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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.
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Doença de Crohn , Ustekinumab , Humanos , Doença de Crohn/tratamento farmacológico , Ustekinumab/uso terapêutico , Masculino , Feminino , Estudos Retrospectivos , Adolescente , Criança , Resultado do Tratamento , Indução de Remissão , Índice de Gravidade de DoençaRESUMO
Inflammatory bowel diseases (IBDs) including Crohn's disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBD-U) are chronic inflammatory disorders which can affect the gastrointestinal tract. Anti-tumor necrosis factors antibodies (anti-TNFα) such as infliximab (IFX) and adalimumab (ADA) are the first line biological therapy for severe or complicated IBDs in pediatric age. Second line therapeutic options as vedolizumab (VDZ) and ustekinumab (UST) are currently used off-label in pediatric age. Furthermore, despite optimization of biologics, a great proportion of patients may fail to respond to biologic agents (up to 30%) or lose response over the time (around 50%) hence these patients may be left without another valid therapeutic option. Consequently, several efforts have been made in the last years in order to develop new drugs and to contrive new therapeutic strategies. Small molecule drugs (SMDs) and combination therapy with either two biologic agents or with a SMD and a biological agent have recently been proposed. Data on safety and efficacy of these new therapeutic options are limited. The objective of the present review is to summarize the most up-to-date available literature in pediatric IBD.
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OBJECTIVES: Investigate the relationship between quantified terminal ileal (TI) motility and histopathological activity grading, Crohn Disease MRI Index (CDMI) and faecal calprotectin. METHODS: Retrospective review of children with Crohn disease or unclassified inflammatory bowel disease, who underwent MR enterography. Dynamic imaging for 25 patients (median age 12, range 5 to 16) was analysed with a validated motility algorithm. The TI motility score was derived. The primary reference standard was TI Endoscopic biopsy Assessment of Inflammatory Activity (eAIS) within 40 days of the MR enterography. Secondary reference standards: (1) the Crohn Disease MRI Index (CDMI) and (2) faecal calprotectin levels. RESULTS: MR enterography median motility score was 0.17 a.u. (IQR 0.12 to 0.25; range 0.05 to 0.55), and median CDMI was 3 (IQR 0 to 5.5). Forty-three percent of patients had active disease (eAIS > 0) with a median eAIS score of 0 (IQR 0 to 2; range 0 to 5). The correlation between eAIS and motility was r = - 0.58 (p = 0.004, N = 23). Between CDMI and motility, r = - 0.42 (p = 0.037, N = 25). Motility score was lower in active disease (median 0.12 vs 0.21, p = 0.020) while CDMI was higher (median 5 vs 1, p = 0.04). In a subset of 12 patients with faecal calprotectin within 3 months of MR enterography, correlation with motility was r = - 0.27 (p = 0.4). CONCLUSIONS: Quantified terminal ileum motility decreases with increasing histopathological abnormality in children with Crohn disease, reproducing findings in adults. TI motility showed a negative correlation with an MRI activity score but not with faecal calprotectin levels. KEY POINTS: ⢠It is feasible to perform MRI quantified bowel motility assessment in children using free-breathing techniques. ⢠Bowel motility in children with Crohn disease decreases as the extent of intestinal inflammation increases. ⢠Quantified intestinal motility may be a candidate biomarker for treatment efficacy in children with Crohn disease.
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Doença de Crohn , Adulto , Criança , Doença de Crohn/diagnóstico por imagem , Estudos de Viabilidade , Humanos , Íleo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Estudos RetrospectivosRESUMO
Biological therapies, especially blocking tumor necrosis factor-α (TNFα) agents have radically changed the therapeutic approach and disease course of pediatric inflammatory bowel disease (IBD). In particular, drugs such as infliximab (IFX) and adalimumab (ADA) have been demonstrated to be effective in inducing and maintaining corticosteroid-free remission in both adult and pediatric patients with Crohns Disease (CD) and Ulcerative colitis (UC). Biosimilar biological (BioS) therapy is increasingly being used in pediatric age even though most knowledge on the safety and efficacy of these agents is based on IFX in adult IBD data. Studies show high rates of clinical response and remission in both IFX naïve patients and in patients switched from originator to BioS with similar risks of adverse events (AEs) as those reported with IFX originator. In the present review indications, efficacy and AEs of biological therapy in pediatric IBD will be discussed, as well as the role of other biological agents such as Golimumab, Vedolizumab and Ustekinumab, the role of BioS biological therapy and utility of therapeutic drug monitoring in clinical practice.
