Effectiveness and Safety of Ustekinumab in Pediatric Ulcerative Colitis: A Multi-center Retrospective Study from the Pediatric IBD Porto Group of ESPGHAN.

BACKGROUND AND OBJECTIVES: Current data on ustekinumab therapy in children with ulcerative colitis (UC) or unclassified inflammatory bowel disease (IBDU) are limited. We aimed to evaluate the effectiveness and safety of ustekinumab in pediatric UC and IBDU. METHODS: This multicenter retrospective study included 16 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. Children with UC or IBDU treated with ustekinumab were enrolled. Demographic, clinical, laboratory, endoscopic, and imaging data as well as adverse events were recorded. Analyses were all based on the intention-to-treat principle. RESULTS: Fifty-eight children (39 UC and 19 IBDU, median age 14.5 [IQR 11.5-16.5] years) were included. All had failed biologic therapies, and 38 (66%) had failed two or more biologics. Corticosteroid-free clinical remission (CFR) was observed in 27 (47%), 33 (57%), and 37 (64%) children at 16, 26, and 52 weeks, respectively. Normalization of C-reactive protein and calprotectin < 150 µg/g were achieved in 60% and 52%, respectively, by 52 weeks. Endoscopic and radiologic remissions were reached in 8% and 23%, respectively. The main predictors of CFR were diagnosis of UC compared with IBDU (hazard ratio [HR] 2.2, 95% CI 1.03-4.85; p = 0.041) and no prior vedolizumab therapy (HR 2.1, 95% CI 1.11-4.27; p = 0.023). Ustekinumab serum levels were not associated with disease activity. Adverse events were recorded in six (10%) children, leading to discontinuation of the drug in three. CONCLUSION: Based on these findings, ustekinumab appears as an effective therapy for pediatric refractory UC and IBDU. The potential efficacy should be weighed against the risks of serious adverse events.

Adherence to ECCO Guidelines for Management of Iron Deficiency and Anemia in Inflammatory Bowel Diseases Among Israeli Adult and Pediatric Gastroenterologists.

OBJECTIVES: The consensus guidelines of the European Crohn's and Colitis Organization (ECCO) for the diagnosis and treatment of iron deficiency anemia (IDA) were published in 2015. We examined the management practices of both adult gastroenterologists (AGs) and pediatric gastroenterologists (PGs) in Israel in treating ID among patients with inflammatory bowel disease (IBD). METHODS: An 18-question multiple-choice anonymous questionnaire was electronically delivered to AGs and PGs. Questions explored 3 areas of interest: physician demographics, adherence to ECCO guidelines, and management practices of IDA in patients with IBD. RESULTS: Completed questionnaires were returned by 72 AGs and 89 PGs. Practice setting and years of practice were similar. A large majority of AGs and PGs (89% and 92%, respectively) measure complete blood count (CBC) and serum ferritin (S-Fr) at least every 3 months in outpatients with active IBD, as recommended by the ECCO guidelines. In contrast, in IBD patients in remission, only 53% and 26% of AGs and PGs, respectively ( P < 0.001), reported adherence to ECCO guidelines, measuring CBC and S-Fr every 6 months. The ECCO treatment guidelines recommend that intravenous (IV) iron should be considered the first-line treatment in patients with clinically active IBD, with previous oral iron intolerance and those with a hemoglobin level <10 g/dL. Study results indicate that only 43% of AGs recommend IV iron for these indications, compared to 54% of PGs ( P > 0.1). CONCLUSIONS: In this study we have demonstrated a relatively low level of adherence to ECCO guideline recommendations among both AGs and PGs, regarding the management of IDA in patients with IBD.

Characterization and Short-Term Outcome of Potential Celiac Disease in Children.

