The influence of subclinical active inflammation on IFX pharmacokinetic modeling and disease progression assessment: findings from a prospective real-world study in inflammatory bowel disease patients.

BACKGROUND AND AIMS: Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment. METHODS: The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model. RESULTS: The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in all its different definitions, when adjusted for several confounding factors. Additionally, alongside FC, both IFX and CL demonstrated a significant impact on the temporal aspect of disease progression. CONCLUSION: In this 2-year real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that subclinical active inflammation, as mirrored by FC or CRP, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of disease progression. These findings underscore the need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.

Thiopurines have no impact on outcomes of Crohn's disease patients beyond 12 months of maintenance treatment with infliximab.

BACKGROUND: The emergence of new treatments the inflammatory bowel diseases (IBD) raised questions regarding the role of older agents, namely thiopurines. AIMS: To clarify the benefits of combination treatment with thiopurines on Crohn's disease (CD) patients in the maintenance phase of infliximab. METHODS: In this analysis of the 2-year prospective multicentric DIRECT study, patients were assessed in terms of clinical activity, faecal calprotectin (FC), C-reactive protein (CRP), and infliximab pharmacokinetics. A composite outcome based on clinical- and drug-related items was used to define treatment failure. RESULTS: The study included 172 patients; of these, 35.5 % were treated with combination treatment. Overall, 18 % of patients achieved the composite outcome, without statistically significant differences between patients on monotherapy and on combination treatment (21.6% vs 11.5 %, p = 0.098). Median CRP, FC, and infliximab pharmacokinetic parameters were similar in both groups. However, in the sub-analysis by infliximab treatment duration, in patients treated for less than 12 months, the composite outcome was reached in fewer patients in the combination group than in the monotherapy group (7.1% vs 47.1 %, p = 0.021). CONCLUSION: In CD patients in maintenance treatment with infliximab, combination treatment does not seem to have benefits over infliximab monotherapy beyond 12 months of treatment duration.

Impact of Percutaneous Endoscopic Gastrostomy Tube Feeding on Nutritional Status in Patients Undergoing Chemoradiotherapy for Oesophageal Cancer.

Introduction: Oesophageal cancer causes dysphagia and weight loss. Malnutrition further worsens with multimodal treatment. Aim: The aim of the study was to evaluate the impact of percutaneous endoscopic gastrostomy (PEG) placement in the nutritional status of patients with oesophageal cancer requiring chemoradiotherapy (CRT). Methods: A comparative study with a prospective arm and a historical cohort was conducted. Oesophageal cancer patients undergoing CRT with dysphagia grade >2 and/or weight loss >10% were submitted to PEG-tube placement (pull method) before CRT. Stoma seeding was evaluated through a swab obtained after placement and, in surgical patients, the resected stoma. A matched historical cohort without PEG placement was used as control (trial ACTRN12616000697482). Results: Twenty-nine patients (intervention group, IG) were compared to 30 patients (control group, CG). Main outcomes did not differ in the IG and CG: weight loss during CRT 8.1 ± 5.5 kg versus 9.1 ± 4.2 kg (p = 0.503); 6-month mortality after CRT or surgery 17.2% versus 26.7% (p = 0.383); perioperative complication rate 54.5% versus 55.6% (p = 1.000); unplanned hospital admissions 34.5% versus 40.0% (p = 0.661). In the CG, during CRT, 14 (46.7%) patients presented with dysphagia grade 3-4, of whom 12 required nasogastric tube feeding (n = 10), surgical gastrostomy (n = 1), and oesophageal dilation (n = 1). In the IG, 89.7% used the PEG tube during CRT, sometimes exclusively in 51.7%. Adverse events were mainly minor (n = 12, 41.4%), mostly late peristomal infections, 1 major complication (exploratory laparotomy due to suspected colonic interposition, not confirmed). There was no cytological or histological evidence of stomal tumour seeding. Conclusion: Weight loss, hospital admissions, surgical complications, and mortality were identical in oesophageal cancer patients referred for CRT, regardless of prophylactic PEG. However, half of the patients required exclusive enteral nutritional support, making PEG-tube placement an alternative to consider.

