Rare and severe adverse events in children with inflammatory bowel disease: analysis of data from the PIBD-SETQuality Safety Registry.

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.

Risk factors for surgery in stricturing small bowel Crohn's disease: A retrospective cohort study from the GETAID pédiatrique.

OBJECTIVES: Previous studies have shown rates of surgical resection of up to 41% in stricturing pediatric Crohn's disease (CD). In this retrospective multicenter study, our aims were to identify clinical risk factors and magnetic resonance enterography (MRE) features of small bowel strictures associated with surgery. METHODS: Pediatric patients with symptomatic stricturing small bowel CD (defined as obstructive symptoms or proximal dilatation on MRE) confirmed by MRE between 2010 and 2020 were recruited from 12 French tertiary hospitals. Patient characteristics were compared by surgical outcome multivariable Cox regression. RESULTS: Fifty-six patients (61% boys) aged 12.2 ± 2.7 years at diagnosis of CD were included. Median duration of CD before diagnosis of stricture was 11.7 months (interquartile range [IQR]: 25-75: 1.2-29.9). Nineteen (34%) patients had stricturing phenotype (B2) at baseline. Treatments received  before stricture diagnosis included MODULEN-IBD (n = 31), corticosteroids (n = 35), antibiotics (n = 10), anti-TNF (n = 27), immunosuppressants (n = 28). Thirty-six patients (64%) required surgery, within 4.8 months (IQR: 25-75: 1.8-17.3) after stricture diagnosis. Parameters associated with surgical resection were antibiotic exposure before stricture diagnosis (adjusted odds ratio [aOR]: 15.62 [3.35-72.73], p = 0.0005), Crohn's disease obstructive symptoms score (CDOS) > 4 (aOR: 3.04 [1.15-8.03], p = 0.02) and dilation proximal to stricture >28 mm (aOR: 3.62 [1.17-11.20], p = 0.03). CONCLUSION: In this study, antibiotic treatment before stricture diagnosis, intensity of obstructive symptoms, and diameter of dilation proximal to small bowel stricture on MRE were associated with risk for surgical resection.

Efficacy of infliximab after loss of response of/intolerance to adalimumab in pediatric Crohn's disease: A retrospective multicenter cohort study of the "GETAID pédiatrique".

BACKGROUND: Infliximab (IFX) and adalimumab (ADA) are recommended for induction and maintenance of remission in pediatric Crohn's disease (CD). ADA is now often used in first line due to its efficacy and tolerability, but a loss of response (LOR) can occur over time. The aim was to assess the efficacy of IFX as second line therapy after LOR or intolerance to ADA in pediatric CD patients at 1 year. METHODS: We conducted a retrospective and multicenter study in France among the "GETAID pédiatrique" centers between April 2019 and April 2022. CD patients under 18 years old and treated with IFX after ADA failure or intolerance were included. We collected anthropometric, clinical, and biological data at baseline (start of IFX), at 6 and 12 months. Clinical remission was defined by a Weighted Pediatric CD Activity Index (wPCDAI) score less than 12.5 points. RESULTS: Of the 32 patients included in our study, 27 (84.4%) were still on IFX at 12 months of the switch. Among them, 13 had discontinued ADA because of a LOR, 12 for insufficient response and 2 due to primary nonresponse. At M12, 22 patients were in corticosteroid free clinical remission (68.7%). Under IFX, the wPCDAI decreased over time (47.5 ± 24.1, 16.6 ± 21.2 and 9.7 ± 19.0 at M0, M6 and M12 respectively). The only factor associated with clinical remission at 12 months was absence of perianal disease at the end of the IFX induction. CONCLUSIONS: IFX is effective in maintaining remission at 1 year in pediatric CD patients experiencing a LOR or intolerance with ADA, and IFX could be an interesting therapeutic choice instead of other biologics in this situation.

Improved clinical outcomes with early anti-tumour necrosis factor alpha therapy in children with newly diagnosed Crohn's disease: real world data from the international prospective PIBD-SETQuality inception cohort study.

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.

Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards.

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.

Adalimumab Therapy in Pediatric Crohn Disease: A 2-Year Follow-Up Comparing "Top-Down" and "Step-Up" Strategies.

