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OBJECTIVES: This study described disease characteristics and long-term outcomes in patients diagnosed with very early onset inflammatory bowel disease (VEOIBD) (diagnosed before 6 years of age) and infantile-IBD (before 2 years). METHODS: Cases from 21 centers worldwide diagnosed with VEOIBD (2008-2018), with minimum 2 years of follow-up, were retrospectively reviewed. RESULTS: The cohort included 243 patients (52% males, median follow-up of 5.8 [range 2-18] years, including 69 [28%]) with infantile-IBD. IBD subtypes included Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU) in 30%, 59%, and 11%, respectively. Among patients with CD, 94% had colonic involvement, and among patients with UC/IBDU, 75% had pancolitis. Patients with infantile-IBD presented with higher rates of IBDU, lower hemoglobin and albumin levels, and higher C-reactive protein, and had lower response rates to first-induction therapy and corticosteroids therapy (P < .05 for all). Colectomy and diversion surgeries were performed in 11% and 4%, respectively, with no significant differences between age groups. Corticosteroid-free remission rates were 74% and 78% after 3 and 5 years, respectively, and 86% at end of follow-up. Genetic testing was performed in 96 (40%) patients. Among tested population, 15 (16%) were identified with monogenic disease. This group demonstrated lower response rates to induction therapies, higher rates of surgical intervention, and higher rates of major infections (P < .05 for all). CONCLUSIONS: Patients with VEOIBD, including infantile-IBD, exhibit low rate of complications and surgical interventions at the long term. Patients with monogenic IBD are at risk for more severe disease course.
Subject(s)
Age of Onset , Humans , Male , Female , Retrospective Studies , Child, Preschool , Infant , Adolescent , Child , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/epidemiology , Inflammatory Bowel Diseases/therapy , Follow-Up Studies , Crohn Disease/diagnosis , Crohn Disease/epidemiology , Crohn Disease/therapy , Crohn Disease/genetics , Crohn Disease/surgery , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/therapy , Colitis, Ulcerative/genetics , Colitis, Ulcerative/surgery , Colitis, Ulcerative/epidemiologyABSTRACT
BACKGROUND AND AIMS: We aimed to identify serum metabolites associated with mucosal and transmural inflammation in pediatric Crohn disease (pCD). METHODS: Fifty-six pCD patients were included through a pre-planned sub-study of the multicenter, prospective, ImageKids cohort, designed to develop the Pediatric Inflammatory Crohn's MRE Index (PICMI). Children were included throughout their disease course when undergoing ileocolonoscopy and magnetic resonance enterography (MRE) and followed for 18 months when MRE was repeated. Serum metabolites were identified using liquid chromatography/mass spectroscopy. Outcomes included: PICMI, the simple endoscopic score (SES), faecal calprotectin (FCP), and C-reactive protein (CRP), to assess transmural, mucosal, and systemic inflammation, respectively. Random forest models were built by outcome. Maximum relevance minimum redundancy (mRMR) feature selection with a j-fold cross validation scheme identified the best subset of features and hyperparameter settings. RESULTS: Tryptophan and glutarylcarnitine were the top common mRMR metabolites linked to pCD inflammation. Random forest models established that amino acids and amines were among the most influential metabolites for predicting transmural and mucosal inflammation. Predictive models performed well, each with an area under the curve (AUC) > 70%. In addition, serum metabolites linked with pCD inflammation mainly related to perturbations in citrate cycle (TCA cycle), aminoacyl-tRNA biosynthesis, tryptophan metabolism, butanoate metabolism, and tyrosine metabolism. CONCLUSIONS: We extend on recent studies, observing differences in serum metabolite between healthy controls and Crohn disease patients, and suggest various associations of serum metabolites with transmural and mucosal inflammation. These metabolites could improve the understanding of pCD pathogenesis and assess disease severity.
