Arterial properties of ulcerative colitis patients and unaffected controls; a cross-sectional outpatient clinic study.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by
a pattern of relapse and remission. UC and its treatment are associated with
inflammation, dyslipidemia and increased cardiovascular disease (CVD) risk.

The status of cardiovascular health can be non-invasively assessed by
structural and functional arterial biomarkers, even prior to the occurrence of
symptomatic vascular disease. In this study we will therefore do arterial
measurements in 90 CU patients and 30 unaffected control subjects. For that
purpose, carotid intima-media thickness (cIMT) using ultrasound, brachial flow
mediated dilatation (FMD) to assess endothelial function (EF), and upper arm
and ankle blood pressures to assess RR and the ankle-brachial index (ABI) will
be assessed.

The results of these studies will create awareness and understanding of the
consequences of inflammatory bowel disease in other organsystems outside the
gastro-intestinal tract and support decisions on prevention of cardiovascular
co-morbidity/mortality in UC patients on top of their IBD.

As safe and efficacious preventive treatments for cardiovascular diseases are
available, UC patients may benefit directly by improving their cardiovascular
health.

This study is aimed at understanding status and future cardiovascular disease
(CVD) risk in UC outpatients in remission undergoing different
anti-inflammatory therapeutic regimens (tofacitinib (a JAK1 - inhibitor),
anti-TNF (infliximab or adalimumab) or mesalamine). as commonly used in
clinical UC practice.

Validated non-invasive biomarkers describing long and short term cardiovascular
health will be assessed in UC patients and unaffected controls.

The study is of scientific interest and has direct clinical relevance when
considering the need for efficacious measures in cardiovascular disease
prevention in those with UC.

A total of 120 subjects will participate in this cross-sectional observational
study.

Vascular assessments will be performed in 90 treated UC patients in addition to
their routine outpatient clinic visit evaluations and treatments.

Clinically, patients are to be in remission of the disease. Three different
anti-inflammatory treatment regimens - tofacitinib (a JAK1 - inhibitor),
anti-TNF (infliximab or adalimumab) or mesalamine - in approximately equally
sized UC groups of 30 are observed. In addition, 30 unaffected age and gender
matched controls will be investigated.

Chronic inflammatory diseases impair arterial structure and function, therefore
the following non-invasive and safe biomarkers will be assessed in patients
and non-patient controls:.

1. The status of atherosclerosis and long term CVD risk is assessed by means of
carotid artery ultrasound intima-media thickness (CIMT) measurements.
Progression of early arterial wall thickness changes and atherosclerosis is
reflected by CIMT increase. Treatment can inhibit this process and decrease
cIMT change. All vascular assessments are completely non-invasive and safe.

2. An automated oscillometric blood pressure measuring device with upper arm
and ankle cuffs will be used to assess blood pressures according to RR, the
ankle-brachial index (ABI = Systolic ankle blood pressure/ Systolic RR) of
subjects, the pulse-pressure (PP) and the brachial ankle pulse wave velocity
(baPWV).

3. Functional arterial properties and short term cardiovascular risk will be
assessed by means of arterial brachial flow mediated dilatation (FMD), a
validated biomarker for endothelial function.

All vascular assessments are completely non-invasive and safe.

Power calculations based on previous endothelial function study observer and
clinical data, and under the assumption of an unpaired Student*s t-test with
α=0,05, a ß=0.9 (power of 90%) were done. These calculations indicate subgroups
of 30 subjects are of sufficient size to detect at least a 1% difference in
brachial flow mediated dilatation (FMD, the primary endpoint of the study).
Between UC patients and the unaffected (90 versus 30 respectively) an even
smaller difference in FMD may be observed.

The overall population size and those of the subpopulations are also of
sufficient size to draw relevant conclusions from the secondary endpoints (CIMT
and ABI measurements).

Vascular assessments will be performed in UC subjects who visit the outpatient
clinic routinely anyway.

Routine Outpatient Assessments

The routine UC outpatient clinic check takes 15 minutes on average and entails
assessment of:

1. General well being and work/functionality
2. The simple clinical colitis activity Index (SCCAI), e.g.:
- Defecation frequency/day
- Defecation frequency night
- Urge
- Blood in stool
- General well being
- Other symptoms (Uevitis, pyoderma gangrenosum, erythema nodusum, arthritis)

Blood values:
- CRP
- Hb
- Hematocrit
- Platelets
- MCV
- Leukocytes
- Creatinine
- eGFR
- Alat
- Asat
- Alk. Phosphatase
- Iron saturation
Fecal examination: Calprotectin

Blood samples are usually drawn a week prior to outpatient appointments. In
patients who use TNF-a inhibitors (infliximab) the values are assessed before
they start infliximab treatment

Physical examination or ultrasound scans are done only if clinically indicated
(i.e., not at the routine consultations). An ultrasound scan of the bowel is
indicated only if no colonoscopy has been done for a longer period of time.


Vascular Assessments (this study)

Potential subjects will have received study and informed consent information
and a request to participate in the vascular assessments at least 2 weeks prior
to the outpatient clinic visit.

In summary, the vascular assessments entail the following:

Assessments are completely non-invasive, well tolerated and safe.
The overall time investment is approximately 45 minutes.

Participants need to be in the fasting state (required for the endothelial
function measurements).
An informed consent and a cardiovascular questionnaire are filled out with the
appointed researcher.

All assessments are done in a quiet and temperature-controlled space.
The participant is examined in the reclined position, comfortably at rest on an
examination couch.
The blood pressure cuffs will be attached prior to the examinations.

Order of assessments is as follows: carotid ultrasound scans, blood pressure
and ABI assessment, endothelial function testing.


Benefits and group relatedness may described as follows:

Inflammatory diseases have major consequences on the cardiovascular system and
CVD risk.

The vascular assessments of our studies describe present structural and
functional arterial status and allow detection of CVD risk prior to the
clinical emergence of coronary and vascular diseases. As efficacious and safe
preventive treatments for cardiovascular diseases are available, UC patients
may benefit directly by improving their cardiovascular health (e.g. preventing
cardiovascular co-morbidity/mortality on top of their inflammatory bowel
disease).

Outcomes of the vascular studies are therefore of direct scientific interest
and of clinical relevance to patients as such.