OBJECTIVES: European Crohn's Colitis Organization (ECCO) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines recommend the early use of anti-tumor necrosis factor (TNF) biologicals in pediatric Crohn disease (CD) patients with positive predictors for poor outcome. The objective of the present study was to compare early "Top-Down" use of adalimumab (ADA) immunomodulator/biologics-naive patients to conventional "Step-Up" management. METHODS: One hundred and twenty consecutive patients with a confirmed diagnosis of CD and treated with ADA between 2008 and 2019 were included and allocated to the ADA-Top Down (n = 59) or ADA-Step Up group (n = 61). The primary endpoint was prolonged steroid-/enteral nutrition-free clinical remission at 24 months, defined by a weighted Pediatric Crohn's Disease Activity Index (wPCDAI) < 12.5. Clinical and biological data were collected at 12 and 24 months. RESULTS: At start of ADA, disease activity was comparable between the ADA-Top Down group and the ADA-Step Up group (wPCDAI = 31 ± 16 vs 31.3 ± 15.2, respectively, P = 0.84). At 24 months, the remission rate was significantly higher in the ADA-Top Down group (73% vs 51%, P < 0.01). After propensity score, the Top-Down strategy is still more effective than the Step-Up strategy in maintaining remission at 24 months [hazard ratio (HR) = 0.36, 95% CI (0.15-0.87), P = 0.02]. Patients in the ADA-Top Down group were mainly on monotherapy compared to patients in the ADA-Step Up group (53/55 vs 28/55 respectively, P < 0.001). Serum levels of ADA were higher in the ADA-Top Down group than in the ADA-Step Up group (12.8 ± 4.3 vs 10.4 ± 3.9 µg/mL, respectively, P < 0.01). There were no serious adverse events. CONCLUSIONS: Early use of ADA appears to be more effective in maintaining relapse-free remission at 2 years, while using it as monotherapy. These findings further favor the recommendation of early anti-TNF use in high-risk CD patients.

Paediatric Inflammatory Bowel Disease: A Multi-Stakeholder Perspective to Improve Development of Drugs for Children and Adolescents.

BACKGROUND AND AIMS: Despite recent approvals for new drugs to treat adults with Crohn's disease or ulcerative colitis, there are only two approved advanced treatment options [infliximab and adalimumab] for children with inflammatory bowel disease [IBD]. There are many potential new therapies being developed for adult and paediatric IBD. Moreover, regulatory agencies in both the European Union and USA have processes in place to support the early planning and initiation of paediatric studies. Nevertheless, unacceptable delays in approvals for use of drugs in children persist, with an average 7-year gap, or longer, between authorization of new IBD drugs for adults and children. METHODS: A 2-day virtual meeting was held during April 14-15, 2021 for multi-stakeholders [clinical academics, patient community, pharmaceutical companies and regulators] to discuss their perspectives on paediatric drug development for IBD. RESULTS: The multi-stakeholder group presented, discussed and proposed actions to achieve expediting the approval of new drugs in development for paediatric IBD. CONCLUSIONS: Collaborative action points for all stakeholders are required to make progress and facilitate new drug development for children with IBD.

A critical review of adalimumab for the treatment of moderate-to-severe active ulcerative colitis in children.

INTRODUCTION: Anti-tumor necrosis factor (TNF) antibodies play a major role in treating inflammatory bowel disease (IBD), both in adult and pediatric patients. While there is a large number of studies on efficacy and safety of infliximab in treating children and adolescents with ulcerative colitis (UC), data on adalimumab (ADA) are scarce. AREAS COVERED: Here, we review published case reports, cohort and real-time data, as well as the first randomized trial, ENVISION I, using ADA for treating pediatric UC. Available evidence confirms good efficacy in inducing and maintaining remission in children and adolescents with UC, with even higher response rates compared to adult UC. ENVISION I showed that in UC patients responding to ADA induction therapy, almost half of the patients remained in remission after 52 weeks of therapy on high-dosing ADA (weekly administration). As already well experienced with other biologics, dosing schemes are different between pediatric and adult patients, with children often requiring higher dosing. EXPERT OPINION: Further data are required to better understand how to optimize ADA therapy. The present and still-growing evidence places subcutaneous (sc.) anti-TNF-medication as alternative first-line therapy also for pediatric UC. This is also reflected by the preference for sc. medication of adolescent patients allowing less frequent and autonomous drug administration.

