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1.
Clin Gastroenterol Hepatol ; 21(13): 3238-3257, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37080261

RESUMO

BACKGROUND & AIMS: Adenoma detection rate (ADR) is inversely correlated with the risk of interval colon cancer and is a key target for quality improvement in endoscopy units. We conducted a systematic review and meta-analysis to identify and evaluate the effectiveness of interventions that can be implemented at the endoscopy unit level to improve ADRs. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search was conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases between January 1990 and December 2022 to identify relevant studies. Both randomized controlled trials and observational studies were eligible. Data for the primary outcome of ADR were analyzed and reported on the log-odds scale with 95% CIs using a random-effects meta-analysis model using the empiric Bayes estimator. RESULTS: From 10,778 initial citations, 34 studies were included in the meta-analysis comprising 371,041 procedures and 1501 endoscopists. The provision of report cards (odds ratio [OR], 1.28; 95% CI, 1.13-1.45; P < .001) and the presence of an additional observer to identify polyps (OR, 1.25; 95% CI, 1.09-1.43; P = .002) were associated with significant increases in ADRs whereas multimodal interventions were borderline significant (OR, 1.18; 95% CI, 1.00-1.40; P = .05) and withdrawal time monitoring was not associated significantly with an increase in ADRs (OR, 1.35; 95% CI, 0.93-1.96; P = .11). CONCLUSIONS: The provision of report cards and the presence of an additional observer to identify polyps are associated with improved ADRs and should be considered for implementation in endoscopy facilities.


Assuntos
Adenoma , Neoplasias do Colo , Pólipos , Humanos , Colonoscopia/métodos , Teorema de Bayes , Adenoma/diagnóstico , Melhoria de Qualidade
2.
Clin Gastroenterol Hepatol ; 21(12): 3019-3029.e5, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37061107

RESUMO

BACKGROUND & AIMS: Identifying patients at high risk of immunogenicity is important when selecting tumor necrosis factor (TNF)-α antagonists in patients with immune-mediated inflammatory diseases (IMIDs). We evaluated the association HLA-DQA1∗05 genotype and risk of immunogenicity with TNF-α antagonists. METHODS: Through a systematic review through July 14, 2022, we identified studies in patients with IMIDs treated with TNF-α antagonists, which reported the risk of immunogenicity and/or secondary loss of response in patients with HLA-DQA1∗05 variants. Primary outcome was risk of immunogenicity. We performed random effects meta-analysis and used GRADE to appraise certainty of evidence. RESULTS: On meta-analysis of 13 studies (3756 patients; median follow-up, 12 months; 41% with variants), HLA-DQA1∗05 variants were associated with 75% higher risk of immunogenicity compared with non-carriers (relative risk, 1.75; 95% confidence interval, 1.37-2.25) with considerable heterogeneity (I2 = 62%) (low certainty evidence). Positive and negative predictive values of HLA-DQA1∗05 variants for predicting immunogenicity were 30% and 80%, respectively. Proactive therapeutic drug monitoring, but not concomitant use of IMMs, IMIDs, and TNF-α antagonist-type, modified this association. Patients with HLA-DQA1∗05 variants experienced 2.2-fold higher risk of secondary loss of response (6 cohorts; relative risk, 2.24; 95% confidence interval, 1.67-3.00; I2 = 0%) (moderate certainty evidence). CONCLUSION: Variants in HLA-DQA1∗05 are associated with an increased risk in immunogenicity and secondary loss of response in patients with IMIDs treated with TNF-α antagonists. However, the positive and negative predictive value is moderate, and decisions on concomitant use of IMMs to prevent immunogenicity should be individualized based on all factors that influence drug clearance.