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OBJECTIVES: Paediatric and adult inflammatory bowel disease (pIBD, aIBD) patients may lose response to anti-tumour necrosis factor (TNF) treatment within the first year. Adult-extrapolated weight-based dosing is incorrect in children, due to age-related pharmacokinetic differences. We investigated biomarkers for initial and maintenance of response to infliximab (IFX) or adalimumab (ADA), comparing pIBD and aIBD patients. METHODS: In this prospective, observational study, pIBD (n = 24) and aIBD (n = 21) patients were included when initiating anti-TNF. Escalation from standard dosing and continued anti-TNF at 12 and 18 months were assessed. Biomarkers included clinical laboratory parameters, faecal calprotectin (FCP) and IFX trough levels (TLs). Plasma proteomics was performed in pIBD. RESULTS: During our study, treatment escalation (in clinical loss of response) occurred more common in pIBD versus aIBD (p = 0.02). We established that IFX therapy escalation in pIBD patients was not due to low infliximab levels. We identified 9 pro-inflammatory proteins that were elevated in patients losing response. CONCLUSION: Anti-TNF exposure-response relationship may be different in pIBD versus aIBD. No biomarkers for maintained response were identified, but 9 inflammatory proteins were of interest as potential predictors for loss of response in pIBD.
Subject(s)
Adalimumab , Biomarkers , Inflammatory Bowel Diseases , Infliximab , Leukocyte L1 Antigen Complex , Tumor Necrosis Factor-alpha , Humans , Infliximab/therapeutic use , Infliximab/administration & dosage , Prospective Studies , Biomarkers/blood , Male , Female , Adalimumab/therapeutic use , Adalimumab/administration & dosage , Child , Adolescent , Adult , Inflammatory Bowel Diseases/drug therapy , Leukocyte L1 Antigen Complex/analysis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Feces/chemistry , Young Adult , Gastrointestinal Agents/therapeutic use , Treatment OutcomeABSTRACT
Ustekinumab is an effective therapy for adult Crohn's disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn's Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7-17.2) with a median follow-up of 7.4 months (IQR 5.6-11.8). Ninety-nine percent had received prior anti-TNF, 63% ≥ 2 anti-TNFα therapies and 22% vedolizumab. Baseline median wPCDAI was 39 (IQR 25-57.5) (71 (70%) patients with moderate-severe activity). Weeks 12 and 52 CS- and EEN-free remission were both 40.5%. Clinical response at week 6, iv induction route and older age at onset of ustekinumab treatment were predictive factors associated with clinical remission at week 12. Seven minor adverse events probably related to ustekinumab were reported. One patient died from an unrelated cause. Conclusion: Our results suggest that ustekinumab is effective and safe in children with chronically active or refractory CD. What is Known: ⢠Ustekinumab is an effective therapy for adult moderate to severe Crohn's disease (CD). ⢠Off-label use of ustekinumab in children is increasing especially in anti-TNF refractory CD. What is New: ⢠Is the largest cohort of real-world use of ustekinumab in paediatric CD to date. ⢠Clinical response at week 6, iv induction and older age at onset of ustekinumab were predictive factors associated with clinical response at week 12.
