Ulcerative Colitis Clinical Trial
Official title:
Investigation of Vascular Endothelial Dysfunction, Thromboembolism and Structural Arterial Disease in Paediatric and Adolescent Inflammatory Bowel Disease (IBD)
Inflammatory Bowel Diseases (IBD) is a group of relapsing and remitting gut inflammatory
conditions acquired due to genetic susceptibility and/or environmental triggers. The disease
manifestations are being increasingly seen in young children and the life-long debilitation
has a severe effect on quality of life. Limited evidence suggests, although rare, in some
young IBD individuals vascular complications may ensue. This leads to increased risk of
vascular problems such as thrombosis, arterial disease and stroke.
In the present project we aim to study and highlight potential vascular changes in young
Inflammatory Bowel Disease (IBD) patients and compare these changes with age and gender
matched controls. Vasculature will be measured in multiple ways including blood analysis in
the laboratory and non-invasive, physiological measures of arterial health (e.g. ultrasound
arterial scan). Our overall goal is to identify biomarkers indicative of increased risk of
vascular dysfunction as this will open new avenues for early therapeutic intervention.
Plan of Investigation:
Patients: 130 children and adolescents (8-21y) with an expected ratio of 60% (n=78) Crohn's
disease (CD), 35% (n=45) Ulcerative colitis (UC) 5% (n=6) Indeterminate colitis (IC). 78 age
and sex-matched controls will be investigated. Sample size calculations are based on
Circulating Endothelial Cells (CECs) as the primary end-point, as suggested by an on-going
study by one of the co-applicants, on healthy children and children with Kawasaki disease
(Brogan P et al, ref published).
40 subjects/ group are required to detect a doubling average of CECs in CD and UC vs.
control with 90% power, significance 0.05 and this should be achievable by our initial
recruitment. Non-normality and the need to use non-parametric or transform prior to
analysis, increases the number to 47; hence we will aim to recruit 50 to the UC group. This
will provide adequate power, and is feasible based on the clinical cohort available to us.
This patient cohort is an appropriate candidate group for the present investigation as
1. Evidence indicates that vascular changes that occur between 10-20 years of age are a
critical determinant of future vasculature health;
2. Initiation into smoking habits is most likely in teenage years and
3. Other established traditional risk factors for atherosclerosis (such as hypertension,
type II diabetes, or even fully established atherosclerotic disease) that would act as
confounding variables, are not yet present in adolescence.
Data will be collated onto a de-identified excel sheet and will include age, sex, age at
diagnosis, coronary artery status at presentation, growth, body mass index, blood pressure,
family history of CVD, and smoking status.
Aim 1: Do Children with IBD have evidence of a MP mediated prothrombotic tendency? MPs will
be identified by flow cytometry as previously described by our group19. Briefly,
platelet-poor plasma (PPP) will be obtained from blood and stored at −80 °C for future batch
testing. 200 μL of PPP will allow sedimentation of MPs which will be resuspended in Annexin
V (AnV) binding buffer prior to staining with FITC- or phycoerythrin -AnV (BD PharMingen).
Endothelial, platelet and neutrophil-derived MPs (EMPs/PMPs/NMPs) and Tissue-Factor (TF)
will be enumerated by detection with anti-human (CD62E, CD41 and CD11b activation epitope
which binds to activated neutrophils respectively, plus relevant isotype controls). Latex
beads (1.1 μm) are used to gate MPs < 1.1 μm. The thrombotic potential of MPs will be
quantified by suspending MPs in control microparticle-free plasma (MPFP) containing trypsin
inhibitor [inhibits contact activation] followed by exposure to calcium-fluorogenic
substrate (Z-G-G-R-AMC). Kinetics of thrombin generation will be recorded up to 90min
post-stimulation. Lag time min, peak thrombin nM, velocity index nM/min and endogenous
thrombin potential (ETP) nM × min will be calculated. To investigate the relative
contribution of PS and TF to MP-mediated thrombin generation, MPs will be pre-incubated with
increasing concentrations of recombinant AnV protein or a blocking anti-TF (or isotype
control) prior to thrombin analysis.
Aim 2. Do Children with IBD have evidence of Endothelial Injury? In addition to
investigating arterial health (below), we will quantify vascular injury by measuring CECs.
