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BACKGROUND & AIMS: The cause of Crohn's disease (CD) is unknown, but the current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. Case-control studies of patients with CD have cataloged alterations in the gut microbiome composition; however, these studies fail to distinguish whether the altered gut microbiome composition is associated with initiation of CD or is the result of inflammation or drug treatment. METHODS: In this prospective cohort study, 3483 healthy first-degree relatives (FDRs) of patients with CD were recruited to identify the gut microbiome composition that precedes the onset of CD and to what extent this composition predicts the risk of developing CD. We applied a machine learning approach to the analysis of the gut microbiome composition (based on 16S ribosomal RNA sequencing) to define a microbial signature that associates with future development of CD. The performance of the model was assessed in an independent validation cohort. RESULTS: In the validation cohort, the microbiome risk score (MRS) model yielded a hazard ratio of 2.24 (95% confidence interval, 1.03-4.84; P = .04), using the median of the MRS from the discovery cohort as the threshold. The MRS demonstrated a temporal validity by capturing individuals that developed CD up to 5 years before disease onset (area under the curve > 0.65). The 5 most important taxa contributing to the MRS included Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus-level group from Oscillospiraceae, and Roseburia. CONCLUSION: This study is the first to demonstrate that gut microbiome composition is associated with future onset of CD and suggests that gut microbiome is a contributor in the pathogenesis of CD.
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Doença de Crohn , Microbioma Gastrointestinal , Inflamação , Humanos , Inflamação/genética , Estudos Prospectivos , Faecalibacterium , Complexo Antígeno L1 LeucocitárioRESUMO
OBJECTIVE: The measure of serum proteome in the preclinical state of Crohn's disease (CD) may provide insight into biological pathways involved in CD pathogenesis. We aimed to assess associations of serum proteins with future CD onset and with other biomarkers predicting CD risk in a healthy at-risk cohort. DESIGN: In a nested case-control study within the Crohn's and Colitis Canada Genetics Environment Microbial Project (CCC-GEM) cohort, which prospectively follows healthy first-degree relatives (FDRs), subjects who developed CD (n=71) were matched with four FDRs remaining healthy (n=284). Using samples at recruitment, serum protein profiles using the Olink Proximity Extension Assay platform was assessed for association with future development of CD and with other baseline biomarkers as follows: serum antimicrobial antibodies (AS: positive antibody sum) (Prometheus); faecal calprotectin (FCP); gut barrier function using the fractional excretion of lactulose-to-mannitol ratio (LMR) assay. RESULTS: We identified 25 of 446 serum proteins significantly associated with future development of CD. C-X-C motif chemokine 9 (CXCL9) had the highest OR with future risk of CD (OR=2.07 per SD, 95% CI 1.58 to 2.73, q=7.9e-5), whereas matrix extracellular phosphoglycoprotein had the lowest OR (OR 0.44, 95% CI 0.29 to 0.66, q=0.02). Notably, CXCL9 was the only analyte significantly associated with all other CD-risk biomarkers with consistent direction of effect (FCP: OR=2.21; LMR: OR=1.67; AS: OR=1.59) (q<0.05 for all). CONCLUSION: We identified serum proteomic signatures associated with future CD development, reflecting potential early biological processes of immune and barrier dysfunction.
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Doença de Crohn , Humanos , Doença de Crohn/metabolismo , Estudos de Casos e Controles , Proteômica , Biomarcadores , ImunidadeRESUMO
BACKGROUND & AIMS: End points to determine the efficacy and safety of medical therapies for Crohn's disease (CD) and ulcerative colitis (UC) are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in inflammatory bowel disease. METHODS: Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists. RESULTS: A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for UC. In CD, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In UC, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities. CONCLUSIONS: This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of CD and UC.