Assuntos
Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa , Humanos , Agentes de Imunomodulação , Genótipo
3.
Dig Dis Sci ; 67(9): 4287-4294, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-34313923

RESUMO

BACKGROUND: Sex and gender refer to biological and social differences between men and women. While well-evaluated in other disciplines, their roles in inflammatory bowel disease (IBD) are not well-defined. This study aimed to characterize differences in healthcare outcomes in men and women with IBD. METHODS: A retrospective single-centre cohort study was conducted to evaluate differences between men and women receiving care for Crohn's disease (CD) and ulcerative colitis (UC) at the Western University Personalized Medicine Clinic from March 2012 to September 2019. The primary endpoint was the proportion of IBD drugs used for all drug classes. Additional outcomes in healthcare utilization and disease phenotype were assessed. Student's t test and Fisher's exact test were used to assess differences RESULTS: A total of 1015 participants were included (CD = 656; UC = 359). In UC and CD, 47.9% and 59.0% were women, respectively. Overall, women were more likely prescribed budesonide than men (23.6% vs. 13.4%; p < 0.0001), while more men were exposed to prednisone for IBD management (73.5% vs. 67.4%; p = 0.04). Immunomodulator use was higher in men with CD versus women (86.6% vs. 78.3%; p = 0.008) and of those exposed, women more commonly experienced ADRs (29.5% vs. 21.2%; p = 0.01). Though no sex-related difference was identified, age was a predictor of biologic exposure in women with CD and men with UC, with those > 55 being less likely to receive biologics. CONCLUSIONS: These findings highlight differences in disease course and treatment approaches between men and women with IBD and support the consideration of sex and gender when researching disease outcomes.


Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Doença Crônica , Estudos de Coortes , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Feminino , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino , Aceitação pelo Paciente de Cuidados de Saúde , Fenótipo , Estudos Retrospectivos
4.
BMC Gastroenterol ; 21(1): 77, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602145

RESUMO

BACKGROUND: The threshold concentration of infliximab during maintenance therapy has not been well-defined in relation to histologic remission. The aim of the study is to dentify the maintenance-phase infliximab concentration associated with histologic remission in inflammatory bowel disease patients (IBD). METHODS: A prospective cohort study was carried out in 104 IBD patients seen at a tertiary care centre in London, Canada. Infliximab trough concentrations were collected during the maintenance phase of treatment and compared between participants with and without evidence of histologic remission. Participants were additionally evaluated for sustained histologic remission, and relapse to active disease. RESULTS: Participants in histologic remission attained higher mean concentrations of infliximab during the maintenance phase (10.34 ± 0.69 µg/ml) compared to those with persistent disease activity (6.23 ± 0.67 µg/ml, p-value < 0.0001). Additionally, during the maintenance phase, sustained histologic remission was also associated with a higher mean concentration of infliximab (10.81 ± 5.46 µg/ml) compared to those who relapsed to active disease (5.68 ± 3.70, p < 0.001). Overall, participants with a mean infliximab trough concentration greater than 8ug/ml were more likely to have histologic remission (area under the receiver operating characteristic curve, AUROC = 0.72, 95%CI = 0.65-0.84, p < 0.0001) and sustained histologic remission (AUC = 0.77, 95%CI = 0.63-0.91, p = 0.002). CONCLUSION: Maintenance-phase infliximab trough concentrations greater than 8 µg/ml, which is higher than the currently recommended target concentration, are highly associated with histologic remission and sustained histologic remission.


Assuntos
Fármacos Gastrointestinais , Doenças Inflamatórias Intestinais , Canadá , Monitoramento de Medicamentos , Fármacos Gastrointestinais/uso terapêutico , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Estudos Prospectivos , Indução de Remissão , Resultado do Tratamento
5.
Dig Dis Sci ; 66(12): 4436-4440, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33428042

