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1.
Aliment Pharmacol Ther ; 60(4): 503-518, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38984819

RESUMO

BACKGROUND: Data about the safety of allopurinol in pregnant women are sparsely reported. AIMS: To investigate the risk of adverse pregnancy outcome and congenital abnormalities after in utero exposure to allopurinol in inflammatory bowel disease (IBD) pregnancies and in general. METHODS: We collected safety data of patients with IBD who were treated with allopurinol during pregnancy between January 2013 and March 2022. Additionally, we performed a systematic review about the teratogenic potential of allopurinol. RESULTS: We collected data from 42 allopurinol-exposed pregnancies, including one twin pregnancy; in all women, allopurinol was combined with a thiopurine. Six pregnancies (14.3%) resulted in miscarriage and one in stillbirth at 32 weeks. A congenital anomaly was observed in one newborn (coarctation of the aorta discovered postpartum). Three pregnancies, including the twin pregnancy, ended in moderate preterm delivery and one in very preterm delivery. Five neonates (15.2%) were small for gestational age. From our literature search, we identified an additional 102 allopurinol-exposed pregnancies resulting in 129 live births, including 36 infants from our cohort. Ten infants (7.8%) were born with a congenital anomaly. Two (1.6%) had a comparable pattern of multiple anomalies. The systematic review sub-analysis including only infants born to mothers with IBD (n = 76) revealed that 2.6% of infants had congenital anomalies after in utero exposure to a low dose of allopurinol. CONCLUSIONS: Overall, the teratogenicity of allopurinol remains inconclusive. Children conceived by mothers treated for IBD with allopurinol/thiopurine co-therapy do not seem to have an increased risk of congenital anomalies.


Assuntos
Anormalidades Induzidas por Medicamentos , Alopurinol , Doenças Inflamatórias Intestinais , Complicações na Gravidez , Resultado da Gravidez , Humanos , Gravidez , Alopurinol/efeitos adversos , Feminino , Complicações na Gravidez/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Recém-Nascido , Adulto , Anormalidades Induzidas por Medicamentos/etiologia
2.
Therap Adv Gastroenterol ; 16: 17562848231197923, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37706094

RESUMO

Background: Many patients with inflammatory bowel disease (IBD) have transitioned from an infliximab originator to a biosimilar. However, some patients retransition to the originator (i.e. stop biosimilar and reinitiate the originator). Whether this sign of potential unsatisfactory treatment response is specifically related to the infliximab biosimilar or the patient and/or the disease including patients' beliefs on the biosimilar is unclear. Objectives: We aimed to compare the risk of and reasons for infliximab discontinuation between retransitioned patients and those remaining on biosimilar. Design: Non-interventional, multicentre cohort study. Methods: IBD patients who transitioned from infliximab originator to biosimilar between January 2015 and September 2019 in two Dutch hospitals were eligible for this study. Retransitioned patients (retransitioning cohort) were matched with patients remaining on biosimilar (biosimilar remainder cohort). Reasons for discontinuation were categorised as the unwanted response (i.e. loss of effect or adverse events) or remission. Risk of unwanted discontinuation was compared using Cox proportional hazards models. Results: Patients in the retransitioning cohort (n = 44) were younger (median age 39.9 versus 44.0 years), more often female (65.9% versus 48.9%) and had shorter dosing intervals (median 48.5 versus 56.0 days) than in the biosimilar remainder cohort (n = 127). Infliximab discontinuation due to unwanted response was 22.7% in the retransitioning and 13.4% in the biosimilar remainder cohort, and due to remission was 2.3% and 9.4%, respectively. Retransitioned patients are at increased risk of discontinuing due to unwanted response compared with biosimilar remainder patients (adjusted HR 3.7, 95% CI: 1.0-13.9). Patients who retransitioned due to an increase in objective disease markers had higher discontinuation rates than patients who retransitioned due to symptoms only (66.7% versus 23.7%). Conclusion: Retransitioned patients are at increased risk of infliximab discontinuation due to unwanted response. Retransitioning appeared related to the patient and/or disease and not the product. Clinicians might switch patients opting for retransitioning to other treatment regimens.