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Produtos Biológicos/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Imunossupressores/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adolescente , Fatores Etários , Produtos Biológicos/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Criança , Pré-Escolar , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/efeitos adversos , Lactente , Masculino , Indução de Remissão , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/efeitos adversosRESUMO
This review tackles the concept of the evolutionary mismatch, in relation with the reduction of the prevalence of the so-called "dirty old friends". These formed the variegated community of parasites and microorganisms, either prokaryotic or eukaryotic, that, over long evolutionary times, co-evolved with humans and their ancestors, inhabiting their digestive tracts, and other body districts. This community of microbial symbionts and metazoan parasites is thought to have evolved a complex network of inter-independence with the host, in particular in relation with their immune stimulating capacity, and with the consequent adaptation of the host immune response to this chronic stimulation. Strictly related to this evolutionary mismatch, the hygiene hypothesis, proposed by David Strachan in 1989, foresees that the increase in the incidence of inflammatory and autoimmune disorders during the twentieth century has been caused by the reduced exposure to parasites and microorganisms, especially in industrialized countries. Among these pathologies, inflammatory bowel diseases (IBDs) occupy a prominent role. From these premises, this review summarizes current knowledge on how variations in the composition of the gut bacterial microbiota, as well as its interactions with fungal communities, influence the overall immune balance, favouring or counteracting gut inflammation in IBDs. Additionally, the effect of worm parasites, either directly on the immune balance, or indirectly, through the modulation of bacterial and fungal microbiota, will be addressed. Finally, we will review a series of studies related to the use of molecules derived from parasitic worms and fungi, which hold the potential to be developed as postbiotics for the treatment of IBDs.
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Fungos/patogenicidade , Hipótese da Higiene , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/parasitologia , Intestinos/microbiologia , Intestinos/parasitologia , Parasitos/patogenicidade , Animais , Evolução Biológica , Fungos/imunologia , Microbioma Gastrointestinal , Interações Hospedeiro-Parasita , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/terapia , Intestinos/imunologia , Parasitos/imunologia , Fatores de RiscoRESUMO
UNLABELLED: This is an 8-year cohort study of 24 HIV-infected patients aged 5-17 years to assess body composition and metabolic changes after switching from lamivudine + stavudine (d4T) + protease inhibitors (PI) to lamivudine + tenofovir (TDF) + efavirenz (EFV). Body composition (dual-energy X-ray absorptiometry) and cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, glucose and insulin were measured annually. Linear mixed models and generalized linear mixed models were used to evaluate time changes of the outcome of interest. Body mass index increased linearly by 0.3 kg/m(2)/year (p < 0.001); waist circumference increased non-linearly from 68 to 74 cm (p = 0.004 for the linear term and p = 0.04 for the quadratic term). Percent body fat, percent trunk fat and percent bone mineral content increased linearly by 0.6%/year (p = 0.005), 1.2%/year (p < 0.001) and 0.02%/year (p = 0.04), respectively. Percent arm fat remained stable (p = 0.5), and percent leg fat decreased linearly by 1.2%/year (p < 0.001). The probability of low HDL was 0.2% at baseline and remained stable during the study. The probability of high triglycerides was 3% at baseline and increased linearly to become 11% at the 8th year of follow-up (p = ns). The probability of high glucose was 1% for the whole study duration. CONCLUSIONS: patients, after switching from d4T to TDF and from PI to EFV, show most of the changes in anthropometry and body composition associated with normal growth and no frankly pathological change in metabolic parameters.
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Adenina/análogos & derivados , Antirretrovirais/administração & dosagem , Benzoxazinas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Organofosfonatos/administração & dosagem , Estavudina/administração & dosagem , Absorciometria de Fóton , Adenina/administração & dosagem , Adolescente , Alcinos , Glicemia/análise , Composição Corporal/efeitos dos fármacos , Criança , Pré-Escolar , Estudos de Coortes , Ciclopropanos , Feminino , Infecções por HIV/metabolismo , Humanos , Lamivudina/administração & dosagem , Modelos Lineares , Lipídeos/sangue , Estudos Longitudinais , Masculino , TenofovirRESUMO
INTRODUCTION: Split-dose thiopurine and allopurinol-thiopurine cotherapy strategies have been suggested as rescue therapeutic options for children with inflammatory bowel disease (IBD) and impaired thiopurine metabolism. We compared the efficacy and safety of these regimens in patients who previously failed conventional thiopurine treatment. METHODS: Children with IBD treated with split-dose thiopurine or low-dose thiopurine-allopurinol cotherapy were retrospectively identified. Medical records were reviewed for demographics, treatment regimen, reason for thiopurine failure, side effects, and discontinuation of treatment. Laboratory findings were evaluated at different time points. RESULTS: After prior therapeutic failure, 42 patients were on split-dose regimen (group A) and 20 patients were on thiopurine-allopurinol cotherapy (group B). Twelve patients crossed from group A to group B because of treatment failure, 1 patient was lost at follow-up, and 1 patient discontinued the treatment. The final cotherapy group comprised 29 children (group C), while the split-dose group (group D) included 31 children. Intention-to-treat analysis showed significant differences between split-dose regimen and thiopurine-allopurinol cotherapy for 6-thioguanine nucleotide (6-TGN)/6-methyl mercaptopurine (6-MeMP) ratio ( P < 0.001), 6-TGN ( P < 0.05), and 6-MeMP ( P < 0.001) at 1-3 months. As per protocol analysis, there was a significant difference between group C and group D at 6 months for 6-MeMP ( P < 0.05) and 6-TGN/6-MeMP ratio ( P < 0.05) and at 12 months for 6-MeMP ( P < 0.05) and 6-TGN/6-MeMP ratio ( P < 0.001). Side effects were more frequent in allopurinol-thiopurine cotherapy ( P < 0.05). DISCUSSION: In children with IBD and impaired thiopurine metabolism, split-dose thiopurine and low-dose thiopurine-allopurinol cotherapy are both effective therapeutic strategies. The latter shows higher efficacy but a higher side effect rate, suggesting the use of split-dose regimen as the first-line approach.