RESUMO

BACKGROUND: Limited data suggest that non-melanoma skin cancer (NMSC) risk is higher in patients with inflammatory bowel disease (IBD) particularly in those on a tumor necrosis factor-α antagonist (TNF antagonist). It remains unknown whether TNF antagonist exposure alters the clinical course of NMSC in patients with IBD or if this therapy should be discontinued. AIMS: To assess the impact of TNF antagonist exposure on NMSC severity, recurrence and need for ancillary treatments. METHODS: Patients with IBD seen at London Health Sciences Centre, London, Canada were assessed for a history of NMSC and pre-diagnosis TNF antagonist exposure. NMSC severity (low risk and high risk), ancillary NMSC therapies, including chemo or radiotherapy, and changes to IBD therapy were assessed. RESULTS: Eleven of 472 patients with IBD reviewed were diagnosed with NMSC. Sixty-four percent (7/11) were on a TNF antagonist at the time of NMSC diagnosis. All patients with TNF antagonist exposure, (7/7) presented with a high-risk lesion based on National Comprehensive Cancer Network (NCCN) clinical practice guidelines. The incidence of positive margins was 42.9% (3/7) and 14.3% (1/7) required ancillary therapy. No metastatic disease was seen. TNF antagonist therapy was discontinued in a single patient due to NMSC diagnosis. Recurrent NMSC lesions were not seen in any of the TNF antagonist exposed patients. CONCLUSIONS: In this case series, TNF antagonist exposure may be associated with a severe NMSC clinical course. Larger studies are needed to confirm whether TNF antagonist discontinuation should be considered in the setting of NMSC diagnosis in IBD.


Assuntos
Doenças Inflamatórias Intestinais/complicações , Recidiva Local de Neoplasia/induzido quimicamente , Neoplasias Cutâneas/induzido quimicamente , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Feminino , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Fenótipo , Estudos Retrospectivos , Pele/patologia , Neoplasias Cutâneas/patologia
7.
Mol Pharm ; 16(9): 4059-4064, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31393129

RESUMO

Cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) have broad substrate overlap and are involved in the metabolism and transport of nearly 50% of currently prescribed medications. In the intestine, CYP3A4 and P-gp are coexpressed in the enterocytes at the intestinal villous tip and act in a coordinated manner to limit drug and xenobiotic oral bioavailability prior to further metabolism and disposition in the liver. Crohn's disease (CD), a form of inflammatory bowel disease, introduces a transmural intestinal insult that disrupts the intestinal barrier function; it therefore has the potential to affect intestinal drug metabolism and transport. We hypothesized that individuals with CD have reduced intestinal expression of CYP3A4 and P-gp. We obtained intestinal biopsy samples from individuals with and without CD and quantified the expression of CYP3A4 and P-gp. When we carried out Western analysis for protein expression, we observed a significant reduction in ileal (45% decrease) and colonic (78% decrease) CYP3A4 protein expression in subjects with CD compared with those without. Similarly, an 85% reduction in colonic P-gp protein expression was seen in the CD patients. Our data highlight important and novel findings pertaining to CD-associated changes to the intestinal expression of CYP3A4 and P-gp that are of relevance to better predict substrate drug dosing for patients with CD.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Doença de Crohn/metabolismo , Citocromo P-450 CYP3A/metabolismo , Mucosa Intestinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Células CACO-2 , Colo Ascendente/metabolismo , Colo Ascendente/patologia , Doença de Crohn/patologia , Enterócitos/metabolismo , Feminino , Humanos , Íleo/metabolismo , Íleo/patologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Adulto Jovem
9.
Dig Dis Sci ; 63(5): 1280-1285, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29516329

RESUMO

BACKGROUND AND AIMS: Melena is a symptom of upper gastrointestinal bleeding and usually indicates bleeding proximal to the ligament of Treitz. However, whether melena predicts bleeding in the proximal small intestine in patients with obscure gastrointestinal bleeding (OGIB) is unknown and the objective of this study. METHODS: A retrospective cohort study of consecutive patients undergoing capsule endoscopy for OGIB between July 2009 and May 2016 was conducted. Subjects were categorized based on the presence of melena, and the primary outcome was identification of a bleeding source within the proximal 2/3 of the small intestine. Multi-variable regression was performed to control for confounders. RESULTS: During the study, 288 patients met the eligibility criteria. Subjects with melena accounted for 37.1% of the cohort and were more likely to be older (mean age 66.9 vs. 63.9, p = 0.0457), take warfarin (15.1 vs. 9.4%, p = 0.0122), and have a lower 12-month hemoglobin nadir (7.3 vs. 8.3 g/dL, p = 0.0002). On crude analysis, 56.1% of patients with melena had a bleeding source within the proximal small intestine compared to 34.8% for those without (RR 1.61, 95% CI 1.24-2.09, p = 0.0004). On multi-variable analysis, the presence of melena doubled the odds of finding a bleeding site within the proximal small intestine (OR 1.97, 95% CI 1.17-3.33, p = 0.010). CONCLUSIONS: The presence of melena doubles the odds of finding a bleeding site within the proximal small intestine among patients with OGIB, and deep enteroscopy, if performed before a capsule study, should begin with an antegrade approach in these patients.


