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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 the majority of its 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. [ABSTRACT FROM AUTHOR]

Background Early biologic therapy within the first 18–24 months after diagnosis is associated with improved clinical outcomes in Crohn's disease [CD]. However, the definition of the best time to initiate biologic therapy remains unclear. We aimed to assess if there is an optimal timing for early biologic therapy initiation. Methods This was a multicentre retrospective cohort study including newly diagnosed CD patients who started anti-tumour necrosis factor [TNF] therapy within 24 months from diagnosis. The timing of initiation of biologic therapy was categorised as ≤6, 7–12, 13–18, and 19–24 months. The primary outcome was CD-related complications defined as a composite of progression of Montreal disease behaviour, CD-related hospitalisations, or CD-related intestinal surgeries. Secondary outcomes included clinical, laboratory, endoscopic, and transmural remission. Results We included 141 patients where 54%, 26%, 11%, and 9% started biologic therapy at ≤6, 7–12, 13–18, and 19–24 months after diagnosis, respectively. A total of 34 patients [24%] reached the primary outcome: 8% had progression of disease behaviour, 15% were hospitalised, and 9% required surgery. There was no difference in the time to a CD-related complication according to the time of initiation of biologic therapy within the first 24 months. Clinical, endoscopic, and transmural remission was achieved in 85%, 50%, and 29%, respectively, but no differences were found according to the time of initiation of biologic therapy. Conclusion Starting anti-TNF therapy within the first 24 months after diagnosis was associated with a low rate of CD-related complications and high rates of clinical and endoscopic remission, although we found no differences with earlier initiation within this window of opportunity. [ABSTRACT FROM AUTHOR]

Background and Aims Interest in histology for ulcerative colitis [UC] has increased recently. This systematic review and meta-analysis aims to assess, for the first time, whether histological outcomes are more informative than endoscopic and clinical outcomes in distinguishing the impact of intervention over placebo in induction trials. Methods MEDLINE, ScienceDirect and Cochrane Central Register of Controlled Trials were searched to identify randomized placebo-controlled trials [RCTs] enrolling moderate-to-severe UC patients. Studies were assessed using the Quality Assessment Tool for Studies with Diverse Designs. We analysed the pooled proportion of patients achieving clinical, endoscopic and histological remission and response after a pharmacological intervention and compared the results with those of placebo-treated patients by using a random-effects model. Results From 889 identified records, 13 RCTs were included. The odds ratio [OR] for remission was higher in patients receiving intervention than in those under placebo for clinical (OR 2.13, 95% confidence interval [CI] 1.33–3.43), endoscopic [OR 1.46, 95% CI 0.19–11.18] and histological remission [OR 1.85, 95% CI 1.20–2.84]. Significant differences were observed for all response outcomes [clinical: OR 2.27, 95% CI 1.84–2.85; endoscopic: OR 2.16, 95% CI 1.51–3.10; histological: OR 3.63, 95% CI, 1.41–9.36]. No significant heterogeneity existed; no subgroup effects were found for duration of the induction or histological scale [ p  > 0.05]. Clinical and histological remission and endoscopic response were concordant in discriminating interventions from placebo. Conclusion Histological outcomes are informative in trials of moderate-to-severe UC. Further studies analysing histology at the end of induction are needed to confirm its relevance in distinguishing the efficacy of an intervention over placebo in comparison to clinical and endoscopic outcomes and to explore its prognostic value. [ABSTRACT FROM AUTHOR]

Background Ulcerative colitis [UC] is a chronic inflammatory disease often accompanied by severe and distressing symptoms that, in some patients, might require a surgical intervention [colectomy]. This study aimed at determining the risk of experiencing progressive disease or requiring colectomy. Material and Methods This was a multicentre study: patients' data [ n = 1481] were retrieved from the Portuguese database of inflammatory bowel disease patients. Bayesian networks and logistic regression were used to build risk matrices concerning the outcomes of interest. Results The derivation cohort included a total of 1210 patients, of whom 6% required a colectomy and 37% had progressive disease [over a median follow-up period of 12 syears]. The risk matrices show that previously hospitalised patients with extensive disease, who are not on immunomodulators and who are refractory to corticosteroid treatment, are the ones at the highest risk of undergoing a colectomy [88%]; whereas male patients, with extensive disease and less than 40 years old at diagnosis, are the ones at the highest risk of experiencing progressive disease [72%]. These results were internally and externally validated, and the AUC [area under the curve] of the ROC [receiver operating characteristic] analysis for the derivation cohort yielded a high discriminative power [92% for colectomy and 72% for progressive disease]. Conclusions This study allowed the construction of risk matrices that can be used to accurately predict a UC patient's likelihood of requiring a colectomy or of facing progressive disease, and can be used to individualise therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background and Aims: Steroid-dependency occurs in up to 30% of patients with ulcerative colitis [UC]. In this setting, few drugs have demonstrated efficacy in inducing steroid-free remission. The aim of this study was to evaluate the efficacy and safety of adding granulocyte/monocyte apheresis [GMA] to oral prednisone in patients with steroid-dependent UC. Methods: This was a randomized, multicentre, open trial comparing 7 weekly sessions of GMA plus oral prednisone [40 mg/day and tapering] with prednisone alone, in patients with active, steroid-dependent UC [Mayo score 4-10 and inability to withdraw corticosteroids in 3 months or relapse within the first 3 months after discontinuation]. Patients were stratified by concomitant use of thiopurines at inclusion. A 9-week tapering schedule of prednisone was pre-established in both study groups. The primary endpoint was steroid-free remission [defined as a total Mayo score ≤2, with no subscore >1] at Week 24, with no re-introduction of corticosteroids. Results: In all 123 patients were included [63 GMA group, 62 prednisone alone]. In the intentionto-treat analysis, steroid-free remission at Week 24 was achieved in 13% (95% confidence interval [CI] 6-24) in the GMA group and 7% [95% CI 2-16] in the control group [p = 0.11]. In the GMA group, time to relapse was significantly longer (hazard ratio [HR] 1.7 [1.16-2.48], P = 0.005) and steroidrelated adverse events were significantly lower [6% vs 20%, P < 0.05]. Conclusions: In a randomized trial, the addition of 7 weekly sessions of GMA to a conventional course of oral prednisone did not increase the proportion of steroid-free remissions in patients with active steroid-dependent UC, though it delayed clinical relapse. [ABSTRACT FROM AUTHOR]