Development, Validation, and Evaluation of the Pediatric Inflammatory Crohn's Magnetic Resonance Enterography Index From the ImageKids Study.

BACKGROUND & AIMS: Cross-sectional imaging is important in the assessment of transmural inflammation in Crohn's disease (CD). Small bowel involvement is often more extensive in pediatric CD, requiring a panentering measuring tool. We undertook to develop a magnetic resonance enterography (MRE)-based index that would measure inflammation in all segments of the intestine, without rectal contrast. METHODS: Children with CD underwent ileocolonoscopy and MRE and half were prospectively followed for 18 months when MRE was repeated. Item generation and reduction were performed by a Delphi panel of pediatric radiologists, a systematic literature review, a cross-sectional study of 48 MREs, and a steering committee. Formatting and weighting were performed using multivariate modeling adjusted by a steering committee. MREs were read locally and centrally. Reliability, validity, and responsiveness were determined using several clinimetric and psychometric approaches. RESULTS: Thirty items were initially generated and reduced to 5 using regression analysis on 159 MREs: wall thickness, wall diffusion weighted imaging, ulcerations, mesenteric edema, and comb sign. In the validation cohort of 81 MREs, the weighted global PICMI correlated well with the radiologist global assessment (r = 0.85; P < .001) and with the simple endoscopic score in a subsample with ileocolonic disease (r = 0.63; P < .001). Interobserver and test-retest reliability were high (interclass correlation coefficients, 0.84; 95% confidence interval [CI], 0.79-0.87; and 0.81, 95% CI, 0.65-0.90, respectively; both P < .001). Excellent responsiveness was found at repeated visits (n = 116 MREs; area under the receiver operating characteristic curve 0.96; 95% CI, 0.93-0.99). Transmural healing was defined as PICMI ≤10 and response as a change of >20 points with excellent discriminative validity (area under the receiver operating characteristic curve = 0.96; 95% CI, 0.93-0.99). CONCLUSIONS: The PICMI is a valid, reliable, and responsive index for assessing transmural inflammation in pediatric CD. It scores the entire bowel length and does not require intravenous contrast or rectal enema and, therefore, is suitable for use in children. (ClinicalTrials.gov, Number: NCT01881490.).

Pharmacokinetics, Safety and Efficacy of Intravenous Vedolizumab in Paediatric Patients with Ulcerative Colitis or Crohn's Disease: Results from the Phase 2 HUBBLE Study.

BACKGROUND AND AIMS: To date, there are no systematic pharmacokinetic [PK] data on vedolizumab in paediatric inflammatory bowel disease [IBD]. We report results from HUBBLE, a dose-ranging, phase 2 trial evaluating the PK, safety and efficacy of intravenous vedolizumab for paediatric IBD. METHODS: Enrolled patients [aged 2-17 years] with moderate to severe ulcerative colitis [UC] or Crohn's disease [CD] and body weight ≥10 kg were randomized by weight to receive low- or high-dose vedolizumab [≥30 kg, 150 or 300 mg; <30 kg, 100 or 200 mg] on Day 1 and Weeks 2, 6 and 14. Week 14 assessments included PK, clinical response and exposure-response relationship. Safety and immunogenicity were assessed. RESULTS: Randomized patients weighing ≥30 kg [UC, n = 25; CD, n = 24] and <30 kg [UC, n = 19; CD, n = 21] had a baseline mean [standard deviation] age of 13.5 [2.5] and 7.6 [3.2] years, respectively. In almost all indication and weight groups, area under the concentration curve and average concentration increased ~2-fold from low to high dose; the trough concentration was higher in each high-dose arm compared with the low-dose arms. At Week 14, clinical response occurred in 40.0-69.2% of patients with UC and 33.3-63.6% with CD in both weight groups. Clinical responders with UC generally had higher trough concentration vs non-responders, while this trend was not observed in CD. Fourteen per cent [12/88] of patients had treatment-related adverse events and 6.8% [6/88] had anti-drug antibodies. CONCLUSIONS: Vedolizumab exposure increased in an approximate dose-proportional manner. No clear dose-response relationship was observed in this limited cohort. No new safety signals were identified.

Increased Use of Anti-Tumor Necrosis Factor Following the Implementation of the ECCO-ESPGHAN Guidelines and its Impact on the Outcome of Pediatric Crohn's Disease: A Retrospective Single-Center Study.