Introdução: A neoplasia do esófago associa-se a disfagia e perda ponderal, sendo a desnutrição agravada pelo tratamento multimodal. Objetivo: Avaliar o impacto da colocação de gastrostomia percutânea endoscópica (PEG) no estado nutricional de doentes com neoplasia do esófago propostos para quimiorradioterapia (QRT). Métodos: Estudo comparativo com braço prospetivo e controlo retrospetivo. Incluídos doentes com neoplasia do esófago propostos para QRT definitiva ou neoadjuvante, com disfagia grau >2 e/ou perda de peso <10%. Colocada PEG (método pull) antes do início de QRT. Avaliada sementeira tumoral por zaragatoa e histologia. Como controlo, utilizada coorte histórica de doentes sem PEG. Registo ACTRN12616000697482. Resultados: 29 doentes (grupo intervenção, GI) foram comparados com 30 controlos (GC). Sem diferença significativa nos principais outcomes: perda de peso durante a QRT 8.1 ± 5.5 kg versus 9.1 ± 4.2 kg (p = 0.503); mortalidade aos 6 meses após QRT ou cirurgia 17.2% versus 26.7% (p = 0.383); taxa de complicações perioperatórias 54.5% versus 55.6% (p = 1.000); admissões hospitalares não planeadas 34.5% versus 40.0% (p = 0.661). No GC, durante a QRT, 14 (46.7%) apresentaram disfagia graus 3­4, dos quais 12 necessitaram de nutrição por sonda nasogástrica (n = 10), gastrostomia cirúrgica (n = 1) ou dilatação esofágica (n = 1). No GI, 89.7% utilizaram a PEG durante QRT, em algum momento de forma exclusiva em 51.7%. Os eventos adversos foram sobretudo minor (n = 12; 41.4%), sobretudo infeções tardias peri-estoma; 1 complicação major (laparotomia exploradora por suspeita de interposição de cólon, não confirmada). Sem evidência citológica ou histológica de sementeira tumoral no estoma. Conclusão: Embora não se tenham observado diferenças na perda de peso, complicações cirúrgicas e mortalidade entre grupos, metade dos utentes necessitou de nutrição entérica exclusiva, tornando a colocação de PEG uma alternativa a considerar.

How many biomarker measurements are needed to predict prognosis in Crohn's disease patients under infliximab?-A prospective study.

BACKGROUND: Timely stratification of Crohn's disease (CD) is essential for patients' management. The use of noninvasive accurate biomarkers is key to monitor treatment and to pursue mucosal healing, the ultimate treatment endpoint in CD. OBJECTIVE: We aimed to evaluate the performance of readily available biomarkers and develop risk matrices to predict CD progression. METHODS: Data from 289 CD patients receiving infliximab (IFX) maintenance therapy for 2 years was collected; those patients were included in DIRECT, a prospective multicenter observational study. Disease progression was evaluated using two composite outcomes incorporating clinical and drug-related factors, the first including IFX dose and/or frequency adjustments. Univariate and multivariable logistic regressions were used to calculate the odds ratios (OR) and to develop risk matrices. RESULTS: The isolated presence of anemia at least once during follow-up was a significant predictor of disease progression (OR 2.436 and 3.396 [p ≤ 0.001] for composite outcomes 1 and 2, respectively) regardless of confounding factors. Isolated highly elevated C-reactive protein (CRP; >10.0 mg/L) and fecal calprotectin (FC; >500.0 µg/g) in at least one visit were also significant predictors, while milder elevations (3.1-10.0 mg/L and 250.1-500.0 µg/g) were only relevant when detected in at least two visits (consecutive or not). The combination of biomarkers in risk matrices had good ability to predict progression; patients simultaneously presenting anemia, highly elevated CRP and FC at least once had 42%-63% probability of achieving the composite outcomes. CONCLUSION: The combined evaluation of hemoglobin, CRP, and FC in at least one time point and their incorporation into risk matrices seems to be the optimal strategy for CD management, as data from additional visits did not meaningfully influence the predictions and may delay decision-making.