This paper is the second in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease [CD] and concerns the surgical management of CD as well as special situations including management of perianal CD and extraintestinal manifestations. Diagnostic approaches and medical management of CD of this ECCO Consensus are covered in the first paper [Gomollon et al. JCC 2016]. [ABSTRACT FROM AUTHOR]

Background and Aims: Histological healing has emerged as a promising therapeutic goal in ulcerative colitis. This is especially important in the context of biological therapies. The objectives of the present study were to investigate the ability of infliximab to induce histological remission in ulcerative colitis [UC] patients and to explore the utility of faecal calprotectin and lactoferrin in predicting histological activity. Methods: Multi-centre, single-cohort, open-label, 52-week trial including moderately to severely biological-naïve UC patients receiving intravenous infliximab [5 mg/kg]. The primary outcome was the proportion of patients with histological remission [Geboes index ≤ 3.0] after 8 weeks of treatment, scored by two independent pathologists. Results: Twenty patients were included. The rate of histological remission increased from 5% at baseline to 15% and 35% at Week 8 and Week 52, respectively. At Week 8, 40% of patients were in clinical remission [Mayo ≤ 2] and 45% achieved mucosal healing [Mayo endoscopy subscore 0–1]. At Week 52, 25% of patients had clinical, endoscopic and histological remission. Faecal calprotectin and lactoferrin showed the highest correlation with histological activity at Week 8 (area under the curve [AUC] 94%, p = 0.017; and 96%, p = 0.013, respectively) and both markers revealed an excellent positive predictive value for this outcome at this time point [100%, p = 0.017; and 94%, p = 0.013, respectively]. Conclusions: Infliximab was able to induce histological remission. There was a good agreement between histology and faecal biomarkers. Faecal calprotectin and lactoferrin were good predictors of histological remission. Our data support inclusion of histology as a treatment target complementary to endoscopy in clinical trials when evaluating therapeutic response in UC. [ABSTRACT FROM AUTHOR]

Abstract: Contemplating the multifactorial nature of Crohn''s disease (CD), the purpose of this study was to compare two neighbouring CD populations from different nations and examine how clinical characteristics of patients can influence therapeutic strategies and consequently different surgical events in routine clinical practice. Cross-sectional study based on data of an on-line registry of patients with CD in northern Portugal and Galicia. Of the 1238 patients, all with five or more years of disease, 568 (46%) were male and 670 (54%) female. The Portuguese and Galician populations were similar regarding Montreal categories, age at diagnosis, and years of follow-up. Galician B2 patients were associated with immunosuppression (OR 3.6; CI 2.2–6.1) and biologic treatment (OR 1.8; CI 1.0–3.1). In both populations ileocolonic disease was associated with immunosuppression and biologic treatment and the penetrating group was linked to immunosuppression. In the north of Portugal 47% and 16% of patients, and in Galicia 63% and 33%, were treated with immunosuppressants and biologic treatment, respectively. In the north of Portugal 44% of patients classified as stricturing behavior were operated without immunomodulation, in contrast to 12% in Galicia. In the latter it was possible to maintain 16% of B2 patients and 40% of B3 patients without surgery with adequate immunosuppression and/or biologic treatment. The delta of surgeries in B2 patients was 8% and in B3 26%. Conclusions: Stratifying patients according to the Montreal classification identified similar clinical patterns in disparate geographic populations, and revealed that differing medical therapeutic practices may influence the occurrence of surgical events. [Copyright &y& Elsevier]