OBJECTIVES: The first ECCO-ESPGHAN guidelines for the medical management of pediatric Crohn disease (CD) were published in 2014. Whether their implementation, and the consequent increased use of an upfront anti-tumor necrosis factor therapy, have changed the course of the disease has not been investigated yet. We aimed at comparing the evolution of pediatric CD patients diagnosed and treated before and after 2014. METHODS: Single-center retrospective study including all children diagnosed with CD from January 2010 to December 2018. Patients diagnosed between 2010 and 2014 (group 1) were compared to those diagnosed after 2014 (group 2). For each patient, at baseline and every 6-month, number of relapses, the occurrence of complication, therapy received and biological parameters were noted, as well as any endoscopic or radiologic evaluation. RESULTS: One hundred and fifty-four patients were included in the analysis, 78 (51%) diagnosed after 2014. The cumulative probability of a relapse-free and surgery-free course was significantly higher for patients treated according to the guidelines (log rank hazard ratio [HR] = 1,818, P = 0.003 and HR = 3,15, 95% confidence interval, P = 0.04, respectively). Mucosal healing rate was significantly higher among patients of group 2 at 1 and 2 years (P = 0.04 and P = 0.05, respectively), while no significant difference was observed for transmural healing rates, as well as for the risk of complications. CONCLUSIONS: The implementation of the 2014 CD guidelines appears to have a significant impact on disease outcomes, with a significantly lower risk for relapse and surgery, while no effect could be observed on the risk of developing complications.

Intestinal immunoregulation: lessons from human mendelian diseases.

The mechanisms that maintain intestinal homeostasis despite constant exposure of the gut surface to multiple environmental antigens and to billions of microbes have been scrutinized over the past 20 years with the goals to gain basic knowledge, but also to elucidate the pathogenesis of inflammatory bowel diseases (IBD) and to identify therapeutic targets for these severe diseases. Considerable insight has been obtained from studies based on gene inactivation in mice as well as from genome wide screens for genetic variants predisposing to human IBD. These studies are, however, not sufficient to delineate which pathways play key nonredundant role in the human intestinal barrier and to hierarchize their respective contribution. Here, we intend to illustrate how such insight can be derived from the study of human Mendelian diseases, in which severe intestinal pathology results from single gene defects that impair epithelial and or hematopoietic immune cell functions. We suggest that these diseases offer the unique opportunity to study in depth the pathogenic mechanisms leading to perturbation of intestinal homeostasis in humans. Furthermore, molecular dissection of monogenic intestinal diseases highlights key pathways that might be druggable and therapeutically targeted in common forms of IBD.

Inflammatory Bowel Disease in Patients with Congenital Chloride Diarrhoea.

BACKGROUND: Congenital chloride diarrhoea [CLD] is a rare autosomal recessive disease caused by mutations in the solute family carrier 26 member 3 [SLC26A3] gene. Patients suffer from life-long watery diarrhoea and chloride loss. Inflammatory bowel disease [IBD] has been reported in individual patients with CLD and in scl26a3-deficient mice. METHODS: We performed an international multicentre analysis to build a CLD cohort and to identify cases with IBD. We assessed clinical and genetic characteristics of subjects and studied the cumulative incidence of CLD-associated IBD. RESULTS: In a cohort of 72 patients with CLD caused by 17 different SLC26A3 mutations, we identified 12 patients [17%] diagnosed with IBD. Nine patients had Crohn's disease, two ulcerative colitis and one IBD-unclassified [IBD-U]. The prevalence of IBD in our cohort of CLD was higher than the highest prevalence of IBD in Europe [p < 0.0001]. The age of onset was variable [13.5 years, interquartile range: 8.5-23.5 years]. Patients with CLD and IBD had lower z-score for height than those without IBD. Four of 12 patients had required surgery [ileostomy formation n = 2, ileocaecal resection due to ileocaecal valve stenosis n = 1 and colectomy due to stage II transverse colon cancer n = 1]. At last follow-up, 5/12 were on biologics [adalimumab, infliximab or vedolizumab], 5/12 on immunosuppressants [azathioprine or mercaptopurine], one on 5-ASA and one off-treatment. CONCLUSIONS: A substantial proportion of patients with CLD develop IBD. This suggests the potential involvement of SL26A3-mediated anion transport in IBD pathogenesis. Patients with CLD-associated IBD may require surgery for treatment failure or colon cancer.

Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND: It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups. METHODS: The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists). RESULTS: We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries. CONCLUSIONS: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.

Physician Practice Patterns in Holding Inflammatory Bowel Disease Medications due to COVID-19, in the SECURE-IBD Registry.

BACKGROUND: We aimed to describe physician practice patterns in holding or continuing IBD therapy in the setting of COVID-19 infection, using the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease [SECURE-IBD] registry. METHODS: IBD medications that were stopped due to COVID-19 were recorded in the SECURE-IBD registry in addition to demographic and clinical data. We conducted descriptive analyses to understand characteristics associated with stopping IBD medications in response to active COVID-19 infection. RESULTS: Of 1499 patients, IBD medications were stopped in 518 [34.6%] patients. On bivariate and multivariable analyses, a diagnosis of ulcerative colitis or IBD-unspecified was associated with a lower odds of stopping medication compared with Crohn's disease (adjusted odds ratio [aOR] 0.6, 95% confidence interval [CI] 0.48, 0.75). When evaluating specific medications, 5-aminosalicylic acid was more likely to be continued [p <0.001] whereas anti-tumour necrosis factor therapy and immunomodulator therapy were more likely to be stopped [global p <0.001]. Other demographic and clinical characteristics did not affect prescription patterns. CONCLUSIONS: IBD medications other than immunomodulators were continued in the majority of IBD patients with COVID-19, in the international SECURE-IBD registry. Future studies are needed to understand the impact of stopping or continuing IBD medications on IBD- and COVID-19 related outcomes.

Infections in Patients with Chronic Granulomatous Disease Treated with Tumor Necrosis Factor Alpha Blockers for Inflammatory Complications.

PURPOSE: Management of inflammatory complications of chronic granulomatous disease (CGD) is challenging. The aim of this study was to assess safety, with a focus on infections, and effectiveness of tumor necrosis factor alpha (TNF-α) blockers in CGD patients. METHODS: A retrospective, single-center cohort study of CGD patients treated by anti-TNF-α agents at Necker-Enfants Malades University Hospital (Paris, France) and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH). RESULTS: Between 2006 and 2019, 14 (X-linked: n = 10, 71.4%; autosomal-recessive: n = 4, 28.6%) CGD patients with gastrointestinal (n = 12, 85.7%), pulmonary (n = 10, 71.4%), cutaneous (n = 3, 21.4%), and/or genitourinary (n = 2, 14.3%) inflammatory manifestations received one or more doses of infliximab because of steroid-dependent (n = 7, 50%), refractory (n = 4, 28.6%) inflammatory disease or as first-line drug (n = 2, 14.3%; missing data, n = 1). All patients received adequate antimicrobial prophylaxis. Infliximab achieved complete (n = 2, 14.3%) or partial (n = 9, 64.3%) response in 11 (78.6%) patients. Seven (50%) patients were switched to adalimumab. During anti-TNF-α treatment, 11 infections (pneumonia, adenitis, invasive candidiasis, each n = 2; intra-abdominal abscess, bacteremic salmonellosis, Pseudomonas aeruginosa-related folliculitis, cat-scratch disease, proven pulmonary mucormycosis, each n = 1) occurred in 7 (50%) patients. All infectious complications had a favorable outcome. Anti-TNF-α treatment was definitively stopped because of infection in two patients. Nine (64.3%) patients finally underwent hematopoietic stem cell transplantation. No death occurred during follow-up. CONCLUSIONS: Anti-TNF-α treatment could improve the outcome of severe inflammatory complications in CGD patients, but increases their risk of infections. We suggest that anti-TNF-α treatment might be of short-term benefit in selected CGD patients with severe inflammatory complications awaiting hematopoietic stem cell transplantation.

Predicting Outcomes in Pediatric Crohn's Disease for Management Optimization: Systematic Review and Consensus Statements From the Pediatric Inflammatory Bowel Disease-Ahead Program.

BACKGROUND & AIMS: A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management. METHODS: A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence. RESULTS: Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density. CONCLUSIONS: These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk.

Benign Evolution of SARS-Cov2 Infections in Children With Inflammatory Bowel Disease: Results From Two International Databases.