Subclinical Persistent Inflammation as Risk Factor for Crohn's Disease Progression: Findings From a Prospective Real-World Study of 2 Years.

BACKGROUND AND AIMS: Subclinical intestinal inflammation is common in Crohn's disease (CD). We aimed to explore its impact in the disease progression of infliximab-treated patients and the usefulness of fecal calprotectin (FC) and C-reactive protein (CRP) as surrogate minimally invasive biomarkers. METHODS: The registry-based, prospective, observational, multicenter DIRECT (study to investigate the correlation of fecal calprotectin with serum Drug levels and development of an antI-dRug antibodiEs among adult patients with inflammatory bowel disease reCeiving anti-TNF-alfa treatment or vedoluzimab treatment) study followed infliximab-treated CD patients for 2 years in a tertiary care setting. Persistent inflammation definition was based on FC (>150 µg/g, >250 µg/g, or >350 µg/g) or serum CRP (>3 µg/mL) concentrations over 2 consecutive or at least 3 visits. Patients were categorized according to a composite outcome reflecting disease progression that incorporated surgery; hospitalizations; new fistulae, abscess, or stricture; and treatment escalation. RESULTS: Of 322 DIRECT study patients, 180 asymptomatic, infliximab treated on maintenance regimen were included in the analysis. Patients developing the composite endpoint (n = 96) presented higher median levels of FC (205 [interquartile range, 98-515] µg/g; P = .045) but not of CRP (2.50 [interquartile range, 0.80-6.00] µg/mL; P = .895). Biomarker-defined persistent subclinical inflammation prevalence ranged from 24% to 81%. Considering FC >250 µg/g in 2 consecutive visits, prevalence was 50%, odds of achieving the endpoint were increased 3-fold (odds ratio, 2.996 [95% confidence interval, 1.557-5.776]), and time-to-outcome occurrence was significantly lower among subjects with persistent inflammation (median time: 11 months). Both clinical-related and treatment-related components were significantly associated with persistent inflammation. Definitions based on CRP >3 µg/mL, FC >150 µg/g, FC >350 µg/g, double biomarkers (FC >250 µg/g and/or CRP >3 µg/mL), or more visits did not improve predictive ability. CONCLUSIONS: Persistent inflammation, defined simply and readily by FC >250 µg/g over 2 consecutive visits, was associated with a significantly higher risk and shorter time to occurrence of a composite outcome reflecting disease progression in asymptomatic infliximab-treated CD patients.

Real-Time Optical Diagnosis of Colorectal Polyps in the Routine Clinical Practice Using the NICE and WASP Classifications in a Nonacademic Setting.

BACKGROUND: Narrow-band imaging (NBI) allows "in vivo" classification of colorectal polyps. OBJECTIVES: We evaluated the optical diagnosis by nonexpert community-based endoscopists in routine clinical practice, the impact of training, and whether the endoscopists could achieve the threshold for the "do not resect" policy. METHODS: This was an observational study performed in two periods (P1 and P2). Endoscopists had no prior experience in NBI in P1 and applied the technique on a daily basis for 1 year before participation in P2. Lesions were classified by applying the NBI International Colorectal Endoscopic (NICE) and Workgroup serrAted polypS and Polyposis (WASP) classifications, simultaneously. RESULTS: A total of 290 polyps were analyzed. The overall accuracy of optical diagnosis was 0.75 (95% CI 0.68-0.81) in P1, with an increase to 0.82 (95% CI 0.73-0.89) in P2 (p = 0.260). The accuracy of the NICE/WASP classifications to differentiate adenomatous from nonadenomatous histology was 0.78 (95% CI 0.72-0.84) in P1 and 0.86 (95% CI 0.77-0.92) in P2 (p = 0.164); assignments made with a high confidence level achieved statistical significance (13% improvement, 95% CI 3-22%; p = 0.022). The negative predictive value for adenomatous histology of diminutive rectosigmoid polyps was 81% (95% CI 64-93%) and 80% (95% CI 59-93%) in P1 and P2, respectively. CONCLUSIONS: Nonexpert endoscopists achieved moderate accuracy for real-time optical diagnosis of colorectal lesions with the NICE/WASP classifications. The overall performance of the endoscopists improved after sustained use of optical diagnosis, but did not achieve the standards for the implementation of the "do not resect" strategy.

