What Is Known
- Predicting short- and long-term prognosis would be essential in the management of inflammatory bowel disease.
- Some studies described that initial CRP is associated with short- and long-term disease course.
- Relation of paediatric inflammatory bowel disease activity indices and prognosis has not been investigated.
What Is New
- Initially, half of the patients had moderate-to-severe disease; this rate decreased to <10% after 1 year.
- Initially, elevated CRP was associated with the need of immunomodulator at 1 year in Crohn disease and ulcerative colitis.
- The Pediatric Crohn's Disease Activity Index at baseline was associated with the need of aggressive therapy.
A marker for prediction of disease progression and relapses would be beneficial in the management of paediatric inflammatory bowel disease (IBD). The ideal marker should be noninvasive and could reliably identify patients at risk for relapse and for surgical interventions, who need initially more aggressive treatment.
Numerous laboratory markers have been evaluated for diagnostic and differential diagnostic purposes, for the assessment of disease activity, the risk of complications, and for the prediction of relapse with some success (1). Essential laboratory parameters C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), platelet count, and albumin have been described to correlate with disease activity in both ulcerative colitis (UC) and Crohn disease (CD). It is also widely reported that CD is associated with a stronger response of laboratory markers, whereas only severe UC tends to present with abnormal laboratory markers (1).
CRP has been shown to be a good marker for evaluating disease course in a number of diseases (eg, cardiovascular diseases), and some studies investigated its role in IBD. Consigny et al (2) analysed a number of biological markers (complete blood count, CRP, ESR, etc) of short-term relapse. Seventy-one adults with CD in remission were followed up, and biological markers were checked every 6 weeks. Two markers were described to predict relapse: CRP >20 mg/L and ESR >15 mm. The negative predictive value was 97%. Furthermore, a Hungarian study (not nationwide study, adult patients) showed that positive (>10 mg/L) high-sensitivity CRP (hs-CRP) at diagnosis is a predictor of short- and medium-term clinical relapses during follow-up. Kiss et al (3) analysed the data of 260 adult patients with CD and found that elevated hs-CRP at diagnosis was associated with subsequent need for azathioprine and infliximab (IFX). In addition, elevated hs-CRP at diagnosis was an independent predictor for relapse at 12 months in patients who were in clinical remission.
Disease activity indices (Pediatric Crohn's Disease Activity Index [PCDAI] and Pediatric Ulcerative Colitis Activity Index [PUCAI]) as noninvasive tools for follow-up have also been developed (4,5). Although some clinical trials applied these indices (6,7), there are only a limited number of reports available with activity indices in a population-based paediatric cohort with IBD (8,9).
Despite the increasing number of epidemiological studies conducted in paediatric IBD, until now the prospective assessment of activity indices at diagnosis and during the first year of the disease from a nationwide study is missing. The relation between laboratory parameters, disease activity indices, and disease phenotype (location, age, and familiarity) and their role in short- and long-term outcomes has not been established. Therefore, our primary aim was to investigate the association between disease activity indices, laboratory parameters, disease phenotype, and short-term outcomes in the Hungarian Pediatric IBD Registry (HUPIR).
The associations among baseline characteristics, initial disease activity indices, laboratory parameters, and disease phenotype of newly diagnosed paediatric patients with IBD were assessed. In addition, the relation between outcome at 1-year follow-up (disease activity indices, surgery, and immunosuppressive and biological therapy) and initial parameters, as baseline disease activity indices, disease location, phenotype, and laboratory parameters were also investigated. We analysed retrospectively the data of patients recorded from the January 1, 2008, to December 31, 2010, (36 months) recorded in the HUPIR.
HUPIR was founded by the Hungarian Pediatric Gastroenterology Society in 2007. Twenty-seven institutes participate (4 academic centres in Hungary; 17 tertiary hospitals, where paediatric gastroenterology is present; 4 secondary hospitals with paediatric gastroenterologists; the rest are paediatric gastroenterology outpatient offices) in this prospective registry to ensure nationwide coverage (10). Private paediatric gastroenterology offices with endoscopy are not available in Hungary. Furthermore, coordinators are in contact with the main adult IBD centres to find adolescents diagnosed in adult centres.