Background and Objectives: Potential Celiac Disease (PCD) is defined by positive celiac serology without villous atrophy. We aimed to describe the short-term outcome of pediatric PCD while consuming a gluten-containing diet (GCD). Materials and Methods: Retrospective analysis of pediatric PCD patients continuing GCD, between December 2018-January 2022. Baseline demographics, celiac serology and duodenal biopsy results were reviewed. Follow-up data included repeated serology and biopsy results when performed. Minimum follow-up was 12 months unless celiac disease (CeD) was diagnosed earlier. Results: PCD was diagnosed in 90 children (71% females) with a mean age of 7.2 (range 1.8-16.5) years. Baseline anti-tissue transglutaminase (TTG) levels were above 10 times the upper limit of normal (ULN) in 17/90 (18.9%), 3-10 × ULN in 56/90 (62.2%) and 1-3 × ULN in 17/90 (18.9%). During follow-up, the mean time was 17.6 (range 5-35) months, TTG normalized in 34/90 (37.8%), was stable in 48/90 (53.3%), and increased or remained >10 × ULN in 8/90 (8.9%). In 20/90 (22.2%) patients, a repeat endoscopy was performed, leading to CeD diagnosis in 12/20 (60%). Thus, at the end of follow-up, CeD was diagnosed in 12/90 (13.3%). In patients with TTG >10 × ULN at diagnosis, TTG normalized in 5/17, decreased to 3-10 × ULN in 8/17, and remained above 10 × ULN in 4/17. Conclusions: During the short-term follow-up of pediatric PCD patients, less than 15% progressed to CeD. A third had normalized TTG levels, including children with TTG >10 × ULN, indicating the need for periodic serological and histological follow-up among PCD patients.

Thiopurines Maintenance Therapy in Children With Ulcerative Colitis: A Multicenter Retrospective Study.

BACKGROUND AND AIMS: Thiopurines are an established treatment for pediatric ulcerative colitis (UC). However, data regarding safety and efficacy are lacking. We aimed to determine short and long-term outcome following thiopurines use in children with UC. METHODS: We conducted a retrospective review of children (2-18 years) with UC treated with thiopurines between January 2008 and January 2019 at 7 medical centers in Israel. The primary outcome was corticosteroid (CS)-free clinical remission at week 52 following thiopurines initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy). RESULTS: A total of 133 children were included [median age at diagnosis of 12.4 (interquartile range 11.0-15.8) years, 30 (23%) left-sided colitis, 113 (85%) with moderate or severe disease at diagnosis]. At diagnosis 58 patients (44%) were treated with 5-aminosalicylates and 72 (54%) with CS. Sixty patients (45%) received thiopurines as 1st line maintenance therapy. Seventy-four patients (56%) had CS-free clinical remission at week 52 without rescue therapy. Predictors of clinical remission were not identified. In a sub-analysis among patients with steroid-responsive moderate to severe UC, 59 (55%) patients achieved this outcome. The likelihood of remaining free of rescue therapy among thiopurines-treated patients was 83%, 62%, 45%, and 37% at 1, 2, 3, and 4 years, respectively. CONCLUSION: More than half of children with UC starting thiopurines without previous or concomitant biologic therapy have CS-free clinical remission at 52 weeks later without the need for rescue therapy. Thiopurines are effective in pediatric UC and could be considered prior to biologics.

Clinical Features and Natural History of Paediatric Patients with Ulcerative Proctitis: A Multicentre Study from the Paediatric IBD Porto Group of ESPGHAN.

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.

Safety and Potential Efficacy of Escalating Dose of Ustekinumab in Pediatric Crohn Disease (the Speed-up Study): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN.

