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1.
Artigo em Inglês | MEDLINE | ID: mdl-32740538

RESUMO

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

2.
Inflamm Bowel Dis ; 24(8): 1745-1754, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29788058

RESUMO

Background: Antidrug antibodies (ADAs) dramatically increase infliximab clearance and are responsible for underexposure to the drug, leading to treatment failure. This pilot study aimed at developing a population pharmacokinetic model to detect and describe an early increase in infliximab clearance due to ADA. Methods: Twenty children with Crohn's disease (CD) were followed for 1 year or until treatment failure. Infliximab trough concentration, ADA, C-reactive protein (CRP), and Paediatric Crohn's Disease Activity Index (PCDAI) were recorded at each visit. A time-varying clearance population pharmacokinetic model was built to detect and describe an increase in infliximab clearance, independent from ADA testing. Factors associated with clearance variation and the relationships between infliximab concentrations, clearance variation, and clinical response were investigated. Results: The model detected important increases in clearance in 4 patients. These patients had suboptimal early response, with higher mean PCDAI (P = 0.0086) and CRP (P = 0.028) compared with other patients. Two of them had detectable ADA. Clearance increase as described by the model and lower infliximab trough concentration at week 2 were associated with poorer outcomes in a multivariate Cox model (P = 0.001 and P = 0.0048, respectively). Conclusions: Being able to detect an increase in infliximab clearance, this model could allow the early detection of immunization to infliximab and therefore could help with dose adjustment in patients with CD. Moreover, the results suggest that clearance variations could be used as a predictive marker of clinical response. These findings need to be confirmed in a larger cohort, however, and predictive factors of clearance increase have to be investigated.


Assuntos
Anticorpos/sangue , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/farmacocinética , Infliximab/farmacocinética , Modelos Biológicos , Adolescente , Proteína C-Reativa/metabolismo , Criança , Monitoramento de Medicamentos , Feminino , França , Fármacos Gastrointestinais/uso terapêutico , Humanos , Infliximab/uso terapêutico , Masculino , Taxa de Depuração Metabólica , Projetos Piloto , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/imunologia
3.
MAbs ; 8(7): 1407-1416, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27589009

RESUMO

Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a one-compartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.


Assuntos
Antirreumáticos/farmacocinética , Doenças Autoimunes/tratamento farmacológico , Infliximab/farmacocinética , Adulto , Antirreumáticos/sangue , Antirreumáticos/uso terapêutico , Criança , Estudos de Coortes , Feminino , Humanos , Infliximab/sangue , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
5.
Dig Liver Dis ; 47(6): 460-4, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25770456

RESUMO

BACKGROUND: Children with inflammatory bowel disease are at risk of vaccine-preventable diseases mostly due to immunosuppressive drugs. AIM: To evaluate coverage after an awareness campaign informing patients, their parents and general practitioner about the vaccination schedule. METHODS: Vaccination coverage was firstly evaluated and followed by an awareness campaign on the risk of infection via postal mail. The trial is a case-control study on the same patients before and after the awareness campaign. Overall, 92 children were included. A questionnaire was then completed during a routine appointment to collect data including age at diagnosis, age at data collection, treatment history, and vaccination status. RESULTS: Vaccination rates significantly increased for vaccines against diphtheria-tetanus-poliomyelitis (92% vs. 100%), Haemophilus influenzae (88% vs. 98%), hepatitis B (52% vs. 71%), pneumococcus (36% vs. 57%), and meningococcus C (17% vs. 41%) (p<0.05). Children who were older at diagnosis were 1.26 times more likely to be up-to-date with a minimum vaccination schedule (diphtheria-tetanus-poliomyelitis, pertussis, H. influenzae, measles-mumps-rubella, tuberculosis) (p=0.002). CONCLUSION: Informing inflammatory bowel disease patients, their parents and general practitioner about the vaccination schedule via postal mail is easy, inexpensive, reproducible, and increases vaccination coverage. This method reinforces information on the risk of infection during routine visits.


