ABSTRACT
OBJECTIVES/BACKGROUND: Pediatric inflammatory bowel disease (PIBD) poses significant challenges not only to patients but also to their families, particularly affecting the work productivity of caregivers. This Spanish multicenter study aims to elucidate the extent of this impact. MATERIALS AND METHODS: A cross-sectional, multicenter study was conducted between February 2021 and June 2023, involving parents or caregivers of PIBD patients aged 10-18 years. The study utilized the Work Productivity and Activity Impairment (WPAI) questionnaires alongside assessing disease activity and socioeconomic status to quantify work productivity loss and its economic implications. RESULTS: The study included 370 patients from 37 centers, highlighting a significant loss of work productivity among caregivers, especially mothers. The global unemployment rate was notably higher in this group compared to national averages (22.9% vs. 13.8%), particularly among females (30.7% vs. 13.7%), with absenteeism and presenteeism rates (26.4% and 39.9%) significantly impacting the caregivers' ability to work. The study also identified active disease and treatment with biologics or steroids as risk factors for increased work productivity loss. CONCLUSIONS: Caregivers of children with inflammatory bowel disease face considerable challenges in maintaining employment, with a notable economic impact due to lost work hours. The findings underscore the need for targeted support and interventions to assist these families, suggesting potential areas for policy improvement and support mechanisms to mitigate the socioeconomic burden of PIBD on affected families.
ABSTRACT
Introduction. The WPAI-UC/CD-Caregiver questionnaires assess the impact of ulcerative colitis (UC) or Crohn's disease (CD) on parents'/caregivers' work life and daily activities. Our objective was to adapt and validate these questionnaires in the Spanish population. Methods. A translation and back-translation were done. The document was assessed by an expert committee and a pilot group of families of patients with pediatric inflammatory bowel disease (p-IBD). For validation, the parents/caregivers of patients with p-IBD (10-18 years old) were recruited. The expert committee and the pilot group conducted a subjective assessment of the format and time necessary to complete the questionnaires. Cronbach's alpha coefficient was estimated and a factor analysis with varimax rotation was done. Kaiser- Meyer-Olkin (KMO) coefficients and Bartlett's sphericity test were estimated to test the adequacy of the factor analysis. Results. A total of 370 patients (median age: 14.1 years) and 263 parents/caregivers of patients with UC or unclassified IBD and 261 parents/caregivers of patients with CD were included. The KMO coefficients (0.6947 and 0.7179) and Bartlett's sphericity test (p < 0.001) confirmed the adequacy of the factor analysis. The 6 items targeted the same domain. The factor model accounted for 99.99% and 94.68% of variance, and Cronbach's alpha coefficients (0.6581 and 0.6968) showed an adequate consistency. The format and the median time of 2 minutes to complete the questionnaires were considered optimal. Conclusions. The versions of the WPAI-Caregiver questionnaires validated in the Spanish population may be used in families whose children have IBD.
Introducción. Los cuestionarios WPAI-UC/CD-Caregiver evalúan la repercusión laboral y en actividades cotidianas de los padres/cuidadores de pacientes con colitis ulcerosa (CU) o enfermedad de Crohn (EC). El objetivo fue adaptar y validar estos cuestionarios en la población española. Métodos. Se realizó la traducción y la retrotraducción. El documento fue evaluado por un comité de expertos y por un grupo piloto de familias de pacientes con enfermedad inflamatoria intestinal pediátrica (EII-p). Para la validación, se reclutaron padres/cuidadores de pacientes con EII-p (10-18 años). El comité de expertos y el grupo piloto evaluaron subjetivamente el formato y el tiempo necesario para completar los cuestionarios. Se calculó el coeficiente alfa de Cronbach y se realizó el análisis factorial con rotación Varimax. Se calcularon los coeficientes de Kaiser-Meyer-Olkin (KMO) y la prueba de esfericidad de Bartlett para comprobar la adecuación del análisis factorial. Resultados. Se incluyeron 370 pacientes (mediana 14,1 años), y 263 padres/cuidadores de pacientes con colitis ulcerosa o EII no clasificada y 261 padres/cuidadores de pacientes con enfermedad de Crohn. Los coeficientes KMO (0,6947 y 0,7179) y la prueba de esfericidad de Barttlet (p <0,001) confirmaron la adecuación del análisis factorial. Los 6 ítems se dirigieron a la misma dimensión. El modelo factorial explicó el 99,99 % y el 94,68 % de la varianza, y los alfa de Cronbach (0,6581 y 0,6968) indicaron buena consistencia. El formato y la mediana de 2 minutos para completarlos se consideraron óptimos. Conclusiones. Las versiones validadas en la población española de los cuestionarios WPAI-Caregiver pueden considerarse para su uso en familias con hijos con EII.