OBJECTIVES: Escalation of the ustekinumab (UST) maintenance dosage was effective in adults with Crohn disease (CD), but no data are available for children. We evaluated the effectiveness and safety of dose escalation of UST in pediatric CD. METHODS: This was a retrospective multicenter study from 25 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. We included children with CD who initiated UST at a standard dosing and underwent either dose escalation to intervals shorter than 8 weeks or re-induction of UST due to active disease. Demographic, clinical, laboratory, endoscopic, imaging, and safety data were collected up to 12 months of follow-up. RESULTS: Sixty-nine children were included (median age 15.8 years, interquartile range 13.8-16.9) with median disease duration of 4.3 years (2.9-6.3). Most children were biologic (98.6%)- and immunomodulator (86.8%)- experienced. Clinical response and remission were observed at 3 months after UST escalation in 46 (67%) and 29 (42%) children, respectively. The strongest predictor for clinical remission was lower weighted Pediatric Crohn Disease Activity Index (wPCDAI) at escalation ( P = 0.001). The median C-reactive protein level decreased from 14 (3-28.03) to 5 (1.1-20.5) mg/L ( P = 0.012), and the fecal calprotectin level from 1100 (500-2300) to 515 (250-1469) µg/g ( P = 0.012) 3 months post-escalation. Endoscopic and transmural healing were achieved in 3 of 19 (16%) and 2 of 15 (13%) patients, respectively. Thirteen patients (18.8%) discontinued therapy due to active disease. No serious adverse events were reported. CONCLUSIONS: Two-thirds of children with active CD responded to dose escalation of UST. Milder disease activity may predict a favorable outcome following UST dose escalation.

Anti TNF treatment of complex perianal fistulas in children without luminal Crohn's disease: Is it an option?

OBJECTIVES: Complex perianal fistulas (CPFs) in children even in the absence of luminal symptoms prompt evaluation for Crohn's disease (CD). Reports of isolated CPF in children, however, are sparse. In perianal CD, antitumor necrosis factor α (anti TNF) therapy is recommended. We aimed to describe our experience with anti TNF therapy in children with isolated CPF without evidence of luminal CD. METHODS: We retrospectively reviewed charts of patients with isolated CPF who were treated with anti TNF agents between 2011 and 2019 in a tertiary center. MRI pelvis findings at baseline versus end of follow up were scored using MAGNIFI-CD. Outcomes included clinical remission, radiological response and radiological remission based on MAGNIFI-CD score at end of follow up. RESULTS: Overall, 17 patients were identified, [10 males (59%), mean age at anti TNF initiation 13.4 ± 2.9 years]. Median time from perianal disease onset to anti TNF was 16.5 months (IQR 9.4-36.4). None of the patients had luminal inflammation. Prior to anti TNF, all patients had been treated with antibiotics without sufficient improvement, and 9/17 with abscess drainage and or Seton insertion. Nine patients (53%) were treated with infliximab while 8 (47%) received adalimumab. Median duration of follow up was 30.7 months (IQR = 12.7-44.8). At the end of follow up 9 patients (53%) achieved clinical remission. When comparing MRI prior to and after anti TNF, 36% (5/14) had radiologic response, of whom 2 (14%) achieved radiologic resolution. CONCLUSION: Anti TNF agents may be an effective treatment option for children with isolated CPF. Whether these patients should be considered part of the CD phenotypic spectrum or a distinct entity is unclear. LEVELS OF EVIDENCE: Therapeutic.

Long-Term Outcomes With Adalimumab Therapy in Pediatric Crohn Disease: Associations With Adalimumab Exposure.