Assuntos
Promoção da Saúde/métodos , Doenças Inflamatórias Intestinais/complicações , Infecções Oportunistas/prevenção & controle , Educação de Pacientes como Assunto/métodos , Vacinação/estatística & dados numéricos , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Esquemas de Imunização , Masculino , Infecções Oportunistas/complicações , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Adulto Jovem
6.
Eur J Pediatr ; 173(5): 603-8, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24305728

RESUMO

Inflammatory bowel diseases have an increased risk of infections due to immunosuppressive therapies. To report the immunization status according to previous recommendations and the reasons explaining a delay, a questionnaire was filled in by the pediatric gastroenterologist, concerning outpatients, in six tertiary centers and five local hospitals, in a study, from May to November 2011. One hundred and sixty-five questionnaires were collected, of which 106 Crohn's diseases, 41 ulcerative colitis, and 17 indeterminate colitis. Sex ratio was 87:78 M/F. Median age was 14.4 years old (4.2-20.0). One hundred and nine patients (66 %) were receiving or had received an immunosuppressive therapy (azathioprine, infliximab, methotrexate, or prednisone). Vaccines were up to date according to the vaccine schedule of French recommendations in 24 % of cases and according to the recommendations for inflammatory bowel disease in 4 % of cases. Coverage by vaccine was the following: diphtheria-tetanus-poliomyelitis 87 %, hepatitis B 38 %, pneumococcus 32 %, and influenza 22 %. Immunization delay causes were as follows: absence of proposal 58 %, patient refusal 41 %, fear of side effects 33 %, and fear of disease activation 5 %. Therefore, immunization coverage is insufficient in children with inflammatory bowel disease, due to simple omission or to refusal. A collaboration with the attending physicians and a targeted information are necessary.


Assuntos
Imunização/estatística & dados numéricos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , França , Humanos , Esquemas de Imunização , Masculino , Inquéritos e Questionários , Adulto Jovem
7.
Inflamm Bowel Dis ; 17(12): 2521-6, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21337668

RESUMO

BACKGROUND: Methotrexate (MTX) is used as an alternative immunosuppressive treatment for patients with inflammatory bowel disease (IBD). The aim of the study was to evaluate effectiveness and tolerance of MTX for children with IBD. METHODS: A retrospective study was conducted in our pediatric IBD center of all children having received MTX for the treatment of their IBD between 2000 and 2008. Remission was defined as discontinuation of steroids and Harvey-Bradshaw Index <4 for Crohn's disease (CD) patients or Pediatric Ulcerative Colitis Activity Index (PUCAI) <10 for ulcerative (UC) or indeterminate colitis (IC) patients. RESULTS: Seventy-five patients had CD, 5 UC, and 13 IC. Mean age at diagnosis was 11 (0.6-17.4) years. Ninety patients were previously treated with purine analogs and 26 with anti-tumor necrosis factor (TNF). Among patients assessed for effectiveness of MTX (n = 79), clinical remission was observed in 29, 37, 25, and 16% of CD patients (n = 63) and 19, 25, 13, and 7% of patients with UC or IC (n = 16), respectively, 3, 6,12, and 24 months after initiation of MTX. The 1-year remission rate for CD patients was significantly higher in patients with colonic disease. Forty-six patients (49%) experienced side effects but only 13 (14%) had to discontinue treatment. CONCLUSIONS: The long-term remission rate with MTX in our pediatric IBD population was low. However, MTX was generally well tolerated and induced and maintained remission in some patients who previously had failed a purine analog and/or anti-TNF. Prospective controlled trials are indicated to determine the place of MTX in the management of pediatric IBD.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Adolescente , Canadá , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Masculino , Dose Máxima Tolerável , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
9.
Pediatrics ; 122(6): e1236-41, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19029197

RESUMO

OBJECTIVES: Although ursodeoxycholic acid has been used to treat various cholestatic liver diseases in children, few data are available about its efficacy in biliary atresia. The aim of this study was to assess the effect of ursodeoxycholic acid treatment on liver function in children who underwent successful surgery for biliary atresia. PATIENTS AND METHODS: We prospectively studied 16 children with biliary atresia who underwent successful portoenterostomies (postoperative conjugated bilirubin concentration: <34 micromol/L) and were treated with ursodeoxycholic acid for at least 18 months after surgery. Ursodeoxycholic acid treatment was then discontinued. Clinical and biological assessment was performed at the time of discontinuation of ursodeoxycholic acid treatment (T0), at follow-up (T1) and, if the clinical or biological status worsened, after resumption of ursodeoxycholic acid treatment (T2). RESULTS: Ursodeoxycholic acid treatment was resumed in 13 cases. In 1 patient, jaundice recurred after ursodeoxycholic acid therapy was discontinued but abated after resumption of treatment. In 13 children, liver function worsened significantly when ursodeoxycholic acid was discontinued. T1 versus T0 concentrations expressed as multiples of the upper limit of the normal range (in parentheses) were as follows: alanine aminotransferase, 3.0 xN (0.8-7.0) vs 1.5 xN (0.5-5.4); gamma glutamyl transpeptidase, 8.0 xN (1.8-30.2) vs 4.2 xN (0.5-27.4); and aspartate aminotransferase, 1.7 xN (0.7-6.0) vs 1.3 xN (0.6-3.4). When ursodeoxycholic acid treatment was resumed, liver function had improved in all patients by T2. Concentrations of endogenous bile acids tended to be elevated at T1 (not significant) and were significantly decreased at T2. CONCLUSION: Our study demonstrates the beneficial effect of ursodeoxycholic acid on liver function in children after successful surgery for biliary atresia.


