[Show abstract][Hide abstract] ABSTRACT: Background:
Reliable tools for patient selection are critical for clinical drug trials.
To evaluate a consensus-based, standardised magnetic resonance enterography (MRE) protocol for selecting patients for inclusion in Crohn's disease (CD) multicenter clinical trials.
This study recruited 20 patients [Crohn's Disease Activity Index (CDAI) scores: <150 (n = 8); 150-220 (n = 4); 220-450 (n = 8)], to undergo ileocolonoscopy and two MREs (with and without colonic contrast) within a 14-day period. Procedures were scored centrally using, Magnetic Resonance Index of Activity (MaRIA), and both Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simplified Endoscopic Score (SES-CD).
37 MREs were acquired. Both MREs were evaluable in 16 patients for calculation of test-retest and inter-reader reliability scores. The MaRIA scores for the terminal ileum had excellent test-retest and inter-reader reliability, with correlations >0.9. The proximal ileum showed strong within-reader agreement (0.90-0.96), and fair between-reader agreement (0.59-0.72). MRE procedures were tolerable. MaRIA scores correlated with CDEIS and SES-CD (0.63 and 0.71), but not with CDAI (0.34). MRE identified 3 patients with intra-abdominal complications, who would otherwise have been included in clinical trials. Furthermore, both MRE and ileocolonoscopy identified active bowel wall inflammation in 2 patients with CDAI <150, and none in 1 patient with CDAI > 220. Data quality was good/excellent in 85% of scans, and fair or better in 96%.
Magnetic resonance enterography of high-quality and reproducibility was feasible in a global multi- centre setting, with evidence for improved selectivity over CDAI and ileocolonoscopy in identifying appropriate CD patients for inclusion in therapeutic intervention trials.
[Show abstract][Hide abstract] ABSTRACT: Ulcerative colitis (UC) is a chronic intestinal inflammatory disease that may undergo periods of activity followed by remission. We aimed to identify the endogenous regulatory mechanisms that may promote disease remission. Transcriptional and protein analysis of the intestinal mucosa revealed that the IL-1 decoy receptor, interleukin-1 receptor type 2 (IL1R2), was upregulated in remission compared with active UC and controls. We identified epithelial cells as being responsible for increased IL-1R2 production during remission. Expression of IL1R2 was negatively regulated by Wnt/beta-catenin signals in colonic crypts or epithelial stem cell cultures; accordingly, epithelial stem cells upregulated IL-1R2 upon differentiation. Blocking IL-1R2 in isolated colonic crypt cultures of UC patients in remission and T-cell cultures stimulated with biopsy supernatant from UC patients in remission boosted IL-1β-dependent production of inflammation-related cytokines. Finally, IL1R2 transcription was significantly lower in patients that relapsed during a 1-year follow-up period compared with those in endoscopic remission. Collectively, our results reveal that the IL-1/IL-1R2 axis is differentially regulated in the remitting intestinal mucosa of UC patients. We hypothesize that IL-1R2 in the presence of low concentrations of IL-1β may act locally as a regulator of intestinal homeostasis.Mucosal Immunology advance online publication 4 November 2015. doi:10.1038/mi.2015.108.
[Show abstract][Hide abstract] ABSTRACT: The introduction of biologic drugs represents the most significant advance in the management of immune-mediated inflammatory diseases for a decade. However, complex proteins are expensive to produce and manufacture. Biosimilar versions of established biologics are becoming available as another version of the reference medicinal product and are expected to provide substantial cost savings. However, because of their complexity, the approval of biosimilars requires strict controls to ensure that all therapeutically relevant characteristics are comparable to the reference medicinal product. This review summarizes the scientific principles and data requirements underpinning regulatory approval of biosimilars and the assumptions that enable extrapolation of data between indications. These important concepts are exemplified by CT-P13 (Remsima(®), Inflectra(®)), the first biosimilar monoclonal antibody approved in Europe.
[Show abstract][Hide abstract] ABSTRACT: Background & aims:
Accurate biomarkers of disease activity and therapeutic response can be valuable for clinical trials. We performed a post-hoc analysis of data from a Phase 2 trial to assess the relationship between concentration of fecal calprotectin (FCP) and clinical and endoscopic outcomes of patients with moderate to severe ulcerative colitis receiving tofacitinib.