BACKGROUND/AIMS: Pediatric Crohn disease (CD) treatment goals have evolved. Among children receiving adalimumab (ADA) we examined long-term durability of clinical remission, linear growth, and associations of trough concentration (TC) with biomarker, endoscopic and imaging outcomes. METHODS: Single-center retrospective study. Pediatric CD activity index, C-reactive protein, fecal calprotectin, and height measured longitudinally. Discontinuation due to secondary loss of response (LOR) was assessed using Cox proportional hazards model. Associations between TC and clinical and biomarker remission, endoscopic and magnetic resonance imaging (MRI) improvements were assessed using Cox regression with time-dependent covariates. RESULTS: Between January 2007 and June 2018, 213 children (median age 14.1 years (interquartile range [IQR] 12.5-15.7) 65% males) initiated ADA. One hundred and seventy-four (82%) achieved clinical remission (PCDAI < 10). During 24.8 (IQR 15.6-38.4) months follow-up, 26 (15%) discontinued ADA due to LOR, and 10 (6%) due to adverse events. Being anti-tumor necrosis factor (TNF) naïve and inflammatory behavior associated with increased likelihood of clinical remission (odds ratio [OR] 2.39, P = 0.033, and 3.13, P = 0.013, respectively) and with decreased LOR (hazard ratio [HR] 0.3, P = 0.002, and HR 0.35, P = 0.01, respectively). Cumulative LOR among 135 anti-TNF naïve patients: 0%, 8%, 15% within 1, 2, 3 years, similarly durable with mono- and immunomodulator combination therapy. Among pre-/early pubertal children mean height (-0.82) normalized to -0.07. TC consistently >7.5 ug/mL was associated with durable clinical remission (HR = 17.24, P < 0.001); TC >10 ug/mL with durable biomarker remission (HR = 6.56, P < 0.001) and endoscopic (OR 10.4, P = 0.002) and MRI (OR 7.6, P = 0.001) improvements. CONCLUSION: ADA monotherapy maintains durable clinical remission. Biomarker remission, mucosal and transmural improvements were associated with greater ADA exposure.

Resolution of iron deficiency following successful eradication of Helicobacter pylori in children.

AIM: To assess correlation between successful Helicobacter pylori (HP) eradication and resolution of iron deficiency in children, without iron supplementation. METHODS: Medical records of children diagnosed with HP infection based on endoscopy were retrospectively reviewed. Among those with non-anaemic iron deficiency (NAID) or iron deficiency anaemia (IDA), haemoglobin, ferritin and CRP levels were compared prior and 6-9 months' post-successful HP eradication. Predictors of resolution of iron deficiency following HP eradication were assessed. RESULTS: Among 60 included children (median age 14.8, IQR12.3-16 years; 62% males), 35% had IDA while the remaining 65% had NAID. Following successful HP eradication, iron normalised in 60% of patients with iron deficiency (ID), without iron supplementation. There were significant improvements in haemoglobin and ferritin concentrations following HP eradication with haemoglobin increasing from 12.3 g/dL to 13.0 g/dL and ferritin increasing from 6.3 µg/L to 15.1 µg/L (p < 0.001). In multiple logistic regression, older age was the only factor associated with resolution of anaemia following HP eradication (OR 1.65, 95% CI 1.16-2.35, p = 0.005). CONCLUSION: Successful HP eradication could be helpful in improving iron status among children with refractory NAID or IDA. Older age may predict this outcome. Screening for HP might be considered in the workup of refractory IDA or ID.

Association of Early Postinduction Adalimumab Exposure With Subsequent Clinical and Biomarker Remission in Children with Crohn's Disease.

BACKGROUND: Data on the association between early postinduction serum adalimumab (ADA) trough levels (TLs) and objective outcomes are scarce. The aim of this study was to investigate whether early ADA TLs at weeks 4 and 8 are associated with clinical and biomarker remission at week 24 in pediatric Crohn's disease (CD). METHODS: Adalimumab TLs at weeks 4 and 8 were prospectively measured in anti-TNF-naïve children initiating treatment with ADA monotherapy for luminal inflammatory CD. The primary outcome was combined clinical and biomarker remission at week 24, defined as achieving steroid-free clinical remission (Pediatric CD activity index <10) and biomarker remission (fecal calprotectin <250 µg/g and CRP <5 µg/mL). RESULTS: Among 65 patients, 39 (60%) achieved combined clinical/biomarker remission at week 24 without dose escalation. Adalimumab TLs at both weeks 4 and 8 were significantly higher in remitters vs nonremitters at week 24 (P < 0.001 and P = 0.002, respectively). Adalimumab levels at weeks 4 and 8 were good predictors of combined clinical/biomarker remission at week 24 (area under the curve, 0.887, 95% CI, 0.798-0.942; and area under the curve, 0.761, 95% CI, 0.632-0.899, respectively). The best ADA TL cutoffs at weeks 4 and 8 for predicting clinical/biomarker remission at week 24 were 22.5 µg/mL (80% sensitivity, 90% specificity, positive likelihood ratio [LR+] 8.0, negative LR [LR-] 0.2) and 12.5 µg/mL (94% sensitivity, 60% specificity, LR+ 2.4, LR- 0.1), respectively. Higher induction doses per m2 correlated positively with TLs at weeks 4 and 8. CONCLUSION: Greater early ADA exposure is associated with superior clinical/biomarker outcomes at week 24.