Assuntos
Endoscopia por Cápsula , Enteropatias/diagnóstico por imagem , Intestino Delgado/diagnóstico por imagem , Melena/etiologia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Enteropatias/complicações , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
Mol Pharm ; 14(1): 310-318, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-27977217

RESUMO

Trimethylamine-N-oxide (TMAO) is a recently identified predictor of cardiovascular and chronic kidney disease. TMAO is primarily generated through gut-microbiome mediated conversion of dietary choline and carnitine to TMA, which is converted to TMAO by hepatic flavin monooxygenase 3 (FMO3) and subsequently undergoes renal elimination. We investigated the role of uptake and efflux drug transporters in TMAO disposition in vitro and in vivo. After screening a large array of uptake transporters, we show organic cation transporter 2 (OCT2) is the key transporter for TMAO cellular uptake. In Oct1/2 knockout mice, we observed increased plasma TMAO levels with reduced renal retention, suggesting the importance of Oct2 in facilitating the uptake of TMAO into renal tubular cells in vivo. Multiple transporters of the ATP-binding cassette (ABC) family, including ABCG2 (BCRP) and ABCB1 (MDR1), were capable of TMAO efflux. In human subjects, clinical, dietary, and pharmacogenetic covariates were evaluated for contribution to TMAO levels in a cohort of dyslipidemic patients (n = 405). Interestingly, genetic variation in ABCG2, but not other transporters, appeared to play a role in modulating TMAO exposure.


Assuntos
Proteínas de Membrana Transportadoras/metabolismo , Metilaminas/metabolismo , Óxidos/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Carnitina/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Oxigenases/metabolismo
14.
Curr Opin Lipidol ; 27(2): 148-54, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26959704

RESUMO

PURPOSE OF REVIEW: This article evaluates the link between trimethylamine-N-oxide (TMAO) and bile acids and the consequent impact on the development of atherosclerosis. RECENT FINDINGS: Elevation in plasma TMAO concentrations is associated with an increased risk of cardiovascular disease in many different patient cohorts. In addition to the recently identified direct effects of TMAO on the development of atherosclerosis, other components involved in TMAO metabolism may also have an impact. Furthermore, the relationship between TMAO and bile acid regulation is emerging as a possible mediator of atherosclerosis. SUMMARY: Studies that are emerging highlight the mechanistic relationship of TMAO to the development atherosclerosis in addition to its role as disease biomarker. The interplay between TMAO and bile acid metabolism mediated through multiple factors, such as the gut microbiome, farnesoid X receptor signaling, and flavin monooxygenase 3 activity may help identify another pathway by which atherosclerosis occurs. In this review, we discuss the most recent data regarding atherosclerosis, TMAO, and bile acid metabolism.


Assuntos
Aterosclerose/metabolismo , Ácidos e Sais Biliares/metabolismo , Microbioma Gastrointestinal , Metilaminas/metabolismo , Animais , Aterosclerose/microbiologia , Firmicutes/fisiologia , Humanos , Oxigenases/metabolismo
15.
Dig Dis Sci ; 60(12): 3620-30, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26160437

