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.
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
Growth impairment is common in children with Crohn’s disease. We aimed to assess the effect of adalimumab treatment on linear growth in children with Crohn’s disease in a post-hoc ...analysis of the PAILOT randomised controlled trial.
Methods
Children 6–17 years old with moderate-to-severe Crohn’s disease, naïve to biologic treatment, who responded to adalimumab induction, were assessed at week 4, 8 andevery8 weeks thereafter until week 72 for anthropometric parameters (height, weight and body mass index, BMI, Z-scores). We also analysed the associations of these parameters with clinical disease activity, inflammatory biomarkers, faecal calprotectin and adalimumab trough concentration.
Results
Overall, 66 patients had available anthropometric parameters between week 4 to 72(29% females, mean age 14.3 ± 2.6 years). The median improvement of height z–score /month was +0.014, 95% CI 0.004–0.024, p = 0.006 with an overall improvement during the study period from -0.62 (IQR −1.6–0.15) to −0.33 (IQR -1.3–0.5). The median increase of weight z- score/month was +0.025, 95% CI 0.015–0.034, p = 0.025 overall increase from -0.54 (IQR −1.2–0.15) to −0.1, (IQR -0.9–0.6), whereas the median increase in BMI z –score/month was +0.02, 95% CI 0.008–0.031, p = 0.001 overall increase from −0.4 (IQR −1.0–0.5) to 0.0 (IQR −0.8–0.9). There was a significant correlation between paediatric Crohn’s disease activity index and erythrocyte sedimentation rate at week 4 and height z-score changes (p = 0.043 and p = 0.048), respectively, and a marginal correlation with C-reactive protein (p = 0.06). There was a significant correlation between sustained clinical and biologic remission (weeks 4–72) and changes in height z-score during follow-up (p = 0.001). Faecal calprotectin, adalimumab trough concentrations and combination therapy with an immunomodulator were not associated with height z-score changes.
Conclusion
Adalimumab treatment significantly improved linear growth, and normalised weight and BMI in children with moderate-to-severe Crohn’s disease.
Abstract
Background
Intestinal permeability (IP) is increased in Crohn’s disease (CD) patients and their first degree relatives. The causes of barrier disruption remain unclear but likely relate to ...inflammation with possible effects of nutrients and microbes. Infliximab has been shown to improve IP in CD but the impact of nutritional therapy on IP is unknown. We prospectively assessed the effects of nutritional therapy on IP in a randomised controlled trial, comparing the Crohn’s disease exclusion diet (CDED) to the gold standard exclusive enteral nutrition (EEN) in children with CD. Mannitol is an easily absorbed small sugar that reflects the small bowel (SB) surface area, whereas the disaccharide lactulose is only absorbed through larger pores and reflects permeability; therefore, the ratio of lactulose/mannitol (L/M) represents SB relative permeability.
Methods
The CDED study was a 12-week prospective, international, multi-centre, randomised controlled trial in children with mild-to-moderate active luminal CD, comparing CDED to EEN. During the first 6 weeks of the study patients in the CDED group received CDED Stage 1 diet + 50% calories from liquid formula (Modulen, Nestle) whereas the EEN group were fed exclusively with Modulen. A L/M test for intestinal permeability was performed at weeks 0 and 3 by administering a sugar solution containing lactulose (5 g) and mannitol (1 g) and then collecting urine for LC-MS/MS analysis. A cut-off L/M ratio of 0.015 was chosen, based on published literature (McOmber et al. JPGN 2010).
Results
L/M ratios were available at both time points for 39 patients (23 CDED and 16 EEN). At baseline, 9/23 (39%) CDED and 8/16 (50%) EEN patients had a normal L/M ratio, whereas at 3 weeks of treatment this increased to 15/23 (65%) and 9/16 (56%), respectively. Using generalised estimating equation analysis there was no difference in change of L/M between groups (p = 0.193). In both groups, 50% of those with abnormal L/M ratio at baseline (ratio > 0.015) normalised at Week 3 (7/14 for CDED; 4/8 with EEN). Interestingly, 1/14 (7%) CDED cases with normal L/M ratio became abnormal at 3 weeks, vs. 3/16 (19%) in the EEN group (NS). These findings indicate an improvement in IP with 3 weeks of nutritional therapy; however, there was no correlation between change in IP status and failure to respond to therapy or poor compliance to the diet at 3 weeks.
Conclusions
Although both EEN and CDED are associated with improved IP, this was not observed in all patients, despite clinical improvement. This suggests that small bowel IP alone may not be a primary mechanism for early clinical response; the effect of IP on sustaining remission following dietary therapy will require further study.