Questionnaires are filled out by gastroenterologists who made the IBD diagnosis. Newly diagnosed patients with IBD <18 years are reported. Exclusion criteria were age at diagnosis >18 years, missing information on ileocolonoscopy and ileocolonic histology, and a diagnostic workup without endoscopic, histologic, and radiologic abnormalities. Coordinators contact monthly the centres via email or phone calls to ask about newly diagnosed patients and actual follow-up data. The questionnaires are collected via email and double-checked by the leader of the coordinators (K.E.M.) and the leader of the HUPIR (G.V.). Age, sex, weight, height, presenting symptoms, concomitant diseases, extraintestinal manifestations (EIM), familiarity (first degree), and complications are recorded. Furthermore, the characteristics of diagnostic procedures including laboratory findings, endoscopy, radiology, histology, disease activity index, surgical interventions, and initial treatment are documented. Data are obtained anonymously. Every child is reevaluated at 3 and 12 months after diagnosis and followed-up yearly. The confirmation of diagnosis, current medical therapy, and previous surgical interventions are reported by physicians at yearly follow-ups. Disease activity indices and anthropometric data are also requested on the follow-up survey.
The diagnosis of IBD is based on the porto criteria (11). Disease activity at baseline is determined using validated multi-item disease activity indices, PUCAI and PCDAI (4,5). The location and phenotype of disease are based on the Paris Classification criteria (12). The site of the disease is evaluated only for those patients who underwent a complete bowel investigation (colonoscopy, esophagogastroduodenoscopy, and/or small and large bowels were visualized for CD; large bowel was visualized up to the cecum for UC). Therapeutic strategy in paediatric IBD in Hungary is based on international guidelines.
The age- and sex-specific demographical data for calculating incidence were obtained from the Hungarian Central Statistical Office. The population, a total of 10.04 million, is predominantly white in Hungary. In 2009, 1.8 million of the inhabitants were <18 years old.
We analysed the data of patients recorded from January 1, 2008 to December 31, 2010 (36 months). Disease activity indices, laboratory parameters (iron, CRP, platelets, and hematocrit), and disease phenotype (age, sex, familial disease, EIM, location, and behaviour) were recorded. Furthermore, the association between initial activity indices, laboratory parameters, and the later need for immunomodulators, biologicals, and bowel resection at 1 year were assessed. CRP >10 mg/L and platelets >450 g/L were regarded as elevated. Iron level was regarded abnormal if it was <7 mmol/L. Abnormal hematocrit meant <34%. The study was approved by the national ethical committee.
Our data did not follow the Gaussian distribution based on Kolmogorov-Smirnov test. Therefore, data are expressed as median and interquartile range, and nonparametric tests were used. Univariate comparisons were applied among different subgroups (sex, age groups according to Paris Classification, familial disease, EIM, involvement of terminal ileum, and upper gastrointestinal involvement) with regard to laboratory parameters and activity indices. Laboratory parameters were categorized as those with normal and abnormal values. The disease activity indices were categorized as recommended in the literature (4,13). The Mann-Whitney test was applied for binomial comparisons. Association between >2 groups of categorical data was evaluated by the χ2 test. To assess the relation between paired activity indices at diagnosis and at 1-year, the Wilcoxon rank sum test was applied. We performed the receiver operator characteristic curve analysis to identify the best cutoff for continuous variables.
A P < 0.05 was considered as significant. Statistical analyses were performed using the SPSS statistical package, version 17.0 (SPSS Inc, Chicago, IL) for Windows.
A total of 421 children with IBD were diagnosed between January 1, 2008 and December 31, 2010, in Hungary. Two-hundred sixty-six had CD (63.2%); the number of children with UC was 124 (29.4%); 31 patients (7.4%) were classified as having inflammatory bowel disease type unclassified. Demographic and clinical characteristics of patients are shown in Table 1. A total of 103 patients with UC (83%) and 240 (90.2%) patients with CD had available data regarding disease activity, therapy, and surgery at the first-year follow-up.