ABSTRACT
BACKGROUND: Tofacitinib has recently been approved for treatment of moderate-to-severe ulcerative colitis (UC) in adults, yet pediatric data are limited. This international multicenter study describes the effectiveness and safety of tofacitinib in pediatric UC. METHODS: This is a retrospective review of children diagnosed with UC treated with tofacitinib from 16 pediatric centers internationally. The primary outcome was week 8 corticosteroid-free clinical remission (Pediatric Ulcerative Colitis Activity Index <10). Secondary outcomes were clinical response (≥20-point decrease in Pediatric Ulcerative Colitis Activity Index) at week 8, corticosteroid-free clinical remission at week 24, and colectomy rate and adverse safety events through to last follow-up. The primary outcome was calculated by the intention-to-treat principle. RESULTS: We included 101 children with a mean age at diagnosis of 12.8â ±â 2.8 years and a median disease duration of 20 months (interquartile range [IQR], 10-39 months). All had treatment failure with at least 1 biologic agent, and 36 (36%) had treatment failure with 3 agents. Median follow-up was 24 weeks (IQR, 16-54 weeks). Sixteen (16%) children achieved corticosteroid-free clinical remission at week 8, and an additional 30 (30%) demonstrated clinical response. Twenty (23%) of 88 children achieved corticosteroid-free clinical remission at week 24. A total of 25 (25%) children underwent colectomy by median 86 days (IQR, 36-130 days). No serious drug-related adverse events were reported; there was 1 case of herpes zoster and 2 cases of minor blood test perturbations. CONCLUSIONS: In this largest real-life pediatric cohort to date, tofacitinib was effective in at least 16% of patients with highly refractory UC by week 8. Adverse events were minor and largely consistent with adult data.
Tofacitinib, widely reported in adult ulcerative colitis, has very limited pediatric data. This international collaboration is the largest pediatric study on the efficacy and safety of tofacitinib to date, providing important supportive data to clinicians and regulators.
ABSTRACT
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.
Subject(s)
Colitis, Ulcerative , Ustekinumab , Humans , Ustekinumab/therapeutic use , Ustekinumab/adverse effects , Colitis, Ulcerative/drug therapy , Retrospective Studies , Male , Female , Adolescent , Child , Treatment Outcome , Remission InductionABSTRACT
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
IMPACT-III and IMPACT-III-P are health-related quality of life (HRQoL) questionnaires for patients with pediatric inflammatory bowel disease (p-IBD) and their parents/caregivers. We aimed to perform a transcultural adaptation and validation for the Spanish context. Translation, back-translation, and evaluation of the questionnaires were performed by an expert committee and 12 p-IBD families. We recruited p-IBD patients aged 10-17 and their parents/caregivers. Utility, content, and face validity were considered. Validation was performed with Cronbach's alpha coefficient and varimax rotation. We confirmed the adequacy of the factor analysis using Kaiser-Meyer-Olkin (KMO) and Bartlett's sphericity tests. A confirmatory factor analysis was performed using the following goodness indexes: chi-square, Normed Fit Index (NFI), Root Mean Square Error of Approximation index (RMSEA), Standardized Root Mean Square Residual (SRMR), and Comparative Fit Index (CFI). The correlation coefficient between IMPACT-III and IMPACT-III-P was analyzed. We included 370 patients and 356 parents/caregivers (37 hospitals). Both questionnaires had good content and face validity and were considered user-friendly. The KMO measure (0.8998 and 0.9228, respectively) and Bartlett's sphericity test (p-value < 0.001 for both) confirmed the adequacy of the factor analysis. The 4-factor model, complying with Kaiser's criterion, explained 89.19% and 88.87% of the variance. Cronbach's alpha (0.9123 and 0.9383) indicated excellent internal consistency. The CFA showed an adequate fit (NFI 0.941 and 0.918, RMSEA 0.048 and 0.053, SRMR 0.037 and 0.044, and CFI 0.879 and 0.913). The correlation coefficient was excellent (0.92). CONCLUSION: The SEGHNP versions of IMPACT-III and IMPACT-III-P are valid and reliable instruments for Spanish p-IBD families. WHAT IS KNOWN: ⢠IMPACT-III and parent-proxy IMPACT-III (IMPACT-III-P) are useful questionnaires for assessing health-related quality of life (HRQoL) in pediatric inflammatory bowel disease (p-IBD) patients and their parents/caregivers and have been translated and validated in several countries. ⢠To date, no transcultural adaptation and validation of these questionnaires have been published for Spanish patients with p-IBD and their families. WHAT IS NEW: ⢠This is the first transcultural adaptation and validation of IMPACT-III and IMPACT-III-P for Spanish p-IBD families. ⢠These are valid and reliable instruments for assessing HRQoL in Spanish families of patients with p-IBD.
