Comparative effectiveness of higher adalimumab maintenance therapy versus standard dose in anti-tumor necrosis factor experienced Crohn's disease patients: A propensity-score matched cohort analysis.

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.

Detection of Small Bowel Mucosal Healing and Deep Remission in Patients With Known Small Bowel Crohn's Disease Using Biomarkers, Capsule Endoscopy, and Imaging.

OBJECTIVES: Mucosal healing (MH) and deep remission (DR) are associated with improved outcomes in Crohn's disease (CD). However, most of the current data pertain to colonic MH and DR, whereas the evidence regarding the prevalence and impact of small bowel (SB) MH is scarce. The aim of this study was to to evaluate the prevalence of SBMH and DR in quiescent SBCD. METHODS: Patients with known SBCD in clinical remission (CDAI<150) or with mild symptoms (CDAI<220) were prospectively recruited and underwent video capsule endoscopy after verification of SB patency. Inflammation was quantified using the Lewis score (LS). SBMH was defined as LS<135, whereas a significant inflammation was defined as LS>790. Clinico-biomarker remission was defined as a combination of clinical remission and normal biomarkers. DR was defined as a combination of clinico-biomarker remission and MH. RESULTS: Fifty-six patients with proven SB patency were enrolled; 52 (92.9%) patients were in clinical remission and 21 (40.4%) in clinico-biomarker remission. SBMH was demonstrated in 8/52 (15.4%) of patients in clinical remission. Moderate-to-severe SB inflammation was demonstrated in 11/52 (21.1%) of patients in clinical remission and in 1/21 (4.7%) of patients in clinical and biomarker remission. Only 7/52 (13.5%) patients were in DR. CONCLUSIONS: SB inflammation is detected in the majority of CD patients in clinical and biomarker remission. SBMH and DR were rare and were independent of treatment modality. Our findings represent the true inflammatory burden in quiescent patients with SBCD.

Clinical Outcomes of Surgery Versus Endoscopic Balloon Dilation for Stricturing Crohn's Disease.

BACKGROUND: Endoscopic balloon dilation and surgery are commonly practiced in stricturing Crohn's disease. Nonetheless, there are still scant data directly comparing these 2 strategies. OBJECTIVE: The aim of this study was to compare the short- and long-term outcomes of endoscopic balloon dilation versus surgical resection in symptomatic Crohn's strictures. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at a single tertiary center. PATIENTS: Seventy-nine patients were identified, 40 in the surgical group and 39 in the endoscopic balloon dilation group (mean age 42.8 ± 13.9 versus 38.5 ± 12.2 years). MAIN OUTCOME MEASURES: The outcomes of all patients referred for endoscopic balloon dilation were compared with patients referred to surgery because of stricturing disease between the years 2006 and 2013. The primary outcome was the need for reintervention (either endoscopic balloon dilation or surgery) for symptomatic Crohn's disease during follow-up. RESULTS: The proportion of patients who required any reintervention during follow-up was significantly lower in the surgical group versus the endoscopic balloon dilation group (OR = 5.62 (95% CI, 1.66-19.01); p = 0.005). The need for surgery/resurgery during follow-up was also significantly lower in the surgically treated group (OR = 3.53 (95% CI, 1.01-12.29); p = 0.047). Reintervention-free survival and surgery-free survival were both significantly shorter in the endoscopically treated group in a Kaplan-Mayer analysis. The rate of major complications was similar in the endoscopically and surgically treated groups (7.6% versus 7.5%; p = 0.7). LIMITATIONS: The small cohort and the retrospective data collection were limitations of this study. CONCLUSIONS: In our cohort of patients with fibrostenotic Crohn's disease, a direct comparison showed reduced need for reinterventions with a similar rate of immediate major complications after surgery compared with endoscopic balloon dilation.

