RESUMEN
BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.
Asunto(s)
Metotrexato , Inhibidores del Factor de Necrosis Tumoral , Niño , Humanos , Femenino , Adolescente , Masculino , Metotrexato/efectos adversos , Adalimumab/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Infliximab/efectos adversos , Factor de Necrosis Tumoral alfa , Resultado del TratamientoRESUMEN
INTRODUCTION: Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). METHODS: The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z -score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. RESULTS: Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 µg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. DISCUSSION: Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.
Asunto(s)
Adalimumab , Índice de Masa Corporal , Enfermedad de Crohn , Quimioterapia Combinada , Infliximab , Metotrexato , Factor de Necrosis Tumoral alfa , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Masculino , Femenino , Infliximab/uso terapéutico , Adalimumab/uso terapéutico , Niño , Adolescente , Metotrexato/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Insuficiencia del Tratamiento , Fármacos Gastrointestinales/uso terapéutico , Obesidad Infantil/complicaciones , Obesidad Infantil/tratamiento farmacológicoRESUMEN
BACKGROUND & AIMS: We aimed to model infliximab (IFX) pharmacokinetics (PK) in pediatric acute severe ulcerative colitis (ASUC) and assess the association between PK parameters, including drug exposure, and clinical response. METHODS: We studied a multicenter prospective cohort of hospitalized children initiating IFX for ASUC or IBD-unclassified. Serial IFX serum concentrations over 26 weeks were used to develop a PK model. We tested the association of PK parameter estimates with day 7 clinical response, week 8 clinical remission, week 26 corticosteroid-free clinical remission (CSF-CR) (using the Pediatric Ulcerative Colitis Activity Index), and colectomy-free survival. RESULTS: Thirty-eight participants received IFX (median initial dose, 9.9 mg/kg). Day 7 clinical response, week 8 clinical remission, and week 26 CSF-CR occurred in 71%, 55%, and 43%, respectively. Albumin, C-reactive protein, white blood cell count, platelets, weight, and antibodies to IFX were significant covariates incorporated into a PK model. Week 26 non-remitters exhibited faster IFX clearance than remitters (P = .013). However, cumulative IFX exposure did not differ between clinical response groups. One (2.7%) and 4 (10.8%) participants underwent colectomy by week 26 and 2 years, respectively. Day 3 IFX clearance >0.02 L/h was associated with colectomy (hazard ratio, 58.2; 95% confidence interval, 6.0-568.6; P < .001). CONCLUSIONS: At median higher-than-label IFX dosing for pediatric ASUC, baseline faster IFX CL was associated with colectomy and at week 26 with lack of CSF-CR. IFX exposure was not predictive of clinical outcomes. Higher IFX dosing may sufficiently optimize early outcomes in pediatric ASUC. Larger studies are warranted to determine whether sustained intensification can overcome rapid clearance and improve later outcomes. CLINICALTRIALS: gov identifier: NCT02799615.
Asunto(s)
Colitis Ulcerosa , Humanos , Niño , Infliximab , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Estudios Prospectivos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To describe racial inequities in pediatric inflammatory bowel disease care and explore potential drivers. METHODS: We undertook a single-center, comparative cohort study of newly diagnosed Black and non-Hispanic White patients with inflammatory bowel disease, aged <21 years, from January 2013 through 2020. Primary outcome was corticosteroid-free remission (CSFR) at 1 year. Other longitudinal outcomes included sustained CSFR, time to anti-tumor necrosis factor therapy, and evaluation of health service utilization. RESULTS: Among 519 children (89% White, 11% Black), 73% presented with Crohn's disease and 27% with ulcerative colitis. Disease phenotype did not differ by race. More patients from Black families had public insurance (58% vs 30%, P < .001). Black patients were less likely to achieve CSFR 1-year post diagnosis (OR: 0.52, 95% CI:0.3-0.9) and less likely to achieve sustained CSFR (OR: 0.48, 95% CI: 0.25-0.92). When adjusted by insurance type, differences by race to 1-year CSFR were no longer significant (aOR: 0.58; 95% CI: 0.33, 1.04; P = .07). Black patients were more likely to transition from remission to a worsened state, and less likely to transition to remission. We found no differences in biologic therapy utilization or surgical outcomes by race. Black patients had fewer gastroenterology clinic visits and 2-fold increased odds for emergency department visits. CONCLUSIONS: We observed no differences by race in phenotypic presentation and medication usage. Black patients had half the odds of achieving clinical remission, but a degree of this was mediated by insurance status. Understanding the cause of such differences will require further exploration of social determinants of health.