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Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Biomarcadores , Proteína C-Reativa/metabolismo , Doença Crônica , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Consenso , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Humanos , Doenças Inflamatórias Intestinais/terapia , Complexo Antígeno L1 Leucocitário , Avaliação de Resultados em Cuidados de Saúde , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND & AIMS: The gut microbiome has been suggested to play a role in gut barrier hemostasis, but data are scarce and limited to animal studies. We therefore aimed to assess whether alterations in gut microbial composition and functional pathways are associated with gut barrier function in a cohort of healthy first-degree relatives of patients with Crohn's disease. METHODS: We used the Crohn's and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy first-degree relatives of patients with Crohn's disease. Gut barrier function was assessed using the urinary fractional excretion of lactulose-to-mannitol ratio (LMR). Microbiome composition was assessed by sequencing fecal 16S ribosomal RNA. The cohort was divided into a discovery cohort (n = 2472) and a validation cohort (n = 655). A regression model was used to assess microbial associations with the LMR. A random forest classifier algorithm was performed to assess microbial community contribution to barrier function. RESULTS: Individuals with impaired barrier function (LMR >0.025) had reduced alpha-diversity (Chao1 index, P = 4.0e-4) and altered beta-diversity (Bray-Curtis dissimilarity index, R2 = 0.001, P = 1.0e-3) compared with individuals with an LMR ≤0.025. When taxa were assessed individually, we identified 8 genera and 52 microbial pathways associated with an LMR >0.025 (q < 0.05). Four genera (decreased prevalence of Adlercreutzia, Clostridia UCG 014, and Clostridium sensu stricto 1 and increased abundance of Colidextribacter) and 8 pathways (including decreased biosynthesis of glutamate, tryptophan, and threonine) were replicated in the validation cohort. The random forest approach revealed that the bacterial community is associated with gut barrier function (area under the curve, 0.63; P = 1.4e-6). CONCLUSIONS: The gut microbiome community and pathways are associated with changes in gut barrier function. These findings may identify potential microbial targets to modulate gut barrier.
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Doença de Crohn , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/genética , Doença de Crohn/microbiologia , RNA Ribossômico 16S/genética , Lactulose , Triptofano , Manitol , Treonina , GlutamatosRESUMO
BACKGROUND & AIMS: Case-control studies have shown that patients with Crohn's disease (CD) have a microbial composition different from healthy individuals. Although the causes of CD are unknown, epidemiologic studies suggest that diet is an important contributor to CD risk, potentially via modulation of bacterial composition and gut inflammation. We hypothesized that long-term dietary clusters (DCs) are associated with gut microbiome compositions and gut inflammation. Our objectives were to identify dietary patterns and assess whether they are associated with alterations in specific gut microbial compositions and subclinical levels of gut inflammation in a cohort of healthy first-degree relatives (FDRs) of patients with CD. METHODS: As part of the Genetic, Environmental, Microbial (GEM) Project, we recruited a cohort of 2289 healthy FDRs of patients with CD. Individuals provided stool samples and answered a validated food frequency questionnaire reflecting their habitual diet during the year before sample collection. Unsupervised analysis identified 3 dietary and 3 microbial composition clusters. RESULTS: DC3, resembling the Mediterranean diet, was strongly associated with a defined microbial composition, with an increased abundance of fiber-degrading bacteria, such as Ruminococcus, as well as taxa such as Faecalibacterium. The DC3 diet was also significantly associated with lower levels of subclinical gut inflammation, defined by fecal calprotectin, compared with other dietary patterns. No significant associations were found between individual food items and fecal calprotectin, suggesting that long-term dietary patterns rather than individual food items contribute to subclinical gut inflammation. Additionally, mediation analysis demonstrated that DC3 had a direct effect on subclinical inflammation that was partially mediated by the microbiota. CONCLUSIONS: Overall, these results indicated that Mediterranean-like dietary patterns are associated with microbiome and lower intestinal inflammation. This study will help guide future dietary strategies that affect microbial composition and host gut inflammation to prevent diseases.
