RESUMO
OBJECTIVES: Sofosbuvir/Ledipasvir (SOF/LDV) has been approved by the European Medicine Agency (EMA) for the treatment of children and adolescents (at least 3 years of age) with chronic hepatitis C (CHC) genotype 1, 3, and 4 infection. The aim of this study was to evaluate the efficacy and safety of SOF/LDV in adolescents (12 to <18 years old) with CHC in the real-world setting. METHODS: Prospective, open-label, multicentre study involving 12 Italian centres. Patients received the fixed-dose combination of SOF/LDV (400/90âmg) once daily ± ribavirin as per EMA approval and recommendations. The key efficacy endpoint was sustained virological response 12 weeks after the end of treatment (SVR12) as per intention-to-treat analysis. Safety was assessed by adverse events and clinical/laboratory data. RESULTS: Seventy-eight consecutive adolescents (median age 15.2 years, range 12-17.9; girls 53.8%) were enrolled and treated between June 2018 and December 2019. Genotype distribution was as follows: genotype 1 (82.1%), 3 (2.5%), and 4 (15.4%). Seventy-six (97.4%) patients completed treatment and follow-up. Overall, SVR12 was 98.7%. One patient was lost to follow-up after 4 weeks of treatment; 1 patient completed treatment and missed the follow-up visit. No virological breakthrough or relapse were observed. No patient experienced grade 3 to 4 adverse event or serious adverse event. CONCLUSIONS: The results of this real-world study confirmed the high efficacy and the optimal safety profile of SOF/LDV for treatment of CHC in adolescents.
Assuntos
Hepatite C Crônica , Sofosbuvir , Adolescente , Antivirais/efeitos adversos , Benzimidazóis , Criança , Quimioterapia Combinada , Feminino , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Humanos , Estudos Prospectivos , Sofosbuvir/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVES: To evaluate the usefulness of colonic ultrasonography (US) in assessing the extent and activity of disease in pediatric ulcerative colitis (UC) and to compare US findings with clinical and endoscopic features. STUDY DESIGN: Consecutive pediatric patients (n = 60) with a diagnosis of UC and suspected disease flare-up were prospectively enrolled; of these, 50 patients were eligible for the study. All underwent clinical evaluation, bowel US with color Doppler examination and colonoscopy. Blind US was performed the day before endoscopy in all patients. The US assessed variables were bowel wall thickness >3 mm, bowel wall stratification, vascularity, presence of haustra coli, and enlarged mesenteric lymph nodes. RESULTS: The endoscopic extent of disease was independently confirmed in 47 patients by US that yielded a 90% concordance with endoscopy (95% CI 0.82-0.96). Multiple regression analysis showed that US measurements with an independent predictive value of severity at endoscopy were increased bowel wall thickness (P < .0008), increased vascularity (P < .002), loss of haustra (P = .031), and loss of stratification of the bowel wall (P = .021). Each variable was assigned a value of 1 if present. The US score strongly correlated with clinical (r = 0.94) and endoscopic activity (r = 0.90) of disease (P < .0001). CONCLUSIONS: Colonic US is a useful first line noninvasive tool to assess the extent and activity of disease in children with UC and to estimate the severity of a flare-up, prior to further invasive tests.