Asunto(s)
Disparidades en Atención de Salud , Enfermedades Inflamatorias del Intestino , Humanos , Estudios de Cohortes , Servicios de Salud , Enfermedades Inflamatorias del Intestino/terapia , Negro o Afroamericano , Blanco , NiñoRESUMEN
We performed transcriptomic analyses on freshly frozen (n=21) and paraffin-embedded (n=35) gastrointestinal (GI) biopsies from children with and without acute acute GI graft-versus-host disease (GvHD) to study differential gene expressions. We identified 164 significant genes, 141 upregulated and 23 downregulated, in acute GvHD from freshy frozen biopsies. CHI3L1 was the top differentially expressed gene in acute GvHD, involved in macrophage recruitment and bacterial adhesion. Mitochondrial genes were among the top downregulated genes. Immune deconvolution identified a macrophage cellular signature. Weighted gene co-expression network analysis showed enrichment of genes in the ERK1/2 cascade. Transcriptome data from 206 ulcerative colitis (UC) patients were included to uncover genes and pathways shared between GvHD and UC. Comparison with the UC transcriptome showed both shared and distinct pathways. Both UC and GvHD transcriptomes shared an innate antimicrobial signature and FCγ1RA/CD64 was upregulated in both acute GvHD (log-fold increase 1.7, P=0.001) and UC. Upregulation of the ERK1/2 cascade pathway was specific to GvHD. We performed additional experiments to confirm transcriptomics. Firstly, we examined phosphorylation of ERK (pERK) by immunohistochemistry on GI biopsies (acute GvHD n=10, no GvHD n=10). pERK staining was increased in acute GvHD biopsies compared to biopsies without acute GvHD (P=0.001). Secondly, plasma CD64, measured by enzyme-linked immunsorbant assay (n=85) was elevated in acute GI GvHD (P<0.001) compared with those without and was elevated in GVHD compared with inflammatory bowel disease (n=47) (P<0.001), confirming the upregulated expression seen in the transcriptome.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedades Inflamatorias del Intestino , Humanos , Niño , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/genética , Perfilación de la Expresión Génica , Transcriptoma , Enfermedades Inflamatorias del Intestino/genética , Biología , Enfermedad AgudaRESUMEN
PURPOSE OF THE REVIEW: This review focuses on recent advancements in anti-TNF therapeutic drug monitoring (TDM), pharmacogenetics and personalized drug selection for children with inflammatory bowel disease (IBD). RECENT FINDINGS: Several real-world studies and one clinical trial in children have demonstrated that proactive TDM, targeting higher exposure concentrations (> 5 µg/mL), can improve disease remission rates and enhance durability of the anti-TNF biologics. Recent data from both adult and pediatric IBD patients have revealed an association between a genetic polymorphism (HLA-DQA1*05) and the development of auto-drug antibodies. The impact of this association on clinical outcomes, considering more routine use proactive TDM and dose optimization in children, is still under investigation. Additionally, recent studies have identified potential inflammatory signatures and biomarkers that may serve as companion diagnostics for anti-TNF biologics. The effective management of anti-TNF therapies in children with IBD requires evidence-based precision dosing strategies, including routine TDM and proactive pharmacodynamic assessments.