Associations of seasonal patterns and vitamin D levels with onset and flares of pediatric inflammatory bowel disease.

BACKGROUND: As inflammatory bowel disease (IBD) might be associated with environmental factors such as seasonal patterns and low vitamin D levels we aimed to assess their association with IBD onset and flares in a large cohort of children. METHODS: The records of 623 pediatric onset IBD patients were reviewed retrospectively including age at onset, gender, severity indices, month of first symptom, and vitamin D levels at diagnosis. For a subgroup of patients, data included date of first flare and vitamin D levels during flare and remission. RESULTS: Median age at diagnosis was 14 years (IQR 11.66-15.58). Disease onset did not vary significantly between either month (P=0.367) or seasons (P=0.460). Vitamin D deficiency at the time of diagnosis was prevalent in 21% of patients with no significant association with month, season or disease's type. Vitamin D deficiency was significantly more prevalent in patients with malnutrition (P<0.001) and was associated with hypoalbuminemia (P=0.02) but did not correlate with low bone mineral density. Analysis of 169 first flares showed that flares were more common in June and less common in April (P=0.016). Mean vitamin D level was significantly lower during flares compared with remission (55.25±19.28 vs. 64.16±26.6, respectively, P=0.012). CONCLUSIONS: IBD onset in school aged children is not associated with seasonal patterns whereas flares may follow a specific monthly pattern. Disease flares are associated with low vitamin D blood levels. Vitamin D deficiency is associated with malnutrition and hypoalbuminemia.

Accurate Classification of Pediatric Colonic Inflammatory Bowel Disease Subtype Using a Random Forest Machine Learning Classifier.

BACKGROUND: The pediatric inflammatory bowel disease (PIBD) classes algorithm was developed to bring consistency to labelling of colonic IBD, but labels are exclusively based on features atypical for ulcerative colitis (UC). AIM: The aim of the study was to develop an algorithm and identify features that discriminate between pediatric UC and colonic Crohn disease (CD). METHODS: Baseline clinical, endoscopic, radiologic, and histologic data, including the PIBD class features in 74 colonic IBD (56: UC, 18: colonic CD) patients were collected. The PIBD class features and additional features common to UC were used to perform initial clustering, using similarity network fusion (SNF). We trained a Random Forest (RF) classifier on the full dataset and used a leave-one-out approach to evaluate model accuracy. The top-features were used to build a new classifier, which we tested on 15 previously unused patients. We then performed clustering with SNF on the top RF features and assessed ability to discriminate between UC and colonic-CD independent of a supervised model. RESULTS: The initial SNF clustering with 58 patients demonstrated 2 groups: group 1 (n = 39, 90% UC) and group 2 (n = 19, 68% colonic-CD). Our RF classifier correctly labelled 97% of the 58 patients based on leave-one-out cross validation and identified the 7 most important features (3 histological and 4 endoscopic) to clinically distinguish these groups. We trained a new RF classifier with the top 7 features and found 100% accuracy in a set of 15 held-out patients. Finally, post hoc clustering with these 7 features revealed 2 groups of patients: group 1 (n = 55, 98% UC) and group 2 (n = 18, 94% colonic-CD). CONCLUSIONS: A combination of supervised and unsupervised analyses identified a short list of features, which consistently distinguish UC from colonic CD. Future directions include validation in other populations.