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Colite Ulcerativa/diagnóstico por imagem , Colo/diagnóstico por imagem , Colonoscopia/métodos , Ultrassonografia Doppler em Cores/métodos , Adolescente , Criança , Pré-Escolar , Colite Ulcerativa/patologia , Colo/patologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
OBJECTIVE: The antitumor necrosis factor α (TNFα) antibodies infliximab and adalimumab are effective in inducing and maintaining remission in pediatric patients with Crohn disease (CD). The aim of the study was to evaluate the long-term efficacy and safety of biological therapy in pediatric patients with CD followed at a referral center. METHODS: This work is a retrospective observational study enrolling patients with CD treated with infliximab or adalimumab beyond the induction protocol. The patients' data were collected from the unit's IBD database (maximum follow-up evaluation after 36 months of treatment). The efficacy was evaluated by the Pediatric Crohn Disease Activity Index score and by analysis of the cumulative probability of continuing therapy; the safety was assessed in terms of adverse events. RESULTS: We enrolled 78 patients; the mean therapy duration was 27.2 ± 16.7 months, and the mean age at enrollment was 15 ± 3.1 years. The Kaplan-Meier analysis showed a cumulative probability of continuing therapy of 81%, 54%, and 33% at 1, 2, and 3 years, respectively, from the introduction of therapy. No association between the patients' baseline characteristics and the long-term outcome was found. The evaluation of the concomitant therapy with immunomodulators and anti-TNFα therapy versus anti-TNFα alone did not show a different outcome. No serious adverse events were recorded. CONCLUSIONS: The study indicates that biological therapy is effective and safe in pediatric patients with CD in a longer follow-up period. The response to treatment was not influenced by the patients' baseline characteristics or by the immunomodulator association.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Doença de Crohn/tratamento farmacológico , Adalimumab , Adolescente , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Terapia Biológica , Criança , Estudos de Coortes , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Infliximab , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Through genomic analysis of mucosa-associated Escherichia coli strains, we found a close genetic association among isolates from pediatric inflammatory bowel disease (IBD) patients. A specific E. coli pathovar, adherent-invasive E. coli (AIEC), was found in Crohn's disease (CD) adult patients - this pathovar has enhanced adhesive and invasive properties, mainly due to the mannose-bonding FimH protein. We aimed to characterize 52 mucosa-associated E. coli strains isolated from pediatric IBD and non-IBD patients. Eleven E. coli strains, showing a strong similarity in fimH gene sequence to that of E. coli AIEC LF82, were characterized for fimH gene sequence, genomic profiling, adhesive and invasive ability, and phylogrouping. The results were compared with E. coli strains AIEC LF82 and MG1655. The 11 E. coli isolates showed 82.4% ± 1.4% fimH sequence similarity and 80.6% ± 1.3% genomic similarity to strain AIEC LF82. All these strains harbored V27A and S78N FimH mutations, as found in LF82. Nine of them belonged to the more virulent B2 and D phylogroups. Neuraminidase treatment, mimicking inflamed mucosa, enhanced adhesion of all 11 strains by 3.5-fold, but none showed invasion ability. It could be argued that the 11 selected strains could be a branch of an E. coli subpopulation (pathobionts), that could take advantage in an inflamed context because of a suitable genomic and (or) genetic backdrop.
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Infecções por Escherichia coli/microbiologia , Escherichia coli/patogenicidade , Doenças Inflamatórias Intestinais/microbiologia , Adesinas de Escherichia coli/genética , Adesinas de Escherichia coli/metabolismo , Adolescente , Aderência Bacteriana/imunologia , Criança , Pré-Escolar , Doença de Crohn/microbiologia , Doença de Crohn/patologia , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Escherichia coli/fisiologia , Infecções por Escherichia coli/patologia , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Feminino , Humanos , Doenças Inflamatórias Intestinais/patologia , MasculinoRESUMO
BACKGROUND: Several mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with unconjugated hyperbilirubinemia. Few reports are available about the p.Pro364Leu mutation (P364L, c.1091C > T) in homozygous newborns. We describe the clinical, laboratory and therapeutic approach in two Chinese neonates with severe jaundice, homozygous for the P364L mutation. CASE PRESENTATION: Two Chinese breastfed female infants presented prolonged unconjugated hyperbilirubinemia at the age of 1 month. Total bilirubin was higher than 15 mg/dl (D < 1). An exhaustive etiological work-up to detect possible causes of hyperbilirubinemia (notably hemolytic ones) was negative. The promoter and coding regions of UGT1A1 were amplified by polymerase chain reaction (PCR) from genomic DNA isolated from leukocytes. Both patients resulted homozygous for a variant site within the coding region of the gene in the 4 exon, c.1091C > T, p.Pro364Leu. In front of the persistently high level of unconjugated bilirubin, phototherapy was performed without persistent results. A treatment with phenobarbital was then begun and bilirubin level progressively decreased, with a complete and persistent normalization. The therapy was stopped. CONCLUSION: UGT1A1 enzyme activity associated with the P364L mutation has been described as 35.6% of the wild-type enzyme activity. Photo-therapy and phenobarbital can be useful in front of persistently high level of unconjugated bilirubin. Our cases presented high bilirubin values, overlapping between Gilbert syndrome (GS) and Crigler-Najjar syndrome type II (CNS), but the complete normalization of bilirubin makes GS more likely. Homozygous P364L variant can be associated with severe neonatal unconjugated hyperbilirubinemia in Chinese infants, but jaundice can completely resolve in a few months, contrary to what happens in Crigler-Najjar syndrome type II.