Asunto(s)
Productos Biológicos , Enfermedades Inflamatorias del Intestino , Adulto , Humanos , Niño , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Factor de Necrosis Tumoral alfa , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Monitoreo de Drogas , Infliximab/uso terapéuticoRESUMEN
Measuring medication adherence in pediatric inflammatory bowel diseases (IBD) is challenging because of complexities in personalized treatment regimens and increased use of biologic mono- and combination therapy. Objective measurement of adherence via electronic monitoring is the gold standard; however, it is not useful for daily monitoring when multiple medication formulations (eg, pills, injections, infusions) as well as vitamins/supplements are prescribed. Although validated subjective measures are available, they are not designed for daily use and do not capture day-to-day variation in adherence. In the following article, a new approach to measuring adherence regardless of a patient's specific medication regimen is presented. Utilizing a micro-longitudinal design, 30 days of daily self-reported medication adherence data was collected from youth with IBD via text message. Results reflect mean adherence rates from studies utilizing pill counts and electronic monitoring, suggesting promise for the use of self-reported daily diaries to assess medication adherence in pediatric IBD.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Cumplimiento de la Medicación , Adolescente , Niño , Suplementos Dietéticos , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , AutoinformeRESUMEN
OBJECTIVES: Subtherapeutic drug concentrations contribute to both primary and secondary nonresponse to infliximab in children with Crohn disease (CD). The aim of this study was to evaluate treatment outcomes and infliximab concentrations at infusions 2 and 3 with an objective to establish infliximab targets during induction for primary responders. METHODS: Single-center, prospective cohort of anti- tumor necrosis factor-alpha naïve CD patients younger than 22 years starting infliximab. Clinical response was defined with the weighted pediatric CD activity index at the fourth infusion. Rates of biological response (>50% improvement in fecal calprotectin) and maintenance concentrations ≥5âµg/mL were secondary outcomes. RESULTS: We enrolled 72 patients with CD with 70 of 72 receiving infliximab monotherapy. Clinical response, biological response, and start of maintenance concentrations ≥5âµg/mL were achieved in 64%, 54%, and 22%, respectively. The median (interquartile range) infliximab concentrations at infusion 2 and 3 in clinical responders were 27.8âµg/mL (19.5-40) and 14âµg/mL (8.3-24) compared to 18.8âµg/mL (9.1-23, Pâ<â0.001) and 7.8âµg/mL (4-13.2, Pâ<â0.01) in nonresponders. Receiver operating characteristic analysis determined that an infliximab concentration ≥15.9âµg/mL at infusion 3 was associated with clinical response (area under the curve [AUC] 0.73), whereas an infusion 3 level ≥18âµg/mL was associated with a start of maintenance concentration >5âµg/mL (AUC 0.85). Independent predictors for infusion 3 levels <18âµg/mL included pretreatment prednisone, low body mass index, elevated erythrocyte sedimentation rate and C-reactive protein, hypoalbuminemia, and an infusion 2 infliximab level <29âµg/mL. CONCLUSIONS: We found that infusion 2 (≥29âµg/mL) and infusion 3 (≥18âµg/mL) infliximab concentrations were strongly associated with improved early outcomes and higher first maintenance dose levels.
Asunto(s)
Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/sangre , Infliximab/administración & dosificación , Infliximab/sangre , Adolescente , Antiinflamatorios/uso terapéutico , Área Bajo la Curva , Niño , Femenino , Fármacos Gastrointestinales/farmacocinética , Fármacos Gastrointestinales/uso terapéutico , Humanos , Infliximab/farmacocinética , Infliximab/uso terapéutico , Infusiones Intravenosas , Quimioterapia de Mantención , Masculino , Prednisona/uso terapéutico , Estudios Prospectivos , Curva ROC , Inducción de Remisión , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: There is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)-few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes. METHODS: We used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center. RESULTS: We measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P = .001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR], 6.469; 95% confidence interval [CI], 1.553-26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330-28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132-25.12). CONCLUSIONS: In an analysis of rectal tissues from treatment-naive pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC.