RESUMO

BACKGROUND: The gastrointestinal (GI) microbiome is recognized for potential clinical relevance in inflammatory bowel disease (IBD). Data suggest that there is a disease-dependent loss of microbial diversity in IBD. Trimethylamine-N-oxide (TMAO) is generated by GI anaerobes through the digestion of dietary phosphatidylcholine and carnitine in a microbial-mammalian co-metabolic pathway. IBD-related changes in the gut microbiome may result in disease-specific changes in TMAO plasma concentrations. AIM: To determine whether TMAO plasma levels in IBD are altered compared to controls and whether they correlate with disease presence or activity. METHODS: Liquid chromatography-tandem mass spectrometry was used to measure TMAO, choline, and carnitine plasma levels in 479 subjects (373 non-IBD controls, 106 IBD). Subjects were also genotyped for the flavin monooxygenase (FMO)3 variants, E158K and E308G. RESULTS: Plasma TMAO levels were 2.27 µM lower in the IBD population compared to the control population (p = 0.0001). Lower TMAO levels were similarly seen in active ulcerative colitis (UC) (1.56 µM) versus inactive disease (3.40 µM) (p = 0.002). No difference was seen in active Crohn's disease (CD) versus inactive CD. No intergroup variation existed in plasma TMAO levels based on FMO3 genotype. Choline levels were higher in IBD, while carnitine levels were similar between the two groups, suggesting that lower TMAO levels in IBD were not due to dietary differences. CONCLUSIONS: Decreased TMAO levels are seen in IBD compared to a non-IBD population. These data suggest that TMAO may have potential as a biomarker to support IBD diagnosis as well as to assess disease activity in UC.


Assuntos
Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/diagnóstico , Metilaminas/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Inflamm Bowel Dis ; 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38717841

RESUMO

BACKGROUND: We aimed to determine the correlation between tissue and plasma infliximab concentrations in an outpatient ulcerative colitis (UC) cohort based on histologic disease activity in addition to their relationship with long-term clinical outcomes. We assessed intraparticipant variability in infliximab concentrations between adjacent intestinal samples and the correlation between disease activity and tumor necrosis factor-α (TNF-α). METHODS: A prospective cohort study was conducted in participants with UC receiving infliximab. Blood and 2 sigmoid colon biopsies were obtained at the index colonoscopy for infliximab and TNF-α quantification. Histological disease activity was assessed. Participants were followed for 2 years for the occurrence of hospitalization, surgery, disease relapse, and infliximab discontinuation. RESULTS: A positive correlation was observed between mean plasma and uninflamed tissue infliximab concentrations only (Rs = 0.75, P = .0071). Lower mean tissue infliximab concentrations correlated with a shorter time to disease relapse vs those with higher mean tissue concentrations (Rs = 0.77, P = .032). This was not seen when using plasma infliximab concentrations. Additionally, no significant intraparticipant variability of infliximab concentrations was observed for all participants independent of disease activity. Neither plasma nor tissue TNF-α correlated with disease activity. CONCLUSIONS: These findings support data generated in patients with Crohn's disease: plasma infliximab concentrations are reflective of infliximab exposure in tissue in the UC patient in remission, but not for those with active disease. Increasing tissue concentrations in the noninflamed tissues may improve durability of infliximab. Neither plasma nor tissue TNF-α appear to correlate with UC disease activity. Larger follow-up studies would be of benefit.


Plasma infliximab concentrations are reflective of infliximab exposure in tissue in the UC patient in remission, but not for those with active disease. Increasing tissue concentrations in the noninflamed tissues may improve durability of infliximab.

