Abstract
Background
Therapy in IBD is recommended in order to treat or prevent complications. In this nationwide study we aimed to assess the incidence of patients with IBD who were not receiving ...maintenance treatment after diagnosis and the duration of non-treatment.
Methods
This study was performed on data from four Health Maintenance Organizations (HMOs), covering 98% of the Israeli population. We included all patients with IBD diagnosed from 2005 to 2019. Non-treatment was defined as lack of drug prescription of maintenance medication for at least six months from diagnosis. Sustainability was defined as lack of maintenance medications and without IBD-related surgeries. Cox regression model was used to explore estimated predictors of sustainability.
Results
A total of 30,168 patients were diagnosed with IBD in Israel since 2005 (16,936 56% Crohn’s disease CD and 13,231 44% ulcerative colitis UC). A total of 5,448 (32%) patients with CD were untreated, compared to 5,158 (39%) with UC (OR 1.35 95%CI 1.3–1.4; p<0.001). Non-treatment was more likely in adult compared to pediatric-onset (34% vs 21%, respectively, p<0.001 in CD; and 41%% vs 22%, respectively, in UC; p<0.001) (Figure 1). Sustainability rate in CD was 72%, 46%, 36% and 28% after one, two, five and ten years from diagnosis, while in UC the corresponding rates were 59%, 39%, 24% and 16%. In CD, sustainability was associated with older age at diagnosis (HR 0.996 95%CI 0.994–0.998) and no induction therapy (HR 0.7 95%CI 0.6–0.9 compared to steroids). In UC, sustainability was associated only with female sex (HR 0.9 95%CI 0.88–0.98).
Conclusion
Most patients with IBD eventually require maintenance therapy. Lack of maintenance treatment is more common in UC. Nevertheless, a third of patients with CD and one quarter with UC who had no medical treatment at six months from diagnosis remained untreated for five years, especially in older patients with CD and those who did not require induction therapy, suggesting milder disease.
Abstract
Background and Aims
Ulcerative proctitis UP is an uncommon presentation in paediatric patients with ulcerative colitis. We aimed to characterize the clinical features and natural history of ...UP in children, and to identify predictors of poor outcomes.
Methods
This was a retrospective study involving 37 sites affiliated with the IBD Porto Group of ESPGHAN. Data were collected from patients aged <18 years diagnosed with UP between January 1, 2016 and December 31, 2020.
Results
We identified 196 patients with UP (median age at diagnosis 14.6 years interquartile range, IQR 12.5–16.0), with a median follow-up of 2.7 years IQR 1.7–3.8. The most common presenting symptoms were bloody stools 95%, abdominal pain 61% and diarrhoea 47%. At diagnosis, the median paediatric ulcerative colitis activity index PUCAI score was 25 IQR 20–35, but most patients exhibited moderate–severe endoscopic inflammation. By the end of induction, 5-aminosalicylic acid administration orally, topically or both resulted in clinical remission rates of 48%, 48%, and 73%, respectively. The rates of treatment escalation to biologics at 1, 3, and 5 years were 10%, 22%, and 43%, respectively. In multivariate analysis, the PUCAI score at diagnosis was significantly associated with initiation of systemic steroids, or biologics, and subsequent acute severe colitis events and inflammatory bowel disease-associated admission, with a score ≥35 providing an increased risk for poor outcomes. By the end of follow-up, 3.1% of patients underwent colectomy. Patients with UP that experienced proximal disease progression during follow-up 48% had significantly higher rates of a caecal patch at diagnosis and higher PUCAI score by the end of induction, compared to those without progression.
Conclusion
Paediatric patients with UP exhibit high rates of treatment escalation and proximal disease extension.
The combination of the severity of pediatric-onset inflammatory bowel disease (IBD) phenotypes and the need for intense medical treatment may increase the risk of malignancy and mortality, but ...evidence regarding the extent of the problem is scarce. Therefore, the Porto Pediatric IBD working group of ESPGHAN conducted a multinational-based survey of cancer and mortality in pediatric IBD.
A survey among pediatric gastroenterologists of 20 European countries and Israel on cancer and/or mortality in the pediatric patient population with IBD was undertaken. One representative from each country repeatedly contacted all pediatric gastroenterologists from each country for reporting retrospectively cancer and/or mortality of pediatric patients with IBD after IBD onset, during 2006-2011.