Disease Activity at Diagnosis and at 1-Year Follow-Up
Disease activity indices were available in 96.4% of the patients (376/390 patients with UC and CD) at diagnosis and in 93.5% of the patients (343/376 patients with CD and UC) at 1-year follow-up. Of these, 124 of 256 patients with CD (48%) and 67 of 120 children with UC (57.3%) had moderate-to-severe disease at onset (PCDAI >31, PUCAI ≥35). Younger patients with CD (A1a) experienced lower disease activity at diagnosis than patients >10 years (A1b) (median PCDAI 20 vs 32.5, P = 0.007).
The proportion of patients with CD with severe disease at diagnosis decreased from 48% to 2.1% (5/240) at 1-year follow-up. The rate of patients with UC with moderate-to-severe disease activity declined from 55% to 7.8% (Fig. 1).
Initial Laboratory Parameters
CRP, hematocrit, platelet count, and iron level were documented in 411 children (97.6%) with IBD (laboratory parameters are presented in supplemental Table 1, http://links.lww.com/MPG/A506). The CRP was >10 mg/L in 177 children with CD (67.3%) at diagnosis. The CRP level in girls was significantly lower than in boys (P = 0.015) with CD. The difference in CRP between the sexes was significant only in children >10 years (A1b) (47.5 vs 28.3 mg/L), whereas CRP level was comparable in male and female patients <10 years (A1a) (34.5 vs 37.5 mg/L, P = NS).
Location According to the Paris Classification at Diagnosis and Association With Initial Disease Activity and Laboratory Markers
A total of 243 (91.4%) patients with CD were eligible for determination of disease location according to the Paris Classification. The L1 location (isolated terminal ileal ± cecal disease) was seen at presentation in 10% of the patients (n = 25), isolated colonic disease (L2) in 22% of the patients (n = 55), and ileocolonic (L3) in 66% of the patients (n = 163) (details of disease location of the recorded patients with CD are shown in supplemental Table 2, http://links.lww.com/MPG/A507). The proportion of patients with inflammatory phenotype (B1, B1p) was 82%. Seven percent of patients with CD had growth retardation.
Patients with CD with terminal ileum involvement had higher PCDAI (P = 0.026). Terminal ileum involvement was associated more often with elevated CRP (P = 0.021). Elevated CRP was significantly more frequent in patients with CD with upper gastrointestinal involvement (P = 0.030) and with stricturing and fistulizing phenotype (B2, B3, or B2B3) (P = 0.01). Upper gastrointestinal involvement in CD was associated with increased platelet count (P < 0.001). Decreased iron concentration (<7 mmol/L) was more characteristic in patients with complicated behaviour (B2, B3, or B2B3) (P = 0.006).
Fifty-seven percent of the patients with UC (n = 69) had pancolitis (E4) and 5% of them had proctitis (E1) (details of disease location of the recorded patients with UC are shown in supplemental Table 3, http://links.lww.com/MPG/A508). Elevated initial CRP was related to disease extent (P = 0.002) at diagnosis. Abnormal iron level was also associated with location in patients with UC (P = 0.004). The PUCAI tended to be higher in more extensive disease, though this tendency was not significant (P = 0.086).
Association Between Initial Disease Activity, Laboratory Parameters, and Medical Therapy
Initial therapy and management at 1 year are presented in Table 2. Thirty-one percent (75/240) of the children with CD were treated with azathioprine initially, and this proportion increased to 51.7% by the end of the first year of disease. Induction therapy was often completed in patients with CD with antibiotics (29%). Exclusive enteral nutrition was applied in a few centres only (10 patients with CD). Cumulative incidence of intestinal resection (small bowel resection or/with partial colectomy) was 4.2% (10/240) at 1 year.