The Effect of Adalimumab Treatment on Linear Growth in Children With Crohn Disease: A Post-hoc Analysis of the PAILOT Randomized Control Trial.

OBJECTIVES: Growth impairment is common in children with Crohn disease (CD). We aimed to assess the effect of adalimumab (ADL) treatment on linear growth in children with CD in a post-hoc analysis of the Pediatric Crohn's Disease AdalImumab Level-based Optimization Treatment randomized controlled trial. METHODS: Children 6 to 17 years who responded to ADL induction were assessed consecutively for anthropometric parameters. Associations of these parameters with disease characteristics and disease activity were analyzed. RESULTS: Overall, 66 patients completed 72 weeks of follow-up (25% girls, mean age of 15.6 ±â€Š2.5 years). Median (interquartile range [IQR]) height z score improved from -0.6 (-1.6-0.15) at baseline to -0.33 (-1.3-0.5) at week 72 (P = 0.005) with lesser improvement in patients with perianal disease. Similar effect was noted in children with growth potential (boys younger than 16 years, girls younger than 14 years). Median (IQR) height velocity standard deviation was -0.32 (-1.5-0.8) at week 26, and +0.11 (-1.1-1.3) at week 72. Median weight z score increased from -0.54 (-1.2-0.15) to -0.1 (-0.9-0.6), P < 0.001 and body mass index from -0.4 (-1.0-0.5) to 0.0 (-0.8-0.9), P = 0.005. Pediatric CD activity index and erythrocyte sedimentation rate at week 4 correlated negatively with height z score changes (P = 0.043 and P = 0.048, respectively), whereas sustained clinical and biologic remission (week 4-72) were positively associated with changes in height z scores. Significant improvement in linear growth was predicted by lower pediatric CD activity index and erythrocyte sedimentation rate at the end of induction and sustained clinical remission (P = 0.05) and sustained normal C-reactive protein (P = 0.001) at all visits. CONCLUSION: In children with moderate-to-severe CD, ADL treatment had a significant effect on linear growth, with normalization of weight and body mass index (clinicaltrials.gov no: NCT02256462).

Automated Analyzers Are Suited for Diagnosing Celiac Disease Without a Biopsy.

OBJECTIVES: The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2012 guidelines, enabled for the first time, a nonbiopsy approach in the diagnosis of celiac disease (CD). We aimed to prospectively assess 4 tissue-transglutaminase (tTg) IgA assays of 4 random-access analyzers and examine their accuracy in diagnosing CD without a biopsy. METHODS: We enrolled 186 consecutive children referred to upper endoscopy and intestinal biopsy. One group included 109 patients with positive tTg that was referred for suspected CD. Another group included 77 patients with negative tTg referred because of other indications. All participants had a blood sample taken at the time of endoscopy. Samples were tested with 4 tTg IgA assays on automated analyzers and 1 Elisa kit. All intestinal biopsies were evaluated by a local pathologist, a central pathologist, and a CD expert blinded to each other. CD was diagnosed when full agreement was reached. Analytical performance of the assays included precision with controls and samples, lot to lot variation, and carryover. RESULTS: In our cohort, all tested tTg IgA-automated assays showed sensitivities above 98% and specificities above 99%. ROC analysis demonstrated AUC (area under the curve) >0.99 for all 4 analyzers. The positive-predictive values (PPV) were all >0.99 and negative-predictive values (NPV) were >0.97. The Elisa kit had sensitivity of 95%, specificity of 96%, AUC of 0.96, PPV of 0.98 and NPV of 0.93. CONCLUSION: CD can be accurately diagnosed without biopsy based on tTg IgA levels at least 10 times the ULN using the 4 high-volume random-access analyzers used in our study.