In a double-blind, placebo-controlled, phase 2 trial, 194 patients were randomly assigned to groups given tofacitinib (0.5, 3, 10, or 15 mg twice daily) or placebo. Clinical and endoscopic outcomes were assessed at week 8 using the Mayo scoring system. Receiver operating characteristics (ROC) were used to evaluate the relationships between FCP concentration and clinical and endoscopic outcomes, and to determine the FCP cutoff concentration that correlated with patient outcome.
Week 8 median concentrations of FCP were significantly lower in responders than non-responders (P<.001): clinical response, 156 mg/kg vs 725 mg/kg; clinical remission, 64 mg/kg vs 617 mg/kg; endoscopic remission, 44 mg/kg vs 489 mg/kg; and mucosal healing, 127 mg/kg vs 753 mg/kg. Area-under-the-curve values for FCP ROC models were 0.80 for clinical remission, 0.81 for endoscopic remission, and 0.78 for mucosal healing. An FCP cutoff of 150 mg/kg achieved the highest summation of sensitivity and specificity for clinical remission (0.68 and 0.79; κ coefficient, 0.44) and endoscopic remission (0.79 and 0.75; κ coefficient, 0.38).
Concentrations of FCP correlate with clinical and endoscopic outcomes of patients with moderate to severe ulcerative colitis receiving tofacitinib, although at an individual level, agreement was moderate. FCP concentration with a cutoff of 150 mg/kg had only fair to good accuracy in classifying clinical and endoscopic outcomes in a clinical trial. (ClinicalTrials.gov no: NCT00787202.).
[Show abstract][Hide abstract] ABSTRACT: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process.
A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely).
The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target.
Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.Am J Gastroenterol advance online publication, 25 August 2015; doi:10.1038/ajg.2015.233.
The American Journal of Gastroenterology 08/2015; 110(9). DOI:10.1038/ajg.2015.233 · 10.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and aims:
Ex-vivo generated autologous tolerogenic dendritic cells (tolDCs) can restore immune tolerance in experimental colitis. The aim of this study was to determine the safety and tolerability of administration of autologous tolDCs in refratory Crohn's disease (CD) patients.
A phase-I, single-center, sequential-cohorts, dose-range study was designed. Stable tolDCs were generated ex-vivo from monocytes following a previously developed protocol and administered by sonography-guided intraperitoneal injection. Six sequential refractory-CD-cohorts were established: the first 3 cohorts received a single intraperitoneal injection of tolDCs at escalating doses (2x10(6)/5x10(6)/10x10(6)) and the last 3 cohorts, three biweekly intraperitoneal injections at same escalating doses. Safety was sequentially evaluated. Patients were assessed from week 0 to 12 and followed up for 1-year period for safety.
Nine patients were included. No adverse effects were detected during tolDCs injection and follow-up. Three patients withdrew the study due to CD worsening. Clinical activity (CDAI) decreased from 274(60) (mean[SD]) to 222(113) (p=0.3): 1 (11%) patient reached clinical remission (CDAI<150) and 2 (22%) clinical response (CDAI decrease≥100). Endoscopic activity (CDEIS) decreased from 18(5) to 13(8) (p=0.4): lesions improved markedly in 3 patients (33%). Quality of life (IBDQ) changed from 125(27) to 131(38) (p=0.7): remission (IBDQ at week 12≥170) was reached in 1 (11%) case and response (IBDQ score increase≥16) in 2 (22%).
Intraperitoneal administration of autologous tolDCs appears safe and feasible in refractory CD patients. Further studies should be developed to test clinical benefit, determine the optimal administration route and dose, and monitor the immune responses. www.eudract.ema.europa.eu, EudraCT number 2007-003469-42; www.aemps.gob.es, number PEI 08-049.
Journal of Crohn s and Colitis 08/2015; DOI:10.1093/ecco-jcc/jjv144 · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The suppression of excessive immune responses by infusion of regulatory T cells would require a product of high purity, adequate ex vivo expansion and functional stability. A description of the process to obtain an autologous cell product fulfilling these characteristics paves the way to develop clinical trials in humans.