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Doença de Crohn , Dieta Mediterrânea , Microbioma Gastrointestinal , Bactérias , Doença de Crohn/diagnóstico , Doença de Crohn/microbiologia , Dieta/efeitos adversos , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Humanos , Inflamação , Complexo Antígeno L1 Leucocitário/análiseRESUMO
INTRODUCTION: We investigated whether early adalimumab drug levels (ADL) at week 4 predicted biological remission at week 24. METHODS: In a prospective study, we assessed clinical and biological remission at weeks 0, 4, 12, and 24 after induction of adalimumab in 33 patients with Crohn's disease. Disease activity was determined by the Harvey-Bradshaw Index, ileocolonoscopy reports, cross-sectional imaging, C-reactive protein (CRP), and fecal calprotectin (FC) levels. Clinical remission was defined as Harvey-Bradshaw Index <5. Biological remission was defined as a combination of FC < 200 µg/g and CRP <5 µg/mL. ADL trough levels were tested using a liquid phase, mobility shift assay. RESULTS: At 24 weeks, 18/33 (55%) of the patients were with biological remission. Ten (30%) patients required dose escalation or withdrawal from adalimumab by week 24 because of lack of response and exhibited significantly higher FC (P = 0.003) and CRP (P = 0.002). ADL levels at week 4 (19.8 µg/mL vs 10.2 µg/mL, P = 0.001) were significantly higher in patients with biological remission vs nonresponders at week 24. ADL levels at week 4 were a good predictor of biological remission at week 24, with area under the curve 0.86, 95% confidence interval (1.1; 1.67) and for combined biological and clinical remission, with area under the curve 0.8. The best ADL cutoff at week 4 that predicted biological remission at week 24 was 13.9 µg/mL (sensitivity 94.4% and specificity 73.3%). DISCUSSION: In individuals with Crohn's disease, higher adalimumab drug levels at week 4 (>13.9 µg/mL) were significantly associated with biological remission at week 24.
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Adalimumab/sangue , Adalimumab/uso terapêutico , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Proteína C-Reativa/metabolismo , Colonoscopia , Doença de Crohn/diagnóstico por imagem , Fezes/química , Feminino , Humanos , Íleo/diagnóstico por imagem , Complexo Antígeno L1 Leucocitário/metabolismo , Modelos Logísticos , Masculino , Estudos Prospectivos , Indução de Remissão , Adulto JovemRESUMO
BACKGROUND: Many Crohn's disease patients treated with anti-tumor necrosis factor (TNF) therapies suffer from loss of response over time and require dose escalation. The aim of this study was to evaluate the efficacy and safety of treating anti-TNF experienced Crohn's disease patients with higher maintenance regimens of adalimumab. METHODS: In a retrospective observational study, Crohn's disease patients receiving adalimumab were categorized according to their maintenance regimen; 40 mg weekly, 80 mg every other week or greater were defined as a high-dose maintenance regimen and 40 mg every other week was defined as a standard maintenance regimen. The primary outcome was time to treatment failure. RESULTS: Thirty-nine patients were started on high-dose regimens following induction and 40 patients received the standard regimen. According to a Kaplan-Meier survival curve analysis, time to treatment failure was significantly longer in patients in the high-dose group (P = 0.0015). Patients on high-dose adalimumab had a lower treatment failure rate (hazard ratio 0.21; P = 0.0005) when compared to patients on the standard regimen, after adjusting for induction dose and concomitant immunomodulator use. No difference in adverse events was identified between the groups (31 vs. 30%; P = 0.94). CONCLUSION: High-dose maintenance regimens were more effective than the standard adalimumab maintenance protocol with better short and long-term clinical outcomes.
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Doença de Crohn , Inibidores do Fator de Necrose Tumoral , Adalimumab/efeitos adversos , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Humanos , Infliximab , Estudos Retrospectivos , Resultado do Tratamento , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND AND AIMS: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDRs) of CD patients is an independent risk factor for future CD development. METHODS: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic location with control FDRs remaining healthy (n = 307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis. RESULTS: High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4-12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation. CONCLUSIONS: Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early predisease event in the development of CD.