17.
EClinicalMedicine ; 70: 102503, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38495522

RESUMO

Background: Propofol is often used for sedation during colonoscopy. We assessed the impact of propofol sedation on colonoscopy related quality metrics and cost in a population-based cohort study. Methods: All colonoscopies performed at 21 hospitals in the province of Ontario, Canada, during an 18-month period, from April 1, 2017 to October 31, 2018, using either propofol or conscious sedation were evaluated. The primary outcome was adenoma detection rate (ADR) and secondary outcomes were sessile serrated polyp detection rate (ssPDR), polyp detection rate (PDR), cecal intubation rate (CIR), and perforation rate. Binary outcomes were assessed using a modified Poisson regression model adjusted for clustering and potential confounders based on patient, procedure, and physician characteristics. Findings: A total of 46,634 colonoscopies were performed, of which 16,408 (35.2%) received propofol and 30,226 (64.8%) received conscious sedation. Compared to conscious sedation, the use of propofol was associated with a lower ADR (24.6% vs. 27.0%, p < 0.0001) but not ssPDR (5.0% vs. 4.7%, p = 0.26), PDR (40.5% vs 40.4%, p = 0.79), CIR (97.1% vs. 96.8%, p = 0.15) or perforation rate (0.04% vs. 0.06%, p = 0.45). On multi-variable analysis, propofol sedation was not associated with any differences in ADR (RR = 0.90, 95% CI 0.74-1.10, p = 0.30), ssPDR (RR = 1.20, 95% CI 0.90-1.60, p = 0.22), PDR (RR = 1.00, 95% CI 0.90-1.11, p = 0.99), or CIR (RR = 1.00, 95% CI 0.80-1.26, p = 0.99). The additional cost associated with propofol sedation was $12,730,496 for every 100,000 cases. Interpretation: The use of propofol sedation was not associated with improved colonoscopy related quality metrics but increased costs. The routine use of propofol for colonoscopy should be reevaluated. Funding: None.

18.
Inflamm Bowel Dis ; 29(3): 437-443, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36112504

RESUMO

BACKGROUND: Multiple variables contribute to variation in patient exposure and response to tumor necrosis factor alpha antagonist biologics such as infliximab. This study aimed to assess the association between maintenance-phase infliximab concentrations and genetic variation in HLADQA1*05G>A and fragment crystallisable (Fc) fragment of IgG receptor and transporter (FCGRT) among patients with inflammatory bowel disease. METHODS: A cross-sectional study was carried out in participants with inflammatory bowel disease prescribed infliximab who were in the maintenance phase of treatment. Participants were genotyped for the presence of the FCGRT variable number tandem repeat (VNTR) and HLADQA1*05G>A (rs74291249). A point estimate of the infliximab trough concentration during the maintenance phase was determined using a standard enzyme-linked immunosorbent assay for each patient. Other variables associated with infliximab pharmacokinetics were collected. RESULTS: A total of 156 participants with inflammatory bowel disease were included from 2 tertiary care centers affiliated with Western University, London, Canada. Median infliximab trough concentrations were lower in participants who carried the FCGRT VNTR 2/3 or 2/2 (4.14 µg/mL; interquartile range [IQR], 6.48 µg/mL) vs wild type individuals (7.00 µg/mL; IQR, 7.66; P = .0027). Median infliximab trough concentrations were significantly lower in participants who were HLADQA1*05G>A variant carriers (4.73µg/mL; IQR, 4.79) vs wild type individuals (7.85µg/mL; IQR, 7.44; P = .0006). A significant decrease in infliximab trough concentrations was seen in individuals who were dual carriers of variant polymorphisms in HLADQA1*05G>A and FCGRT VNTR (no variants, 8.96µg/mL; IQR, 6.84 vs one variant, 4.96 µg/mL; IQR, 4.95 vs dual variants, 0.86µg/mL; IQR, 5.82). CONCLUSION: FCGRT VNTR and HLADQA1*05G>A are associated with lower maintenance-phase infliximab concentrations, particularly among patients who carry both variants.


HLADQA1*05G>A and FCGRT VNTR are associated with lower maintenance-phase infliximab concentrations, particularly among patients who carry both variants.


Assuntos
Doenças Inflamatórias Intestinais , Repetições Minissatélites , Recém-Nascido , Humanos , Infliximab/uso terapêutico , Estudos Transversais , Doenças Inflamatórias Intestinais/tratamento farmacológico , Genótipo , Fármacos Gastrointestinais/uso terapêutico
19.
Inflamm Bowel Dis ; 29(6): 866-874, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35851799