Subject(s)
Crohn Disease , Ustekinumab , Humans , Crohn Disease/drug therapy , Ustekinumab/therapeutic use , Male , Female , Retrospective Studies , Adolescent , Child , Treatment Outcome , Remission Induction , Severity of Illness IndexABSTRACT
BACKGROUND: Rare and severe adverse events can occur in children with inflammatory bowel disease (IBD), and the relationship with disease or drug treatment is often uncertain. We aimed to establish a method of reporting adverse events of interest in children with IBD, allowing for estimates of incidence rates with comparison between different regions, and, if possible, to compare with published data on rates of adverse events in children overall. METHODS: For this analysis, we used data from the Paediatric Inflammatory Bowel Disease Network for Safety, Efficacy and Treatment and Quality improvement of care (PIBD-SETQuality) Safety Registry, which collects data on multiple rare and severe adverse events in children younger than 19 years with IBD. Overall, the registry collected data on ten prespecified rare and severe adverse events in children with IBD, as established by a panel of paediatric IBD experts, via reports from paediatric gastroenterologists at participating hospitals between Nov 1, 2016, and March 31, 2023. Reporting physicians, who could only be paediatric gastroenterologists or IBD nurses reporting on behalf of paediatric gastroenterologists, were recruited through invitations sent to both national and international IBD networks and at conferences. Once per month, participating paediatric gastroenterologists received an email with an anonymous and unique link to an online survey asking them to report whether any of ten rare and severe adverse events had occurred in a patient in their paediatric-IBD population in the previous month. Prevalent or retrospective rare and severe adverse events were excluded, as were events occurring in children with an unconfirmed diagnosis of IBD or for whom inflammatory colitis was part of a monogenic immunodeficiency disorder. Duplicates and events that did not meet the definitions and criteria were excluded. Physicians could also report other, non-categorised adverse events if they considered them rare and severe. In case of no response, up to two reminders were sent for each per-month survey. Annual denominator data surveys were sent to obtain the total number of person-years for the estimation of incidence rates, which were calculated via Poisson regression models. FINDINGS: Responses were gathered from 220 paediatric gastroenterologists from 167 centres. 121 centres were in Europe, 23 centres were in North America, 17 centres were in Asia, and six centres were in Oceania. Combined, the total population with paediatric IBD consisted of an estimated 30 193 children with 114 528 person-years of follow-up. 451 adverse events were initially reported. After excluding and reorganising adverse events, 402 were eligible; 261 (65%) were categorised and 141 (35%) were non-categorised. The most frequently reported adverse events were venous-thromboembolic events (n=66), renal failure (n=43), opportunistic infections (n=42), and cancer (n=33). Haemophagocytic lymphohistiocytosis (n=4) and liver failure (n=3) were the least frequently reported adverse events. Incidence rates per 10 000 person-years were 5·50 (95% CI 4·25-6·97) for venous-thromboembolic events, 3·75 (2·74-4·99) for renal failure, 3·67 (2·67-4·89) for opportunistic infection, and 2·88 (2·01-3·98) for cancer. Of 66 venous-thromboembolic events, 31 (47%) involved cerebral venous sinus thrombosis at an incidence rate of 2·71 (95% CI 1·86-3·77). INTERPRETATION: The PIBD-SETQuality Safety Registry enabled us to identify incidence rates of rare and severe adverse events in children with IBD. Our findings can guide physicians and enhance awareness of the incidence of adverse events in children with IBD that are considered to be rare. FUNDING: EU Horizon 2020 Research and Innovation Programme.
Subject(s)
Inflammatory Bowel Diseases , Registries , Humans , Child , Inflammatory Bowel Diseases/drug therapy , Adolescent , Male , Female , Incidence , Child, Preschool , Drug-Related Side Effects and Adverse Reactions/epidemiology , InfantABSTRACT
BACKGROUND: Data on cost-effectiveness of first-line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed. AIM: To investigate the cost-effectiveness of first-line infliximab compared to conventional treatment in children with moderate-to-severe Crohn's disease. METHODS: We included patients from the Top-down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate-to-severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks. RESULTS: We included 89 patients (44 in the first-line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were 36,784 for first-line infliximab treatment and 36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first-line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03-2.35, p = 0.036). CONCLUSIONS: First-line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate-to-severe Crohn's disease. TRIAL REGISTRATION NUMBER: NCT02517684.