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Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Proteína C-Reativa/análise , Doença de Crohn/imunologia , Mucosa Intestinal/metabolismo , Adolescente , Adulto , Doenças Assintomáticas , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Doença de Crohn/sangue , Doença de Crohn/genética , Doença de Crohn/microbiologia , Feminino , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/sangue , Israel , Masculino , Análise de Mediação , América do Norte , Permeabilidade , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND AND AIM: Crohn's disease (CD) patients who previously failed anti-tumor necrosis factor (TNF) therapy are at higher risk of treatment failure with subsequent biologics. This study aims to determine the effectiveness and safety of higher maintenance dose regimens of adalimumab compared with standard doses in CD patients who failed anti-TNF. METHODS: In this retrospective observational study, CD patients who failed anti-TNF and received adalimumab were categorized according to their post-induction maintenance regimen; 40 mg subcutaneous (sc) weekly or 80 mg sc every other week were defined as a high-dose (HD) maintenance regimen, and 40 mg sc every other week was defined as a standard-dose (SD) maintenance regimen. The primary outcome was time to treatment failure. Cox proportional hazards regression was used to adjust for confounders. Sensitivity analysis was conducted using propensity scores to create a cohort of matched participants with similar distribution of baseline covariates. RESULTS: Forty patients started on HD regimens following induction, and 77 patients received the SD regimen. The median time to failure in the HD group was 6.6 years (interquartile range [IQR] 4.0-9.6) and 3.0 years (IQR 0.9-9.4) in the SD group (log-rank test P = 0.006). Patients on HD adalimumab had a lower hazard rate of treatment failure (hazard ratio: 0.27; 95% confidence interval [0.12, 0.62]; P = 0.002) compared with SD patients. No difference in adverse events was identified between groups (30% vs 31.2%, P = 1.0). Results were similar in the propensity score-matched cohort. CONCLUSIONS: High-dose maintenance regimens were associated with longer time-to-failure as compared with SD regimens in CD patient who failed anti-TNF.
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Doença de Crohn , Adalimumab/efeitos adversos , Estudos de Coortes , Doença de Crohn/tratamento farmacológico , Humanos , Infliximab , Pontuação de Propensão , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfaRESUMO
Tumor necrosis factor-α inhibitors, adalimumab and infliximab, are at the forefront of biologic therapy for the management of moderate-to-severe hidradenitis suppurativa, with adalimumab as currently the only approved medication for this condition. In treating patients, primary or secondary lack of response (also termed suboptimal response) is a major burden for both patients and healthcare systems and is a challenge with biologics in part owing to the development of anti-drug antibodies following treatment. To overcome this, therapeutic drug monitoring may be conducted proactively or reactively to a patient's suboptimal response guided by measurements of trough serum drug concentrations and levels of anti-drug antibodies. While strong evidence to support the utility of therapeutic drug monitoring exists in patients with inflammatory bowel disease, current information is limited in the context of hidradenitis suppurativa. We sought to summarize the available evidence and to present the role of therapeutic drug monitoring and other dose optimization strategies in improving clinical response in patients with hidradenitis suppurativa treated with tumor necrosis factor-α inhibitors.