RESUMO

INTRODUCTION: With the expanding therapeutic armamentarium for inflammatory bowel disease (IBD), real-world data may help inform drug positioning. We assessed clinical, endoscopic, imaging, and biochemical response/remission outcomes in patients with Crohn's disease (CD) treated with ustekinumab in a large Canadian IBD center. METHODS: A retrospective cohort study of CD patients was treated with ustekinumab. Clinical, endoscopic, radiological, and biochemical response and remission outcomes were stratified by prior biologic exposure status. Hazard ratios for biologic exposure status were estimated using Cox proportional hazard models and subgroup-specific incidence rates for healing. RESULTS: A total of 231 patients (55.9% female, median 45.8 years) were identified as receiving ustekinumab during the study period, with 2 patients subsequently excluded (N = 229). Of these patients, 79.0% (181 of 229) were bio-experienced, with 38.7% (70 of 181) having failed 1 biologic and 61.3% (111 of 181) having failed ≥2 biologics. At 3 months of follow-up after induction, clinical remission (Harvey-Bradshaw Index ≤4) was achieved by 59.1% (62 of 105) of bio-experienced patients and 79.4% (27 of 34) of bio-naïve patients (relative risk [RR], 1.34; 95% CI, 1.06-1.70; P = .013). Endoscopic remission (absence of mucosal ulcers) was achieved in 37.9% (33 of 87) cases. Rate of endoscopic healing (either endoscopic response or remission) per 1000 person-months was 72.7 (95% CI, 42.4-125.1) and 50.2 (37.9-66.4); and the median time to endoscopic response was 8.4 months (95% CI, 6.4-9.8) and 15.4 months (95% CI, 10.3-17.9) in bio-naïve vs bio-experienced patients, respectively. Imaging response/remission and steroid-free remission rates were higher in bio-naïve patients. CONCLUSION: In this large real-world cohort of CD patients with complex phenotypes and high rates of prior biologic exposure, we observed that ustekinumab was effective and safe with higher rates of improvement in bio-naïve subjects across a range of end points.


In this large real-world study of patients with Crohn's Disease treated with ustekinumab, we observed high rates of clinical, endoscopic, radiological, and biochemical response and remission rates. Effectiveness was greater in bio-naïve compared with bio-experienced patients.


Assuntos
Doença de Crohn , Ustekinumab , Doença de Crohn/tratamento farmacológico , Doença de Crohn/epidemiologia , Ustekinumab/uso terapêutico , Canadá/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso
20.
Aliment Pharmacol Ther ; 55(11): 1379-1388, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35312094

RESUMO

BACKGROUND: Tumour necrosis factor (TNF) antagonists are an efficacious therapy used in the management of several immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD) and psoriasis. However, since being prescribed more widely, reports of new-onset psoriatic lesions have began to emerge in the literature and are known as paradoxical psoriasis. AIM: To review the evidence available in both the dermatology and gastroenterology literature pertaining to the entity known as paradoxical psoriasis as it relates to IBD and to create a comprehensive guide to assist clinicians who treat this challenging patient population. METHODS: A literature search was conducted in PubMed to identify manuscripts that presented, discussed or summarised data pertaining to paradoxical psoriasis presenting in individuals with IBD. RESULTS: Paradoxical psoriasis is now thought to be a contradictory effect of TNF antagonist therapy leading to psoriatic lesions often within the first year of treatment. The underlying pathogenesis, although not completely understood, is likely related to an imbalance of inflammatory cytokines. The histological appearance, while similar to classical psoriasis, does have unique features. The clinical presentation can vary among patients but often presents during maintenance therapy for inflammatory bowel disease. Treatment options should be determined based upon the severity of the skin lesion, activity of the underlying inflammatory bowel disease and the patient's unique clinical history. CONCLUSIONS: The approach to paradoxical psoriasis in IBD should be discussed with a multidisciplinary team to optimise and preserve intestinal disease remission and to ensure the resolution of debilitating skin lesions.


Assuntos
Doenças Inflamatórias Intestinais , Psoríase , Dermatopatias , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Infliximab/uso terapêutico , Psoríase/tratamento farmacológico , Psoríase/epidemiologia , Dermatopatias/induzido quimicamente , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Fator de Necrose Tumoral alfa
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