Assuntos
Síndrome de Crigler-Najjar , Doença de Gilbert , Hiperbilirrubinemia Neonatal , Bilirrubina , Síndrome de Crigler-Najjar/diagnóstico , Síndrome de Crigler-Najjar/genética , Síndrome de Crigler-Najjar/terapia , Feminino , Doença de Gilbert/diagnóstico , Doença de Gilbert/genética , Glucuronosiltransferase/genética , Humanos , Hiperbilirrubinemia/genética , Hiperbilirrubinemia Neonatal/diagnóstico , Hiperbilirrubinemia Neonatal/genética , Hiperbilirrubinemia Neonatal/terapia , Lactente , Recém-Nascido , Mutação , FenobarbitalRESUMO
Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.
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Colestase , Medicina Baseada em Evidências , Gastroenterologia/normas , Doenças do Recém-Nascido , Guias de Prática Clínica como Assunto , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
OBJECTIVES: Our work is aimed at identifying ex vivo new transcription factors, potentially involved in the pathogenesis of pediatric inflammatory bowel disease (IBD), by using a microarray approach. PATIENTS AND METHODS: Microarray, including 84 transcription factors, was performed in inflamed and uninflamed mucosal tissues of pediatric patients with Crohn disease (CD) and in healthy controls. Real-time polymerase chain reaction was used to confirm microarray results on a larger size of CD and patients with ulcerative colitis (UC). Protein expression was evaluated by Western blot assay. RESULTS: Microarray assay showed 40 genes differentially regulated in the inflamed mucosa and 17 in the uninflamed mucosa of patients with CD as compared with controls. Real-time polymerase chain reaction analysis revealed 10 transcripts in CD and 4 in UC, selected among those with higher differences as compared with healthy controls, significantly overexpressed in the inflamed tissues of patients. Moreover, 4 transcripts in CD and 2 in UC were found significantly upregulated in the uninvolved tissue. A further investigation evidenced an increased protein expression of activating transcription factor 3 and hypoxia-inducible transcription factor-1α in patients with CD as well as in Caco2 cell line stimulated by cytokines and hypoxia. CONCLUSIONS: The present study shows an evident upregulation of several transcription factors in the inflamed and uninflamed mucosa of children with IBD, suggesting that the inflammatory process is somehow activated at molecular levels even in the macroscopically normal mucosa of patients. A differential pattern of gene expression between CD and UC indicates distinct molecular mechanisms underlying the pathogenesis of 2 diseases. Finally, activating transcription factor 3 and hypoxia-inducible transcription factor-1α are proposed as new transcription factors potentially involved in the onset and maintenance of IBD.
Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Regulação da Expressão Gênica , Inflamação/genética , Mucosa Intestinal/metabolismo , Fatores de Transcrição/metabolismo , Adolescente , Biópsia , Criança , Pré-Escolar , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Feminino , Humanos , Lactente , Inflamação/metabolismo , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Valores de Referência , Regulação para CimaRESUMO
Objectives: In the era of Coronavirus 2019 (COVID-19), concern has been raised for immunosuppressed patients, including children with inflammatory bowel diseases (IBD). We aimed to collect data from IBD tertiary centers of Lombardy during pandemic. Methods: A cross-sectional survey enrolling IBD children has been completed by seven major IBD centers in Lombardy during lockdown. The clinical form included questions on any symptom consistent with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the IBD adherence treatment. Furthermore, we have reviewed all IBD medical records including new IBD diagnoses and flares in known IBD patients after the lockdown. Results: Questionnaires of 290 IBD children were returned during lockdown. Out of them, 24 children (8%) complained of mild symptoms suspicious of SARS-CoV-2 infection without needing hospitalization or changing IBD treatment. During the lockdown, one patient presented with IBD flare and one had infectious colitis, with no new IBD cases. Conversely, after lockdown, 12/290 (4%) children relapsed and 15 children were newly diagnosed with IBD. Last year, in the same timeframe, 20/300 (7%) children presented with IBD flare, while 17 children had IBD onset with no statistical difference. Conclusions: Our data on children with IBD in a high COVID-19 prevalence region are reassuring. Only a minority of IBD children had mild symptoms, and no hospitalization or treatment modification was needed. Standard IBD treatments including biologics were safely continued. New IBD diagnoses and flares in known IBD children occurred after the lockdown phase, although no significant difference was found compared with the previous year.