Initial PCDAI and elevated CRP at diagnosis were associated with azathioprine use at 1 year (PCDAI: odds ratio [OR] 2.3, 95% confidence interval [CI] 1.33–3.96, P = 0.01, AUCPDCAI (AUC, area under the curve) 0.585, cutoff 30; CRP: OR 2.6, 95% CI 1.48–4.49, P = 0.0007, AUCCRP 0.636, cutoff 20). Elevated CRP at diagnosis was also associated with the administration of IFX at 12 months in children with CD (CRP: OR 2.98, 95% CI 0.38–23.25, P = 0.297). Patients with CD receiving IFX at 1 year had higher PCDAI at diagnosis (χ2 = 16.54, P < 0.001).
Initial use of the immunomodulator was 3.2% (n = 4) in UC. IFX was not available in paediatric UC patients during this period. No patient with UC underwent surgery during the first year of disease course.
The initial PUCAI was not related to treatment strategies in UC; in contrast, elevated CRP and platelets were associated with subsequent use of azathioprine (CRP: OR 6.2, 95% CI 2.3–16.4, P = 0.003, AUCCRP 0.663, cutoff 18; platelet: OR 0.43, 95% CI 0.17–1.07, P = 0.073, AUCPLT 0.651, cutoff 400) (Fig. 2). Abnormal iron levels were also more frequent at diagnosis in patients receiving azathioprine at 1 year (iron P = 0.018).
This is the first nationwide paediatric incident cohort study reporting activity indices for IBD (PCDAI and PUCAI) at diagnosis and 1-year later. Furthermore, we evaluated the relation between initial laboratory parameters and disease characteristics based on the database of HUPIR. The association of laboratory findings and short-term disease outcome (surgery and disease activity) were analysed. In addition, associations of disease activity indices with disease phenotype and short-term disease outcome were investigated.
Our study demonstrated that half of the newly diagnosed patients with IBD had moderate-to-severe disease at diagnosis, and this proportion decreased to a 10th of the children by the end of the first year, which may be because of the therapy. PCDAI and elevated CRP at diagnosis were correlated to the need of azathioprine at 1-year follow-up. In contrast, the PUCAI did not show similar association; however, all of the analysed laboratory parameters were associated with the subsequent need for azathioprine. Furthermore, we found that patients with CD <10 years had lower PCDAI. As in adult studies, Crohn colitis was associated with lower disease activity and less frequently elevated CRP (14). Complicated disease behaviour was also related to abnormal laboratory results (CRP and iron levels). In this cohort, patients with UC and pancolitis had more frequently elevated CRP and lower iron levels. Finally, higher CRP was also more characteristic in children with UC and EIM.
Our study presents disease activity indices at diagnosis and 1 year later. In a retrospective study from western Slovenia, 53% of the children with CD (39/73) and 8% of the children with UC (3/35) had severe disease activity (PCDAI >31 and PUCAI >16) (9). The only study that reported both PUCAI and PCDAI is a population-based incident cohort from the southeastern part of Norway in 39 patients with paediatric-onset CD and 19 patients with UC (8). The median PCDAI was 25 and median PUCAI was 35, as in this report. These results are in concordance with earlier findings, in which >70% of the children had moderate-to-severe disease at diagnosis based on clinical symptoms (15) or physician global assessment (16).
In a previous study, Dubner et al (17) evaluated the bone mineral density and structure in a smaller cohort of patients with CD, and described that median PCDAI decreased from 36 (at diagnosis) to 5 (12 months after diagnosis), respectively. The proportion of patients with moderate-to-severe disease activity was 5%, 12 months after diagnosis in the article by Pfefferkorn et al (18), who analysed growth outcome in children with CD. Taken together, our results are remarkable and unique because these activity indices represent a common paediatric IBD population (not only highly specialized IBD centres). In addition, this is the first study related to PCDAI and PUCAI at diagnosis and at 1-year of follow-up in a nationwide incident cohort. Studies on the development of PUCAI have not been found in the literature.