Subject(s)
Biosimilar Pharmaceuticals , Cost-Benefit Analysis , Crohn Disease , Gastrointestinal Agents , Infliximab , Humans , Crohn Disease/drug therapy , Crohn Disease/economics , Infliximab/economics , Infliximab/therapeutic use , Male , Female , Child , Adolescent , Gastrointestinal Agents/economics , Gastrointestinal Agents/therapeutic use , Biosimilar Pharmaceuticals/economics , Biosimilar Pharmaceuticals/therapeutic use , Treatment Outcome , Azathioprine/therapeutic use , Azathioprine/economics , Immunosuppressive Agents/economics , Immunosuppressive Agents/therapeutic use , Adrenal Cortex Hormones/therapeutic use , Adrenal Cortex Hormones/economics , Adrenal Cortex Hormones/administration & dosage , Health Care Costs/statistics & numerical dataABSTRACT
Stratified and precision nutrition refers to disease management or prevention of disease onset, based on dietary interventions tailored to a person's characteristics, biology, gut microbiome, and environmental exposures. Such treatment models may lead to more effective management of inflammatory bowel disease (IBD) and reduce risk of disease development. This societal position paper aimed to report advances made in stratified and precision nutritional therapy in IBD. Following a structured literature search, limited to human studies, we identified four relevant themes: (a) nutritional epidemiology for risk prediction of IBD development, (b) food-based dietary interventions in IBD, (c) exclusive enteral nutrition (EEN) for Crohn's disease (CD) management, and (d) pre- and probiotics for IBD management. There is scarce literature upon which we can make recommendations for precision or stratified dietary therapy for IBD, both for risk of disease development and disease management. Certain single-nucleotide polymorphisms related to polyunsaturated fatty acid (PUFA) metabolism may modify the effect dietary PUFA have in increasing the risk of IBD development. Non-colonic CD, mild-to-moderate CD, and high microbiota richness may predict success of EEN and may be used both for prediction of treatment continuation, but also for early cessation in nonresponders. There is currently insufficient evidence to make recommendations for precision or stratified dietary therapy for patients with established IBD. Despite the great interest in stratified and precision nutrition, we currently lack data to support conclusive recommendations. Replication of early findings by independent research groups and within structured clinical interventions is required.
Subject(s)
Crohn Disease , Inflammatory Bowel Diseases , Humans , Child , Translational Research, Biomedical , Public Opinion , Inflammatory Bowel Diseases/therapy , Crohn Disease/therapy , Remission Induction , Allied Health PersonnelABSTRACT
BACKGROUND: The use of concomitant azathioprine may improve efficacy and pharmacokinetic (PK) properties of infliximab (IFX) but is also associated with an increased risk of adverse events. Proactive therapeutic drug monitoring (pTDM) of IFX monotherapy is an alternative strategy to improve PK. The aim of this study was to evaluate whether IFX with an immunomodulator (combo) has PK benefits over IFX-pTDM (mono) in pediatric Crohn's disease (CD). METHODS: This PK analysis included pediatric CD patients who started either IFX combo (TISKids study) or IFX mono with pTDM (REFINE cohort). Combo and mono IFX trough levels (TLs) and antibodies-to-infliximab were assessed at infusion 3, 4, and 5. A population PK model was built to compare IFX PK outcomes (clearance [CL], TLs and cumulative exposure) between combo and mono groups at infusion 4 and 5. Clinical response and steroid-free clinical remission (SFCR) was assessed at infusion 4 and 5. RESULTS: This study included 128 pediatric CD patients (66 mono and 62 combo). At infusion 5, there was no significant difference between mono and combo median TLs 4.1 µg/mL (2.1, 7.8) vs 5.9 µg/mL (3.2, 9.4; P = .14) or median CL 0.26 L/d (0.21, 0.32) vs 0.26 L/d (0.21, 0.33; P = .81). Mono patients had a lower SFCR rate at infusion 5 (53% [31 of 59] vs 80% [32 of 40]; P = .01). Clinical response rates were significantly higher among combo than mono patients at both infusion 4 and 5. CONCLUSIONS: This study suggests that there are no PK differences (TLs and CL) between combo and mono therapy in pediatric CD patients who started IFX.
This study compared the pharmacokinetics of infliximab combination therapy with azathioprine vs infliximab with proactive therapeutic drug monitoring as monotherapy among pediatric patients with Crohn's disease within the first 22 weeks. No pharmacokinetic differences were found between monotherapy and combination therapy.