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Alopurinol , Doenças Inflamatórias Intestinais , Humanos , Criança , Alopurinol/efeitos adversos , Azatioprina/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Quimioterapia Combinada , Mercaptopurina/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/induzido quimicamenteRESUMO
Background: Inflammatory bowel disease (IBD) patients show a higher risk of developing metabolic and cardiovascular diseases due to the presence of systemic low-grade chronic inflammation. Exercise can improve cardiovascular fitness and modulate the inflammatory processes. We evaluated the physical activity (PA) level and the fitness performance of children and adolescents with IBD. Patients and methods: We considered 54 pediatric patients with IBD (14.6 ± 2.2; 22 M), including CD (n = 27) UC (n = 24) and IBD unclassified (n = 3), and 70 healthy children. In all children, the Physical Activity Questionnaire (PAQ-C) and the International Fitness Enjoyment Scale were self-reported and recorded. Results: PAQ-C showed significant difference in PA levels in patients with IBD compared to controls (p < 0.001). A decrease in general fitness (p = 0.003), cardiorespiratory fitness (p = 0.002), strength (p = 0.01), speed agility (p = 0.003), and flexibility (p = 0.01) were also detected between patients and controls. Speed agility was related to age (p = 0.02) and BMI z-score (p = 0.01), and flexibility to BMI z-score (p = 0.05). We noted a correlation between PA levels and physician global assessment (p = 0.021) and activity disease severity (p = 0.025). Conclusions: A poorer PA level and poor physical competence were found in patients with IBD compared to healthy children and adolescents. Monitored exercise could provide multiple benefits at both physical and psychological levels.
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BACKGROUND: Although intravenous ferric carboxymaltose (FCM) is effective in treating iron deficiency anemia (IDA) in paediatric inflammatory bowel disease (pIBD), no data are available on its post-infusion related risks. AIMS: We assessed the efficacy of FCM and the rate of post-infusion hypophosphatemia in a large cohort of children with IBD and IDA. METHODS: All children with IBD with IDA treated with FCM over 5-year period were reviewed. Disease activity, biohumoral assessment and treatments were evaluated at baseline, 4-6 and 12 weeks after each infusion. RESULTS: 128 patients [median age at first infusion: 13 years] were identified, 81 (63.3%) were <14 years, 10 (7.8%) <6 years. Eighty-three children (64.8%) received one infusion, whilst 45 (35.2%) repeated infusions. A significant increase in Hb (p<0.001), iron (p<0.001) and ferritin (p<0.001) was observed 4-6 and 12 weeks post-infusion. Hb gain was unrelated to disease severity. Low baseline iron was the main predicting factor for repeated infusions (p<0.05). Three patients reported infusion reactions, none <6 years. Twenty-five children had low post-infusion serum phosphate (11 were <14 years, 3 <6 years). Two children developed severe hypophosphatemia. CONCLUSIONS: FCM administration is effective for IDA management in pIBD, including children <6 years. Due to the high prevalence of post-infusion hypophosphatemia, serum phosphate monitoring should be mandatory.