Differentiation of Colonic Inflammatory Bowel Disease: Re-examination of Paediatric Inflammatory Bowel Disease Classes Algorithm With Resected Colon As the Criterion Standard.

OBJECTIVES: Differentiation of Crohn disease (CD) from ulcerative colitis (UC) is challenging when inflammation is predominantly colonic. The paediatric inflammatory bowel disease (PIBD) classes algorithm was developed to bring consistency to labelling, but used physician-assigned diagnosis as the criterion standard. We aimed to reassess the PIBD classes using pathology of subsequently resected colon as the criterion standard. METHOD: Single-centre study of patients diagnosed with colonic IBD between 2002 and 2017 and subsequently treated with colectomy. Baseline pretreatment data were reviewed and the PIBD classes algorithm was independently applied by 2 reviewers to assign a label of UC/IBD-unclassified (IBD-U)/colonic-CD. Concordance between the algorithm-based, precolectomy clinical, and pathologic examination of resected colon diagnosis were assessed. Changes in diagnosis during postcolectomy follow-up were recorded. RESULTS: Sixty-two children underwent colectomy for medically refractory colonic IBD. Diagnosis based on pathologic review of resected colon CD:4;UC:56;IBDU:2. The clinical, PIBD classes algorithm, and colectomy diagnoses were concordant in 51 of 62 patients (81%, Fleiss kappa 0.48). Precolectomy clinical diagnosis was concordant with colectomy diagnosis in 58 of 62 patients (94%, weighted-kappa 0.65). The PIBD classes label was concordant with colectomy diagnosis in 51 of 62 patients (82%, weighted-kappa 0.38); resected colon pathology was typical of UC in 6 patients with PIBD classes label of IBD-U based on single class 2 feature and in 3 with PIBD classes label of CD based on single class 1 feature. CONCLUSIONS: Concordance of PIBD classes algorithm diagnosis applied before colectomy with a diagnostic label based on pathologic examination of a subsequently resected colon is only fair. Caution is needed in stringent application of colonic CD and IBD-U labels based on presence of single feature.

Prevalence and Predictors of Growth Impairment and Short Stature in Pediatric-Onset Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Growth impairment is common in children with inflammatory bowel diseases (IBD). However, the magnitude of short stature at adulthood is not well characterized. We aimed to determine the prevalence and predictors of growth impairment at diagnosis and adulthood in children with IBD. METHODS: Height z-scores at diagnosis of IBD and at adulthood among 291 children with Crohn's disease (CD) and 125 with ulcerative colitis (UC) were retrieved retrospectively and compared to matched controls. Growth impairment at diagnosis was defined as height z-score for age less than or equal to -1 and short stature at adulthood as less than or equal to -2. RESULTS: Mean height z-score at adulthood in subjects with CD or UC was significantly different from controls although mean height did differ in males only (CD 172.3 cm ± 6.7, UC 172.7 cm ± 5.3, controls: 174.2 cm ± 7.3, p = 0.003 and p = 0.047, respectively). Diagnosis prior to final stage of puberty and male gender were risk factors for being short statured at adulthood in CD (mean difference [MD] 2.5, p = 0.013 and MD 6.25, p = 0.001, respectively) and UC (MD 4.9, p = 0.011 and MD 3.3, p = 0.034, respectively). CONCLUSION: Increased proportion of pediatric-onset IBD patients has growth impairment at adulthood. Male gender and diagnosis prior to puberty were found to impose risk for reduced adult height in both diseases.

Micronutrient Deficiencies in Children With Inflammatory Bowel Diseases.