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BACKGROUND: Current data on dual biologic therapy in children are limited. This multicenter study aimed to evaluate the effectiveness and safety of dual therapy in pediatric patients with inflammatory bowel disease (IBD). METHODS: A retrospective study from 14 centers affiliated with the Pediatric IBD Interest and Porto Groups of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. Included were children with IBD who underwent combinations of biologic agents or biologic and small molecule therapy for at least 3 months. Demographic, clinical, laboratory, endoscopic, and imaging data were collected. Adverse events were recorded. RESULTS: Sixty-two children (35 Crohn's disease, 27 ulcerative colitis; median age 15.5 [interquartile range, 13.1-16.8] years) were included. They had all failed previous biologic therapies, and 47 (76%) failed at least 2 biologic agents. The dual therapy included an anti-tumor necrosis factor agent and vedolizumab in 30 children (48%), anti-tumor necrosis factor and ustekinumab in 21 (34%) children, vedolizumab and ustekinumab in 8 (13%) children, and tofacitinib with a biologic in 3 (5%) children. Clinical remission was observed in 21 (35%), 30 (50%), and 38 (63%) children at 3, 6, and 12 months, respectively. Normalization of C-reactive protein and decrease in fecal calprotectin to <250 µg/g were achieved in 75% and 64%, respectively, at 12 months of follow-up. Twenty-nine (47%) children sustained adverse events, 8 of which were regarded as serious and led to discontinuation of therapy in 6. CONCLUSIONS: Dual biologic therapy may be effective in children with refractory IBD. The potential efficacy should be weighed against the risk of serious adverse events.
This multicenter study describes 62 children with refractory inflammatory bowel disease who received dual biologic therapy. Clinical remission was observed in 21 (35%), 30 (50%), and 38 (63%) children at 3, 6, and 12 months, respectively. Several serious adverse events were reported.
Subject(s)
Biological Products , Colitis, Ulcerative , Inflammatory Bowel Diseases , Humans , Child , Adolescent , Ustekinumab/therapeutic use , Retrospective Studies , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/chemically induced , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/chemically induced , Biological Products/therapeutic use , Necrosis/chemically induced , Necrosis/drug therapyABSTRACT
BACKGROUND & AIMS: Treatment guidelines for paediatric Crohn's disease (CD) suggest early use of anti-tumour necrosis factor alpha (anti-TNF) in high-risk individuals. The aim is to evaluate the effect of early anti-TNF in a real-world cohort. METHODS: Children with newly-diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF (<90 days after diagnosis) and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission (SSFR) without treatment intensification (specified as SSFR*) and sustained steroid-free mild/inactive disease without treatment intensification (specified as SSFMI*). Penalised logistic regression model-based standardisation was applied to estimate the relative risks (RR) of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients based on presence of predictors of poor outcome (POPOs) and disease activity at diagnosis. RESULTS: In total, 331 children (median age 13.9 years [IQR 12.2 - 15.3]) were enrolled, with 135 (41%) receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* (30% vs. 14%, p<0.001) and SSFMI* (69% vs. 33%, p<0.001), with RRs of 2.95 (95%CI 1.63-5.36) and 4.67 (95%CI 2.46-8.87) respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared to mild/inactive disease at diagnosis (5.50 [95%CI 2.51-12.05]) vs. 2.91 [95%CI 0.92-9.11]), and those with any POPO compared to no POPO (5.05 [95%CI 2.45-10.43] vs. 3.41 [95%CI 0.54-21.7]). CONCLUSION: In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients.
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Owing to advances in genomics that enable differentiation of molecular aetiologies, patients with monogenic inflammatory bowel disease (mIBD) potentially have access to genotype-guided precision medicine. In this Expert Recommendation, we review the therapeutic research landscape of mIBD, the reported response to therapies, the medication-related risks and systematic bias in reporting. The mIBD field is characterized by the absence of randomized controlled trials and is dominated by retrospective observational data based on case series and case reports. More than 25 off-label therapeutics (including small-molecule inhibitors and biologics) as well as cellular therapies (including haematopoietic stem cell transplantation and gene therapy) have been reported. Heterogeneous reporting of outcomes impedes the generation of robust therapeutic evidence as the basis for clinical decision making in mIBD. We discuss therapeutic goals in mIBD and recommend standardized reporting (mIBD REPORT (monogenic Inflammatory Bowel Disease Report Extended Phenotype and Outcome of Treatments) standards) to stratify patients according to a genetic diagnosis and phenotype, to assess treatment effects and to record safety signals. Implementation of these pragmatic standards should help clinicians to assess the therapy responses of individual patients in clinical practice and improve comparability between observational retrospective studies and controlled prospective trials, supporting future meta-analysis.