INTRODUÇÃO: O narrow-band imaging (NBI) permite a classificação "in-vivo" dos pólipos colo-rectais. OBJECTIVOS: Avaliámos o diagnóstico óptico na prática clínica diária em endoscopistas da comunidade, sem experiência prévia em NBI, o impacto do treino e se estes conseguiam atingir o limiar da estratégia de "não ressecar". MÉTODOS: Estudo observacional, realizado em dois períodos (P1 e P2). Os endoscopistas não apresentavam experiência prévia em NBI em P1 e aplicaram a técnica diariamente durante um ano antes da participação em P2. As lesões foram classificadas aplicando as classificações NBI International Colorectal Endoscopic (NICE) e Workgroup serrAted polypS and Polyposis (WASP), simultaneamente. RESULTADOS: Foram analisados 290 pólipos. A acuidade global do diagnóstico óptico foi de 0.75 (IC 95%, 0.68-0.81) em P1, aumentando para 0.82 (IC 95%, 0.73-0.89) em P2 (p = 0.260). A acuidade das classificações de NICE/WASP na diferenciação de histologia adenomatosa de não-adenomatosa foi de 0.78 (IC 95%, 0.72-0.84) em P1, e 0.86 (IC 95%, 0.77-0.92) em P2 (p = 0.164); as predições realizadas com alto grau de confiança alcançaram significado estatístico (melhoria de 13%, IC 95%, 3-22%; p = 0.022). O valor preditivo negativo para histologia adenomatosa dos pólipos diminutos recto-sigmóides foi de 81% (IC 95%, 64-93%) e 80% (IC 95%, 59-93%), em P1 e P2, respetivamente. CONCLUSÕES: Endoscopistas sem experiência em NBI alcançaram acuidade moderada no diagnóstico óptico em tempo real de lesões colo-rectais, utilizando as classificações de NICE/WASP. O desempenho global melhorou após a utilização contínua do diagnóstico óptico, mas não alcançou o limiar definido para a implementação da estratégia de "não ressecar".

Endoscopic Full-Thickness Resection of Colorectal Lesions with the New FTRD System: Single-Center Experience.

BACKGROUND AND AIMS: Endoscopic full-thickness resection (EFTR) is an emerging technique for the treatment of various conditions for which classic endoscopic resection techniques have failed or were considered to be at high risk for perforation. The full-thickness resection device (FTRD) is an over-the-scope system which allows a single-step EFTR. The aim of our study is to describe our experience in EFTR of colorectal lesions using the FTRD. METHODS: Nine patients (10 colorectal lesions) were proposed for EFTR. Safety, R0 resection and endoscopic treatment success were evaluated. RESULTS: Reasons for referral included nonlifting adenomas (n = 4), nonlifting adenoma recurrence (n = 5), and submucosal lesion (n = 1). EFTR was technically successful in all patients. The mean duration of the procedure was 55 min. R0 resection was obtained in all patients. No major complications were detected. All lesions were successfully treated by the endoscopic technique and no patient was referred for surgery. In patients with available follow-up (n = 6), no recurrence was detected. CONCLUSIONS: EFTR is a feasible, reasonable time-consuming, safe, and promising endoscopic resection technique. KEY MESSAGES: FTRD is an additional tool for difficult-to-treat colorectal lesions.