We identified 18 cases of cancers and/or 31 deaths in 44 children (26 males) who were diagnosed with IBD (ulcerative colitis, n = 21) at a median age of 10.0 years (inter quartile range, 3.0-14.0). Causes of mortality were infectious (n = 14), cancer (n = 5), uncontrolled disease activity of IBD (n = 4), procedure-related (n = 3), other non-IBD related diseases (n = 3), and unknown (n = 2). The most common malignancies were hematopoietic tumors (n = 11), of which 3 were hepatosplenic T-cell lymphoma and 3 Ebstein-Barr virus-associated lymphomas.
Cancer and mortality in pediatric IBD are rare, but cumulative rates are not insignificant. Mortality is primarily related to infections, particularly in patients with 2 or more immunosuppressive agents, followed by cancer and uncontrolled disease. At least 6 lymphomas were likely treatment-associated by virtue of their phenotype.
Several descriptions of acetaminophen‐associated liver injury caused by therapeutic or a dosage slightly above the recommended dosage have been described. Our hypothesis is that in sick febrile ...infants and children, who may also be calorie depleted, there might be an increased hepatic vulnerability to acetaminophen. Aim: (1) To correlate serum acetaminophen levels in febrile infants and children with the following parameters: aspartate aminotransferase (AST) levels, fever, vomiting and/or decreased caloric intake; and (2) to assess parental knowledge regarding the medication dosage and hazards of acetaminophen. Methods: Healthy children with an acute febrile illness, who had received acetaminophen, were eligible to participate in the study. AST and acetaminophen levels were drawn, and a detailed questionnaire was completed for every child. Results: 107 children participated in the study; 50 girls and 57 boys with ages ranging from 1 mo to 16 y (mean 33 mo). All serum acetaminophen levels were within the safety range. Although 32% of parents administered a single acetaminophen dose above 15 mg/kg and 46% gave a daily dose above 60 mg/kg/d, no significant differences were observed in the serum acetaminophen and AST levels compared to those who received the appropriate dose. In about 60% of cases, the high doses were recommended by a physician. Young age and high fever were associated with significantly higher acetaminophen levels. We could not find an association between acetaminophen levels and vomiting, decreased caloric intake and AST levels. Only 24 parents (22%) were aware of the possible toxicity of acetaminophen.
Conclusions: No evidence of increased hepatic vulnerability to acetaminophen was noted in a cohort of febrile infants and children. Furthermore, significant numbers of parents and physicians were unaware of acetaminophen dangers.
Abstract
Background
Limited data are available on the use of Vedolizumab (VDZ) in paediatric Crohn’s Disease (CD) and Ulcerative Colitis (UC). We evaluated the effectiveness and safety of VDZ to ...induce remission at week 14 in the prospective, multicenter VEDOKIDS study.
Methods
We enrolled children (age 0–18 years) with CD or UC commenced on VDZ with a standardized dosing of 177mg/BSA up to 300mg at 0, 2, 6 and q8 weeks thereafter. Non-responders had their dose escalated to q4wks at the discretion of the local physician. Explicit demographic, clinical and safety data were prospectively recorded via REDcap. Clinical remission was defined as steroid- and EEN-free remission (i.e. wPCDAI<12.5 or PUCAI<10) without the need for new medications. Complete remission was defined as clinical remission with normal CRP and ESR. Predictors of response were explored by Logistic regression.
Results
128 children were enrolled, 60 (47%) with CD, and 68 (53%) with UC (58 (45%) males, mean age 13.8±3.6, 93 (73%) failed previous anti-TNF, median disease duration 2.3 years (IQR 0.9–4.7)). Using the ITT principle, clinical and complete remission rates for CD at week 14 were 30% and 20%, respectively, and for UC 50% and 38%, respectively (Fig 1). Clinical remission rates of those receiving VDZ as first line biologics versus second line were 57% and 34%, respectively (p=0.019; Fig 2); the corresponding complete remission rates were 49% and 23% (p=0.004).
In the UC group, disease activity at baseline measured by the PUCAI predicted clinical remission at week 14 (OR=0.95, 95%CI 0.93–0.98; median baseline PUCAI 15 (IQR 0–30) in those achieving remission and 45 (20–55) in those who did not; p=0.002). ESR (OR=0.94, 95%CI 0.89–0.98; p=0.009) and a trend towards extensive disease (L3 vs. L1 and L2; OR 0.14, 95%CI 0.18–1.036, p=0.054) predicted clinical remission in CD.
During the 14 weeks, 113 adverse events (AE) were recorded in 58 children: 28 AEs were possibly related to VDZ, all of which were mild-moderate and only 3 (11%) led to discontinuation of VDZ (leukocytoclastic vasculitis, myalgia and dyspnea). There were 18 serious AEs, only one was graded as possibly related to VDZ (headache). There were 18 non-serious cases (19%) of upper respiratory infections (pharyngitis, tonsilitis, parotitis, and otitis media) and one Campylobacter jejuni which was graded as serious.