Subject(s)
Inflammatory Bowel Diseases , Parents , Psychometrics , Quality of Life , Translations , Humans , Male , Female , Child , Adolescent , Spain , Surveys and Questionnaires , Reproducibility of Results , Inflammatory Bowel Diseases/psychology , Parents/psychology , Caregivers/psychology , Factor Analysis, StatisticalABSTRACT
(1) Background: Transition is a planned movement of paediatric patients to adult healthcare systems, and its implementation is not yet established in all inflammatory bowel disease (IBD) units. The aim of the study was to evaluate the impact of transition on IBD outcomes. (2) Methods: Multicentre, retrospective and observational study of IBD paediatric patients transferred to an adult IBD unit between 2017-2020. Two groups were compared: transition (≥1 joint visit involving the gastroenterologist, the paediatrician, a programme coordinator, the parents and the patient) and no-transition. Outcomes within one year after transfer were analysed. The main variable was poor clinical outcome (IBD flare, hospitalisation, surgery or any change in the treatment because of a flare). Predictive factors of poor clinical outcome were identified with multivariable analysis. (3) Results: A total of 278 patients from 34 Spanish hospitals were included. One hundred eighty-five patients (67%) from twenty-two hospitals (65%) performed a structured transition. Eighty-nine patients had poor clinical outcome at one year after transfer: 27% in the transition and 43% in the no-transition group (p = 0.005). One year after transfer, no-transition patients were more likely to have a flare (36% vs. 22%; p = 0.018) and reported more hospitalisations (10% vs. 3%; p = 0.025). The lack of transition, as well as parameters at transfer, including IBD activity, body mass index < 18.5 and corticosteroid treatment, were associated with poor clinical outcome. One patient in the transition group (0.4%) was lost to follow-up. (4) Conclusion: Transition care programmes improve patients' outcomes after the transfer from paediatric to adult IBD units. Active IBD at transfer impairs outcomes.
ABSTRACT
BACKGROUND: Recent trials suggested that the Crohn's disease (CD) exclusion diet (CDED) plus partial enteral nutrition (PEN) is a safe and effective strategy in remission induction of paediatric-onset CD. However, real-world evidence regarding the safety and efficacy of the CDED plus PEN approach is still lacking. The present case-series study reported our experience with the outcomes of CDED plus PEN in the paediatric-onset CD at disease onset and after the loss of response to biologics. METHODS: We conducted a retrospective chart review on children who were treated with CDED plus PEN through the period from July 2019 and December 2020. Clinical and laboratory data were retrieved and compared at baseline, 6, 12, and 24 weeks of treatment. The primary endpoint of the present study was the rate of clinical remission. RESULTS: The present study retrieved the data from 15 patients. Of them, nine patients were treatment naïve at the time of initiation of CDED plus PEN (group A) and the remaining patients relapsed on biologics before treatment. All patients in groups A and B exhibited clinical remission in week six, which was sustained until week 12. At the end of the follow-up, the clinical remission rate was 87% and 60% in groups A and B, respectively. No side effects were observed in both groups. In group A, the faecal calprotectin (FC) and albumin improved at week six, week 12, and week 24 (p < 0.05). The erythrocyte sedimentation rate (ESR) improved significantly at week 12 (p = 0.021) and week 24 (p = 0.027). At the same time, the haemoglobin and iron levels showed significant improvement only at week 24. For group B, only FC showed numerical reductions over time that did not reach the level of statistical significance. CONCLUSION: Treatment with CDED plus PEN was well tolerated and achieved an excellent clinical remission rate in treatment-naive patients. However, the benefit of CDED plus PEN was less in patients who initiated the strategy after losing the response to biologics.