BACKGROUND: Children with inflammatory bowel diseases (IBDs) are at risk of developing nutrition deficiencies, particularly because of reduced intake, restrictive diets, malabsorption, and excessive nutrient loss. In this study, we aimed to assess the status of trace elements, minerals, and vitamins in a large cohort of children with IBDs. METHODS: Medical records of children diagnosed with IBDs during 2000-2016 were reviewed retrospectively. Retrieved data included demographics, disease characteristics, disease activity indices, anthropometric measures, and specific trace elements, minerals, and vitamins at diagnosis and during follow-up. RESULTS: Out of 359 children with IBD (158 [44%] females, median age at diagnosis 14.1 years, interquartile range [IQR] 12.0-16.0), 240 (67%) were diagnosed with Crohn's disease (CD) and 119 (33%) with ulcerative colitis (UC). Median follow-up time was 7 years (IQR 5-10). The prevalence of deficiencies in patients with CD at diagnosis and last follow-up, respectively, were iron (88% and 39.5%), zinc (53% and 11.5%), vitamin D (39% and 36%), and folic acid (10% and 13%). In patients with UC, frequencies were: iron (77% and 40%), vitamin D (49% and 33%), zinc (31% and 10%), and folic acid (3.8% and 9.7%). Magnesium and vitamin B12 deficiencies were rare. For both diseases, iron deficiency was associated with hypoalbuminemia. Deficiencies in iron and zinc were more common in patients with CD than those with UC. CONCLUSIONS: Deficiencies in iron, zinc, and vitamin D are common at pediatric IBD diagnosis with limited improvement during follow-up, whereas deficiencies in magnesium and vitamin B12 are rare.

Combination Therapy of Adalimumab With an Immunomodulator Is Not More Effective Than Adalimumab Monotherapy in Children With Crohn's Disease: A Post Hoc Analysis of the PAILOT Randomized Controlled Trial.

BACKGROUND: The PAILOT trial was a randomized controlled trial aimed to evaluate proactive vs reactive therapeutic drug monitoring in children with Crohn's disease (CD) treated with adalimumab. Our aim in this post hoc analysis of the PAILOT trial was to assess the efficacy and safety of adalimumab combination treatment in comparison with monotherapy at week 72 after adalimumab induction. METHODS: Participants were children 6-17 years old, biologic naïve, with moderate to severe CD, who responded to adalimumab induction at week 4. Patients receiving immunomodulators at baseline maintained a stable dose until week 24; patients could then discontinue immunomodulators. At each visit, patients were assessed for disease index, serum biomarkers, fecal calprotectin, adalimumab trough concentration, and anti-adalimumab antibodies. RESULTS: Out of the 78 patients (29% female; mean age, 14.3 ± 2.6 years), 34 patients (44%) received combination therapy. During the study period, there was no significant difference in the rates of sustained corticosteroid-free clinical remission (25/34, 73%, vs 28/44, 63%; P = 0.35) or sustained composite outcome of clinical remission, C-reactive protein ≤0.5 mg/dL, and calprotectin ≤150 µg/g (10/34, 29%, vs 14/44, 32%; P = 0.77) between the combination group and the monotherapy group, respectively. Clinical and biological outcomes did not differ between the proactive and reactive subgroups within the combination and monotherapy groups. Adalimumab trough concentrations and immunogenicity were not significantly different between groups. The rate of serious adverse events was not significantly different between groups but was numerically higher in the monotherapy group. CONCLUSIONS: Combination therapy of adalimumab and an immunomodulator was not more effective than adalimumab monotherapy in children with CD (ClinicalTrials.gov No. NCT02256462).

Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn's Disease Compared With Reactive Monitoring.

BACKGROUND & AIMS: Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). METHODS: We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 µg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). RESULTS: The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 µg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). CONCLUSIONS: In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.

Musculoskeletal Manifestations as Presenting Symptoms of Inflammatory Bowel Disease in Children and Adolescents.

A comparison of 23 children with inflammatory bowel disease presenting with musculoskeletal symptoms and 46 children with arthritis of other causes yielded significantly higher rates in the inflammatory bowel disease group of sacroiliitis, arthralgia, additive and recurrent arthritis, microcytic anemia, elevated inflammatory markers, and hypoalbuminemia. Clinical awareness of these findings could expedite diagnosis and treatment.