Conclusion
In this prospective multicenter study, VDZ was safe and effective for inducing remission in a refractory cohort of paediatric IBD, more so in UC. Disease severity and extent at baseline may predict clinical response.
Abstract
Background
Ulcerative proctitis (UP) is an uncommon presentation in paediatric patients with ulcerative colitis, accounting for <10% of cases. Here we aimed to characterize the clinical ...features and natural history of paediatric patients with UP, and to identify predictors of poor outcomes.
Methods
A retrospective cohort study involving 37 sites affiliated with the IBD Interest group of ESPGHAN. Data were collected at different timepoints from patients diagnosed with UP aged <18 years between 01/01/2016-31/12/2020. Outcomes included time to initiation of systemic steroids, thiopurines or biologics, time to acute severe colitis (ASC), IBD-related admission and colectomy. Univariate cox regression was used to study the association between potential predictors and study outcomes.
Results
Two hundred and fifty patients with UP were included, with a median age at diagnosis of 14.5 (IQR 12.3-15.9) years, and a median follow-up of 2.7 (IQR 1.7-3.9) years. The most common presenting symptoms were bloody stools (94%), abdominal pain (59%) and diarrhea (53%). At diagnosis, the median pediatric ulcerative colitis activity index (PUCAI) score was 25 (IQR 20-35), and only 3 patients (1.3%) presented with ASC. Most children had normal inflammatory markers and albumin levels. the median fecal calprotectin level was 720 mcg/g (IQR 310-1800), while 16 patients (9.9%) had a calprotectin level <100mcg/g at diagnosis. Administration of oral or topical 5-ASA resulted in clinical remission rates of 52% and 48%, respectively, by the end of induction, while the combination of both led to remission in 73% of patients. The rates of treatment escalation to thiopurines and biologics at 1, 3 and 5 years were 11%, 27% and 45%, and 11%, 23% and 45%, respectively (Figure 1). Within 5 years from diagnosis, 20% of patients had presented with ASC. The PUCAI score at diagnosis of UP was highly associated with initiation of systemic steroids, thiopurines or biologics, as well as later ASC event and IBD admission, while a Mayo endoscopic score of 3 was associated with the initiation of biologics and subsequent ASC event and IBD admission (Table 1). Seven patients (4%) underwent colectomy by the end of follow-up. Among the 151/250 patients who had a repeat endoscopy, only 16% achieved mucosal healing and in 48% inflammation extended proximally. Cecal patch (P=0.009) and higher PUCAI score (P=0.009) at diagnosis, as well as higher PUCAI score (P=0.009) and lack of steroid-free clinical remission (P=0.005) by the end of induction were associated with proximal disease extension.
Conclusion
Disease burden is significant in paediatric patients that present with UP, with high rates of proximal disease extension and requirement for treatment escalation.
Abstract
Background
Dietary therapies are increasingly utilised to induce remission in children with active Crohn’s disease (CD). Medical therapies such as steroids and anti-TNF induce rapid response ...within the first 2–3 weeks. The goal of this study was to evaluate the early response rate (significant response or remission) in response to two different dietary therapies by Week 3 and to assess whether response by Week 3 was predictive of remission by Week 6.
Methods
We utilised the data from the 3 and 6 week visits in the Crohn’s disease exclusion diet (CDED) trial, which was a multi-centre randomised controlled trial using two different and successful strategies for induction of remission. It was conducted among children with mild-to-moderate luminal CD, receiving either exclusive enteral nutrition (EEN), using 100% of calories from EN (Modulen, Nestle Health) or the CDED with partial enteral nutrition (PEN; 50% of calories from PEN). Patients were evaluated at baseline, Week 3, and Week 6. Remission was assessed by the use of the paediatric Crohn’s disease activity index (PCDAI; defined as a PCDAI ≤10) using intention to treat (ITT) analysis. Response was defined as a drop in ITT PCDAI of 12.5 points or remission. Response, remission, CRP, albumin, and adherence to diet were evaluated at each visit.
Results
Seventy-four patients were randomised, 40 allocated to CDED+PEN and 34 to EEN. Mean (±standard deviation) age was 14.2 ± 2.7 years in total cohort. Pooled response rate was present in 61/74 (82.4%) patients by Week 3. Pooled remission rate was obtained in 69% by Week 3. By Week 6, 56/74 patients were in ITT clinical remission (75.6%). Among patients in remission at Week 6, 85% were already in clinical remission by Week 3, and a significant drop in inflammation was present (Table 1)
Table 1. Clinical and inflammatory parameters.