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Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2, spreading in Italy during the first months of 2020, abruptly changed the way of practicing medicine in this country. As a consequence of the lockdown, the diagnostic and therapeutic management of paediatric chronic conditions, such as inflammatory bowel disease (IBD) has been affected. During the peak of COVID-19 pandemic, elective visits, endoscopies and infusions have been postponed, with potential clinical and psychological impact on disease course and a high likelihood of increasing waiting lists. While slowly moving back towards normality, clinicians need to recognize the best ways to care for patients with IBD, carefully avoiding risk factors for new potential epidemic outbreaks. In this uncertain scenario until the development and spread of COVID-19 vaccine, it is necessary to continue to operate with caution. Hereby we provide useful indications for a safer and gradual restarting of routine clinical activities after COVID-19 peak in Italy.
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COVID-19 , Controle de Doenças Transmissíveis/métodos , Gastroenterologia , Doenças Inflamatórias Intestinais , Pediatria , COVID-19/epidemiologia , COVID-19/prevenção & controle , Criança , Gastroenterologia/métodos , Gastroenterologia/organização & administração , Gastroenterologia/tendências , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/terapia , Itália , Inovação Organizacional , Pediatria/métodos , Pediatria/organização & administração , Pediatria/tendências , Risco Ajustado , SARS-CoV-2RESUMO
INTRODUCTION: The ability to predict risk for poor outcomes in Crohn's disease [CD] would enable early treatment intensification. We aimed to identify children with CD with complications at baseline and throughout the study period who are at risk for surgery 2 years from diagnosis. METHODS: Newly diagnosed children with CD were enrolled into a prospective, multicentre inception cohort. Disease characteristics and serological markers were obtained at baseline and week 12 thereafter. Outcome data including disease activity, therapies, complications and need for surgery were collected until the end of 104 weeks. A chi-square automatic interaction detection [CHAID] algorithm was used to develop a prediction model for early surgery. RESULTS: Of 285 children enrolled, 31 [10.9%] required surgery within 2 years. Multivariate analysis identified stricturing disease at baseline (odds ratio [OR] 5.26, 95% confidence interval [CI] 2.02-13.67 [p = 0.001]), and Paediatric Crohn's Disease Activity Index [PCDAI] >10 at week 12 (OR 1.06, 95% CI 1.02-1.10 [p = 0.005]) as key predictors for early surgery. CHAID demonstrated that absence of strictures at diagnosis [7.6%], corticosteroid-free remission at week 12 [4.1%] and early immunomodulator therapy [0.8%] were associated with the lowest risk of surgery, while stricturing disease at diagnosis [27.1%, p < 0.001] or elevated PCDAI at week 12 [16.7%, p = 0.014] had an increased risk of surgery at follow-up. Anti-OmpC status further stratified high-risk patients. DISCUSSION: A risk algorithm using clinical and serological variables at diagnosis and week 12 can categorize patients into high- and low-risk groups from diagnosis.
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Doença de Crohn/complicações , Doença de Crohn/cirurgia , Adolescente , Algoritmos , Criança , Estudos de Coortes , Doença de Crohn/diagnóstico , Feminino , Humanos , Masculino , Seleção de Pacientes , Valor Preditivo dos Testes , Fatores de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Autoimmune liver disease (AILD) includes autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC). AILD is often associated with other extra-hepatic immune-mediated disorders (EDs), but there are few pediatric studies available to date. In this study we evaluated the association between AILD and EDs in our pediatric series. METHODS: In this single centre retrospective study 48 patients (39 AIH and 9 ASC children) were evaluated. Thirty-six children were primarily referred to our Centre for liver disease suspicion, while the remaining twelve had a previous diagnosis of EDs. All the patients were screened for various EDs at AILD diagnosis and yearly during the follow-up. RESULTS: Mean duration of follow-up was 9â¯years and 1 month. Twenty-two (46%) patients had a diagnosis of EDs. Ulcerative colitis (UC) was the most frequent EDs (9 patients), followed by autoimmune thyroid disease (5 patients) and celiac disease (5 patients). In 7 out of 9 UC patients, ASC was present. CONCLUSIONS: Our study showed a high association (46%) between AILD and EDs. In particular, in 8 out of 9 ASC patients UC was diagnosed (p-value 0.007). It is important to look for EDs in AILD children and, conversely, AILD in EDs children with abnormal liver function tests.