Asunto(s)
Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Inmunidad Mucosa/genética , Interleucinas/genética , Mucosa Intestinal/inmunología , Adolescente , Área Bajo la Curva , Estudios de Casos y Controles , Niño , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Colon/patología , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Femenino , Expresión Génica , Humanos , Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/genética , Interleucina-17/genética , Interleucina-23/genética , Interleucina-5/genética , Mucosa Intestinal/metabolismo , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , ARN Mensajero/análisis , Curva ROC , Recto , Transcriptoma , Regulación hacia ArribaRESUMEN
OBJECTIVES: Therapeutic drug monitoring (TDM) that guides infliximab (IFX) intensification strategies has been shown to improve IFX efficacy. We conducted a review to evaluate the utility of TDM in the assessment and subsequent management of IFX loss of response in our pediatric population with Crohn disease (CD). METHODS: Single-center retrospective study of patients with CD receiving IFX that had TDM from December 2009 to September 2013. We defined subtherapeutic trough as a drug level below the detection limit of the Prometheus enzyme-linked immunoabsorbant assay and Anser reference values (1.4 and 1 µg/mL, respectively) or a mid-interval level <12 µg/mL. RESULTS: One hundred ninety-one IFX concentration tests were performed on 72 patients with CD with loss of response to therapy as the primary indication (72%). 34% of all TDM were subtherapeutic. After initial TDM, 25 of the 72 patients received regimen intensification with 72% in clinical remission at 6 months. Including all of the TDM that resulted in IFX dose intensification, we found a significant improvement in 6-month remission rates whether intensification followed mid-interval (88% remission) or trough (56% remission) testing (Pâ=â0.026). Antibody to infliximab was found in 14 patients with 5 occurring in the first year of therapy. Furthermore, 71% of patients with antibody to infliximab that were switched to an alternative anti-tumor necrosis factor achieved clinical remission at six months. In multivariable regression analysis, we found IFX dose (mg/kg), IFX dosing frequency (weeks), and the erythrocyte sedimentation rate at the previous infusion were significantly associated with the IFX concentration. CONCLUSIONS: TDM in our pediatric population with CD led to informed clinical decisions and improved rates of clinical remission.
Asunto(s)
Enfermedad de Crohn/metabolismo , Fármacos Gastrointestinales/farmacocinética , Infliximab/farmacocinética , Adolescente , Niño , Enfermedad de Crohn/tratamiento farmacológico , Cálculo de Dosificación de Drogas , Monitoreo de Drogas , Ensayo de Inmunoadsorción Enzimática , Femenino , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/uso terapéutico , Humanos , Infliximab/administración & dosificación , Infliximab/uso terapéutico , Masculino , Ohio , Análisis de Regresión , Estudios Retrospectivos , Insuficiencia del TratamientoRESUMEN
Here, we describe a 7-year-old girl who was diagnosed with an early-onset Crohn's disease in the setting of COVID-19 illness. Her disease process responded poorly to standard infliximab dosing, necessitating repeat hospitalizations and red blood cell transfusions. Remission was subsequently induced using a personalized infliximab pharmacokinetic profile based on therapeutic drug monitoring. While the initial data does not support a link, several case reports suggest an association between COVID-19 illness and de-novo development of IBD, especially in young female patients. We report, to our knowledge, the youngest patient who developed early-onset Crohn's disease in the setting of concomitant SARS-CoV-2 infection.
RESUMEN
INTRODUCTION: The only biologic therapy currently approved to treat moderate to severe Crohn's disease in children (<18 years old) are those that antagonise tumour necrosis factor-alpha (anti-TNF). Therefore, it is critically important to develop novel strategies that maximise treatment effectiveness in this population. There is growing evidence that rates of sustained corticosteroid-free clinical remission, endoscopic healing and drug durability considerably improve when patients receive early anti-TNF dose optimisations guided by reactive or proactive therapeutic drug monitoring and pharmacodynamic monitoring. In response, our team has developed a personalised and scalable infliximab dosing intervention that starts with dose selection and continues throughout maintenance to optimise drug exposure. We hypothesise that a precision dosing strategy starting from induction and targeting dose-specific pharmacokinetic and pharmacodynamic endpoints throughout therapy will significantly improve outcomes compared with a conventional dosing strategy. METHODS AND ANALYSIS: Conduct a clinical trial to assess rates of deep remission between Crohn's disease patients receiving infliximab with precision dosing (n=90) versus conventional care (n=90). Patients (age 6-22 years) will be recruited from 10 medical centres in the USA. Each centre has been selected to provide either precision dosing or conventional care dosing. Precision dosing includes the use of a clinical decision support tool (RoadMAB) from the start of infliximab to achieve specific (personalised) trough concentrations and specific pharmacodynamic targets (at doses 3, 4 and 6). Conventional care includes the use of a modified infliximab starting dose (5 or 7.5 mg/kg based on the pretreatment serum albumin) with a goal to achieve maintenance trough concentrations of 5-10 µg/mL. The primary endpoint is year 1 deep remission defined as a combination of clinical remission (paediatric Crohn's disease activity index<10 (child) or a Crohn's disease activity index<150 (adults)), off prednisone>8 weeks and endoscopic remission (simple endoscopic severity-Crohn's disease≤2). ETHICS AND DISSEMINATION: ). The study protocol has been approved by the Cincinnati Children's Hospital Medical Centre Institutional Review Board. Study results will be disseminated in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05660746.