3.
J Crohns Colitis ; 17(5): 738-745, 2023 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-36521000

RESUMO

BACKGROUND: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. METHODS: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. RESULTS: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. CONCLUSION: In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes.


Assuntos
Aborto Espontâneo , Doenças Inflamatórias Intestinais , Complicações na Gravidez , Gravidez , Recém-Nascido , Criança , Humanos , Feminino , Adulto , Tioguanina/efeitos adversos , Resultado da Gravidez/epidemiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Natimorto/epidemiologia , Aborto Espontâneo/induzido quimicamente , Aborto Espontâneo/epidemiologia , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia
4.
Gut Microbes ; 14(1): 2139979, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36369736

RESUMO

BACKGROUND: Screening for colorectal cancer (CRC) reduces its mortality but has limited sensitivity and specificity. Aims We aimed to explore potential biomarker panels for CRC and adenoma detection and to gain insight into the interaction between gut microbiota and human metabolism in the presence of these lesions. METHODS: This multicenter case-control cohort was performed between February 2016 and November 2019. Consecutive patients ≥18 years with a scheduled colonoscopy were asked to participate and divided into three age, gender, body-mass index and smoking status-matched subgroups: CRC (n = 12), adenomas (n = 21) and controls (n = 20). Participants collected fecal samples prior to bowel preparation on which proteome (LC-MS/MS), microbiota (16S rRNA profiling) and amino acid (HPLC) composition were assessed. Best predictive markers were combined to create diagnostic biomarker panels. Pearson correlation-based analysis on selected markers was performed to create networks of all platforms. RESULTS: Combining omics platforms provided new panels which outperformed hemoglobin in this cohort, currently used for screening (AUC 0.98, 0.95 and 0.87 for CRC vs controls, adenoma vs controls and CRC vs adenoma, respectively). Integration of data sets revealed markers associated with increased blood excretion, stress- and inflammatory responses and pointed toward downregulation of epithelial integrity. CONCLUSIONS: Integrating fecal microbiota, proteome and amino acids platforms provides for new biomarker panels that may improve noninvasive screening for adenomas and CRC, and may subsequently lead to lower incidence and mortality of colon cancer.


Assuntos
Adenoma , Neoplasias Colorretais , Microbioma Gastrointestinal , Humanos , Proteoma/análise , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Cromatografia Líquida , RNA Ribossômico 16S , Aminoácidos , Espectrometria de Massas em Tandem , Adenoma/diagnóstico , Fezes/química
5.
J Gastrointestin Liver Dis ; 31(1): 18-24, 2022 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-35306553

RESUMO

BACKGROUND AND AIMS: The dose and duration of mesalazine treatment for ulcerative colitis (UC) is a potentially important determinant of effectiveness, with evidence suggesting that continuing the induction dose for 6-12 months may improve outcomes; however, real-world data are lacking. We assessed mesalazine use in Dutch clinical practice, including how differences in dose and duration affected UC outcomes. METHODS: Adults with mild-to-moderate UC who received oral prolonged-release mesalazine de novo or had a dose escalation for an active episode were followed for 12 months in this non-interventional study (ClinicalTrials.gov identifier: NCT02261636). The primary endpoint was time from start of treatment to dose reduction (TDR). Secondary endpoints included recurrence rate, adherence, and work productivity. RESULTS: In total, 151 patients were enrolled, of whom 108 (71.5%) were newly diagnosed with UC. The majority (120; 79.5%) received a dose of ≥4 g/day. Nearly one-third (48; 31.8%) underwent dose reduction, with mean TDR being 8.3 months. Disease extent and endoscopic appearance did not influence duration of induction therapy, while TDR increased with higher baseline UCDAI scores. TDR was longer in patients without (mean 8.8 months) than with (4.1 months) recurrence, although not significantly (p=0.09). Patients on ≥4 g/day had a significantly lower chance of recurrence versus those on 2-<4 g/day (26.6% vs 62.5%, respectively; p=0.04). Longer treatment duration was associated with significantly reduced recurrence risk [hazard ratio >6 months vs 3-6 months: 0.19 (95%CI: 0.08-0.46); p<0.05], particularly for those on ≥4 g/day [0.15 (0.06-0.40) vs 0.26 (0.01-11.9) for 2-<4 g/day). Patients reported significantly increased work productivity, which was maintained throughout follow-up. CONCLUSIONS: Mesalazine was effective induction therapy, with treatment duration not meaningfully influenced by disease extent and endoscopic appearance at initiation. A higher induction dose of oral mesalazine (≥4 g/day) and longer duration of treatment (>6 months) was associated with a lower recurrence risk.