Subject(s)
Biological Products , Crohn Disease , Humans , Child , Crohn Disease/drug therapy , Retrospective Studies , Biological Therapy , Biological Products/therapeutic use , Elimination Diets , Leukocyte L1 Antigen ComplexABSTRACT
The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.
Subject(s)
Inflammatory Bowel Diseases , Tumor Necrosis Factor Inhibitors , Adult , Humans , Child , Adolescent , Infliximab/therapeutic use , Adalimumab/pharmacology , Adalimumab/therapeutic use , Tumor Necrosis Factor Inhibitors/therapeutic use , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/genetics , Polymorphism, Single Nucleotide , DNA/therapeutic use , Retrospective StudiesABSTRACT
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.
Subject(s)
Crohn Disease , Ustekinumab , Humans , Adult , Child , Adolescent , Ustekinumab/adverse effects , Crohn Disease/drug therapy , Retrospective Studies , Wound Healing , Treatment Outcome , Remission InductionABSTRACT
BACKGROUND: Patients enrolled in randomised controlled trials (RCTs) may differ from the target population due to restricted eligibility criteria. AIM: To compare treatment response to biologics in routine practice for children with inflammatory bowel diseases (IBD) who would and would not have been eligible for enrolment in the regulatory RCT of the same drug. METHODS: We enrolled children with IBD who initiated adalimumab, infliximab, vedolizumab or ustekinumab. The eligibility criteria as defined in the RCT of the corresponding biologic were applied to each patient. The primary outcome was 12-month steroid-free remission (SFR) without switching biologics or undergoing surgery. RESULTS: We screened 289 children (198 [68%] with Crohn's disease [CD], 91 [32%] with ulcerative colitis [UC]) with 326 initiations of biologics. Only 62 of 164 (38%) children with moderate-to-severe disease would have been eligible for inclusion in the original RCTs. The SFR rate was higher in the eligible children (51%) than in the ineligible children (31%; OR 2.3 [95%CI 1.2-4.5]; p = 0.01). The main exclusion criterion was prohibited previous therapies (47%). Ineligible CD patients were older, more often had a family history of IBD and had higher levels of CRP than eligible children; in UC there were no differences between the groups. CONCLUSION: Most children with IBD who initiate biologics would not have been eligible to be included in the corresponding regulatory RCTs. The outcomes of ineligible patients were worse than for eligible patients. Results from RCTs should be interpreted with caution when applied to clinical practice.