Asunto(s)
Enfermedad de Crohn , Adulto , Humanos , Niño , Adolescente , Adulto Joven , Infliximab/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Inducción de Remisión , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND: Pediatric acute pancreatitis (AP) is associated with significant morbidity. Therefore, improved understanding of children who will develop severe AP is critical. Adult studies have reported AP associated gut dysbiosis, but pediatric studies are lacking. AIMS: Assess stool microbial taxonomic and functional profiles of children with first attack of AP compared to those of healthy controls (HC), and between mild and severe AP METHODS: Children under 21 years hospitalized at a tertiary center (n = 30) with first AP attack were recruited including HC (n = 34) from same region. Shotgun metagenomic sequencing was performed on extracted DNA. RESULTS: Demographics were similar between AP and HC. Alpha diversity (-0.68 ± 0.13, p-value < 0.001), and beta-diversity (R2=0.13, p-value < 0.001) differed, in children with AP compared to HC. Species including R.gnavus, V.parvula, E.faecalis, C.innocuum were enriched in AP. MetaCyc pathways involved in amino acid metabolism and fatty acid beta-oxidation were enriched in AP. Beta-diversity (R2=0.06, p-value = 0.02) differed for severe AP compared to mild AP with enrichment in E.faecalis and C.citroniae. CONCLUSIONS: Gut dysbiosis occurs in pediatric AP and is associated with AP severity. A multicenter study confirming these findings could pave way for interventional trials manipulating the gut microbiome to mitigate AP severity.
Asunto(s)
Microbioma Gastrointestinal , Pancreatitis , Adulto , Niño , Humanos , Enfermedad Aguda , Disbiosis/complicaciones , Disbiosis/metabolismo , Heces/química , Pancreatitis/complicacionesRESUMEN
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.
RESUMEN
Pragmatic clinical research is 1 of the 5 focus areas of the Challenges in IBD Research 2024, a multidisciplinary effort by scientists, clinicians, patients, and funders to identify priorities for patient-centric research. This summary provides a comprehensive overview of current gaps in inflammatory bowel disease (IBD) clinical research and actionable approaches to address them. This review is focused on identifying research that is needed to achieve the best outcomes for patients in clinical practice. Research gaps include understanding the needs of understudied patient groups and addressing barriers to care so all patients receive optimal care, validating and using biomarkers to enable early diagnosis and result in better outcomes for adults and children with IBD, and determining the optimal sequencing of treatments (medical, surgical, adjunct) in children and adults. Inclusive pragmatic research is needed to address these gaps and lead to improvements in patient care and outcomes for all populations of patients with IBD.
Pragmatic clinical research focuses on improving evidence for how to best treat patients to improve quality of life and disease outcomes in real-world practice. This includes evaluating and improving healthcare delivery and decreasing barriers for all patients.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Humanos , Enfermedades Inflamatorias del Intestino/terapia , Enfermedades Inflamatorias del Intestino/diagnóstico , Investigación Biomédica , Biomarcadores/análisisRESUMEN
The use of biologic therapies has changed the treatment landscape for children with inflammatory bowel disease. While the novel biologics have improved clinical outcomes, there remains a significant gap in achieving endoscopic remission, prolonged steroid-free remission, and drug durability. Contributing to this gap is the paucity of real-world pharmacokinetic studies in children and a failure to dose optimize therapy during induction. Emerging data from a pediatric clinical trial and several observational studies have shown that the combination of proactive therapeutic drug monitoring and achievement of early therapeutic concentrations is effective in achieving improved outcomes. The next steps will be to leverage these past studies to develop more innovative clinical trials to properly assess the safety and effectiveness of proactive therapeutic drug monitoring in children.
