Towards the identification of molecular pathways predicting response to vedolizumab (Entyvio®) in Crohn*s disease deploying Systems Medicine: BullsEye Study

Crohn's disease is an immune-mediated disease that results in chronic
inflammation in genetically predisposed individuals exposed to an appropriate
environment. The introduction of monoclonal antibodies has revolutionized the
treatment of Crohn*s disease (CD). Unfortunately, the utility of these agents
have been hampered by loss of response in a significant proportion of patients.

Recently, vedolizumab, an integrin *4*7 antagonist, has been licensed for the
treatment of CD and UC. Response rates vary between 31% for CD and 47% for UC
at week 6 (1;2). In bio-naive patients response rates may be up to 40% at week
6 and 47% at week 10 (unpublished results from Gemini 2 en 3 studies).
However, a considerable proportion of patients do not respond to vedolizumab.
Since the use of this treatment modality is associated with substantial
financial expenditures, tools to identify patients in whom the drug will be
effective are highly warranted.

Although in general criteria for starting immunosuppressive therapy and
biologicals (mainly anti-TNFs) have clearly been stated in guidelines and
consensus reports, no tools or algorithms are available that reliably guide the
clinician selecting patients in whom biological therapy will successfully
induce and maintain remission. Several studies have attempted to identify
predictors of response to anti-TNF in IBD, mainly in Crohn*s disease (3-6).
Although some of parameters, such as increased CRP levels, deep ulcers on
endoscopy and short disease duration may identify a subgroup of likely anti-TNF
responders, they are often not helpful in daily practice. For vedolizumab no
studies on predictors of response are available.

Systems Medicine is an approach, which exploits a multitude of *OMICS* layers
(transcriptome, genome, proteome, metabolome and epigenome of individual cells
in addition to the fecal microbiome and metabolome) and ultimately integrates
these data layers with sophisticated computational approaches to an underlying
network of nodes leading to disease. Previously, our group successfully applied
an element of this approach to reveal an important initial insight as to how
altered plasmacytoid dendritic cells function contributes to pathology in
scleroderma (7). In addition, using this approach we were recently able to
identify the molecular pathways that identify rheumatoid arthritis patients
that could stop anti-TNF therapy successfully

In the present study, we propose to explore whether a Systems Medicine approach
can identify biomarkers that predict the clinical outcome in patients with
Crohn*s disease in whom vedolizumab is started.

Treatment
Vedolizumab 300 mg- induction at 0, 2 and 6 and 10 weeks - every 8 weeks

Safety
Routine screening prior to initiation of biological treatment will include:
-Stool cultures and clostridium toxin
-Chest X-ray, Mantoux, Quantiferon test

Baseline (prior to start of vedolizumab):
All patients will undergo colonoscopy at to objectivate disease activity.
Biopsies will be taken and stored at -70 C. Fecal and blood samples (80 mL of
blood for Systems Medicine and two fecal samples for microbiome profiling) will
be obtained at baseline. Clinical disease activity will be assessed using HBS.
Bloodcount, CRP and fecal calprotectine will be assessed. Patients will be
requested to fill-out the EuroQOL five dimensions questionnaire (EQ5D) and the
Inflammatory Bowel Disease Questionnaire (IBDQ).

Follow-up:
At week 6 and 20 (third and fifth gift of vedolizumab, respectively) and after
a year or in case of therapy failure patients will be requested to provide 40
mL of blood, which will be drawn from the infusion prior to the vedolizumab gift
At 20 and 52 weeks, patients will be requested to provide a fecal sample for
microbiome profiling. Therapeutic drug levels, CRP and fecal calprotectin
levels will be determined as part of the routine laboratory screening. EQ5D,
PRO-3 and IBDQ will be assessed. Clinical disease activity will be evaluated by
the HBS. At 12 months or in case of clinical relapse of disease, the endoscopy
with biopsies will be repeated and blood for Systems Medicine will be collected.
If patients agree, an additional colonoscopy of only the rectum will be
performed at week 20 for extra biopsies.

Minimal burden, no risks

Extra:
Questionnaires and collecting stoolsamples
Minimal risk associated with obtaining extra biopsies during routine
colonoscopies