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Fatores Biológicos/farmacocinética , Monitoramento de Medicamentos , Hidradenite Supurativa/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/administração & dosagem , Adalimumab/farmacocinética , Fatores Biológicos/administração & dosagem , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Hidradenite Supurativa/sangue , Hidradenite Supurativa/imunologia , Humanos , Infliximab/administração & dosagem , Infliximab/farmacocinética , Psoríase/sangue , Psoríase/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: In patients with inflammatory bowel diseases (IBDs), symptoms do not always associate with the severity of endoscopic inflammation and can persist after mucosal healing. We investigated whether symptoms in patients with successfully treated IBD are related to the composition of the intestinal microbiome. METHODS: We analyzed 590 tissue biopsy specimens from 215 patients with IBD and 48 healthy individuals (controls). We obtained mucosal biopsy specimens from 2 colon sites (ascending and rectosigmoid) and from the terminal ileum along with clinical data. Bacterial DNA was extracted from the biopsy specimens and the V4 region of 16s ribosomal RNA sequenced by Miseq and processed using the QIIME v1.9 pipeline. RESULTS: Mucosal biopsy specimens from patients with Crohn's disease (CD) who achieved mucosal healing (Mayo scores of 0-1 or segmental endoscopic severity CD scores of 0-5) had lower Chao1 diversity than biopsy specimens from patients with ulcerative colitis (UC) or unclassified IBD (IBD-U), or controls. After endoscopic evidence of improvement in patients with UC or IBD-U, diversity of the tissue-associated microbiota did not differ significantly from that of controls. Colon biopsy specimens from patients with CD had lower microbial diversity, before and after healing (segmental endoscopic severity CD scores, 0-2), than colon biopsy specimens from controls (P < .002). In patients with CD who achieved mucosal healing, residual clinical activity (CD activity index scores >150; P = .03) and persistent diarrhea were associated with reduced microbial diversity (P = .01). Continued diarrhea was associated with a trend toward dysbiosis, based on the microbial dysbiosis index (P = .059). In patients with UC or IBD-U with moderate to severe inflammation, increasing severity of diarrhea was associated with reduced microbial diversity (P = .03). CONCLUSIONS: In an analysis of biopsy specimens from patients with IBD and controls, we found that despite endoscopic evidence of improvement or remission, α-diversity of the tissue-associated intestinal microbiome remained lower in patients with CD than in controls. This observation, along with the reduced Chao1 diversity and greater dysbiosis in intestinal microbiota of patients with residual symptoms of IBD, indicates that microbiome composition could be associated with persistent diarrhea.
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Colite Ulcerativa , Doença de Crohn , Microbioma Gastrointestinal , Doença de Crohn/complicações , Diarreia , Disbiose , Humanos , Mucosa IntestinalRESUMO
BACKGROUND: The IBD disability index (IBDDI) has been shown to be valid and reliable. We compared the distributional and predictive properties of the IBDDI, when collected from five populations of people living with IBD- from Winnipeg, Chicago, Toronto, Hong Kong, and Jerusalem. METHODS: People with IBD from five jurisdictions were invited to complete a survey including the IBDDI, the World Health Organization Disability Assessment Scale, the Work and Social Adjustment Scale, the IBDQ, the Kessler-6 distress scale, and the Stanford presenteeism scale. Between sites, we compared the correlation between IBDDI and the other 4 measures of disability/quality of life/distress, and the association between IBDDI and presenteeism and having been hospitalized in the past year. RESULTS: There were 1121 participants from Winnipeg, 511 from Chicago, 147 from Toronto, 97 from Hong Kong, and 96 from Jerusalem. The majority had Crohn's disease. Although the mean IBDDI score varied by site, the correlation between IBDDI and each of the other 4 measures of disability/QOL/distress was nearly identical. Similarly, the regression coefficient showing the association between IBDDI and presenteeism was nearly identical in all sites, and the risk ratios showing the association between hospitalization and high IBDDI was similar in all sites. CONCLUSION: The correlation between IBDDI and different measures of disability/QOL/distress was similar across all sites. There is strong evidence of the association between IBD-related disability and presenteeism, and between hospitalization and high IBD-related disability, and that the associations are the same across different populations. The severity of disability that an individual with a given IBDDI score has is directly comparable across populations.