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Doença Celíaca/epidemiologia , Colangite Esclerosante , Colite Ulcerativa/epidemiologia , Hepatite Autoimune , Tireoidite Autoimune/epidemiologia , Autoimunidade , Ductos Biliares/diagnóstico por imagem , Biópsia , Doença Celíaca/imunologia , Criança , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/epidemiologia , Colangite Esclerosante/imunologia , Colite Ulcerativa/imunologia , Correlação de Dados , Feminino , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/epidemiologia , Hepatite Autoimune/imunologia , Humanos , Testes Imunológicos/métodos , Imunossupressores/uso terapêutico , Itália , Fígado/imunologia , Fígado/patologia , Testes de Função Hepática/métodos , Masculino , Estudos Retrospectivos , Tireoidite Autoimune/imunologiaRESUMO
BACKGROUND: Exclusive enteral nutrition [EEN] and corticosteroids [CS] induce similar rates of remission in mild to moderate paediatric Crohn's disease [CD], but differ with regard to mucosal healing. Our goal was to evaluate if EEN at diagnosis was superior to CS for improving long-term outcomes. METHODS: We prospectively followed newly diagnosed children aged < 17 years, with mild to moderate CD at baseline, for 2 years in the GROWTH CD study. Patients were evaluated at baseline and at 8, 12, 78, and 104 weeks. Remission, relapses, complications [fibrostenotic disease, penetrating disease, and active perianal disease] and growth were recorded throughout the study. A propensity score analysis was performed. RESULTS: A total of 147 children [mean age 12.9 ± 3.2 years], treated by EEN [n = 60] or CS [n = 87] were included. New complications developed in 13.7% of CS [12/87] versus 11.6% of EEN [7/60], p = 0.29. Remission was achieved in 41/87 [47%] in CS and 38/60 [63%] EEN, p = 0.036. Median time to relapse did not differ [14.4 ± 1 months with CS, 16.05 ± 1.1 EEN, p = 0.28]. Mean height Z scores decreased from Week 0 to Week 78 with CS [-0.34 ± 1.1 to -0.51 ± 1.2, p = 0.01], but not with EEN [-0.32 ± 1.1 to -0.22 ± 0.9, p = 0.56]. In a propensity score analysis, EEN was superior to CS for inducing remission [p = 0.05] and trended to superiority for height Z score [p = 0.055]. CONCLUSIONS: Use of EEN was associated with higher remission rates and a trend toward better growth but with similar relapse and complication rates in new-onset mild to moderate paediatric CD.
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Corticosteroides/uso terapêutico , Estatura , Doença de Crohn/terapia , Nutrição Enteral , Fístula Retal/etiologia , Indução de Remissão , Abscesso/etiologia , Adolescente , Produtos Biológicos/uso terapêutico , Criança , Constrição Patológica/etiologia , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Feminino , Humanos , Masculino , Pontuação de Propensão , Estudos Prospectivos , Recidiva , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Paediatric Crohn's disease is characteried by frequently relapsing disease which may lead to hospitalisations and complications. AIM: To develop predictive models for early relapse following first remission. METHODS: The GROWTH CD prospective inception cohort was designed to predict risk for early disease relapse and poor outcomes. Newly diagnosed children underwent endoscopies and imaging. They were phenotyped and followed at scheduled visits through 78 weeks for relapses. Twenty-eight dichotomous and continuous variables were assessed at baseline and week 12, including phenotype, inflammatory markers, disease activity (PCDAI) and other markers. Clinical relapses defined as PCDAI >10 after remission were recorded using a relapse form. Logistic regression & risk modelling was performed. RESULTS: We enrolled 282 eligible patients of whom 178 (63.6%) patients achieved steroid free remission by week 12. Disease complications developed in 22/76(29%) of patients with relapse compared to 20/206 (9.7%) without relapse (P = 0.01). Multivariable analysis demonstrated that while variables from age/gender at diagnosis were not predictive, week 12 variables including PCDAI >5 (P = 0.02), CRP >20 mg/L (P = 0.02), and faecal calprotectin >400 µg/g (P = 0.03) as optimal cut-offs were associated with increased risk of relapse. A prediction model for patients in remission including gender, age, week 12 PCDAI, calprotectin and CRP had sensitivity 43%, specificity 92%, PPV 78%, NPV 71% for relapse. CONCLUSIONS: Early relapses were associated with a higher risk for disease complications at followup. Relapse prediction based on week 12 disease activity or inflammation is superior to prediction using data from diagnosis.