INTRODUÇÃO E OBJETIVOS: A ressecção endoscópica transmural (RET) é uma técnica promissora para o tratamento de várias lesões não passíveis de ressecção endoscópicapelas técnicas convencionais ou naquelas em que estes procedimentos apresentam elevado risco de complicações.O "full-thickness resection device" (FTRD) é um sistema pré-montado, que se acopla ao colonoscópio e que permite efetuar RET com um procedimento único. Pretende-se descrever a experiência do nosso centro na realização de RET com o FTRD. MÉTODOS: Nove doentes (10 lesões cólicas) foram propostos para RET. Foram avaliadas a segurança, ressecção R0 e taxa de sucesso do procedimento endoscópico. RESULTADOS: As indicações para o procedimento incluíram adenomas (n = 4), recidivas de adenomas (n = 5) sem elevação após injeção submucosa e lesão submucosa (n = 1). A RET foi tecnicamente bemsucedida em todos os doentes. A duração média dos procedimentos foi de 55 minutos. Ressecções R0 em todos os doentes. Não se registaram complicações major. Todas as lesões foram eficazmente tratadas com a ressecção endoscópica e nenhum doente foi proposto para cirurgia. Nos doentes já submetidos a exames de vigilância (n = 6) não foram detetadas recorrências. CONCLUSÕES: A RET é uma técnica exequível e segura para a terapêutica de lesões coloretais. MENSAGENS CHAVE: A RET parece ser uma promissora ferramenta adicional para manejo de lesões colo-rectais difíceis de tratar.

Evaluation of fatigue in inflammatory bowel disease - a useful tool in daily practice.

Background: Fatigue is a common symptom reported in inflammatory bowel disease (IBD) patients. It can be severe and modify the self-perception of disease. Objective: To evaluate the contribution of clinical and demographic factors to the level of fatigue in IBD patients. Methods: Patients consecutively observed in an outpatient IBD clinic during a 9-month period were studied. Demographic and clinical data were collected. Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). A FACIT-F score <30 was considered as severe fatigue. Results: One hundred and five patients were evaluated. Of them, 57.1% had Crohn´s Disease (CD) and 42.9% had Ulcerative Colitis. Also 85.0% and 77.8% were in clinical remission, respectively. The mean FACIT-F score was 39.63 ± 9.67. Severe fatigue was observed in 17.1% of patients. Female gender and active CD were significantly associated with a severe level of fatigue (p = .05 and p = .04). There was no significant correlation between the level of fatigue (severe vs. non-severe) and type of IBD, hemoglobin, C-reactive protein, ferritin levels or previous surgeries. Patients under biological therapy had a significantly higher level of fatigue and a higher rate of previous hospitalizations (p = .02). Conclusions: Fatigue level is a simple and useful tool to evaluate the disease's impact in patients' life, and it should, therefore, be included in clinical practice. Biological therapy was associated to higher levels of fatigue. Future studies should evaluate the impact of therapy on the level of fatigue.

Buried Barrett's Esophagus with High-Grade Dysplasia after Radiofrequency Ablation.

Radiofrequency ablation therapy is an effective endoscopic option for the eradication of Barrett's esophagus that appears to reduce the risk of esophageal cancer. A concern associated with this technique is the development of subsquamous/buried intestinal metaplasia, whose clinical relevance and malignant potential have not yet been fully elucidated. Fewer than 20 cases of subsquamous neoplasia after the successful radiofrequency ablation of Barrett's esophagus have been reported to date. Here, we describe a new case of subsquamous neoplasia (high-grade dysplasia) following radiofrequency ablation that was managed with endoscopic resection. Our experience suggests that a meticulous endoscopic inspection prior to and after radiofrequency ablation is fundamental to reduce the risk of buried neoplasia development.