Assuntos
Colite Ulcerativa , Mesalamina , Administração Oral , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Duração da Terapia , Humanos , Mesalamina/efeitos adversos , Indução de Remissão , Resultado do Tratamento
6.
Gut Microbes ; 14(1): 2038863, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35188868

RESUMO

The risk of recurrent dysplastic colonic lesions is increased following polypectomy. Yield of endoscopic surveillance after adenoma removal is low, while interval colorectal cancers occur. To longitudinally assess the dynamics of fecal microbiota and amino acids in the presence of adenomatous lesions and after their endoscopic removal. In this longitudinal case-control study, patients collected fecal samples prior to bowel preparation before scheduled colonoscopy and 3 months after this intervention. Based on colonoscopy outcomes, patients with advanced adenomas and nonadvanced adenomas (0.5-1.0 cm) who underwent polypectomy during endoscopy (n = 19) were strictly matched on age, body-mass index, and smoking habits to controls without endoscopic abnormalities (n = 19). Microbial taxa were measured by 16S RNA sequencing, and amino acids (AA) were measured by high-performance liquid chromatography (HPLC). Adenoma patients were discriminated from controls based on AA and microbial composition. Levels of proline (p = .001), ornithine (p = .02) and serine (p = .02) were increased in adenoma patients compared to controls but decreased to resemble those of controls after adenoma removal. These AAs were combined as a potential adenoma-specific panel (AUC 0.79(0.64-0.94)). For bacterial taxa, differences between patients with adenomas and controls were found (Bifidobacterium spp.↓, Anaerostipes spp.↓, Butyricimonas spp.↑, Faecalitalea spp.↑ and Catenibacterium spp.↑), but no alterations in relative abundance were observed after polypectomy. Furthermore, Faecalitalea spp. and Butyricimonas spp. were significantly correlated with adenoma-specific amino acids. We selected an amino acid panel specifically increased in the presence of adenomas and a microbial signature present in adenoma patients, irrespective of polypectomy. Upon validation, these panels may improve the effectiveness of the surveillance program by detection of high-risk individuals and determination of surveillance endoscopy timing, leading to less unnecessary endoscopies and less interval cancer.


Assuntos
Adenoma , Neoplasias Colorretais , Microbioma Gastrointestinal , Adenoma/diagnóstico , Adenoma/patologia , Aminoácidos , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Humanos , Fatores de Risco
7.
Crohns Colitis 360 ; 4(3): otab001, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36777418

RESUMO

Background: Quality of life (QoL) data for patients with inflammatory bowel disease switched from the reference infliximab to biosimilar CT-P13 is lacking. This study aims to demonstrate noninferiority for QoL and efficacy after switching. Methods: OoL and clinical efficacy were measured prior to and after 2, 4, and 6 CT-P13 infusions. Results: One hundred seventy-eight patients were included. Noninferiority was established for QoL [ratio 97.95% (95% confidence interval 95.93 to 100.01)] and efficacy [difference -0.02 (95% confidence interval -0.68 to 0.64)]. Five patients reported 6 nonrelated, serious adverse events. Conclusions: Switching from reference infliximab to CT-P13 did not affect the QoL or disease activity and was well tolerated.