Pancreatobiliary manifestations of nonalcoholic fatty liver disease: a retrospective case-control multicenter study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become a major cause of chronic liver disease. Several extrahepatic manifestations have been reported in relation to NAFLD. However, data regarding pancreatobiliary manifestation are scarce. AIM: We aimed to explore the association of pancreatobiliary manifestation with NAFLD. METHODS: A retrospective multicenter study that included all patients who underwent an endoscopic ultrasound performed for hepatobiliary indications and for whom the endosonographer reported on the presence or absence of fatty liver. The endoscopic ultrasound reports were reviewed and all pathological findings were reported. RESULTS: Overall, 545 patients were included in the study, among them, 278 patients had fatty liver (group A) as compared to 267 who did not have (group B). The average age in group A was 64.5 ± 13.5 years vs. 61.2 ± 14.7 years in group B. Male sex constituted 49.6 and 58% in groups A and B, respectively. On multivariate analysis, fatty pancreas [odds ratio (OR) 4.02; P = 0.001], serous cystadenoma (SCA) (OR 5.1; P = 0.0009), mucinous cystadenoma (MCA) (OR 9.7; P = 0.005), side-branch intraductal papillary mucinous neoplasm (IPMN) (OR 2.76; P < 0.0001), mixed-type IPMN (OR 16.4; P = 0.0004), pancreatic neuroendocrine tumor (NET) (OR 8.76; P < 0.0001), gallbladder stones (OR 1.9; P = 0.02) and hilar lymphadenopathy (OR 6.8; P < 0.0001) were significantly higher among patients with NAFLD. After adjustment for fatty pancreas, the association remained significant for SCA (OR 3; P = 0.01), MCA (OR 4.6; P = 0.03), side-branch IPMN (OR 1.7; P = 0.02), mixed-type IPMN (OR 5.5; P = 0.01) and pancreatic NET (OR 4.5; P = 0.001). CONCLUSION: Pancreatobiliary manifestations are common among patients with NAFLD. Assessment of these coexistent manifestations should be considered in the setting of patients with NAFLD.

Pancreatic and hepatobiliary manifestations of nonalcoholic fatty pancreatic disease: a referral multi-center experience.

BACKGROUND: Nonalcoholic fatty pancreatic disease (NAFPD) is an increasingly recognized disease with accumulating evidence of associated co-morbidities. However, data linked with other pancreatic and hepatobiliary disorders are still being studied. AIMS: To investigate the association of pancreato-hepato-biliary disorders with NAFPD. METHODS: At two Israeli medical centers, a total of 569 patients were analyzed who underwent endoscopic ultrasound for hepatobiliary indications. They were divided into groups depending on the presence or absence of NAFPD. RESULTS: Seventy-eight patients (13.7%) had NAFPD (NAFPD group) vs. 491 patients (86.3%) without (non-NAFPD group). NAFPD was significantly associated with obesity [odds ratio (OR) 4.98, 95% confidence interval (CI) 3.02-8.24, P < 0.0001], hypertension (OR 2.55, 95% CI 1.57-4.15, P = 0.0002), active smoking (OR 2.02, 95% CI 1.04-3.93, P = 0.03), and hyperlipidemia (OR 2.86, 95% CI 1.58-5.18, P = 0.0005). On multivariate regression analysis: fatty liver (OR 5.49, 95% CI 2.88-10.49, P < 0.0001), main duct intraductal papillary mucinous neoplasm (M-IPMN) (OR 2.69, 95% CI 1.05-6.9, P = 0.04), and gallstones (OR 1.93, 95% CI 1.1-3.38, P = 0.02) were the most endoscopically and ultrasonographically detected diseases that significantly correlated with NAFPD. CONCLUSION: NAFPD was associated with several diseases, most importantly the premalignant M-IPMN. Further investigation for these coexisting diseases should be considered.

Higher adalimumab maintenance regimen is more effective than standard dose in anti-TNF experienced Crohn's disease patients.

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.

Early Changes in Serum Albumin Predict Clinical and Endoscopic Outcomes in Patients With Ulcerative Colitis Starting Anti-TNF Treatment.

BACKGROUND: Up to 60% of patients with ulcerative colitis (UC) ultimately fail anti-tumor necrosis factor (TNF) treatment. We aimed to investigate early predictive markers of clinical and endoscopic outcomes in patients with UC who were anti-TNF-naïve commencing anti-TNF treatment, with particular focus on changes in albumin and C-reactive protein levels in the first 2 weeks of treatment. METHODS: We retrospectively investigated 210 patients with UC who started infliximab or adalimumab between 2009 and 2016 (male, 62.4%; median age at diagnosis, 37.9 years [interquartile range, 25.5-48.9 years]; median follow-up duration, 3.3 years [1.9-5.0 years]). Logistic and Cox proportional-hazards regressions were performed to identify variables associated with primary nonresponse (PNR), endoscopic outcomes, time-to-colectomy, and anti-TNF failure. RESULTS: Forty-one patients (19.5%) experienced PNR; week 0/week 2 ratio serum albumin was associated with PNR (adjusted odds ratio [aOR], 1.8; 95% confidence interval [CI], 1.1-2.9, per interquartile range increase). Week 0/week 2 ratio albumin was also associated with endoscopic response (aOR, 0.28; 95% CI, 0.31-0.82) and endoscopic remission (aOR, 0.61; 95% CI, 0.39-0.96) at weeks 8 to 14, time-to-colectomy (adjusted hazard ratio, 2.12; 95% CI, 1.29-3.49) and time-to-anti-TNF failure (adjusted hazard ratio, 1.54; 95% CI, 1.22-1.96), regardless of age, disease severity, or in-patient status. Association with time-to-colectomy and anti-TNF failure was externally validated in an independent cohort of inpatients with UC starting infliximab. CONCLUSIONS: Change in serum albumin within the first 2 weeks of anti-TNF treatment is predictive of PNR, endoscopic outcomes, time-to-colectomy, and anti-TNF failure in patients with UC. Timely access to this biomarker enables early identification of patients with UC at risk of anti-TNF failure and may guide early optimization of anti-TNF treatment to improve disease outcomes.