Assuntos
Atresia Biliar/tratamento farmacológico , Atresia Biliar/cirurgia , Colagogos e Coleréticos/administração & dosagem , Ácido Ursodesoxicólico/administração & dosagem , Atresia Biliar/diagnóstico , Atresia Biliar/mortalidade , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Lactente , Recém-Nascido , Fígado/efeitos dos fármacos , Fígado/enzimologia , Testes de Função Hepática , Masculino , Portoenterostomia Hepática/métodos , Probabilidade , Estudos Prospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas
10.
Ther Drug Monit ; 28(2): 169-74, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16628126

RESUMO

An enzyme-linked immunosorbent assay (ELISA) measuring serum infliximab concentrations in treated patients was developed. Microtiter plates were sensitized with tumor necrosis factor alpha (TNF-alpha) and saturated with phosphate-buffered saline (PBS) containing 1% bovine serum albumin (BSA). Samples diluted 1:100 in PBS-1% BSA were added and bound infliximab was detected using peroxidase-conjugated goat anti-human immunoglobulin G specific for Fc fragment (HRP-anti hIgG). Reading was performed using an ELISA plate reader. The limit of detection, calculated by assaying 10 replicates of a drug-free serum sample or blank sample and defined as the lowest concentration distinguishable from zero at 2 standard deviations, was 0.014 microg/mL. Each quality control sample was tested on 7 occasions on 1 day and on 5 separate days. The intraday precision indices of the method were (percent coefficients of variation, CV%) 11.7%, 6.2%, and 6.9% for 0.04 microg/mL, 2 microg/mL, and 4.5 microg/mL, respectively. The corresponding bias measures (percent deviation) were -5.5%, -1.9%, and -7.9%, respectively. The between-days precision was 9.8%, 5.3%, and 5.3% for 0.04 microg/mL, 2 microg/mL, and 4.5 microg/mL, respectively. The corresponding bias were +0.3%, -0.3%, and -7.8%, respectively. Lower limit of quantitation and upper limit of quantitation were 0.04 microg/mL and 4.5 microg/mL, respectively. Trough serum concentrations of infliximab were measured in 6 adult patients with various diseases and in 5 pediatric patients with Crohn's disease. For the latter group, samples drawn 1 hour after the end of the infusion and repeated measurements also were available. Data were described using a 1-compartment population pharmacokinetic model. Terminal elimination half-life was 10.9 days. This method is rapid, accurate, and reproducible, and may be useful in therapeutic drug monitoring of infliximab.


Assuntos
Anticorpos Monoclonais/sangue , Monitoramento de Medicamentos/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Disponibilidade Biológica , Doença de Crohn/tratamento farmacológico , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/farmacocinética , Meia-Vida , Humanos , Infliximab , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Valores de Referência , Reprodutibilidade dos Testes
11.
Pharmacogenet Genomics ; 16(1): 37-42, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16344720

RESUMO

We recently showed an association between the FCGR3A V/F polymorphism and the biological response [assessed on the basis of a C-reactive protein (CRP) concentration decrease] to infliximab in Crohn's disease. The CRP and FCGR3A genes are located on the same 1q23 locus. The present study aimed: (i) to exclude a linkage disequilibrium (LD) between the two genes and (ii) to study the association between CRP polymorphisms and the response to infliximab, particularly the decrease in CRP after treatment, in Crohn's disease patients. FCGR3A (V/F) polymorphism and three CRP polymorphisms (-717G/A, 1444C/T, CRP 4A/G) were determined in 206 healthy blood donors and 189 Crohn's disease patients who had received infliximab for either refractory luminal or fistulizing Crohn's disease. Clinical response was defined as complete, partial or absent according to the same definition as in controlled trials. The biological response was defined on the basis of CRP decrease. There was no LD between CRP and FCGR3A in healthy donors or Crohn's disease patients. CRP polymorphisms had no impact on CRP decrease after infliximab. The proportions of Crohn's disease having a positive clinical or biological response were not statistically different among the various genotypes of CRP polymorphisms. There was no LD between CRP and FCGR3A polymorphisms. CRP polymorphisms were not associated with the response to infliximab in Crohn's disease.


Assuntos
Anticorpos Monoclonais/farmacologia , Proteína C-Reativa/metabolismo , Doença de Crohn/sangue , Polimorfismo Genético/genética , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Proteína C-Reativa/genética , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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