8.
Pharmacol Res Perspect ; 9(4): e00843, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34302442

RESUMO

The aim of this study was to assess switching patterns and determinants for switching in patients initiating TNFα inhibitor (TNFα-i) treatment. Patients were included who started TNFα-i treatment between July 1, 2012 and December 31, 2017, from three Dutch hospitals, and were diagnosed with rheumatic diseases (RD), inflammatory bowel disease (IBD), or psoriasis. Outcomes were switching, defined as initiating another biological; switching patterns including multiple switches until the end of follow-up; determinants for first switch, assessed using multivariate logistic regression. A total of 2228 patients were included (median age 43.3 years, 57% female), of which 52% (n = 1155) received TNFα-i for RD, 43% (n = 967) for IBD, and 5% (n = 106) for psoriasis. About 16.6% of RD patients, 14.5% of IBD patients, and 16.0% of psoriasis patients switched at least once, mainly to another TNFα-i. TNFα-i dose escalation (OR 13.78, 95% CI 1.40-135.0) and high-dose corticosteroids initiation (OR 3.62, 95% CI 1.10-12.15) were determinants for switching in RD patients. TNFα-i dose escalation (OR 8.22, 95% CI 3.76-17.93), immunomodulator initiation/dose escalation (OR 2.13, 95% CI 1.04-4.34), high-dose corticosteroids initiation (OR 6.91, 95% CI 2.81-17.01) and serum concentration measurement (OR 5.44, 95% CI 2.74-10.79) were determinants for switching in IBD patients. Switching biological treatment occurred in about one in six patients. RD patients with TNFα-i dose escalation and/or high-dose corticosteroids initiation were more likely to switch. IBD patients with TNFα-i or immunomodulator initiation/dose escalation, high-dose corticosteroids initiation or serum concentration measurement were more likely to switch. These findings might help clinicians anticipating switching in TNFα-i treatment.


Assuntos
Produtos Biológicos/uso terapêutico , Substituição de Medicamentos/estatística & dados numéricos , Fatores Imunológicos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Psoríase/tratamento farmacológico , Doenças Reumáticas/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Dig Liver Dis ; 52(7): 745-752, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32402741

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) is diagnosed and monitored using endoscopic assessment, which is invasive and costly. In this study, potential of faecal volatile organic compounds (VOC) analysis for IBD detection and identification of disease activity was evaluated. METHODS: IBD patients visiting outpatient clinics of participating tertiary hospitals were included. Active disease was defined as FCP ≥250 mg/g, remission as FCP <100 mg/g with Harvey Bradshaw Index <4 for Crohn's disease (CD) or Simple Clinical Colitis Activity Index <3 for ulcerative colitis (UC). Healthy controls (HC) were patients without mucosal abnormalities during colonoscopy. Faecal samples were measured using gas chromatography-ion mobility spectrometry. RESULTS: A total of 280 IBD patients collected 107 CDa, 84 CDr, 80 UCa and 63 UCr samples. Additionally, 227 HC provided one faecal sample. UC and CD were discriminated from HC with high accuracy (AUC (95%CI): UCa vs HC 0.96(0.94-0.99); UCr vs HC 0.95(0.93-0.98); CDa vs HC 0.96(0.94-0.99); CDr vs HC 0.95(0.93-0.98)). There were small differences between UC and CD (0.55(0.50-0.6)) and no differences between active disease and remission (UCa vs UCr 0.63(0.44-0.82); CDa vs CDr 0.52(0.39-0.65)). CONCLUSION: Our study outcomes imply that faecal VOC analysis holds potential for identifying biomarkers for IBD detection but not for monitoring disease activity.


