventions. Finally, we did not investigate extra intestinal manifestations of the disease and neoplasm incidence in our participants. Those limitations did not allow us to conclude long-term outcomes in our patients. However, the analysis of the current variables provided several important findings regarding the natural history of UC in children. While it is hard to predict how, the natural history of UC in children is going to change when the financial and national boundaries are crossed and biologic therapies are more available, as well as new biologic agents are introduced. More prospective cohort population-based studies with a long follow-up period are needed. CONCLUSIONS The changes observed during colonoscopy in children with UC have a widespread localization and aggressiveness. 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204 Monika Meglicka et al. 16. D Haens G, Ferrante M, Vermeire S, et al. Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2218-2224. 17. Ruemmele FM, Turner D. Differences in the management of pediatric and adult onset ulcerative colitis--lessons from the joint ECCO and ESPGHAN consensus guidelines for the management of pediatric ulcerative colitis. J Crohns Colitis. 2014;8(1):1-4. Author s contributions/wkład Autorów According to the order of the Authorship/Według kolejności Conflicts of interest/konflikt interesu The Authors declare no conflict of interest. Autorzy pracy nie zgłaszają konfliktu interesów. Received/Nadesłano: 08.06.2016 r. Accepted/Zaakceptowano: 21.09.2016 r. Published online/dostępne online Address for correspondence: Monika Meglicka Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics The Children s Memorial Health Institute Aleja Dzieci Polskich 20 04-730 Warsaw, Poland tel. +48 (22) 815-73-84 e-mail: m.meglicka@ipczd.pl