Subject(s)
Biological Products , Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Biological Products/therapeutic use , Child , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Humans , Inflammatory Bowel Diseases/drug therapy , Infliximab/therapeutic use , Randomized Controlled Trials as TopicABSTRACT
Vedolizumab is a humanised monoclonal antibody that binds to integrin α4ß7 expressed in T-cells, inhibiting its binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is specifically expressed in the small intestine and colon, playing a fundamental role in T-cell migration to the gastrointestinal tract. Vedolizumab has been shown to be effective in treating adults with inflammatory bowel disease; however, efficacy data for paediatric use are scarce. The objective of the present study was to assess the effectiveness and safety of vedolizumab for inducing and maintaining clinical remission in children with inflammatory bowel disease. We conducted a retrospective multicentre study of patients younger than 18 years with inflammatory bowel disease refractory to anti-tumour necrosis factor alpha (anti-TNF-α) drugs, who underwent treatment with vedolizumab. Clinical remission was defined as a score < 10 points in the activity indices. We included 42 patients, 22 of whom were male (52.3%), with a median age of 13.1 years (IQR 10.2-14.2) at the start of treatment. Of the 42 patients, 14 (33.3%) had Crohn's disease (CD) and 28 (66.7%) had ulcerative colitis (UC). At the start of treatment with vedolizumab, the Paediatric Crohn's Disease Activity Index was 36 (IQR 24-40) and the Paediatric Ulcerative Colitis Activity Index was 47 (IQR 25-65). All of them had received prior treatment with anti-TNF and 3 patients ustekinumab. At week 14, 69% of the patients responded to the treatment (57.1% of those with CD and 75% of those with UC; p=0.238), and 52.4% achieved remission (35.7% with CD and 60.7% with UC; p=0.126). At 30 weeks, the response rate was 66.7% (46.2% and 78.3% for CD and UC, respectively; p=0.049), and 52.8% achieved remission (30.8% and 65.2% for CD and UC, respectively; p=0.047). Among the patients with remission at week 14, 80% of the patients with CD and 84.5% of those with UC maintained the remission at 52 weeks. Adverse effects were uncommon and mild. Three patients (7.1%) presented headaches, 1 presented alopecia, 1 presented anaemia and 1 presented dermatitis.Conclusion: The results show that treatment with vedolizumab is a safe and effective option for achieving clinical remission in paediatric patients with inflammatory bowel disease with primary failure or loss of response to other treatments, especially in UC. What is Known: ⢠Vedolizumab is effective in inducing and maintaining remission in adult patients with inflammatory bowel disease. ⢠Most studies and clinical trials have been performed on adult populations, and there is currently no indication for paediatric populations. What is New: ⢠Children with inflammatory bowel disease refractory to anti-TNF presented higher clinical remission rates than those published for adults. ⢠There are few publications of this magnitude on paediatric populations treated with vedolizumab and with long-term follow-up (52 weeks).
Subject(s)
Colitis, Ulcerative , Inflammatory Bowel Diseases , Adolescent , Antibodies, Monoclonal, Humanized , Child , Colitis, Ulcerative/drug therapy , Female , Gastrointestinal Agents/adverse effects , Humans , Inflammatory Bowel Diseases/drug therapy , Male , Remission Induction , Retrospective Studies , Treatment Outcome , Tumor Necrosis Factor InhibitorsABSTRACT
BACKGROUND: Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. METHODS: An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab (29 responders and nine non-responders). Whole gene expression profiles from total RNA isolated from whole blood samples of six responders and six non-responders taken before administration of the biologic and after two weeks of therapy were analyzed using next-generation RNA sequencing. The expression of six selected genes was measured for purposes of validation in all of the 38 patients recruited using qPCR. RESULTS: Genes were differentially expressed in non-responders and responders (32 before initiation of treatment and 44 after two weeks, Log2FC (Fold change) >0.6 or <-0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05). CONCLUSION: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD.
Subject(s)
Azathioprine , Crohn Disease , Enteral Nutrition , Remission Induction , Azathioprine/therapeutic use , Causality , Crohn Disease/therapy , HumansABSTRACT
AIMS: Identifying DNA variants associated with trough serum anti-tumour necrosis factor (TNF) levels could predict response to treatment in inflammatory bowel disease (IBD). To date, no specific studies have been performed in children. The aim of this study was to identify genetic variants associated with trough serum anti-TNF levels and whether these variants are differential markers for infliximab and adalimumab. METHODS: We included 154 children (age < 18 years) from 17 hospitals who had been diagnosed with IBD and actively treated with infliximab or adalimumab. Twenty-one polymorphisms were genotyped using real-time PCR. Trough serum anti-TNF levels were measured using enzyme-linked immunosorbent assay (ELISA). The association between DNA polymorphisms and the therapeutic range or the absolute values of anti-TNF drugs was analysed by Fisher exact test, student's t-test and logistic regression. RESULTS: The variants rs5030728 (TLR4) and rs11465996 (LY96) were associated with subtherapeutic infliximab levels. rs1816702 (TLR2) was associated with supratherapeutic levels and rs3397 (TNFRSF1B) with subtherapeutic levels of adalimumab (P < .05). In addition, rs1816702 (TLR2) and rs2569190 (CD14) were associated with absolute values of trough serum adalimumab, and rs2569190 (CD14) was associated with absolute values of trough serum adalimumab and infliximab (P < .05). CONCLUSION: Genotyping of these DNA variants before starting treatment may help to select the best anti-TNF drug in paediatric patients. The SNP rs1816702 is the most promising marker for tailoring the anti-TNF regimen in children with IBD. For the first time, DNA variants are associated with trough serum anti-TNF levels.