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Doença de Crohn , Doenças Inflamatórias Intestinais , Avaliação da Deficiência , Humanos , Qualidade de Vida , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
BACKGROUND & AIMS: Increased intestinal permeability has been associated with Crohn's disease (CD), but it is not clear whether it is a cause or result of the disease. We performed a prospective study to determine whether increased intestinal permeability is associated with future development of CD. METHODS: We assessed the intestinal permeability, measured by the urinary fractional excretion of lactulose-to-mannitol ratio (LMR) at recruitment in 1420 asymptomatic first-degree relatives (6-35 years old) of patients with CD (collected from 2008 through 2015). Participants were then followed up for a diagnosis of CD from 2008 to 2017, with a median follow-up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017. We used the Cox proportional hazards model to evaluate time-related risk of CD based on the baseline LMR. RESULTS: An abnormal LMR (>0.03) was associated with a diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64-5.63; P = 3.97 × 10-4). This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62; 95% CI, 1.051-2.50; P = .029). CONCLUSIONS: Increased intestinal permeability is associated with later development of CD; these findings support a model in which altered intestinal barrier function contributes to pathogenesis. Abnormal gut barrier function might serve as a biomarker for risk of CD onset.
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Doença de Crohn/epidemiologia , Mucosa Intestinal/patologia , Adolescente , Adulto , Criança , Doença de Crohn/patologia , Feminino , Seguimentos , Humanos , Lactulose/administração & dosagem , Lactulose/metabolismo , Lactulose/urina , Masculino , Manitol/administração & dosagem , Manitol/metabolismo , Manitol/urina , Permeabilidade , Estudos Prospectivos , Eliminação Renal , Fatores de Risco , Adulto JovemRESUMO
INTRODUCTION: Golimumab is approved as a therapy for ulcerative colitis (UC) patients. Recent data also demonstrate efficacy in Crohn's disease (CD); however, little is known about target drug levels to achieve endoscopic remission. METHODS: We performed a retrospective analysis of IBD patients on maintenance golimumab. Median trough levels were compared using Kruskal-Wallis test, and logistic regression was used to construct a probabilistic model to determine sensitivity and specificity of levels predicting mucosal healing. RESULTS: Fifty-eight patients on maintenance golimumab were included (n = 39 CD, n = 19 UC/IBD-unclassified [IBDU]). Forty percent (n = 23) were cotreated with an immunomodulator, 95% (n = 55) of patients were anti-TNF experienced, and 15.5% (n = 9) had 3 or more prior biologic therapies. Forty-four percent of patients achieved mucosal healing with endoscopic response in a further 26% of patients. Clinical remission was recorded in 41% of patients, and 82% had clinical response. Patients were treated with doses generally higher than the approved maintenance dose. In CD patients, median golimumab trough levels were higher in patients with mucosal healing (8.8 µg/mL vs 5.08 µg/mL, P = 0.03). After calculation of a receiver operating characteristic (ROC) curve for mucosal healing vs nonresponse, a trough level >8 µg/mL was associated with mucosal healing, with 67% sensitivity, 88% specificity, and a likelihood ratio of 3:4. CONCLUSION: Treatment with golimumab was associated with mucosal healing in 44% of all IBD patients. Higher golimumab levels were associated with mucosal healing in CD. These findings support the need for prospective studies to determine target golimumab levels in IBD, which may impact current clinical practices in relation to selection of maintenance dosing.
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Anticorpos Monoclonais/sangue , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Monitoramento de Medicamentos/estatística & dados numéricos , Inibidores do Fator de Necrose Tumoral/sangue , Adulto , Anticorpos Monoclonais/administração & dosagem , Colite Ulcerativa/sangue , Colite Ulcerativa/patologia , Doença de Crohn/sangue , Doença de Crohn/patologia , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Modelos Logísticos , Quimioterapia de Manutenção/métodos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Valores de Referência , Estudos Retrospectivos , Sensibilidade e Especificidade , Inibidores do Fator de Necrose Tumoral/administração & dosagemRESUMO
BACKGROUND & AIMS: Crohn's disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. METHODS: We performed a systematic review to identify published studies of the management of CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. RESULTS: The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent. CONCLUSIONS: Optimal management of CD requires careful patient assessment, acknowledgement of patient preferences, evidence-based use of existing therapies, and thorough assessment to define treatment success.