Identification of Target Golimumab Levels in Maintenance Therapy of Crohn's Disease and Ulcerative Colitis Associated With Mucosal Healing.

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.

The Unfinished Symphony: Golimumab Therapy for Anti-Tumour Necrosis Factor Refractory Crohn's Disease.

BACKGROUND AND AIMS: Golimumab is approved for the treatment of moderate-to-severely active ulcerative colitis. However, there have been no formal trials to assess its utility in Crohn's disease [CD]. Our aim was to determine the efficacy and safety of golimumab in patients with anti-tumour necrosis factor [TNF] refractory CD. METHODS: Patients with CD treated with golimumab between 2010 and 2017 were included in a retrospective observational study. The vast majority of patients failed two anti-TNF agents. Clinical response was defined as a significant reduction in symptoms and biochemical markers of CD, and no requirement for surgery or introduction of immune-suppressants. RESULTS: Forty-five patients were included, with a median follow-up of 22 months [interquartile range 12-34] following initiation of golimumab. Induction and maintenance regimens were generally higher than standard dosing with first month cumulative doses of 400 mg and above in 75% of the patients. Monthly maintenance doses ≥200 mg were administered in 52% of patients. Clinical response at 3 months was achieved in 35/45 [77.7%] patients. The cumulative probabilities that patients with an initial response maintained their clinical response for 12 and 36 months after introduction of golimumab were 81% and 64%, respectively. Endoscopic improvement and mucosal healing at 12 months was achieved in 73% and 47% of patients, respectively. CONCLUSIONS: This study demonstrates the efficacy of golimumab in anti-TNF refractory CD patients. Further studies should be performed in CD to formally assess the efficacy of golimumab in a randomized controlled trial and to establish the optimal dosing regimen.

Higher Infliximab Levels Are Not Associated With an Increase in Adverse Events in Inflammatory Bowel Disease.

Background: Patients requiring optimization of therapy for suboptimal response and/or targeting more robust outcomes may eventually reach high serum levels. Data evaluating the relationship between infliximab concentration and toxicity are limited. The aim of this study was to evaluate the frequency of adverse events (AEs) in inflammatory bowel disease (IBD) patients with infliximab higher-range (HR) and lower-range (LR) trough levels. Methods: We performed a retrospective analysis of 180 patients with at least 1 measurement of serum infliximab from 2012 to 2016. The cohort was divided according to an infliximab level cutoff of 15 µg/mL (HR and LR). The primary outcome was frequency of AEs, including infections, dermatological manifestations, and infusion reactions, between the 2 groups. The secondary outcomes included frequencies of all AEs (dermatological manifestations, infusion reactions, autoimmune reactions, and opportunistic and serious infections) in both groups. AEs were also compared against observed infliximab level quartiles using logistic regression analysis. Results: A total of 53 AEs in 47 patients were reported in the overall cohort. In the LR group, there were 36 AEs recorded in 30 patients, whereas in the HR group, 17 AEs were experienced by 17 patients. Patients with HR levels did not have a higher prevalence of infections in comparison with patients with LR levels (12.2% vs 18.8%; P = 0.3). Stratification of infliximab levels by quartiles showed a comparable frequency of infection. Conclusions: Our findings indicate that higher infliximab serum concentrations are not associated with a higher frequency of infections.

Diffusion-weighted magnetic resonance enterography for prediction of response to tumor necrosis factor inhibitors in stricturing Crohn's disease.