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Doença de Crohn/diagnóstico , Doença de Crohn/metabolismo , Fatores Imunológicos/uso terapêutico , Índice de Gravidade de Doença , Adolescente , Biomarcadores/química , Biomarcadores/metabolismo , Criança , Pré-Escolar , Doença de Crohn/tratamento farmacológico , Fezes/química , Feminino , Humanos , Complexo Antígeno L1 Leucocitário/metabolismo , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Recidiva , Indução de Remissão/métodos , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: There is growing evidence that in Crohn's disease the achievement and maintenance of mucosal healing (MH) through anti-TNFα antibodies may change the natural history of the disease. Few studies evaluating such outcome as a therapeutic goal are available in paediatrics. The primary aim of the study was to assess the efficacy of biologics in obtaining MH in a paediatric Crohn's disease cohort. The secondary aims were: (1) to assess response based on early or late treatment introduction and on combination therapy with immunomodulators versus biologics alone; and (2) to evaluate clinical outcome 2 years after the second endoscopy. METHODS: Biologic-naive paediatric Crohn's disease patients starting anti-tumour necrosis factor α (TNFα) treatment were enrolled. Patients' demographic and treatment data were recorded. Clinical [Pediatric Crohn's Disease Activity Index (PCDAI)] and endoscopic [Simple Endoscopic Score for Crohn's Disease (SES-CD)] evaluations were performed at time 0 (T0) and after 9-12 months (follow-up). Appropriate induction and maintenance therapeutic schemes were applied. RESULTS: Thirty-seven patients were enrolled. At enrolment, mean age was 12.3 ± 3.4 years and mean disease duration was 13.0 ± 16 months. At follow-up there was a significant decrease in PCDAI and SES-CD compared with T0 (p < 0.01). No statistical difference in frequency of MH between the early and late treatment introduction groups was found. Combination therapy was superior in obtaining complete plus partial MH (p < 0.01). One and 2 years after the second endoscopy, all and 79% of patients with complete MH and 75 and 67% of those with partial MH were still in clinical remission, respectively. CONCLUSIONS: Biologics improve mucosal lesions, apparently more effectively if given in combination with immunomodulators. MH appears to sustain a better disease course.
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Produtos Biológicos/administração & dosagem , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Adolescente , Criança , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Fatores Imunológicos/administração & dosagem , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Mucosa Intestinal/fisiopatologia , Estimativa de Kaplan-Meier , Masculino , Razão de Chances , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Resultado do Tratamento , Fator de Necrose Tumoral alfa/administração & dosagemRESUMO
BACKGROUND: Crohn's disease is a chronic inflammatory disease characterized by a progressive transmural bowel damage leading to complications. Anti-TNFα therapy is effective in achieving mucosal healing (MH), but its efficacy on transmural inflammation has been poorly investigated. The aim of this study is to evaluate, in pediatric Crohn's disease, the efficacy of anti-tumor necrosis factor α agents in inducing transmural healing (TH) as assessed by ultrasonography (US). METHODS: Children with Crohn's disease requiring anti-tumor necrosis factor α therapy were prospectively enrolled. Clinical activity, laboratory tests, endoscopic activity, and transmural disease assessed by small intestine contrast US (SICUS) were evaluated at baseline (T0) and then after 9 to 12 months of therapy (T1). We evaluated US quantitative and qualitative parameters: disease extension (centimeters), bowel wall (BW) thickness >3 mm, BW vascularity and stratification strictures, and prestenotic dilatation. TH was defined as a BW thickness <3 mm and normalization of all US parameters at T1. RESULTS: Thirty-two patients were included. Patients with mucosal healing (MH) showed a significant decrease of BW thickness and disease extension at T1 (4.3 ± 1.4 mm and 8 ± 6.3 cm versus 6.1 ± 2.3 mm and 13 ± 5 cm at baseline, respectively) (P < 0.001). Increased vascularity of the BW was found in 80% of patients at T0 and in 18% at T1 (P < 0.001). These parameters did not change in patients without MH, despite clinical and laboratory remission. The presence of stenosis and prestenotic dilatation did not modify in any group. A complete TH was achieved in 14% of patients, all of them showing complete MH. CONCLUSIONS: Biologics induce clinical and laboratory remission and MH in pediatric CD. Although caution is needed due to the small sample size, our data suggest that transmural inflammation also improves during therapy, but a complete TH is achieved only in a small percentage of patients.