Assuntos
Fezes/química , Doenças Inflamatórias Intestinais/diagnóstico , Espectrometria de Mobilidade Iônica/métodos , Compostos Orgânicos Voláteis/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Testes Respiratórios , Estudos de Casos e Controles , Colite Ulcerativa/diagnóstico , Colonoscopia , Doença de Crohn/diagnóstico , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Países Baixos , Curva ROC , Adulto Jovem
10.
J Breath Res ; 13(4): 046001, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31170704

RESUMO

INTRODUCTION: Fecal volatile organic compounds (VOCs) are gaseous metabolic products which are increasingly considered potential non-invasive biomarkers for the detection of various (gastrointestinal) diseases. The influence of lifestyle factors on fecal VOC patterns remains unexplored but is of importance prior to implementation of VOC analysis as a diagnostic tool. The aim of this study was to investigate the effects of age, gender, body mass index, smoking status, dietary preferences, medication use and co-morbidity on fecal VOC patterns. METHODS: For this study, fecal samples of patients undergoing a colonoscopy were collected prior to endoscopy. All participants completed a questionnaire on lifestyle factors, co-morbidity and medication use. Patients without colonic abnormalities were included in this study. Fecal VOC patterns were analyzed by means of an electronic nose (eNose) device (Cyranose® 320). RESULTS: From the 1039 participants willing to participate in the initial study, 211 were eligible as controls. All unique lifestyle variables investigated in this study affected the fecal VOC composition. The strongest influences were caused by low BMI, a vegetarian diet and an active smoking status, whereas the least influence was found for the variables gender, age > 55 years and previous smokers. DISCUSSION: Age, gender, BMI, smoking habits, dietary preferences, co-morbidity and medication use all have unique effects on fecal VOC composition. Future studies should carefully consider this influence on VOC outcome when defining VOC signatures as biomarker for diagnostic purposes.


Assuntos
Nariz Eletrônico , Fezes/química , Estilo de Vida , Compostos Orgânicos Voláteis/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Testes Respiratórios , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
J Med Econ ; 21(9): 869-877, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29857775

RESUMO

AIMS: Budesonide with multi-matrix technology (MMX) is an oral corticosteroid, shown to have high topical activity against ulcerative colitis (UC) while maintaining low systemic bioavailability with few adverse events. The aim of this study was to evaluate the cost-effectiveness of budesonide MMX versus commonly used corticosteroids, in the second-line treatment of active mild-to-moderate UC in the Netherlands. MATERIALS AND METHODS: An eight-state Markov model with an 8 week cycle length captured remission, four distinct therapy stages, hospitalization, possible colectomy and mortality. Remission probability for budesonide MMX was based on the CORE-II study. Population characteristics were derived from the Dutch Inflammatory Bowel Disease South Limburg cohort (n = 598) and included patients with proctitis (39%), left-sided (42%) and extensive disease (19%). Comparators (topical budesonide foam and enema, oral budesonide and prednisolone) were selected based on current Dutch clinical practice. Treatment effects were evaluated by network meta-analysis using a Bayesian framework. Cost-effectiveness analysis was performed over a 5 year time horizon from a societal perspective, with costs, health-state and adverse event utilities derived from published sources. Outcomes were weighted by disease extent distribution and corresponding comparators. RESULTS: Budesonide MMX was associated with comparable quality-adjusted life year (QALY) gain versus foam and oral formulations (+0.01 QALYs) in the total UC population, whilst being cost-saving (EUR 366 per patient). Probabilistic sensitivity analysis evaluated an 86.6% probability of budesonide MMX being dominant (cost-saving with QALY gain) versus these comparators. Exploratory analysis showed similar findings versus prednisolone. LIMITATIONS: Differing definitions of trial end-points and remission across trials meant indirect comparison was not ideal. However, in the absence of head-to-head clinical data, these comparisons are reasonable alternatives and currently offer the only comparison of second-line UC treatments. CONCLUSIONS: In the present analysis, budesonide MMX was shown to be cost-effective versus comparators in the total UC population, for the second-line treatment of active mild-to-moderate UC in the Netherlands.


Assuntos
Anti-Inflamatórios/uso terapêutico , Budesonida/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/economia , Budesonida/administração & dosagem , Budesonida/economia , Colite Ulcerativa/patologia , Análise Custo-Benefício , Feminino , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Serviços de Saúde/economia , Serviços de Saúde/estatística & dados numéricos , Hospitalização/economia , Humanos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Econométricos , Países Baixos , Prednisolona/economia , Prednisolona/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Indução de Remissão , Índice de Gravidade de Doença
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