Abstract
Background
Exclusive enteral nutrition (EEN; consumption of a liquid formula without other food for 6–8 weeks) is the recommended first-line therapy for induction of remission in children ...with mild-to-moderate Crohn’s disease (CD). The CD exclusion diet (CDED) is a whole food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components hypothesised to negatively affect the microbiome, intestinal barrier, and innate immunity.
Methods
The CDED study was a 12-week prospective, international, multi-centre RCT in children with mild-to-moderate luminal CD <3 years comparing CDED to EEN. Children aged 6–18 years with a paediatric CD activity index (PCDAI) ≥10, + elevated inflammatory markers, were randomised to one of the two groups: Group 1, CDED Stage 1 diet + 50% calories from PEN (Modulen, Nestle) for 6 weeks, followed by CDED Stage 2 + 25% PEN for the next 6 weeks; Group 2 EEN for 6 weeks (Modulen) followed by 6 weeks of free diet with 25% supplemental calories from PEN. The primary endpoint was tolerance to diet, measured by withdrawals for refusal to continue diet and poor adherence (measured by a modified MARS questionnaire and physician’s assessment). Secondary endpoints included Week 6 intention to treat (ITT) remission defined by PCDAI ≤10 but also with the more stringent definition (PCDAI < 10), and corticosteroid (CS) free ITT sustained remission Week 12.
Results
Seventy-eight patients meeting inclusion exclusion criteria were randomised to CDED+PEN (40)or to EEN (38), four withdrew because of intolerance to diet by 48 h (all EEN). Seventy-four remaining patients (mean age 14.2 ± 2.7 years) were included in the remission analysis. Median PCDAI at baseline was 25 (IQR 20–35) for CDED and 27.5 (IQR 18.75–32.5) in EEN; p = 0.89. Tolerance was present in 39/40 (97.5%) CDED and in 28/38(73.7%) EEN (p = 0.003). Poor compliance was similar 7/40 (17.5%) vs. 8/34 (23.5%); p = 0.52. Week 6 ITT CS-free remission PCDAI ≤10 occurred in 32/40 (80%) in CDED vs. 25/34 (73.5%) with EEN (p = 0.51). Using the more stringent PCDAI < 10, remission was 30/40(75%) CDED and 20/34 (59%) EEN p = 0.38. Median CRP decreased from Week 0 to 6 in both groups (23.6 to 5 g/l with CDED; p < 0.001; 24 to 4 g/l with EEN; p < 0.001). Sustained CS free remission at Week 12 PCDAI ≤10 was 28/40 (70%) with CDED+PEN and 14/34 (41.2%), in the EEN followed by PEN +free diet p = 0.01.
Conclusions
Both diets result in high rates of ITT CS free remission with a significant decrease in inflammation. CDED with PEN has superior tolerance and sustained remission by Week 12. These data support the use of CDED+PEN as a first-line therapy for children with luminal mild-to-moderate active CD. They also support the concept that diet plays a role in inflammation in CD
Abstract
Background
Childhood is a critical time for accrual of bone density, which peaks at age 18–20 years. Both the inflammatory burden of CD and corticosteroid therapy have a negative effect on ...bone density, hence exclusive enteral nutrition (EEN) is the preferred treatment option to induce remission. We aimed to explore the effect of nutritional therapy on bone health in paediatric CD.
Methods
This was a planned sub-study of a randomised controlled trial of children with mild-to-moderate CD who were randomised to receive either 6 weeks of EEN followed by 6 weeks of 25% PEN with free diet or 6 weeks of 50% partial enteral nutrition (PEN) with a Crohn’s disease exclusion diet (CDED) followed by 6 weeks of 25% PEN+CDED. For the aim of this ancillary study, we measured bone mineral density (BMD) by DXA scan at baseline and Week 24 (total body less head adjusted for age and height). In addition, bone formation was measured at baseline, Week 12 and Week 24, by the serum biomarker C-Propeptide of Type I Procollagen (CICP) and bone resorption was measured by serum Type I Collagen N-Telopeptide (NTX).