BACKGROUND AND AIMS: Distinguishing between fibrotic and inflammatory strictures in Crohn's disease (CD) is still challenging. The capacity of diffusion-weighted (DWI) magnetic resonance (MRE) to identify intestinal fibrosis was recently demonstrated; however, the therapeutic implications of this association have never been evaluated. The aim of the current study was to identify imaging features, including DWI, which can predict response to anti-inflammatory treatment in patients with stricturing CD. METHODS: Consecutive CD patients with intestinal strictures that initiated treatment with anti-tumor necrosis alpha (anti-TNF) between June 2012 and April 2017 with MRE adjacent to treatment onset were retrospectively collected. The primary outcome was treatment failure, defined as drug discontinuation, CD-related surgery, or endoscopic dilatation of the stricture. Clinical, demographic, and imaging data were compared between patients who did and did not develop treatment failure within 12 months of anti-TNF treatment initiation. RESULTS: A total of 21 patients were included in the study; 9/21 (42.8%) developed treatment failure. None of the clinical/demographic parameters were associated with the risk of treatment failure. Among imaging parameters, only ADC value (< 1 × 10-3 mm2/s) was significantly associated with the risk of treatment failure (AUC = 0.81, 66% vs. 0%, p = 0.015). CONCLUSIONS: Our results suggest that ADC value on DWI MRE may predict the risk of treatment failure in stricturing CD. If replicated in larger studies, these results may guide therapeutic decisions and suggest avoiding anti-TNF treatment.

The Impact of Magnetic Resonance Enterography and Capsule Endoscopy on the Re-classification of Disease in Patients with Known Crohn's Disease: A Prospective Israeli IBD Research Nucleus (IIRN) Study.

BACKGROUND AND AIMS: The classification of Crohn's disease (CD) is usually determined at initial diagnosis and is frequently based on ileocolonoscopic and cross-sectional imaging data. Advanced endoscopic and imaging techniques such as small-bowel video capsule endoscopy (VCE) and magnetic resonance enterography (MRE) may provide additional data regarding disease extent and phenotype. Our aim was to examine whether VCE or MRE performed after the initial diagnosis may alter the original disease classification. METHODS: Consecutive patients with known small-bowel CD in clinical remission or mild disease were prospectively recruited and underwent MRE and VCE (if small-bowel patency was confirmed by a patency capsule (PC). Montreal classifications before and after evaluation were compared. RESULTS: Seventy-nine patients underwent MRE and VCE was performed in 56. Previously unrecognized disease locations were detected with VCE and MRE in 51 and 25%, respectively (p < 0.01) and by both modalities combined in 44 patients (55%). Twenty-two patients (27%) were reclassified as having an advanced phenotype (B2/B3). MRE and VCE reclassified the phenotype in 26 and 11% of cases, respectively (p < 0.05). Overall, both modalities combined altered the original Montreal classification in 49/76 patients (64%). CONCLUSION: VCE and MRE may lead to reclassification of the original phenotype in a significant percentage of CD patients in remission. VCE was more sensitive for detection of previously unrecognized locations, while MRE was superior for detection of phenotype shift. The described changes in the disease classification may have an important impact on both clinical management and long-term prognosis in these patients.

Magnetic resonance enterography versus capsule endoscopy activity indices for quantification of small bowel inflammation in Crohn's disease.

BACKGROUND: Video capsule endoscopy (VCE) and magnetic resonance enterography (MRE) are the prime modalities for the evaluation of small bowel (SB) Crohn's disease (CD). Mucosal inflammation on VCE is quantified using the Lewis score (LS). Diffusion-weighted (DW) magnetic resonance imaging (MRI) allows for accurate assessment of SB inflammation without administration of intravenous contrast material. The Magnetic Resonance Index of Activity (MaRiA) and the Clermont index are quantitative activity indices validated for contrast-enhanced MRE and DW-MRE, respectively. The aim of this study was to compare the quantification of distal SB inflammation by VCE and MR-related activity indices. METHODS: Patients with known quiescent SB CD were prospectively recruited and underwent MRE and VCE. LS, MaRIA and Clermont scores were calculated for the distal SB. RESULTS: Both MRI-based indices significantly correlated with the LS and the Clermont index (r = 0.50, p = 0.001 and r = 0.53, p = 0.001, respectively). Both MaRIA and Clermont scores were significantly lower in patients with mucosal healing (LS < 135). The area under the curve (AUC) with both MR scores was moderate for prediction of any mucosal inflammation (LS ⩾ 135) and excellent for prediction of moderate-to-severe inflammation (LS ⩾ 790) (0.71 and 0.74 versus 0.93 and 0.91 for MaRIA and Clermont score, respectively). CONCLUSIONS: Modest correlation between VCE- and MRE-based quantitative indices of inflammation in patients with quiescent SB CD was observed. Between-modality correlation was higher in patients with endoscopically severe disease. DW-MRE gauged by Clermont score was at least as accurate as contrast-enhanced MRE for quantification of SB inflammation.