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Fatores Biológicos/uso terapêutico , Doença de Crohn/tratamento farmacológico , Intestino Delgado/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ultrassonografia/métodos , Adolescente , Criança , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/patologia , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Intestino Delgado/diagnóstico por imagem , Masculino , Estudos Prospectivos , Resultado do TratamentoRESUMO
Inflammatory bowel diseases are characterized by a chronic relapsing course, high morbidity and impaired quality of life. Their incidence is rising, and about 25% of cases are diagnosed in pediatric age. Anti-TNF-α antibodies, such as infliximab and adalimumab (ADA), are usually administered in patients refractory to conventional therapies. However, increasing evidence suggests that they can be introduced earlier in the course of the disease, especially in patients with aggressive and extensive disease since diagnosis. ADA is a fully human anti-TNF-α antibody recently approved for pediatric Crohn's disease not only in patients unresponsive to infliximab, but also as a first-line anti-TNF-α therapy. In this review, we aim to summarize the current knowledge on the use of ADA in pediatric Crohn's disease and to discuss open issues regarding safety as well as future perspectives.
Assuntos
Adalimumab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Crohn/tratamento farmacológico , Adalimumab/efeitos adversos , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Criança , Humanos , Infecções/induzido quimicamente , Indução de Remissão , Dermatopatias/induzido quimicamente , Resultado do TratamentoRESUMO
BACKGROUND: The effectiveness of medical therapy in paediatric acute severe colitis is scarcely described. We aimed to assess the efficacy of infliximab in children prospectively enrolled at Sapienza University of Rome between May 2010 and 2012. METHODS: Clinical assessment and laboratory data were recorded at admission and at day 3 and 5. All patients received corticosteroids; infliximab was administered in refractory patients. Colectomy rate was assessed at 2-year follow-up. RESULTS: Thirty-one patients (mean age 10.6±4.9 years, 52% females) were included: 21 responded to corticosteroids (68%), 10 were refractory and received infliximab (32%). Among the latter, 2 required urgent colectomy (20%); 80% responded, however 50% of these required elective colectomy during follow-up. Patients refractory to corticosteroids showed a significantly shorter interval from ulcerative colitis diagnosis to acute severe colitis compared to responders (7.4±9.6 vs. 23.1±21.6 months, respectively; p=0.01), and a higher rate of colectomy at follow-up (50% vs. 14%, respectively; p=0.007). More than 2 courses of corticosteroids before acute severe colitis were predictive of surgical need (OR 4.4). CONCLUSION: Despite its short-term efficacy, infliximab did not modify the long-term surgical rate of paediatric acute severe colitis in our cohort. Children with an early severe colitis commonly need a second-line therapy, whilst frequent courses of corticosteroids are predictive of a poor outcome.
Assuntos
Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Colectomia/estatística & dados numéricos , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Infliximab/uso terapêutico , Adolescente , Criança , Colite Ulcerativa/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Índice de Gravidade de Doença , Falha de Tratamento , Resultado do TratamentoRESUMO
The medical management of chronic inflammatory disorders in children, including mainly inflammatory bowel diseases and rheumatic diseases, has evolved dramatically over recent years with the advent of disease-modifying drugs such as immunomodulators and biological agents capable of interrupting the inflammatory cascade underlying these disorders. These agents are generally administered in patients who are refractory to conventional therapies. However, there is growing support that their use in the initial phases of these disorders, especially in pediatric patients, could interrupt and cease the inflammatory process. Thus, the aims of therapy have transitioned from symptomatic control to the achievement of deeper remission, including the healing of the inflammatory lesions combined with symptomatic remission. Therefore, more patients are currently receiving immunomodulators or biologics, frequently in addition to corticosteroids. Immunosuppression due to these therapies increases safety concerns, particularly regarding the risk of infections and malignancies. The available literature highlights how the combination of more than one of these therapies, especially if the combination includes corticosteroids, amplifies the risk of severe opportunistic infections. Otherwise, the infections described are mainly mild. Regarding malignancies, the overall risk associated with treatment appears non-significant in pediatric populations, but an appropriate benefit/risk assessment is recommended prior to the introduction of aggressive treatments such as immunomodulants and biologics. The background cancer risk related to the disease itself remains an issue. Protracted follow-up programs are needed, and the results from international multicenter registries are awaited to better understand the true risk related to therapy of these pediatric populations.