Asunto(s)
Productos Biológicos , Enfermedades Inflamatorias del Intestino , Humanos , Niño , Monitoreo de Drogas , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Resultado del Tratamiento , Inducción de Remisión , Productos Biológicos/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Infliximab/uso terapéuticoRESUMEN
BACKGROUND: Vedolizumab for inflammatory bowel disease (IBD) is often intensified based on distinct pharmacokinetics in children. Prior adult-specific population pharmacokinetic models have identified limited covariates of drug clearance. AIMS: To establish a population pharmacokinetic model for children and young adults to identify novel covariates of drug clearance to better account for paediatric-specific inter-patient variability in vedolizumab pharmacokinetics; a key secondary exploratory aim was to identify microbial signatures of pharmacokinetic outcomes in a subset of patients. METHODS: The study included data from 463 observed vedolizumab concentrations (59 peaks and 404 troughs) from 74 patients with IBD (52 with Crohn's disease and 22 with ulcerative colitis or unclassified IBD, median age 16 years). Pharmacokinetic analysis was conducted with non-linear mixed effects modelling. For the evaluation of the exposure-response relationship, clinical outcomes were evaluated by trough levels, clearance and vedolizumab exposure. Whole-genome metagenomic sequencing was conducted at baseline and week 2. RESULTS: A two-compartment population pharmacokinetic model was identified with a clear correlation between CL and weight, erythrocyte sedimentation rate, and hypoalbuminemia. Trough concentrations before infusion 3 (37 µg/ml) and before infusion 4 (20 µg/ml) best predicted steroid-free clinical remission at infusion 4. Using faecal metagenomics, we identified an early (baseline and week 2) abundance of butyrate-producing species and pathways that were associated with an infusion 4 trough concentration >20 µg/ml. CONCLUSIONS: This novel paediatric vedolizumab pharmacokinetic model could inform precision dosing. While additional studies are needed, an abundance of faecal butyrate producers is associated with early response to vedolizumab, suggesting that microbial analysis may be beneficial to biological selection.
Asunto(s)
Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Humanos , Niño , Adulto Joven , Adolescente , Resultado del Tratamiento , Fármacos Gastrointestinales , Anticuerpos Monoclonales Humanizados/efectos adversos , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamenteRESUMEN
BACKGROUND: Antibodies to infliximab (ATI) are associated with secondary loss of response and increased risk for drug reactions. Limited studies have associated ATI with increased infliximab clearance. AIMS: We assessed the impact of ATI on infliximab clearance and loss of response in an inception paediatric Crohn's disease cohort with 1-year follow-up. METHODS: This multi-centre prospective cohort study collected peak and trough serum infliximab/ATI concentrations from 660 infusions (78 patients) during the first year of therapy. Clinicians were blinded to these research labs. The primary outcome was the difference in infliximab clearance between ATI-positive (ATI) and ATI-negative (no-ATI) patients. Secondary outcomes included pre-treatment predictors of ATI (including HLA-DQA1 genotyping). Clinical remission, loss of response and infliximab clearance were compared between pre-ATI, during ATI and following ATI resolution with MANOVA. Time to ATI was calculated by Cox proportional Hazards model. RESULTS: ATI were detected in 68% (53/78) patients with a median concentration of 76 ng/mL (range 23-1828). Maximum ATI concentration was <200 ng/mL in 73.6% (39/53). Median clearance in ATI patients was higher (with higher clearance if loss of response), compared to no-ATI patients (P < 0.001). Neutrophil CD64 ratio >6 and starting dose <7.5 mg/kg independently predicted ATI in multivariable regression, while HLA-DQA1*05 presence did not. Dose adjustment resolved ATI in 37.5% (12/32) patients with concomitant infliximab concentration and clearance recovery. A maximum ATI level of ≤99 ng/mL predicted ATI resolution (area under the receiver operating curve 0.80 [95% CI 0.64-0.96]). CONCLUSIONS: In this real-world cohort, ATI as low as 23 ng/mL impacted drug clearance. Our data suggest that dose optimisation for low-level ATI can improve infliximab clearance and prevent loss of response.