Subject(s)
Precision Medicine , Humans , Prospective Studies , Retrospective StudiesABSTRACT
OBJECTIVES: Transition readiness can predict a successful transition from pediatric to adult care. This study aimed to validate and develop age-dependent reference scores for the (Dutch version of) Transition Readiness Assessment Questionnaire (TRAQ), in adolescents and young adults (AYAs) with inflammatory bowel disease (IBD). METHODS: TRAQ has 20 items (score 1-5) distributed over 5 domains (total sum score 100) and is completed by AYAs. Following the COnsensus-based Standards for the selection of health Measurement INstruments methodology, we conducted the translation, back-to back translation, pretesting, and validation of the final Dutch version of TRAQ (TRAQ-NL) questionnaire. We used a Rasch model for structural validation, hypothesis testing for construct validity, and Cronbach alpha to demonstrate reliability. Reference scores were calculated using percentiles. RESULTS: Two hundred fifty TRAQ questionnaires were evaluated in 136 AYAs with IBD [56% Crohn disease, 58% male, median age 17.5 years (range 15.7-20.4)]. The overall mean item score was 3.87 (range 1.45-5). With good reliability (Cronbach alpha 0.87), TRAQ-NL discriminated well between knowledge levels, especially in the lower levels. Transition readiness was defined as low, moderate, adequate, or excellent in patients with TRAQ percentile scores (PC) <25th (<3.375 mean item score), 25th-50th (3.375-3.9), 50th-90th (3.91-4.7), or >90th (>4.7). Younger patients, concomitant illness, fewer visits to the transition clinic, and parental dependence were associated with significantly lower TRAQ scores. CONCLUSION: TRAQ(-NL) is reliable and valid, with age-dependent PC to identify (in)adequate transfer readiness. TRAQ can now be more easily used as a patient-reported outcome measure to monitor transition readiness longitudinally in routine care for AYAs IBD patients.
Subject(s)
Crohn Disease , Inflammatory Bowel Diseases , Transition to Adult Care , Humans , Male , Adolescent , Young Adult , Child , Adult , Female , Reproducibility of Results , Surveys and Questionnaires , Inflammatory Bowel Diseases/diagnosis , Crohn Disease/diagnosisABSTRACT
BACKGROUND: Several studies have proposed models to predict disease outcomes in paediatric ulcerative colitis (UC), notably PROTECT, Schechter and PIBD-ahead, but none has been validated by external cohorts AIM: To explore these models in a prospective multicentre inception cohort METHODS: Children newly diagnosed with UC in 17 centres were followed at disease onset and 3 and 12 months thereafter, as well as at last visit. Outcomes included steroid-free remission (SFR) and acute severe colitis (ASC). RESULTS: Of the 223 included children, 74 (34%), 97 (43%) and 52 (23%) presented with mild, moderate and severe disease, respectively. SFR rate was 35% at 3 months and 47% at 12 months (62% of those with mild disease at diagnosis vs. 41% in moderate-severe disease; p = 0.01). Thirty-six (16%) children developed ASC during the first month after diagnosis, and 53 (24%) during the first year. The AUC of the PROTECT model for predicting SFR at 3 and 12 months was 0.78 [95% CI 0.65-0.92] and 0.57 [95% CI 0.47-0.66], respectively. The sensitivity/specificity/PPV/NPV of Schechter's criteria to predict sustained SFR at 12 months was 50%/60%/35%/74%. ASC was predicted only by the PUCAI score at diagnosis and at 3 months. CONCLUSIONS: The PROTECT model had a good predictive utility for SFR at 3 months, but not at 12 months. The other predictive models did not achieve sufficient accuracy, which was far from that reported in the original studies. This highlights the necessity for external validation of any prediction model prior to its implementation into clinical practice.