Results
Repeated BMD was completed for 23 children and showed BMD < -1 SD in 17 (74%) and BMD < −2 in 7 (30%) at baseline. DXA results did not improve at Week 24 (BMD -1.52 ± 0.72 at baseline vs. −1.65 ± 0.81 at Week 24; p = 0.36). The change was also not significant in analysis of the individual treatment arms. In the subset of patients who achieved remission at Week 12, DXA scores did not worsen but did not improve either (median change of −0.01, IQR 0.17--0.26); compared with patients not in remission, the difference was not significant. Serial biomarkers were available for 29 children. Median CICP improved from 130 ng/ml (IQR 3–1 189-106)) at baseline to 223 (258-143)) at Week 12 and 189 (227–145) at Week 24 (p = 0.016 for both). Median NTX remained unchanged, from 36 nmol bone collagen equivalents/l (IQR 58–30) at baseline to 50 (66–28) at Week 12 (p = 0.45) and 37 (66–24) at Week 24 (p = 0.37). Analysis of individual treatment arms was not possible for the bone biomarkers due to small sample size.
Conclusions
BMD did not improve in children with active CD treated with nutrition. However, CICP, a much more responsive and sensitive marker of bone formation increased significantly, raising the possibility that bone improvement is slow and should be further examined in longer-term studies.
Abstract
Background
Standardised management protocols of paediatric Crohn's disease (CD) are lacking in Israel, leading to a wide heterogeneity of care across paediatric centres. In this quality ...improvement Programme, named QPID, we aimed to construct a population-based non-research platform that records clinically important quality indicators of CD in all paediatric IBD centres in Israel, to improve treatment outcomes across the country.
Methods
Representative of all 20 paediatric IBD centres in Israel formed part of a Delphi group to select quality indicators for the QPID (including process and outcome indicators). Eligibility criteria for this program were children with CD seen in clinic, age 2–18 years, not recorded in during the previous 2 months. Children with disease duration <3 months were excluded and a cap of 20 patients per month per site avoided dominance effect of large centres. The indicators were recorded on a REDCap eCRF platform, managed at a data coordinating centre (DCC). Global assessment of longitudinal disease activity and medications were captured to account for patient-mix at each centre. Centres were coded and their allocation was concealed from all involved parties. Monthly reports were distributed, comparing the performance of the specific centre with previous months and other blinded centres.
Results
The indicators of 1657 visits were recorded from 09/2017 to 08/2018 (mean children age 14.5 ± 2.9 years; median disease duration 1.92 years (IQR 0.92–3.42)). The majority of visits reported quiescent longitudinal global assessment (55%), 30% reported mild activity, and 15% reported moderate–severe activity. On average, 66% of children were treated with biologics with increasing rates over the year (65% to 70%; p = 0.047) (figure)
QPID Quality Indices
https://planner.smart-abstract.com/ecco2019/submission/en/abstract/12600/image/add.html . A slight increase in measures indicating mucosal healing was note, from 53% to 64% among those with disease duration of at least 1 year (p = 0.001; figure). Clinical remission rate was stable at 72%. Use of steroids was <5% of all reports reflecting the wide use of nutritional therapy in Israel.
Conclusions
Quality improvement programs at a country level may be implemented with limited resources while facilitating a national standardisation of care. No causal relationship can be elucidated between the program and the observed improved endpoints. Nonetheless, providing anonymous comparisons with other centres may increase awareness and motivation to improve quality indicators.
Introduction:The aim of this study was to assess the clinical significance and prognosis of a prolonged isolated elevation of serum aminotransferases without cholestasis (>3 months) in infants and ...young children, investigated for a variety of conditions, and to determine a protocol for their follow-up and investigation.Methods:A combined prospective-retrospective analysis of apparently healthy babies and young children with isolated elevation of serum aminotransferases of at least 1.5 times above the norm for age which persisted for at least 3 months and whose creatine phosphokinase (CK), gamma glutamyltransferase (GGT), alkaline phosphatase and bilirubin levels remained normal throughout the study duration. The children underwent the following investigations: abdominal ultrasound and infectious, metabolic and/or immunological investigation depending on the duration of the abnormality.Results:Six children were eliminated following the finding of positive cytomegalovirus (CMV) antigen in the urine. 72 children were investigated (47 males and 25 females). The duration of serum aminotransferases elevation was 3–36 months (average 12.4, median 11.5 months). The initial, maximal and final alanine aminotransferase (ALT) values were 85.5, 140.5 and 39.8 IU/l, respectively. Of seven children who had liver biopsies performed, three (42.8%) were suspected of having a glycogen storage disease which was not confirmed enzymatically. Four biopsies revealed non-specific histological changes.Conclusions:Isolated elevation of serum aminotransferases in healthy looking young children is mostly a benign condition that usually resolves within a year. If no pathology is found during routine investigation, these children can be followed conservatively. Liver biopsy does not contribute much to the diagnosis and is probably unnecessary.
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