RESUMO
BACKGROUND & AIMS: Crohn's disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. METHODS: We performed a systematic review to identify published studies of the management of CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. RESULTS: The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent. CONCLUSIONS: Optimal management of CD requires careful patient assessment, acknowledgement of patient preferences, evidence-based use of existing therapies, and thorough assessment to define treatment success.
Assuntos
Antibacterianos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Azatioprina/uso terapêutico , Budesonida/uso terapêutico , Canadá , Gastroenterologia , Humanos , Quimioterapia de Indução , Quimioterapia de Manutenção , Mesalamina , Metotrexato/uso terapêutico , Prednisolona/uso terapêutico , Sociedades Médicas , Sulfassalazina/uso terapêutico , Resultado do Tratamento , Ustekinumab/uso terapêuticoRESUMO
BACKGROUND: While progress has been made in the identification of Crohn's disease (CD) susceptibility loci, efforts to identify a genetic basis for disease progression have been less fruitful. The specific aim of this study was to build upon the major genetic advances made in IBD by applying genome-wide technologies toward predicting disease progression in CD. METHODS: Crohn's disease cases (n = 1495) from 3 IBD centers were reviewed by experienced physicians. Clinical and demographic details were collected, focusing on the time to first disease progression. Genome-wide association (GWA) analysis was carried out on 3 clinical outcomes: 1) time to disease progression; 2) time to first abdominal surgery; and 3) a binary analysis of indolent vs progressive disease. Cox-proportional hazard and logistic regression models were used. RESULTS: A GWA analysis was carried out to determine any genetic variation associated with the time to disease progression; 662 cases were included after quality control (QC) and exclusion of any cases with B2/B3 behavior at baseline (n = 450). There were 1360 cases included after QC in the time to abdominal surgery analysis. No variant reached genome-wide significance in any of the 3 analyses performed. Eight known IBD susceptibility single nucleotide polymorphism (SNPs) were found to be associated with time-to-abdominal surgery SMAD3 (rs17293632), CCR6 (rs1819333), CNTF (rs11229555), TSPAN14 (rs7097656), CARD9 (rs10781499), IPMK (rs2790216), IL10 (rs3024505), and SMURF1 (rs9297145) (P < 0.05). CONCLUSION: Our GWA study failed to show any SNP-phenotype association reaching genome-wide significance. It is likely that multiple variables affect disease progression, with genetic factors potentially having only a small effect size.
Assuntos
Doença de Crohn/genética , Doença de Crohn/patologia , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Tempo para o Tratamento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Doença de Crohn/cirurgia , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
Background: Fistulas occur in about 25% of patients with Crohn's disease (CD) and can be difficult to treat. The aim of this consensus was to provide guidance for the management of patients with perianal fistulizing CD. Methods: A systematic literature search identified studies on the management of fistulizing CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform using a modified Delphi process, then finalized, and voted on by a group of specialists. Results: The quality of evidence for treatment of fistulizing CD was generally of very low quality, and because of the scarcity of good randomized controlled trials (RCTs), these consensus statements generally provide conditional suggestions (5 of 7 statements). Imaging and surgical consultations were recommended in the initial assessment of patients with active fistulizing CD, particularly those with complicated disease. Antibiotic therapy is useful for initial symptom control. Antitumor necrosis factor (anti-TNF) therapy was recommended to induce symptomatic response, and continued use was suggested to achieve and maintain complete remission. The use of concomitant immunosuppressant therapies may be useful to optimize pharmacokinetic parameters when initiating anti-TNF therapy. When there has been an inadequate symptomatic response to medical management strategies, surgical therapy may provide effective fistula healing for some patients. Conclusions: Optimal management of perianal fistulizing CD requires a collaborative effort between gastroenterologists and surgeons and may include the evidence-based use of existing therapies, as well as surgical assessments and interventions when needed. 10.1093/ibd/izy247_video1izy247.video15978518763001.