Subject(s)
Colitis, Ulcerative , Child , Humans , Prospective Studies , Colitis, Ulcerative/diagnosisABSTRACT
BACKGROUND: Despite its efficacy, rational guidance for starting/stopping first-line biologic treatment in individual paediatric Crohn's disease [CD] patients is needed. We assessed how serum immune profiles before and after first-line infliximab [FL-IFX] or conventional [CONV] induction therapy associate with disease remission at week 52. METHODS: Pre- [nâ =â 86], and 10-14-week post-treatment [nâ =â 84] sera were collected from patients with moderate-to-severe paediatric CD in the TISKids trial, randomized to FL-IFX [nâ =â 48; five 5-mg/kg infusions over 22 weeks] or CONV [nâ =â 43; exclusive enteral nutrition or oral prednisolone]; both groups received azathioprine maintenance. The relative concentrations of 92 inflammatory proteins were determined with Olink Proteomics; fold changes [FC] with |log2FC| > 0.5 after false discovery rate adjustment were considered significant. RESULTS: FL-IFX modulated a larger number of inflammatory proteins and induced stronger suppression than CONV; 18/30 proteins modulated by FL-IFX were not regulated by CONV. Hierarchical clustering based on IFX-modulated proteins at baseline revealed two clusters of patients: CD-hi patients had significantly higher concentrations of 23/30 IFX-modulated proteins [including oncostatin-M, TNFSF14, HGF and TGF-α], and higher clinical disease activity, C-reactive protein and blood neutrophils at baseline than CD-lo patients. Only 24% of CD-hi FL-IFX-treated patients maintained remission without escalation at week 52 vs 58% of CD-lo FL-IFX-treated patients. Similarly, 6% of CD-hi CONV-treated patients achieved remission vs 20% of CONV-treated CD-lo patients. Clustering based on immune profiles post-induction therapy did not relate to remission at week 52. CONCLUSION: FL-IFX leads to stronger reductions and modulates more immune proteins than CONV. Stratification on pre-treatment profiles of IFX-modulated proteins directly relates to maintenance of remission without treatment escalation. TRIAL REGISTRATION NUMBER: NCT02517684.
Subject(s)
Crohn Disease , Child , Humans , Infliximab/therapeutic use , Crohn Disease/metabolism , Azathioprine/therapeutic use , C-Reactive Protein , Remission Induction , Treatment Outcome , Gastrointestinal Agents/therapeutic useABSTRACT
OBJECTIVE/BACKGROUND: Endoscopic balloon dilatation (EBD) has been shown to be effective and safe in adults with stricturing Crohn disease (CD) yet pediatric data is sparse. We aimed to assess efficacy and safety of EBD in stricturing pediatric CD. METHODS: International collaboration included 11 centers from Europe, Canada, and Israel. Recorded data included patient demographics, stricture features, clinical outcomes, procedural adverse events, and need for surgery. Primary outcome was surgery-free over 12 months and secondary outcomes were clinical response and adverse events. RESULTS: Eighty-eight dilatations were performed over 64 dilatation series in 53 patients. Mean age at CD diagnosis was 11.1 (±4.0) years, stricture length 4 cm [interquartile range (IQR) 2.8-5], and bowel wall thickness 7 mm (IQR 5.3-8). Twelve of 64 (19%) patients underwent surgery in the year following the dilatation series, at a median of 89 days (IQR 24-120; range 0-264) following EBD. Seven of 64 (11%) had subsequent unplanned EBD over the year, of whom two eventually underwent surgical resection. Two of 88 (2%) perforations were recorded, 1 of whom was managed surgically, and 5 patients had minor adverse events managed conservatively. There was a significant improvement in all clinical measures following EBD with weighted pediatric CD activity index-defined remission increasing from 13% at baseline to 44%, 46%, and 61%, and absence of obstructive symptoms in 55%, 53%, and 64% of patients at week 2, 8, and 24 respectively. CONCLUSIONS: In this largest study of EBD in pediatric stricturing CD to date, we demonstrated that EBD is effective in relieving symptoms and avoiding surgery. Adverse events rates were low and consistent with adult data.