Asunto(s)
Enfermedad de Crohn , Anticuerpos , Niño , Fármacos Gastrointestinales/uso terapéutico , Humanos , Infliximab , Estudios ProspectivosRESUMEN
BACKGROUND AND AIMS: We aimed to determine whether a targeted gene expression panel could predict clinical outcomes in paediatric ulcerative colitis [UC] and investigated putative pathogenic roles of predictive genes. METHODS: In total, 313 rectal RNA samples from a cohort of newly diagnosed paediatric UC patients (PROTECT) were analysed by a real-time PCR microfluidic array for expression of type 1, 2 and 17 inflammation genes. Associations between expression and clinical outcomes were assessed by logistic regression. Identified prognostic markers were further analysed using existing RNA sequencing (RNA-seq) data sets and tissue immunostaining. RESULTS: IL13RA2 was associated with a lower likelihood of corticosteroid-free remission (CSFR) on mesalamine at week 52 (pâ =â .002). A model including IL13RA2 and only baseline clinical parameters was as accurate as an established clinical model, which requires week 4 remission status. RORC was associated with a lower likelihood of colectomy by week 52. A model including RORC and PUCAI predicted colectomy by 52 weeks (area under the receiver operating characteristic curve 0.71). Bulk RNA-seq identified IL13RA2 and RORC as hub genes within UC outcome-associated expression networks related to extracellular matrix and innate immune response, and lipid metabolism and microvillus assembly, respectively. Adult UC single-cell RNA-seq data revealed IL13RA2 and RORC co-expressed genes were localized to inflammatory fibroblasts and undifferentiated epithelial cells, respectively, which was supported by protein immunostaining. CONCLUSION: Targeted assessment of rectal mucosal immune gene expression predicts 52-week CSFR in treatment-naïve paediatric UC patients. Further exploration of IL-13RÉ2 as a therapeutic target in UC and future studies of the epithelial-specific role of RORC in UC pathogenesis are warranted.
Asunto(s)
Colitis Ulcerosa , Niño , Adulto , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/genética , Colitis Ulcerosa/diagnóstico , Mesalamina/uso terapéutico , Membrana Mucosa/patología , Corticoesteroides/uso terapéutico , Expresión GénicaRESUMEN
BACKGROUND: Anti-drug antibodies (ADAs) to anti-tumor necrosis factor alpha (anti-TNF) drugs are associated with increased drug clearance and loss of response. We aimed to assess the effectiveness of starting an immunomodulator (IM) drug in patients with newly detected ADAs on anti-TNF monotherapy. METHODS: We reviewed the medical records of pediatric patients with inflammatory bowel disease on infliximab or adalimumab monotherapy with first-time detection of significant ADAs between 2014 and 2018. Patients who started an IM within 3 months of ADA detection were compared with those who did not (No-IM). Outcomes included steroid-free clinical and biochemical remission on the same anti-TNF , anti-TNF durability, and ADA reversal. RESULTS: We identified 89 patients with ADAs: 30 IM patients and 59 No-IM patients. The initial anti-TNF was stopped shortly after ADA detection in 36% of the No-IM patients vs none of the IM patients, driving longer survival on the initial anti-TNF in the IM group (Pâ =â 0.005). At 12 months, steroid-free clinical and biochemical remission on the same anti-TNF occurred in 53.9% of the IM group vs 26.8% in the No-IM group (P = 0.025). Drug levels rose higher (P = 0.003) and ADA levels fell farther (P = 0.037) in the IM group than in the No-IM group. Baseline ADA level predicted ADA reversal in the No-IM patients with an area under the receiver operating characteristic of 0.79 (P = 0.006). An ADA level <329 ng/mL had a 76.2% sensitivity and an 83.3% specificity for ADA reversal without IM. CONCLUSIONS: Pediatric patients with inflammatory bowel disease on anti-TNF monotherapy who started an IM for significant ADA levels exhibited longer anti-TNF durability and a higher likelihood of steroid-free clinical and biochemical remission on the same anti-TNF. Patients not treated with an IM were unlikely to reverse ADAs >329 ng/mL.