Subject(s)
Inflammatory Bowel Diseases , Tumor Necrosis Factor Inhibitors , Adalimumab , Adolescent , Child , Humans , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/genetics , Infliximab , Pharmacogenetics , Tumor Necrosis Factor Inhibitors/pharmacokineticsABSTRACT
Background and Aims: Diagnostic delay (DD) is especially relevant in children with inflammatory bowel disease, leading to potential complications. We examined the intervals and factors for DD in the pediatric population of Spain. Methods: We conducted a multicentric prospective study, including 149 pediatric inflammatory bowel disease patients, obtaining clinical, anthropometric, and biochemical data. Time to diagnosis (TD) was divided into several intervals to identify those where the DD was longer and find the variables that prolonged those intervals. Missed opportunities for diagnosis (MODs) were also identified. Results: Overall TD was 4.4 months (interquartile range [IQR] 2.6-10.4), being significantly higher in Crohn's disease (CD) than in ulcerative colitis (UC) (6.3 [IQR 3.3-12.3] vs. 3 [IQR 1.6-5.6] months, p = 0.0001). Time from the visit to the first physician until referral to a pediatric gastroenterologist was the main contributor to TD (2.4 months [IQR 1.03-7.17] in CD vs. 0.83 months [IQR 0.30-2.50] in UC, p = 0.0001). One hundred and ten patients (78.3%) visited more than one physician (29.9% to 4 or more), and 16.3% visited the same physician more than six times before being assessed by the pediatric gastroenterologist. The number of MODs was significantly higher in CD than that in UC patients: 4 MODs (IQR 2-7) vs. 2 MODs ([IQR 1-5], p = 0.003). Referral by pediatricians from hospital care allowed earlier IBD diagnosis (odds ratio 3.2 [95% confidence interval 1.1-8.9], p = 0.025). Conclusions: TD and DD were significantly higher in CD than those in UC. IBD patients (especially those with CD) undergo a large number of medical visits until the final diagnosis.
ABSTRACT
OBJECTIVES: Inflammatory bowel disease (IBD) is more complex in children and they will have to live with the disease for much longer. For this reason, it is necessary to optimize treatment. The polymorphisms associated with the response to anti-tumor necrosis factor (TNF) drugs in adults with IBD have not been analyzed in children. The aim of the study was to identify genetic variants associated with the long-term response to anti-TNF drugs in children with IBD. METHODS: An observational, longitudinal, ambispective cohort's study was conducted. We recruited 209 anti-TNF-treated children diagnosed with IBD and genotyped 21 polymorphisms previously studied in adults with Crohn disease (CD) using real-time PCR. The association between single-nucleotide polymorphisms (SNPs) and time-to-failure was analyzed using the log-rank test. RESULTS: After multivariate analysis, 3 SNPs in IL10, IL17A and IL6 were significantly associated with response to anti-TNF treatment among patients diagnosed with CD (rs1800872-HR, 4.749 (95% confidence interval [CI] 1.156-19.517), P valueâ<â0.05; rs2275913-HR, 0.320 [95% CI 0.111-0.920], P value â<â0.05; and rs10499563-HR, 0.210 [95% CI 0.047-0.947], P value 0.05, respectively). None of these SNPs were associated with response to infliximab in adults diagnosed with CD. Among patients diagnosed with ulcerative colitis (UC), 1 SNP in LY96 was significantly associated with response to anti-TNF treatment (rs-11465996-HR, 10.220 [95% CI 1.849-56.504] P valueâ<â0.05). CONCLUSIONS: Genotyping of these DNA variants before starting treatment may help to identify children who are long-term responders to anti-TNF drugs, and thus tailor treatment of pediatric IBD.