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Anemia Ferropriva/tratamento farmacológico , Compostos Férricos/administração & dosagem , Hipofosfatemia/induzido quimicamente , Doenças Inflamatórias Intestinais/complicações , Maltose/análogos & derivados , Fosfatos/sangue , Administração Intravenosa , Adolescente , Anemia Ferropriva/sangue , Anemia Ferropriva/etiologia , Criança , Pré-Escolar , Feminino , Compostos Férricos/efeitos adversos , Ferritinas/sangue , Hemoglobinas/efeitos dos fármacos , Humanos , Hipofosfatemia/epidemiologia , Doenças Inflamatórias Intestinais/sangue , Ferro/sangue , Masculino , Maltose/administração & dosagem , Maltose/efeitos adversos , Prevalência , Fatores de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Inflammatory Bowel Diseases (IBDs) are gastrointestinal disorders characterized by chronic, relapsing inflammation, with growing incidence worldwide over the last decades and distinctive features in the pediatric age. An increasing body of evidence indicates that gut microbiota plays a major role in inflammatory disorders, including IBDs. In this review we will discuss the most recent evidences on dysbiotic changes associated with gut inflammation, as well as environmental and genetic factors contributing to IBD pathogenesis, with a focus on the peculiarities of the pediatric age.
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Colite Ulcerativa/microbiologia , Doença de Crohn/microbiologia , Microbioma Gastrointestinal , Criança , Pré-Escolar , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Disbiose , Humanos , Lactente , Recém-NascidoRESUMO
BACKGROUND: Currarino syndrome is a rare condition characterized by presacral mass, anorectal malformation and sacral dysgenesis. CASE PRESENTATION: We report the case of a child that presented chronic constipation, encopresis and mycrocephaly. The characteristics were initially compatible with a case of functional constipation and a therapy with polyethylene glycol was prescribed. After a year, because of poor response, a plain abdominal X-ray was performed, detecting sacrum abnormalities. Finally, a CGH-array analysis was performed and a form of Currarino Syndrome caused by a rare 7q36 microdeletion, was diagnosed. CONCLUSION: Occult spinal dysraphism should be suspected in case of poor polyethylene glycol responder constipation, even when evident sacral abnormalities on the physical examination are not detected.
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Canal Anal/anormalidades , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Anormalidades do Sistema Digestório/diagnóstico , Anormalidades do Sistema Digestório/genética , Microcefalia/diagnóstico , Microcefalia/genética , Reto/anormalidades , Sacro/anormalidades , Siringomielia/diagnóstico , Siringomielia/genética , Pré-Escolar , Feminino , Proteínas de Homeodomínio/genética , Humanos , Fatores de Transcrição/genéticaRESUMO
Cow's milk allergy (CMA) is one of the most common food allergies, especially during childhood. CMA is an immunological mediated adverse reaction to one or more cow's milk proteins, which are normally harmless to a non-allergic individual, as the result of a failure of oral tolerance. To make a correct diagnosis of CMA and a proper treatment is critical in clinical practice. Application of proteomics along with new bio-informatics tools in the field of food allergy is one of the hot topics presented in recent years. In the present review, we focus on recent applications of proteomics to the field of cow's milk allergy, from allergens quantification to the diagnosis, treatment and prognosis. Furthermore, we also shed a light on potential future directions and developments, that are parts of personalized medicine but also of the One Health approach. SIGNIFICANCE: The field of food allergies is becoming a milestone in public health. Food allergies, in fact, can cause life-threatening reactions and profoundly influence the quality of life. Precise, fast and reliable diagnosis of food allergies, and in particular milk allergies is essential to avoid severe allergic reactions and also to prevent dangerous and eventually unnecessary dietary restrictions; but this can be difficult also due to a complex interaction of genetic background, environment, and microbiota. In this sense, proteomics represents steps toward researching food and milk allergy integrated with the clinic to improve pathophysiology, diagnosis, therapy, and prognosis.
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Hipersensibilidade Alimentar/imunologia , Hipersensibilidade a Leite/diagnóstico , Medicina de Precisão/métodos , Proteômica/métodos , Alérgenos/análise , Animais , Bovinos , Humanos , Hipersensibilidade a Leite/imunologia , Hipersensibilidade a Leite/terapia , Proteínas do Leite/análise , Proteínas do Leite/imunologiaRESUMO
Nutrition is involved in several aspects of pediatric inflammatory bowel disease (IBD), ranging from disease etiology to induction and maintenance of disease. With regards to etiology, there are pediatric data, mainly from case-control studies, which suggest that some dietary habits (for example consumption of animal protein, fatty foods, high sugar intake) may predispose patients to IBD onset. As for disease treatment, exclusive enteral nutrition (EEN) is an extensively studied, well established, and valid approach to the remission of pediatric Crohn's disease (CD). Apart from EEN, several new nutritional approaches are emerging and have proved to be successful (specific carbohydrate diet and CD exclusion diet) but the available evidence is not strong enough to recommend this kind of intervention in clinical practice and new large experimental controlled studies are needed, especially in the pediatric population. Moreover, efforts are being made to identify foods with anti-inflammatory properties such as curcumin and long-chain polyunsaturated fatty acids n-3, which can possibly be effective in maintenance of disease. The present systematic review aims at reviewing the scientific literature on all aspects of nutrition in pediatric IBD, including the most recent advances on nutritional therapy.