The coronavirus disease 2019 (COVID-19) pandemic caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents most often with mild clinical symptoms, but the severe forms are of major concern.1 SARS-CoV-2 enters human cells via the angiotensin-converting enzyme 2 receptor, expressed on epithelial and endothelial cells.2 Because the highest angiotensin-converting enzyme 2 expression is in the terminal ileum and colon, and up-regulated further during inflammation, and many COVID-19 patients experience gastrointestinal symptoms, longitudinal data are necessary to determine whether inflammatory bowel disease (IBD) patients are at risk for severe or complicated COVID-19. A recent analysis in IBD patients from the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry showed older age, steroid medication, and comorbidities as risk factors for severe evolution, and the same study showed that the 29 IBD patients younger than age 20 had only mild disease courses.3 This report describes the disease course of COVID-19 in an expanded sample of pediatric IBD patients from 2 international databases.

Predicting Outcomes in Pediatric Ulcerative Colitis for Management Optimization: Systematic Review and Consensus Statements From the Pediatric Inflammatory Bowel Disease-Ahead Program.

BACKGROUND & AIMS: A better understanding of prognostic factors in ulcerative colitis (UC) could improve patient management and reduce complications. We aimed to identify evidence-based predictors for outcomes in pediatric UC, which may be used to optimize treatment algorithms. METHODS: Potential outcomes worthy of prediction in UC were determined by surveying 202 experts in pediatric UC. A systematic review of the literature, with selected meta-analysis, was performed to identify studies that investigated predictors for these outcomes. Multiple national and international meetings were held to reach consensus on evidence-based statements. RESULTS: Consensus was reached on 31 statements regarding predictors of colectomy, acute severe colitis (ASC), chronically active pediatric UC, cancer and mortality. At diagnosis, disease extent (6 studies, N = 627; P = .035), Pediatric Ulcerative Colitis Activity Index score (4 studies, n = 318; P < .001), hemoglobin, hematocrit, and albumin may predict colectomy. In addition, family history of UC (2 studies, n = 557; P = .0004), extraintestinal manifestations (4 studies, n = 526; P = .048), and disease extension over time may predict colectomy, whereas primary sclerosing cholangitis (PSC) may be protective. Acute severe colitis may be predicted by disease severity at onset and hypoalbuminemia. Higher Pediatric Ulcerative Colitis Activity Index score and C-reactive protein on days 3 and 5 of hospital admission predict failure of intravenous steroids. Risk factors for malignancy included concomitant diagnosis of primary sclerosing cholangitis, longstanding colitis (>10 years), male sex, and younger age at diagnosis. CONCLUSIONS: These evidence-based consensus statements offer predictions to be considered for a personalized medicine approach in treating pediatric UC.

Clinical Remission and Psychological Management are Major Issues for the Quality of Life in Pediatric Crohn Disease.

OBJECTIVES: Crohn disease (CD) can affect patient's quality of life (QOL) with physical, social, and psychological impacts. This study aimed to investigate the QOL of children with CD and its relationship with patient and disease characteristics. METHODS: Children ages from 10 to 17 years with diagnosed CD for more than 6 months were eligible to this cross-sectional study conducted in 35 French pediatric centers. QOL was assessed by the IMPACT-III questionnaire. Patient and disease characteristics were collected. RESULTS: A total of 218 children (42% of girls) were included at a median age of 14 years (interquartile range [IQR]: 13--16). Median duration of CD was 3.2 years (IQR: 1.7-5.1) and 63% of children were in clinical remission assessed by wPCDAI. Total IMPACT-III score was 62.8 (±11.0). The lowest score was in "emotional functioning" subdomain (mean: 42.8 ±â€Š11.2). Clinical remission was the main independent factor associated with QOL of children with CD (5.74 points higher compared with those "with active disease", 95% confidence interval [CI] 2.77--8.70, P < 0.001). Age of patient at the evaluation was found negatively correlated with QOL (-0.76 per year, 95% CI: -1.47 to -0.06, P = 0.009). Presence of psychological disorders was associated with a lower QOL (-9.6 points lower to those without, 95% CI: -13.34 to -5.86, P < 0.0001). Total IMPACT-III and its subdomains scores were not related to sex, disease duration, or treatments. CONCLUSIONS: These results not only confirm that clinical remission is a major issue for the QOL of patients, but also highlights the importance of psychological care.