Assuntos
Anti-Inflamatórios/efeitos adversos , Fatores Biológicos/efeitos adversos , Fatores Imunológicos/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Fatores Biológicos/uso terapêutico , Criança , Humanos , Fatores Imunológicos/uso terapêutico , Terapia de Imunossupressão , Inflamação/tratamento farmacológico , Neoplasias/etiologia , Infecções Oportunistas/etiologiaRESUMO
IBD includes two classic entities, Crohn's disease and ulcerative colitis, and a third undetermined form (IBD-U), characterized by a chronic relapsing course resulting in a high rate of morbidity and impaired quality of life. Children with IBD are vulnerable in terms of growth failure, malnutrition and emotional effects. The aims of therapy have now transitioned from symptomatic control to the achievement of mucosal healing and deep remission. This type of therapy has been made possible by the advent of disease-modifying drugs, such as biologic agents, which are capable of interrupting the inflammatory cascade underlying IBD. Biologic agents are generally administered in patients who are refractory to conventional therapies. However, there is growing support that such agents could be used in the initial phases of the disease, typically in paediatric patients, to interrupt and cease the inflammatory process. Until several years ago, most therapeutic programmes in paediatric patients with IBD were borrowed from adult trials, whereas paediatric studies were often retrospective and uncontrolled. However, guidelines on therapeutic management of paediatric IBD and controlled, prospective, randomized trials including children with IBD have now been published. Here, the current knowledge concerning treatment options for children with IBD are reported. We also highlight the effectiveness and safety of new therapeutic advances in these paediatric patients.
Assuntos
Terapia Biológica/tendências , Imunomodulação , Doenças Inflamatórias Intestinais/terapia , Terapia Nutricional/tendências , Adolescente , Fatores Etários , Criança , Pré-Escolar , Colite Ulcerativa/terapia , Doença de Crohn/terapia , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: Noninvasive biomarkers of high- and low-grade intestinal inflammation and of mucosal healing (MH) in patients with inflammatory bowel disease are currently lacking. We have recently shown that fecal high mobility group box 1 (HMGB1) protein is a novel biomarker of gut inflammation. We aimed at investigating in a mouse model if HMGB1 was able to foresee both a clinically evident and a subclinical gut inflammation and if its normalization indicated MH. We also aimed at confirming the results in patients with Crohn's disease (CD) and ulcerative colitis. METHODS: C57BL6/J mice were treated with increasing doses of dextran sodium sulphate to induce colitis of different severity degrees; 28 with CD, 23 with ulcerative colitis, and 17 controls were also enrolled. Fecal HMGB1 was analyzed by enzyme-linked immunosorbent assay and immunoblotting. RESULTS: Fecal HMGB1 increased by 5-, 11-, 18-, and 24-folds with dextran sodium sulphate doses of 0.25%, 0.50%, 1%, and 4%, respectively, showing that the protein detected a high-grade and a subclinical inflammation. After a recovery time of 4-week posttreatment, HMGB1 returned to control levels, paralleling MH. In patients, fecal HMGB1 significantly correlated with endoscopic indexes (Simple Endoscopic Score for Crohn's Disease [SES-CD], endoscopic Mayo subscore), but not with the disease activity indexes (Crohn's disease Activity Index, partial Mayo score). CONCLUSIONS: Fecal HMGB1 is a robust noninvasive biomarker of clinically overt and subclinical gut inflammation; it can also be a surrogate marker of MH. We suggest the use of fecal HMGB1 to monitor the disease course and assess therapy outcomes in inflammatory bowel disease.