Assuntos
Canal Anal/patologia , Doença de Crohn/complicações , Guias de Prática Clínica como Assunto/normas , Fístula Retal/terapia , Terapia Combinada , Consenso , Humanos , Metanálise como Assunto , Prognóstico , Fístula Retal/etiologiaRESUMO
BACKGROUND:: Patients with immune-mediated diseases on immunosuppressive therapies have more infectious episodes than healthy individuals, yet vaccination practices by physicians for this patient population remain suboptimal. OBJECTIVES:: To evaluate the safety and efficacy of vaccines in individuals exposed to immunosuppressive therapies and provide evidence-based clinical practice recommendations. METHODS:: A literature search for vaccination safety and efficacy in patients on immunosuppressive therapies (2009-2017) was conducted. Results were assessed using the Grading of Recommendation, Assessment, Development, and Evaluation system. RESULTS:: Several immunosuppressive therapies attenuate vaccine response. Thus, vaccines should be administered before treatment whenever feasible. Inactivated vaccines can be administered without treatment discontinuation. Similarly, evidence suggests that the live zoster vaccine is safe and effective while on select immunosuppressive therapy, although use of the subunit vaccine is preferred. Caution regarding other live vaccines is warranted. Drug pharmacokinetics, duration of vaccine-induced viremia, and immune response kinetics should be considered to determine appropriate timing of vaccination and treatment (re)initiation. Infants exposed to immunosuppressive therapies through breastmilk can usually be immunized according to local guidelines. Intrauterine exposure to immunosuppressive agents is not a contraindication for inactivated vaccines. Live attenuated vaccines scheduled for infants and children ⩾12 months of age, including measles, mumps, rubella, and varicella, can be safely administered as sufficient time has elapsed for drug clearance. CONCLUSIONS:: Immunosuppressive agents may attenuate vaccine responses, but protective benefit is generally maintained. While these recommendations are evidence based, they do not replace clinical judgment, and decisions regarding vaccination must carefully assess the risks, benefits, and circumstances of individual patients.
Assuntos
Hospedeiro Imunocomprometido , Guias de Prática Clínica como Assunto , Vacinação , Humanos , Doenças do Sistema Imunitário , Imunossupressores/uso terapêuticoRESUMO
BACKGROUND: Paradoxical development of psoriasis in patients on anti-TNF agents has been increasingly reported. AIM: The aim was to characterize the prevalence and clinical characteristics of anti-TNF-associated psoriasis in a large cohort of inflammatory bowel disease patients. METHODS: Medical records of patients with Crohn's disease or ulcerative colitis treated with anti-TNF therapy at a single, tertiary IBD center were identified between 2004 and 2016. Patients identified as having developed psoriasis while on anti-TNF underwent detailed retrospective review of dermatologic features and changes in IBD treatment prompted by the development of psoriasis. RESULTS: Among 676 patients treated with anti-TNF (infliximab or adalimumab), the incidence of psoriasis was 10.7% (N = 72). Female gender (OR 1.88 [95% CI 1.12-3.17], p = 0.017), stricturing or fistulizing Crohn's disease (OR 1.83 [95% CI 1.04-3.21], p = 0.036) and upper GI Crohn's disease (OR 3.03 [95% CI 1.06-8.33], p = 0.039) were associated with psoriasis development. The median time to psoriasis onset was 569 days from initiation of anti-TNF, with onset occurring earlier in patients who developed psoriasis on adalimumab versus infliximab (457 vs. 790.5 days, p = 0.008). Overall, in 15/72 (20.8%), cases, cessation of the anti-TNF was required as a result of psoriasis. Plaque psoriasis was the most common type of psoriatic lesion (75%). Topical corticosteroids were the most common treatment for psoriasis. CONCLUSION: We report a high incidence of anti-TNF-associated psoriasis that was associated with female gender, foregut disease location, and fistulizing and stricturing disease behavior. More prospective studies and genetic analyses evaluating possible pathophysiologic underpinnings of this problem are needed.