At the time of data collection, there was no available guideline regarding the management of paediatric IBD in Hungary. Initially, published trials showed oral 5-aminosalicylate acid to be an effective treatment for active ileal, ileocolic, or colonic CD. As a consequence, mesalazine became a popular treatment with limited toxicity for mild disease (19). Comparing with other reports, the use of 5-aminosalicylate acid was not more frequent in Hungary than in other countries at that time (20,21).
The relation between disease activity indices and prognosis has not yet been investigated. Initially, higher PCDAI was associated with subsequent azathioprine. PCDAI includes items that are not sensitive for rapid changes (perirectal disease, EIM, and height velocity) (22). These parameters, however, are associated with poor prognosis. PCDAI may be related to disease course because it includes parameters that change slowly. In contrast, PUCAI was not related to short-term disease course that may reflect the difference between these 2 tools. PUCAI consists of clinical signs purely and does not contain laboratory tests or other less responsive items. In conclusion, the combination of rapidly and slowly responsive items seems to be effective in predicting disease course.
Laboratory parameters correlate with disease activity, but their value in the evaluation of disease course has not been established in paediatric IBD. In the present study initially, increased CRP was associated with the need for azathioprine and IFX at 1 year. This finding supports earlier results that demonstrated a role of CRP in predicting relapses (2,23) and short-term disease course (3,24). The IBSEN study group described that CRP is a long-term predictor of surgery in subgroups of patients with either UC or CD (25). Based on these results CRP is probably a factor that contributes to the relation of PCDAI and disease course.
There is few data on the value of laboratory markers in assessing disease course of UC. In a Korean study, 256 adult patients with UC were followed for 5 years after diagnosis; haemoglobin <10.5 g/dL was an independent predictor of relapses (26). Bitton et al (27) aimed to assess whether clinical, biological, and histologic parameters in quiescent UC predict time to clinical relapse. A total of 74 patients with clinically and endoscopically determined inactive UC were followed up for 1 year. Younger age, multiple previous relapses, and basal plasmacytosis on rectal biopsy specimens were independent predictors of earlier relapse, but laboratory parameters could not predict relapses reliably.
Moreover, we demonstrated the relation between location and CRP. Previous reports showed that ileal disease is associated with elevated CRP (28,29). It is of interest that children with ileocolonic CD had higher CRP than patients with no ileal involvement or UC (28–30). It seems that its involvement is related to higher levels of CRP. The increased level of CRP may be because of the more intensified cytokine production of the Peyer patches. The number of Peyer patches increases during childhood and reaches a peak in late adolescence, and then it starts to regress (31). This observation may be the link between the lower CRP levels in Crohn colitis.
Of note, the observation that younger patients have lower PCDAI have not been reported yet. The explanation for that is may be the location of the disease. Children <10 years have mostly colonic localization, and patients with isolated colonic localization have usually lower PCDAI, as discussed. Children <10 years have mostly colonic localization, but this fact did not explain the lower PCDAI in this subgroup.
Although this is the first population-wide study describing the activity indices at diagnosis and at 1-year follow-up, it has some limitations. First of all, this is a post hoc analysis of prospectively collected data. Furthermore, it is of note that medication use during the 1 year of disease course was relatively subjective before the era of published international guidelines. In addition, activity indices and follow-up data were not available for every patient. Detailed information regarding relapses and steroid-dependency are not collected, which would allow analysing more precisely the relation of the disease course and activity indices and laboratory parameters.
In summary, this is the first study in which disease activity indices are presented in a paediatric incident cohort and their relation with the first year disease course is analysed. Based on these results, half of the children had moderate-to-severe disease activity (PCDAI and PUCAI) at diagnosis, and after 1 year of therapy only one tenth of the children had moderate-to-severe disease activity. The association of PCDAI with ileal localization and age indicates that PCDAI differs in distinct phenotypes in CD. The initial CRP level correlated positively with the need for azathioprine at 1 year of follow-up in patients with CD and UC.
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