Among patients in remission at Week 6, 54/56 (96.4%) had obtained a good response or remission to therapy by 3 weeks.
Conclusions
Dietary therapy caused a rapid clinical improvement and response by Week 3, which was equivalent with both diets. Patients who failed to respond by Week 3 were unlikely to reach remission by Week 6.
Abstract
Background
Early treatment of IBD is associated with more favourite outcomes, but this requires prompt diagnosis. Unfortunately, the delay from onset of symptoms to the diagnosis of IBD may ...range from 6–24 months. We thus aimed to develop and validate a screening tool intended for primary care physicians that can identify early symptomatic patients as being at risk for having IBD, thereby guiding early referral.
Methods
A Delphi group of 13 experts in adult and paediatric IBD generated a list of symptoms and signs associated with IBD, supplemented by review of the literature. The list was reduced in an iterative process based on applicability and graded based on importance. For validation and data-driven formatting, the charts of 300 consecutive subjects were reviewed: 100 adult IBD patients, 100 paediatric IBD patients, and 100 controls visiting the gastroenterology clinics but not having IBD. For each subject the IBD-REFER items were scored as well as the contending available Red Flag criteria from the International Organization for the study of IBD (IOIBD). Final adjustments were applied to optimise sensitivity and specificity.
Results
The Delphi process retained 5 items as major criteria (in which ≥1 item is sufficient for early referral) and 11 as minor (≥2 items required for referral). Following removal of uninformative items and further formatting in the data-driven chart review, 11 core items were retained: 3 as major and 8 as minor (Figure).
IBD reffer criteria
https://planner.smart-abstract.com/ecco2019/submission/en/abstract/12651/content#
The final IBD-REFER criteria had a sensitivity/specificity of 98%/94% in children, and 94%/88% in adults. The concurrent performance of the IOIBD Red-Flags criteria was inferior (60%/96% in children and 63%/88% in adults, respectively).
Conclusions
The IBD-REFER criteria is a new toll suggested for guiding the selection of patients for expedited gastrointestinal consultation. In addition, gastroenterology clinics can utilise these criteria for prioritising urgent cases.
Abstract
Background
The clinical benefit of proactive therapeutic drug measurement of anti-TNF agents for maintaining a pre-defined trough level compared with reactive measurement performed during ...exacerbations of Crohn’s disease is debated. We performed the first paediatric randomised controlled trial to determine whether proactive therapeutic drug monitoring to maintain serum levels of adalimumab above 5 μg/ml is associated with higher rates of clinical remission than the reactive approach which is based on drug measurement when clinically indicated.
Methods
This was a multi-centre non-blinded randomised controlled trial, in which biological-naïve children (6–18 years) with luminal Crohn’s disease who responded to adalimumab induction (Week 4), were randomly assigned into proactive and reactive groups. In the proactive group trough concentrations were measured at Week 4, 8, and every 8 weeks thereafter until Week 72, and dose (when lower than 40 mg) or intervals were adjusted in-order to maintain levels higher than 5 μg/ml. In the reactive group, physicians were informed of the trough levels only when clinically indicated (based on symptoms or elevated CRP or faecal calprotectin) and dose/intervals adjusted based upon the levels. The primary endpoint was sustained corticosteroid-free clinical remission from Week 8 to Week 72 (defined as Pediatric Crohn’s Disease Activity Index PCDAI <10) using non-responder imputation.
Results
Eighty patients (54 males, mean age 14.1 ± 2.6 years, 43% with combination therapy with immunomodulators) were randomised, 39 in the proactive, and 41 in the reactive groups. Baseline variables were similar between groups. The primary endpoint was met by 34 children (87%) in the proactive group and 21 (49%) in the reactive group (p < 0.001, Figure). At Week 72, steroid-free clinical remission on adalimumab was noted in 32 (82%) in the proactive group and 19 (46%) in the reactive group (p < 0.001). Clinical indices, CRP, and faecal calprotectin correlated with adalimumab trough concentrations. Faecal calprotectin reduction rate was significantly higher in the proactive group. There were more patients undergoing dose/interval adjustments in the proactive group (32, 82% vs. 18, 44%, p < 0.001).
Kaplan–Meyer curve representing time to disease exacerbation.
Conclusions
Repeated proactive trough measurements together with tight control based on clinical indices, CRP, and faecal calprotectin were superior to tight control alone combined with reactive trough measurements resulting in higher corticosteroid-free sustained remission rates. ClinicalTrials.gov Identifier: NCT02256462.
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