CECs will be isolated by immunomagnetic bead extraction (based on an international consensus
protocol) and counted using a Nageotte chamber/fluorescence microscopy. CEC enumeration is
defined as Ulex-europaeus-lectin bright cells of >10 μm in size, with 5 magnetic beads
attached19. Data will be analysed in the context of EMP data (Aim 1) as the combination will
give an insight into the degree of endothelial injury in IBD versus control.
Aim 3. Do Children with IBD have evidence of Structural Arterial Disease? Pulse Wave
Velocity (PWV) will be an indicator of arterial structural health. Pressure waveforms will
be recorded simultaneously at two sites (carotid-femoral) using the VICORDER analysis
software (Skidmore Medical Limited);
Aim 4. What is the relationship between indices of inflammation and established mediators of
vascular Injury? Levels of hs-CRP, serum amyloid A (SAA), TNF-α, IL-1α, IL-1β, IL-6, MCP-1,
VEGF, fasting lipids and angiopoietin 1/2 will be correlated with validated clinical
assessment of disease activity [Paediatric UC Activity Index20 (PUCAI) & Paediatric CD
Activity Index (PCDAI)] in addition to conventional markers (CRP, ESR, D-Dimers and
platelets in active and inactive disease). In many cases, conventional circulating markers
do not correlate with endoscopic findings in active disease; the non-conventional markers
may show a higher sensitivity in detecting those with on-going active inflammation.
Methodology:
1. Clinical data collection: Subject clinical data will be collated onto a de-identified
excel spread sheet from a paper data collection proforma as used in the pilot study.
Clinical data collected will include age, sex, age at IBD diagnosis, coronary artery
status at presentation and currently, growth and body mass index, blood pressure,
family history of cardiovascular disease, and smoking status.
2. Chronic inflammation will be assessed using Meso Scale Discovery (MSD, Maryland, USA)
multi-array electrochemiluminescence detection of plasma: hs-CRP, SAA, TNF-α, IL-6, 8
and 10, MCP-1, VEGF, angiopoietin 1 and 2 (the latter mediating endothelial detachment
in systemic vasculitis (66). This technique allows many parameters to be assayed from
very small amounts of blood and was used (as per manufacturer instructions) with great
success in the pilot study; d. Endothelial activation/injury will be assessed by: CEC
count quantified by immunomagnetic bead (IB) isolation from whole blood using
anti-CD146 coated beads, then stained with FITC-conjugated Ulex and enumerated using
fluorescent microscopy and a Nageotte counting chamber as previously described by our
group and others (46;67); EMPs expressing CD105, E-selectin, ICAM-1, VCAM-1 CD144,
CD31, but negative for the platelet markers CD42a, or CD62P will be quantified from
platelet poor plasma using a BD FACSArray flow cytometer as previously described by our
group (44); e. Endothelial repair potential will be assessed in a total of 45 subjects
(15 from each group: KD CAA+, CAA-, and healthy controls) by assessing (i) EPC colony
forming unit (CFU) capacity (68), and (ii) EPC potential to incorporate into HUVEC
vascular structures in matrigel (69), and now routinely performed by our group (see
below). EPCs are prepared from PBMCs isolated from 5ml of blood are plated into culture
dishes coated with human fibronectin and maintained in EGM-2 supplemented with 20%
fetal calf serum and 40ng/ml VEGF. After 4 days in culture, non-adherent cells are
removed by washing with phosphate buffered saline and the adherent cells maintained in
culture until day 7. Early EPC colony forming units are then counted. Amplified EPCs
harvested as described above are then labelled with Di -I-LDL and replated with HUVEC
on top of a solidified matrigel layer and incubated at 37 °C for 24 h. Fluorescent
microscopy is used to assess incorporation of EPCs into the HUVEC capillary lattice,
and HUVEC tubule formation (structure exhibiting length four times its width) will be
compared using EPC from KD (+/- CAA) to healthy controls. Five independent fields are
assessed for each well, and the mean number of tubules/×100 field are determined. f.
Vascular stiffness and carotid IMT will be assessed by: (i) carotid-femoral and
carotid-radial pulse wave velocity (PWV) using the Vicorder device (Skidmore Medical
Limited); All these techniques are routinely performed by our group in accordance with
AHA recommendations (70), as illustrated by our pilot data and our previously published
studies (71-73).
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